Asymmetric synthesis of the C14-C26 building block of eribulin mesylate

Article abstract of DOI:10.1002/ejoc.201201119

An alternative route for the synthesis of the C14-C26 building block of the anticancer drug eribulin mesylate is described. The key steps involved in the synthesis are a Julia-Kocienski olefination between aldehyde 4 and sulfone 5 and a tandem Sharpless asymmetric dihydroxylation/S_N2 cyclisation reaction on mesyl compound 3. Copyright

Full text of DOI:10.1002/ejoc.201201119

FULL PAPER
DOI: 10.1002/ejoc.201201119
Asymmetric Synthesis of the C14–C26 Building Block of Eribulin Mesylate
Akondi Srirama Murthy,[a] Bodugum Mahipal,[a] and Srivari Chandrasekhar*[a]
Keywords: Natural products / Olefination / Asymmetric synthesis / Cyclization / Synthetic methods
An alternative route for the synthesis of the C14–C26 build-
ing block of the anticancer drug eribulin mesylate is de-
scribed. The key steps involved in the synthesis are a Julia–
Kocienski olefination between aldehyde 4 and sulfone 5 and
a tandem Sharpless asymmetric dihydroxylation/SN2 cyclis-
ation reaction on mesyl compound 3.
Our research group has a focus on the total synthesis
of scarce marine natural products.[5] Undoubtedly, eribulin
mesylate has been a natural choice for this effort owing to
its complexity and clinical use. Towards this, herein we re-
port full details pertaining to the synthesis of the C14–C26
fragment encompassing one furan ring, four asymmetric
carbon atoms and one exocyclic methylene group in high-
yielding steps.
Introduction
Eribulin mesylate (Halaven®) is an approved drug for
treatment of metastatic cancer for patients who have al-
ready undergone chemotherapy (Figure 1). This is the most
complex synthetic molecule launched in the market requir-
ing over 60 linear steps for its total synthesis. This molecule
is the truncated version of marine natural product
Halichondrin B isolated from the sponge Halichondria oka-
dai.[1] A very special feature of this drug is low levels of
neurotoxicity relative to other chemical candidates. Eribulin
exerts the anticancer activity through the triggering of
apoptosis of cancer cells.[2]
Results and Discussion
According to our retrosynthetic analysis depicted in
Scheme 1, the desired molecule could be expected from key
intermediate 2, which in turn could be derived from 3
through a tandem Sharpless asymmetric dihyroxylation/SN2
cyclisation reaction. Compound 3 was envisioned through
a Julia–Kocienski olefination between aldehyde 4 and sulf-
one 5. Interestingly, both 4 and 5 could be obtained from
the same starting material, 1,4-butanediol, by using an
asymmetric Maruoka allylation as the key reaction.
Figure 1. Structure of eribulin mesylate.
Preparation of Aldehyde 4
Eribulin is complex and contains several oxygen hetero-
cycles, a ketal functionality and two exocyclic methylene
groups as well as 15 stereogenic centers and fused pyran
rings with trans ring junctions. These complex features and
outstanding applications in cancer chemotherapy prompted
several research groups across the globe to initiate synthetic
studies. Kishi et al.[3] are the only group to date to com-
pletely synthesize this truncated natural product. However,
a good number of efforts are still in progress, and a number
of partial syntheses have been reported.[4]
Our synthesis began with the Maruoka allylation[6] of
aldehyde 6 (obtained from 1,4-butanediol)[7] by using the
titanium complex from (R)-BINOL and allyltributylstan-
nane to furnish chiral (S)-homoallylic alcohol 7 in 76%
yield with 96% enantiomeric excess (determined by chiral
HPLC).[8,9] The secondary hydroxy group was protected
with methoxymethyl (MOM) chloride in CH2Cl2 to give
MOM ether 8 in 80% yield. Compound 8 on debenzylation
with lithium naphthalenide gave primary alcohol 9 in 95%
yield. Primary alcohol 9 was oxidized to acid 10 in 80%
yield by using TEMPO and bis(acetoxy)iodobenzene
(BAIB) in CH2Cl2 and H2O. Acid 10 was coupled with
Evans auxiliary 11 through the mixed anhydride at –20 °C
by using Et3N in anhydrous THF to furnish imide 12 in
93% yield.
[a] Division of Natural Product Chemistry, CSIR – Indian Insti-
tute of Chemical Technology
Hyderabad 500007, India
Fax: +91-40-27160512
E-mail: srivaric@iict.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201119.
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A. S. Murthy, B. Mahipal, S. Chandrasekhar
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18 in 70% yield with 95% enantiomeric excess.[13] The sec-
ondary hydroxy group was protected with tert-butyldi-
methylsilyl chloride (TBSCl) in CH2Cl2 with imidazole to
give 19 in 70% yield. Compound 19 on ozonolysis in
CH2Cl2/MeOH and subsequent reduction with NaBH4
gave alcohol 20 in 70% yield. The primary alcohol was con-
verted into sulfide 21 in 98% yield under Mitsunobu condi-
tions. Oxidation of the sulfide with ammonium molybdate
tetrahydrate and aqueous H2O2 in EtOH gave required sulf-
one 5 in 98% yield (Scheme 3).
Construction of the C14–C26 Segment from 4 and 5
With successful completion of desired fragments 4 and
5, we next turned our attention to couple them under Julia–
Kocienski olefination[14] conditions that gave exclusively
(E)-selective olefinic compound 22 in 60% yield (Scheme 4).
Selective TBS deprotection with pyridinium p-toluenesulf-
onate in EtOH at 55 °C gave secondary alcohol 23 in 70%
yield.[15] Mesylation of 23 with MsCl and Et3N in CH2Cl2
gave mesyl compound 3 quantitatively. Tandem Sharpless
asymmetric dihydroxylation (SAD)/SN2 cyclisation[16] on 3
by using AD mix-α and methanesulfonamide in tBuOH/
H2O at 0 °C furnished hydroxytetrahydrofuran 2 in 65%
yield with a 86% de. Oxidation of the secondary alcohol
with Dess–Martin periodinane in CH2Cl2 gave 4-oxotetra-
hydrofuran 24 in 70% yield. Finally, methylenation under
Wittig conditions gave target molecule 1 in 85% yield. The
trans relationship between the two substituents on the five-
membered ring was confirmed by NOESY studies.
Conclusions
We have demonstrated a highly stereoselective synthesis
of the C14–C26 fragment of eribulin mesylate having three
OH groups with differential protective groups to allow fur-
ther extensions at will by using Julia–Kocienski olefination
and tandem SAD/SN2 cyclisation reactions as key transfor-
mations. The desired chiral centers were successfully in-
stalled through Maruoka allylation, Evans diastereoselec-
tive methylation and Sharpless asymmetric dihydroxylation
reaction. We believe that the approach described herein is
potentially useful in the total synthesis of eribulin mesylate.
Studies in this direction are underway.
Scheme 1. Retrosynthetic analysis of the C14–C26 building block
of eribulin mesylate.
Diastereoselective methylation of lithium enolate of 12
with MeI gave 13 in 65% yield, 85% de, and the dia-
stereomers were separated by column chromatography.[10,11]
Upon treatment with NaBH4 in THF/H2O[10] at room tem-
perature, 13 gave alcohol 14 in 90% yield. Alcohol 14 was
protected by tert-butyldiphenylsilyl chloride (TBDPSCl) in
CH2Cl2 and imidazole to furnish 15 in 85% yield. Com-
pound 15 was subjected to hydroboration followed by oxi-
dation with BH3·Me2S in THF and NaOH/H2O2 to give
alcohol 16 in 85% yield. Oxidation of alcohol 16 with
Dess–Martin periodinane in CH2Cl2 gave desired aldehyde
4 in 67% yield (Scheme 2).
Experimental Section
General Methods: 1H and 13C NMR spectroscopic data were re-
corded in CDCl3 with 300, 400, 500, or 75 MHz spectrometers at
ambient temperature. FTIR spectroscopic data were recorded as
KBr discs or neat. Optical rotations were measured with a digital
polarimeter with a 2 mL cell with a 1 dm path length. All the rea-
gents and solvents were reagent grade and used without purifica-
tion unless specified otherwise. Technical grade ethyl acetate and
hexanes used for column chromatography were distilled prior to
use. When used as a reaction solvent, THF was freshly distilled
Synthesis of Sulfone 5
Maruoka allylation with the titanium complex from (S)-
BINOL and allyltributylstannane on aldehyde 17 (again ob-
tained from 1,4-butanediol)[12] gave (R)-homoallylic alcohol from sodium/benzophenone ketyl. Column chromatography was
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Asymmetric Synthesis of the C14–C26 Building Block of Eribulin Mesylate
Scheme 2. Synthesis of aldehyde fragment 4.
Scheme 3. Synthesis of sulfone fragment 5.
carried out with silica gel (60–120 mesh and 100–200 mesh) packed
in glass columns. All the reactions were performed under nitrogen
in flame-dried or oven-dried glassware with magnetic stirring.
CHCl ). IR (neat): ν = 2931, 2854, 1736, 1455, 1361, 1099, 1039,
˜
3
916, 734, 698 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.50–1.75
(m, 4 H), 2.27 (t, J = 7.0 Hz, 2 H), 3.33 (s, 3 H), 3.44 (t, J = 6.3 Hz,
2 H), 3.59 (quint, J = 5.5 Hz, 1 H), 4.47 (s, 2 H), 4.60 (dd, J = 7.0,
14.7 Hz, 2 H), 5.01–5.08 (m, 2 H), 5.70–5.85 (m, 1 H), 7.30–7.26
(m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.8, 30.6, 38.9,
55.5, 70.3, 72.8, 76.5, 95.4, 117.1, 127.4, 127.6, 128.3, 134.6,
138.5 ppm. MS (ESI): m/z = 287 [M + Na]+. HRMS (ESI): calcd.
for C16H24O3Na [M + Na]+ 287.1617; found 287.1616.
(S)-{[4-(Methoxymethoxy)hept-6-enyloxy]methyl}benzene (8): To a
stirred, cooled (0 °C) solution of alcohol 7 (6.40 g, 29.04 mmol) in
CH2Cl2 (290 mL) were added N,N-diisopropylethylamine
(50.6 mL, 290.50 mmol) and chloromethyl methyl ether (11.1 mL,
145.25 mmol). The reaction mixture was allowed to reach room
temperature within 12 h with stirring before it was treated with
saturated aqueous NaHCO3 solution (150 mL), and the phases
were separated. After extraction of the aqueous layer with diethyl
ether (2ϫ250 mL), the combined extracts were washed with brine
(150 mL), dried (Na2SO4), filtered, and concentrated in vacuo.
Flash chromatography (silica gel, 5% EtOAc in hexane) of the resi-
due provided MOM ether 8 (6.13 g, 80%) as a colorless viscous oil.
Rf = 0.5 (silica gel, 10% EtOAc in hexane). [α]3D5 = –13.6 (c = 1.5,
(S)-4-(Methoxymethoxy)hept-6-en-1-ol (9):[6] To a stirred solution
of naphthalene (14.54 g, 113.60 mmol) in THF (145 mL), was
added lithium metal (0.79 g, 113.60 mmol) in small pieces. The re-
action mixture was stirred at room temperature under argon until
the metal had completely dissolved (2 h). The resulting dark green
solution of lithium naphthalenide was then cooled to –20 °C, fol-
lowed by dropwise addition of a solution of compound 8 (6.0 g,
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A. S. Murthy, B. Mahipal, S. Chandrasekhar
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Scheme 4. Construction of the C14–C26 building block.
22.72 mmol) in THF (30 mL) over 5 min. The resulting mixture
was stirred at –20 °C for 20 min. Then – after quenching excess
lithium naphthalenide with saturated aqueous ammonium chloride
(30 mL) and water (30 mL) – the resulting solution was extracted
with EtOAc (3ϫ120 mL), the combined extracts were washed with
water (100 mL) and brine (100 mL), dried with anhydrous Na2SO4
and concentrated in vacuo. The crude product was purified by col-
umn chromatography (silica gel, 10% EtOAc in hexane) to afford
9 (3.75 g, 95%) as a colorless liquid. Rf = 0.3 (20% EtOAc in hex-
(R)-4-Benzyl-3-[(S)-4-(methoxymethoxy)hept-6-enoyl]oxazolidin-
2-one (12): To a stirred solution of acid 10 (3.0 g, 15.95 mmol) and
Et3N (5.5 mL, 39.87 mmol) in anhydrous THF (30 mL) at –20 °C
was added pivaloyl chloride (2.2 mL, 17.54 mmol) dropwise, and
the mixture was stirred for 1 h. Anhydrous LiCl (1.01 g,
23.93 mmol) was then added, and the mixture was stirred for
30 min. To this mixture, a solution of auxiliary 11 (2.82 g,
15.95 mmol) in anhydrous THF was added, and the mixture was
stirred at –20 °C for 1 h, then allowed to warm to room tempera-
ture. After stirring at ambient temperature for 2 h, the reaction
mixture was quenched with saturated aqueous NH4Cl solution
(25 mL). The organic layer was separated, and the aqueous layer
was extracted with ethyl acetate (210 mL). The combined organic
ane). [α]2D0 = –29.4 (c = 0.36, CHCl ). IR (neat): ν = 3438, 2928,
˜
3
1632, 1149, 1099, 1037 cm–1. 1H NMR (300 MHz, CDCl3): δ =
1.53–1.67 (m, 4 H), 2.34–2.25 (m, 2 H), 3.35 (s, 3 H), 3.58–3.67 (m,
3 H), 4.63 (dd, J = 7.0, 16.6 Hz, 2 H), 5.03–5.10 (m, 2 H), 5.70–
5.85 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.3, 30.4, layers were washed with brine (100 mL), dried with Na2SO4 and
38.7, 55.6, 62.8, 76.6, 95.4, 117.2, 134.4 ppm.
concentrated. The crude product was subjected to column
chromatography (silica gel, 15% EtOAc in hexane) to obtain imide
12 (5.50 g, 93%). Rf = 0.4 (silica gel, 20% EtOAc in hexane).
(S)-4-(Methoxymethoxy)hept-6-enoic Acid (10):[6] TEMPO (1.29 g,
8.73 mmol) and BAIB (23.31 g, 72.41 mmol) were added to a vigor-
ously stirred solution of 9 (3.60 g, 20.69 mmol) in CH2Cl2 (30 mL)
and H2O (10 mL) at 0 °C. The reaction mixture was stirred at room
temperature for 4 h followed by quenching with a saturated solu-
tion of Na2S2O3 (40 mL). The organic layer was separated, and the
aqueous phase was extracted with dichloromethane (2ϫ50 mL).
The combined organic phases were washed with brine (60 mL) and
dried with anhydrous Na2SO4. After evaporation of the solvent un-
der vacuum, the crude acid was subjected to flash column
chromatography (silica gel, 10% EtOAc in hexane) to obtain acid
10 (3.11 g, 80%). Rf = 0.3 (silica gel, 25% EtOAc in hexane).
[α]2D0 = –41.8 (c = 2.5, CHCl ). IR (neat): ν = 3018, 2927, 1782,
˜
3
1215, 756 cm–1. H NMR (300 MHz, CDCl3): δ = 1.75–2.00 (m, 2
1
H), 2.28–2.38 (m, 2 H), 2.65–2.76 (m, 1 H), 2.95–3.05 (m, 2 H),
3.36 (s, 3 H), 3.66 (br. quint, J = 6.0 Hz, 1 H), 4.10–4.20 (m, 3 H),
4.62 (m, 3 H), 5.05–5.15 (m, 2 H), 5.74–5.89 (m, 1 H) 7.18–7.34
(m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.4, 31.7, 37.9,
39.0, 55.1, 55.7, 66.2, 75.9, 95.6, 117.6, 127.4, 128.9, 129.4, 134.3,
135.3, 153.5, 173.1 ppm. MS (ESI): m/z = 370 [M + Na]+. HRMS
(ESI): calcd. for C19H25O5NNa [M + Na]+ 370.1655; found
370.1625.
[α]2D0 = –27.9 (c = 8.0, CHCl ). IR (neat): ν = 3500, 2500, 1710,
(R)-4-Benzyl-3-[(2R,4R)-4-(methoxymethoxy)-2-methylhept-6-
˜
3
1149, 1099, 1037 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.69–1.93 enoyl]oxazolidin-2-one (13): To a stirred solution of 12 (5.45 g,
(m, 2 H), 2.20–2.38 (m, 2 H), 2.40–2.50 (m, 2 H), 3.36 (s, 3 H), 15.61 mmol) in anhydrous THF (55 mL) under nitrogen was added
3.63 (br. quint, J = 5.6 Hz, 1 H), 4.62 (dd, J = 7.0, 18.7 Hz, 2 H),
5.05–5.10 (m, 2 H), 5.71–5.84 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 28.9, 30.0, 38.9, 55.6, 75.8, 95.5, 117.6, 134.1,
179.3 ppm.
LiHMDS (1.06 m in THF, 29.45 mL, 31.22 mmol) at –78 °C. After
stirring for 0.5 h, methyl iodide (3.90 mL, 62.4 mmol) was added,
and the mixture was stirred at –78 °C for another 3.5 h. The reac-
tion mixture was quenched with saturated aqueous NH4Cl solution
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Asymmetric Synthesis of the C14–C26 Building Block of Eribulin Mesylate
(40 mL), the organic layer was separated, and the aqueous layer
was extracted with ethyl acetate (100 mL). The combined organic
layers were washed with brine (100 mL), dried with Na2SO4, and
the solvent was evaporated. The crude product was subjected to
column chromatography (silica gel, 13% EtOAc in hexane) to ob-
tain 13 (3.68 g, 65%). Rf = 0.5 (silica gel, 25% EtOAc in hexane).
stirred for 2 h. After cooling, saturated aqueous NaCl (30 mL) was
added, and THF was removed in vacuo. The remaining aqueous
phase was extracted with Et2O (2ϫ60 mL) and EtOAc
(2ϫ60 mL), the combined organic layers were dried with MgSO4,
and the solvents were evaporated. Flash chromatography of the
crude product (silica gel, 20% EtOAc in hexane) afforded primary
alcohol 16 (2.56 g, 85%) as a colorless oil. Rf = 0.3 (20% EtOAc
[α]2D0 = –68.8 (c = 0.84, CHCl ). IR (neat): ν = 2931, 1780, 1697,
˜
3
1386, 1035, 916 cm–1. H NMR (300 MHz, CDCl3): δ = 1.24 (d, J in hexane). [α]2D0 = 9.9 (c = 1.0, CHCl ). IR (neat): ν = 3431, 2929,
1
˜
3
= 6.8 Hz, 3 H), 1.46–1.54 (m, 1 H), 2.02–2.11 (m, 1 H), 2.22–2.34 2856, 1427, 1111, 1037 cm–1. 1H NMR (300 MHz, CDCl3): δ =
(m, 2 H), 2.68–2.76 (m, 1 H), 3.30 (s, 3 H), 3.34–3.39 (m, 1 H), 0.95 (d, J = 6.8 Hz, 3 H), 1.05 (s, 9 H), 1.23–1.43 (m, 4 H), 1.45–
3.50–3.57 (m, 1 H), 3.82–3.92 (m, 1 H), 4.10–4.20 (m, 2 H), 4.50
(dd, J = 6.8, 15.7 Hz, 2 H), 4.57–4.67 (m, 1 H), 5.03–5.13 (m 2 H), H), 4.55 (s, 2 H), 7.32–7.42 (m, 6 H), 7.62 (d, J = 9.2 Hz, 4 H)
5.70–5.85 (m, 1 H), 7.16–7.33 (m, 5 H) ppm. 13C NMR (75 MHz, ppm. 13C NMR (75 MHz, CDCl3): δ = 17.3, 19.2, 26.8, 28.0, 30.6,
1.65 (m, 4 H), 3.31 (s, 3 H), 3.44–3.50 (m, 2 H), 3.54–3.64 (m, 3
CDCl3): δ = 18.5, 27.6, 37.6, 37.9, 39.4, 55.3, 55.8, 66.0, 75.4, 95.8, 32.5, 37.7, 55.5, 62.9, 68.6, 75.7, 95.4, 127.5, 129.5, 133.8,
117.5, 127.3, 128.8, 129.4, 134.2, 135.2, 152.8, 176.8 ppm. MS
135.6 ppm. MS (ESI): m/z = 467 [M + Na]+. HRMS (ESI): calcd.
(ESI): m/z
=
384 [M
+
Na]+. HRMS (ESI): calcd. for
for C26H40O4NaSi [M + Na]+ 467.2588; found 467.2572.
C20H27O5NNa [M + Na]+ 384.1781; found 384.1784.
(4R,6R)-7-(tert-Butyldiphenylsilyloxy)-4-(methoxymethoxy)-6-meth-
ylheptanal (4): Dess–Martin periodinane (1.73 g, 4.11 mmol) was
added at 0 °C under nitrogen to a solution of alcohol 16 (1.52 g,
3.42 mmol) in CH2Cl2 (20 mL). The resulting mixture was stirred
at room temperature for 1 h. A 1:1 saturated NaHCO3/Na2S2O3
solution (10 mL) was then added, the aqueous phase was separated
and extracted with CH2Cl2 (75 mL). The combined organic ex-
tracts were dried (MgSO4), filtered and concentrated. Purification
of the residue by flash chromatography (silica gel, 3% EtOAc in
hexane) gave aldehyde 4 (1.01 g, 67%) as colorless oil. Rf = 0.8
(20% EtOAc in hexane). [α]2D0 = 20.9 (c = 1.0, CHCl3). IR (neat):
(2R,4R)-4-(Methoxymethoxy)-2-methylhept-6-en-1-ol (14): NaBH4
(1.46 g, 38.56 mmol) was added to a stirred solution of imide 13
(3.50 g, 9.64 mmol) in THF/H2O (1:1, 40 mL) at 0 °C, and the re-
sulting mixture was stirred at room temperature for 1 h. After com-
pletion of the reaction, the mixture was extracted with EtOAc
(2ϫ100 mL), and the combined organic layers were washed with
brine (75 mL), dried with Na2SO4, and the solvent was evaporated
under reduced pressure. The crude primary alcohol was subjected
to column chromatography (silica gel, 20% EtOAc in hexane) to
obtain primary alcohol 14 (1.63 g, 90%). Rf = 0.3 (silica gel, 30%
EtOAc in hexane). [α]2D0 = –27.0 (c = 1.04, CHCl ). IR (neat): ν =
ν = 2925, 2857, 1725, 1631, 1108, 1036, 702 cm–1. 1H NMR
˜
˜
3
3414, 2929, 1440, 1039, 916, 756 cm–1. 1H NMR (300 MHz, (300 MHz, CDCl3): δ = 0.95 (d, J = 6.6 Hz, 3 H), 1.05 (s, 9 H),
CDCl3): δ = 0.92 (d, J = 6.8 Hz, 3 H), 1.44–1.54 (m, 2 H), 1.80– 1.54–1.79 (m, 4 H), 1.84–1.97 (m, 1 H), 2.52 (t, J = 7.2 Hz, 2 H),
1.92 (m, 1 H), 2.07 (br., 1 H), 2.26–2.35 (m, 2 H), 3.36 (s, 3 H), 3.33 (s, 3 H), 3.49 (d, J = 5.6 Hz, 2 H), 3.56–3.71 (m, 1 H), 4.55
3.39–3.53 (m, 2 H), 3.73–3.79 (m, 1 H), 4.64 (dd, J = 6.8, 15.1 Hz,
2 H), 5.03–5.09 (m, 2 H), 5.71–5.84 (m, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 17.7, 31.9, 38.4, 38.8, 55.7, 68.1, 75.5, 95.5,
117.4, 134.4 ppm. MS (ESI): m/z = 206 [M + NH4]+.
(s, 2 H), 7.36–7.46 (m, 6 H), 7.66 (d, J = 6.0 Hz, 4 H), 9.77 (s, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.2, 19.3, 26.5, 26.8,
32.5, 37.7, 39.5, 55.6, 68.5, 75.0, 95.4, 127.6, 129.6, 133.8, 135.6,
202.3 ppm. MS (ESI): m/z = 465 [M + Na]+.
(5R,7R)-5-Allyl-7,11,11-trimethyl-10,10-diphenyl-2,4,9-trioxa-10-
siladodecane (15): A solution of 14 (1.55 g, 3.64 mmol) and imid-
(R)-4-Hydroxyhept-6-enyl Pivalate (18): To a stirred solution of
TiCl4 (1 m in CH2Cl2, 0.71 mL, 0.71 mmol) in CH2Cl2, was added
azole (0.49 g, 7.28 mmol) in CH2Cl2 (150 mL) was treated with dried Ti(OiPr)4 (0.64 mL, 2.15 mmol) at 0 °C under argon. The
TBDPSCl (1.05 mL, 4.0 mmol) for 30 min. The reaction mixture
was then quenched with water (30 mL). The aqueous phase was
extracted with CH2Cl2 (2ϫ30 mL), and the combined organic
phases were washed with brine (30 mL), dried (MgSO4), filtered,
and concentrated. Purification of the residue by flash chromatog-
raphy (silica gel, 3% EtOAc in hexane) gave TBDPS ether 15
solution was warmed to room temperature. After 1 h, silver(I) ox-
ide (332 mg, 1.43 mmol) was added, and the mixture was stirred at
room temperature in the dark for 5 h. The mixture was diluted with
CH2Cl2 and treated with (S)-binaphthol (820 mg, 2.86 mmol) at
room temperature for 2 h to furnish the chiral bis[TiIV oxide] (S,S)-
1. In-situ generated (S,S)-1 in CH2Cl2 was cooled to –15 °C and
(2.98 g, 85%) as colorless oil. Rf = 0.8 (silica gel, 10% EtOAc in treated sequentially with aldehyde 17 (2.434 g, 14.32 mmol) and all-
hexane). [α]2D0 = –2.0 (c = 1.05, CHCl ). IR (neat): ν = 2928, 2857,
yltributylstannane (4.83 mL, 15.75 mmol) at –15 °C. The mixture
was warmed to 0 °C and stirred for 5 h. The reaction mixture was
quenched with saturated NaHCO3 solution (50 mL) and extracted
with CH2Cl2 (2ϫ100 mL). The combined organic layers were
˜
3
1631, 1427, 1108, 1040, 702 cm–1. H NMR (300 MHz, CDCl3): δ
1
= 0.96 (d, J = 6.8 Hz, 3 H), 1.06 (s, 9 H), 1.27–1.33 (m, 1 H), 1.57–
1.66 (m, 1 H), 1.74–1.83 (m, 1 H), 2.19–2.26 (m, 2 H), 3.29 (s, 3
H), 3.43–3.53 (m, 2 H), 3.56–3.62 (m, 1 H), 4.54 (dd, J = 6.8, washed with brine (30 mL), dried (MgSO4), filtered, and concen-
18.1 Hz, 2 H), 5.00–5.07 (m, 2 H), 5.69–5.84 (m, 1 H), 7.31–7.38
trated in vacuo. The residue was purified by flash chromatography
(silica gel, 10% EtOAc in hexane) to give alcohol 18 (2.15 g, 70%)
(m, 6 H), 7.62 (d, J = 6.0 Hz, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 17.5, 19.3, 26.8, 32.3, 37.8, 39.0, 55.4, 68.4, 75.4, 95.4, as colorless oil. Rf = 0.5 (20% EtOAc in hexane). [α]3D6 = 8.0 (c =
117.1, 127.5, 129.5, 133.8, 134.6, 135.6 ppm. MS (ESI): m/z = 449
[M + Na]+. HRMS (ESI): calcd. for C26H38O3NaSi [M + Na]+
449.2482; found 449.2466.
1.56, CHCl ). IR (neat): ν = 3460, 2972, 2931, 1728, 1620, 1481,
˜
3
1
1163 cm–1. H NMR (500 MHz, CDCl3): δ = 1.19 (s, 9 H), 1.44–
1.57 (m, 2 H), 1.59–1.73 (m, 2 H), 2.12–2.19 (m, 1 H), 2.24–2.34
(m, 1 H), 3.62–3.70 (m, 1 H), 4.08 (d, J = 6.5 Hz, 2 H), 5.10–5.15
(m, 2 H), 5.75–5.85 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 24.9, 27.1, 33.1, 38.9, 42.0, 64.2, 70.2, 118.3, 134.4, 178.8 ppm.
MS (ESI): m/z = 237 [M + Na]+.
(4R,6R)-7-(tert-Butyldiphenylsilyloxy)-4-(methoxymethoxy)-6-meth-
ylheptan-1-ol (16): To a solution of 15 (2.9 g, 6.80 mmol) in anhy-
drous THF (30 mL), BH3·Me2S (7.6 mL of a 2 m solution in THF,
15.32 mmol) was added dropwise at 0 °C. After stirring at 0 °C for
4 h, the reaction mixture was treated with 15% aqueous sodium
hydroxide (30 mL) followed by 30% aqueous H2O2 (18 mL) and
(R)-4-(tert-Butyldimethylsilyloxy)hept-6-enyl Pivalate (19): A solu-
tion of 18 (2.10 g, 9.80 mmol) in CH2Cl2 (21 mL) was stirred with
Eur. J. Org. Chem. 2012, 6959–6966
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6963

A. S. Murthy, B. Mahipal, S. Chandrasekhar
FULL PAPER
imidazole (1.33 g, 19.61 mmol), DMAP (35 mg, 0.29 mmol), and
TBSCl (2.21 g, 14.7 mmol) at room temperature for 6 h. After the
addition of water (30 mL), the aqueous phase was extracted with
CH2Cl2 (60 mL), and the combined organic layers were washed
with brine (30 mL), dried (MgSO4), filtered, and concentrated in
vacuo. The residue was purified by flash chromatography (silica
gel, 5% EtOAc in hexane) to give TBS ether 19 (2.25 g, 70%) as a
colorless oil. Rf = 0.8 (20% EtOAc in hexane). [α]3D7 = –18.6 (c =
(R)-4-(tert-Butyldimethylsilyloxy)-6-(1-phenyl-1H-tetrazol-5-yl-
sulfonyl)hexyl Pivalate (5): To a stirred solution of 21 (1.90 g,
3.62 mmol) in EtOH (20 mL) at room temperature was added drop-
wise a solution of ammonium molybdate tetrahydrate (0.46 g,
0.37 mmol) in aqueous 30 % hydrogen peroxide (4.1 mL,
36.2 mmol). The resulting mixture was stirred vigorously for 14 h
and partitioned between diethyl ether (60 mL) and water (50 mL).
The layers were separated, and the aqueous phase was extracted
0.56, CHCl ). IR (neat): ν = 2956, 2929, 2856, 1730, 1593, 1471, with diethyl ether (60 mL). The combined organic phases were
˜
3
1251, 999, 839 cm–1. H NMR (500 MHz, CDCl3): δ = 0.05 (d, J washed with water (70 mL) and brine (50 mL), dried with MgSO4,
1
= 3.9 Hz, 6 H), 0.89 (s, 9 H), 1.19 (s, 9 H), 1.44–1.57 (m, 2 H),
and concentrated in vacuo. The residue was purified by column
1.59–1.73 (m, 2 H), 2.20–2.24 (m, 2 H), 3.73 (quint, J = 5.5 Hz, 1
chromatography (silica gel, 3% EtOAc in hexane) to give 5 (1.98 g,
H), 4.05 (d, J = 6.2 Hz, 2 H), 5.01–5.07 (m, 2 H), 5.75–5.85 (m, 1 98%) as a colorless oil. Rf = 0.8 (20% EtOAc in hexane). [α]2D0
=
H) ppm. 13C NMR (75 MHz, CDCl3): δ = –4.5, –4.4, 24.5, 25.8,
27.2, 29.6, 32.9, 38.7, 41.8, 64.5, 71.4, 116.8, 135.0, 178.7 ppm. MS
(ESI): m/z = 351 [M + Na]+. HRMS (ESI): calcd. for C18H37O3Si
[M + H]+ 329.2508; found 329.2506.
–0.30 (c = 1.0, CHCl ). IR (neat): ν = 3020, 2956, 2929, 2858, 1722,
˜
3
758 cm–1. H NMR (300 MHz, CDCl3): δ = 0.08 (d, J = 3.8 Hz, 6
H), 0.90 (s, 9 H), 1.20 (s, 9 H), 1.72–1.52 (m, 4 H), 2.01–2.21 (m,
2 H), 3.77–3.85 (m, 2 H), 3.88–3.97 (m, 1 H), 4.06 (t, J = 6.0 Hz,
2 H), 7.57–7.65 (m, 3 H), 7.68–7.72 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = –4.6, –4.5, 17.9, 24.4, 25.8, 27.2, 33.1, 38.7,
63.9, 69.4, 125.0, 129.7, 131.4, 133.0, 153.4, 178.5 ppm. MS (ESI):
m/z = 547 [M + Na]+. HRMS (ESI): calcd. for C24H40O5N4NaSSi
[M + Na]+ 547.2370; found 547.2380.
1
(R)-4-(tert-Butyldimethylsilyloxy)-6-hydroxyhexyl Pivalate (20):
Ozone was bubbled at –78 °C through a solution of alkene 19
(2.10 g, 6.40 mmol) in a 1:1 mixture of CH2Cl2 (5 mL) and MeOH
(5 mL). After a few minutes, the mixture turned deep blue. When
no trace of starting material was detected by TLC anymore, excess
ozone was purged with nitrogen until the blue color disappeared.
Solid NaBH4 (0.243 g, 6.40 mmol) was then added, and the mixture
(4R,10R,12R,E)-4-(tert-Butyldimethylsilyloxy)-13-(tert-butyldi-
phenylsilyloxy)-10-(methoxymethoxy)-12-methyltridec-6-enyl Pival-
was warmed to room temperature. An excess of NaBH4 (0.243 g, ate (22): Potassium bis(trimethylsilyl)amide (3.2 mL, 0.5 m in tolu-
2 mmol) was then introduced, and the mixture was stirred for 12 h.
The reaction mixture was then hydrolyzed with a saturated solution
of NH4Cl (25 mL). The organic layer was decanted, and the aque-
ous layer was extracted with EtOAc (2ϫ50 mL). The combined
extracts were washed with a saturated solution of NH4Cl (5 mL),
ene, 1.6 mmol) was added dropwise at –78 °C to a solution of sulf-
one 5 (0.85 g, 1.6 mmol) in dry THF (8 mL). The resulting bright
yellow-orange solution was stirred at the same temperature for
40 min, after which aldehyde 4 (0.6 g, 1.36 mmol) in dry THF
(6 mL) was added dropwise. The reaction mixture was stirred at
brine (2ϫ10 mL) and then dried with MgSO4. The solvents were the same temperature for 1 h, and it was partitioned between H2O
removed in vacuo, and the residue was purified by column
chromatography on silica gel (20% EtOAc in hexane) affording pri-
mary alcohol 20 (1.48 g, 70%) as a colorless oil. Rf = 0.3 (20%
(40 mL) and Et2O (50 mL). The phases were separated, and the
aqueous phase was extracted with Et2O (40 mL). The combined
organic layers were washed with water (60 mL) and brine (50 mL),
dried (Na2SO4), filtered, and concentrated. The residue was puri-
EtOAc in hexane). [α]3D7 = –7.44 (c = 4.5, CHCl ). IR (neat): ν =
˜
3
3446, 2956, 2929, 2856, 1730, 1159, 837, 775 cm–1. 1H NMR fied by flash chromatography (silica gel, 2% EtOAc in hexane) to
(300 MHz, CDCl3): δ = 0.09 (d, J = 5.7 Hz, 6 H), 0.90 (s, 9 H),
1.20 (s, 9 H), 1.60–1.86 (m, 6 H), 2.27 (br., 1 H), 3.66–3.77 (m, 1
H), 3.77–3.88 (m, 1 H), 3.92–3.99 (m, 1 H), 4.06 (t, J = 5.9 Hz, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = –4.7, –4.5, 17.9, 24.5,
25.8, 27.2, 33.1, 37.8, 60.0, 64.3, 70.9, 178.6 ppm. MS (ESI): m/z =
give 22 (0.6 g, 59.6%) as a colorless oil. Rf = 0.8 (15% EtOAc in
hexane). [α]2D5 = 6.4 (c = 1.01, CHCl ). IR (neat): ν = 2956, 2929,
˜
3
1730, 1631, 1153, 1108, 1041, 703 cm–1
.
1H NMR (300 MHz,
CDCl3): δ = 0.04 (s, 6 H), 0.88 (s, 9 H), 0.95 (d, J = 6.6 Hz, 3 H),
1.05 (s, 9 H), 1.19 (s, 9 H), 1.52–1.82 (m, 9 H), 1.95–2.23 (m, 4 H),
355 [M
+
Na]+. HRMS (ESI): calcd. for C17H36O4NaSi 3.33 (s, 3 H), 3.45–3.53 (m, 2 H), 3.54–3.62 (m, 1 H), 3.63–3.71 (m,
[M + Na]+ 355.2275; found 355.2275.
1 H), 4.04 (t, J = 6.4 Hz, 2 H), 4.60 (s, 2 H),5.38–5.45 (m, 2 H),
7.35–7.45 (m, 6 H), 7.66 (d, J = 5.3 Hz, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = –4.6, –4.5, 17.4, 19.3, 24.4, 24.6, 25.8, 26.8,
27.2, 28.2, 32.4, 32.9, 34.3, 37.9, 40.5, 55.5, 64.5, 68.6, 71.8, 75.6,
95.4, 126.5, 127.6, 129.5, 132.5, 133.9, 135.6, 178.5 ppm. MS (ESI):
m/z = 763 [M + Na]+. HRMS (ESI): calcd. for C43H76NO6Si2 [M
+ NH4]+ 758.5206; found 758.5201.
(R)-4-(tert-Butyldimethylsilyloxy)-6-(1-phenyl-1H-tetrazol-5-
ylthio)hexyl Pivalate (21): To a stirred solution of 20 (1.35 g,
4.06 mmol) in dry THF (14 mL) at room temperature under nitro-
gen was added 1-phenyl-1H-tetrazole-5-thiol (0.868 g, 4.88 mmol)
and triphenylphosphane (1.27 g, 4.88 mmol). The resulting solu-
tion was cooled to 0 °C, and diisopropyl azodicarboxylate
(0.96 mL, 4.88 mmol) was added dropwise. The mixture was
warmed to room temperature, stirred for 2 h, and the solvent was
removed in vacuo. The residue was purified by column chromatog-
raphy (silica gel, 3% EtOAc in hexane) to give 21 (1.96 g, 98%) as
a colorless oil. Rf = 0.8 (20% EtOAc in hexane). [α]2D0 = –10.7 (c =
(4R,10R,12R,E)-13-(tert-Butyldiphenylsilyloxy)-4-hydroxy-10-
(methoxymethoxy)-12-methyltridec-6-enyl Pivalate (23): To a solu-
tion of 22 (550 mg, 0.74 mmol) in absolute ethanol (10 mL) was
added pyridinium p-toluenesulfonate (PPTS, 185 mg, 0.74 mmol)
with stirring at room temperature. The reaction mixture was stirred
0.4, CHCl ). IR (neat): ν = 2954, 2927, 1728, 1500, 1157, 759 cm–1. at 55 °C for 6 h, and the solvent was evaporated to dryness. The
˜
3
1H NMR (500 MHz, CDCl3): δ = 0.07 (s, 6 H), 0.90 (s, 9 H), 1.20
residue was purified by flash chromatography on a short column
(s, 9 H), 1.62–1.52 (m, 2 H), 1.63–1.73 (m, 2 H), 1.93–2.05 (m, 2 (silica gel, 15% EtOAc in hexane) to afford 23 (323 mg, 70%) as a
H), 3.33–3.49 (m, 2 H), 3.88 (quint, J = 5.6 Hz, 1 H), 4.06 (t, J = colorless oil. Rf = 0.37 (15% EtOAc in hexane). [α]2D0 = 8.0 (c =
6.4 Hz, 2 H), 7.52–7.65 (m, 5 H) ppm. 13C NMR (75 MHz,
0.5, CHCl ). IR (neat): ν = 2956, 2929, 2856, 1728, 1427, 1155,
˜
3
1
CDCl3): δ = –4.6, –4.4, 17.9, 24.2, 25.8, 27.2, 33.2, 35.9, 38.7, 64.2, 1111, 1039, 702 cm–1. H NMR (300 MHz, CDCl3): δ = 0.95 (d, J
70.3, 123.7, 129.7, 130.0, 133.6, 154.2, 178.5 ppm. MS (ESI): m/z
= 515 [M + Na]+. HRMS (ESI): calcd. for C24H40O3N4NaSSi [M
+ Na]+ 515.2482; found 515.2467.
= 6.0 Hz, 3 H), 1.05 (s, 9 H), 1.19 (s, 9 H), 1.44–1.83 (m, 13 H),
2.00–2.15 (m, 2 H), 2.16–2.29 (m, 1 H), 3.35 (s, 3 H), 3.45–3.53 (m,
1 H), 3.54–3.66 (m, 1 H), 4.07 (d, J = 6.0 Hz, 2 H), 4.60 (s, 2 H),
6964
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6959–6966

Asymmetric Synthesis of the C14–C26 Building Block of Eribulin Mesylate
5.32–5.47 (m, 1 H), 5.48–5.62 (m, 1 H), 7.35–7.45 (m, 6 H), 7.66
ture for 1 h, and a saturated NaHCO3/Na2S2O3 solution (2 mL,
(d, J = 5.3 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.3, 1:1) was added. The aqueous phase was separated and extracted
19.2, 22.9, 24.9, 26.7, 27.1, 28.1, 32.4, 32.9, 34.0, 37.9, 40.7, 55.5,
64.3, 68.6, 70.3, 75.3, 95.3, 125.8, 127.5, 139.5, 133.8, 134.3, 135.5,
178.5 ppm. MS (ESI): m/z = 644 [M + NH4]+. HRMS (ESI): calcd.
for C37H62NO6Si [M+ NH4]+ 644.4341; found 644.4301.
with CH2Cl2 (15 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated. Purification of the residue by
flash chromatography on silica gel (5 % EtOAc in hexane) gave
ketone 24 as colorless oil (68 mg, 70%). Rf = 0.7 (20% EtOAc in
hexane). IR (neat): ν = 3446, 2956, 2931, 2859, 1727, 1154, 1106,
˜
(4R,10R,12R,E)-13-(tert-Butyldiphenylsilyloxy)-10-(methoxy-
methoxy)-12-methyl-4-(methylsulfonyloxy)tridec-6-enyl Pivalate (3):
Et3N (69 μL, 0.492 mmol) and mesyl chloride (38 μL, 0.492 mmol)
were added to a solution of 23 (280 mg, 0.447 mmol) in CH2Cl2
(4 mL) at 0 °C. After stirring at room temperature for 1 h, the reac-
tion mixture was quenched by the addition of aqueous saturated
NH4Cl (4 mL). The organic phase was then concentrated, and the
aqueous phase was extracted with Et2O (32 mL). The combined
organic phases were dried (MgSO4) and concentrated to afford 3
as a pale yellow oil in quantitative yield. Rf = 0.4 (15% EtOAc in
1035, 703 cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.95 (d, J =
7.0 Hz, 3 H), 1.06 (s, 9 H), 1.20 (s, 9 H), 1.36–1.40 (m, 1 H), 1.52–
1.81 (m, 10 H), 2.21 (dd, J = 7.0, 17.9 Hz, 1 H), 2.57 (dd, J = 7.0,
17.9 Hz, 1 H), 3.33 (s, 3 H), 3.47–3.53 (m, 2 H), 3.59–3.63 (m, 1
H), 3.88–3.92 (m, 1 H), 4.08–4.13 (m, 2 H), 4.30–4.35 (m, 1 H),
4.59 (s, 2 H), 7.35–7.43 (m, 6 H), 7.66 (d, J = 6.0 Hz, 4 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 17.3, 19.3, 24.8, 26.0, 26.8, 27.2,
29.9, 31.9, 32.4, 37.8, 38.7, 42.4, 55.5, 63.8, 68.6, 74.6, 79.4, 95.3,
127.5, 129.5, 133.8, 135.6, 178.4, 216.0 ppm. MS (ESI): m/z = 663
[M + Na]+. HRMS (ESI): calcd. for C37H56O7SiNa [M + Na]+
663.3671; found 663.3674.
hexane). [α]2D0 = 10.9 (c = 0.5, CHCl ). IR (neat): ν = 3438, 2923,
˜
3
2860, 1726, 1359, 1171, 911, 705 cm–1
.
1H NMR (500 MHz,
3-{(2S,5S)-5-[(3R,5R)-6-(tert-Butyldiphenylsilyloxy)-3-(methoxy-
methoxy)-5-methylhexyl]-4-methylenetetrahydrofuran-2-yl}propyl
Pivalate (1): Methyltriphenylphosphonium bromide (67 mg,
0.18 mmol) was suspended in THF (1.2 mL), and a potassium tert-
butoxide solution in THF (21 mg, 0.18 mmol) was added dropwise.
After the resultant yellow solution had been stirred for 1 h, ketone
24 (40 mg, 0.06 mmol) in THF (1.0 mL) was added. The reaction
mixture was stirred for 75 min and then quenched with EtOAc
(10 mL) and H2O (10 mL). The layers were separated, and the
aqueous layer was extracted with EtOAc (10 mL). The combined
organic extracts were washed with brine, dried with MgSO4, fil-
tered, and concentrated. The crude material was purified by flash
column chromatography (silica gel, 5% EtOAc in hexane) to yield
1 (34 mg, 85% yield). Rf = 0.7 (15% EtOAc in hexane). IR (neat):
CDCl3): δ = 0.96 (d, J = 6.2 Hz, 3 H), 1.06 (s, 9 H), 1.20 (s, 9 H),
1.31–1.41 (m, 1 H), 1.47–1.57 (m, 2 H), 1.58–1.66 (m, 1 H), 1.69–
1.82 (m, 5 H), 2.04–2.16 (m, 2 H), 2.40–2.44 (m, 2 H), 2.98 (s, 3
H), 3.34 (s, 3 H), 3.48–3.54 (m, 2 H), 3.55–3.61 (m, 1 H), 4.06–4.12
(m, 2 H), 4.59 (s, 2 H), 4.69–4.75 (m, 1 H), 5.36–5.42 (m, 1 H),
5.54–5.60 (m, 1 H), 7.35–7.45 (m, 6 H), 7.66 (d, J = 7.0 Hz, 4 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 17.3, 19.2, 22.9, 24.2, 26.7,
27.1, 28.0, 30.4, 30.6, 32.1, 32.3, 33.9, 37.7, 38.6, 55.5, 63.5, 68.6,
75.3, 82.3, 95.3, 123.5, 127.5, 129.4, 134.9, 135.5, 178.5 ppm. MS
(ESI): m/z = 727 [M + Na]+. HRMS (ESI): calcd. for C38H60O8-
NaSSi [M + Na]+ 727.3670; found 727.3657.
3-{(2S,4S,5S)-5-[(3R,5R)-6-(tert-Butyldiphenylsilyloxy)-3-(meth-
oxymethoxy)-5-methylhexyl]-4-hydroxytetrahydrofuran-2-yl}propyl
Pivalate (2): To a stirred solution of AD-mix-α (518 mg, 1.46 g/
mmol) in tBuOH/H2O (5 mL, 1:1) were added methanesulfonamide
(67.45 mg, 0.71 mmol) and K2OsO2(OH)4 (1 crystal). The solution
was stirred well for 15 min until one phase was present. The reac-
tion mixture was cooled to 0 °C, and a solution of mesylate 3
(250 mg, 0.355 mmol) in tBuOH/H2O (3 mL, 1:1) was added. The
reaction mixture was warmed to room temperature over 2 h and
stirred overnight. The mixture was quenched with a saturated solu-
tion of Na2SO3 (2 mL) and stirred for 1 h. The aqueous layer was
extracted with CH2Cl2, and the combined organic extracts were
dried with MgSO4, filtered, and concentrated under reduced pres-
sure. The product was purified by flash chromatography on silica
gel (15 % EtOAc in hexane) to give tetrahydrofuran 2 (148 mg,
65%) as a 93:7 inseparable diastereomeric mixture as a viscous yel-
ν = 2956, 2927, 2856, 1729, 1283, 1261, 1153, 1104, 1038, 704 cm–1.
˜
1H NMR (500 MHz, CDCl3): δ = 0.95 (d, J = 7.0 Hz, 3 H), 1.06
(s, 9 H), 1.20 (s, 9 H), 1.31–1.41 (m, 1 H), 1.45–1.83 (m, 10 H),
2.25 (dd, J = 6.2, 15.6 Hz, 1 H), 2.67 (dd, J = 6.2, 15.6 Hz, 1 H),
3.33 (s, 3 H), 3.47–3.53 (m, 2 H), 3.58–3.66 (m, 1 H), 4.00–4.05 (m,
1 H), 4.05–4.10 (m, 2 H), 4.32–4.37 (m, 1 H), 4.57–4.62 (m, 2 H),
4.84 (d, J = 1.6 Hz, 1 H), 4.97 (d, J = 1.6 Hz, 1 H), 7.35–7.43 (m,
6 H), 7.66 (d, J = 7.0 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 17.5, 19.3, 25.3, 26.9, 27.2, 29.7, 30.3, 30.8, 31.6, 32.4, 38.0,
38.8, 55.5, 64.3, 68.6, 79.9, 95.3, 104.8, 127.6, 129.5, 133.9, 135.6,
151.5, 178.6 ppm. MS (ESI): m/z = 661 [M + Na]+. HRMS (ESI):
calcd. for C38H62NO6Si [M + NH4]+ 656.4341; found 656.4390.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra for all compounds.
low oil. R = 0.4 (25% EtOAc in hexane). IR (neat): ν = 3453, 2932,
˜
f
2860, 1727, 1157, 1107, 705 cm–1. H NMR (500 MHz, CDCl3): δ
1
= 0.95 (d, J = 6.6 Hz, 3 H), 1.06 (s, 9 H), 1.20 (s, 9 H), 1.36–1.44
(m, 1 H), 1.45–1.54 (m, 1 H), 1.55–1.80 (m, 10 H), 1.85–1.90 (m,
1 H), 2.09 (dd, J = 5.5, 13.2 Hz, 1 H), 3.33 (s, 3 H), 3.47–3.53 (m,
2 H), 3.59–3.63 (m, 1 H), 3.73–3.78 (m, 1 H), 4.06–4.10 (m, 2 H),
4.19–4.24 (m, 2 H), 4.61 (s, 2 H), 7.35–7.43 (m, 6 H), 7.66 (d, J =
6.6 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.3, 19.3,
24.7, 25.4, 26.8, 27.2, 29.6, 30.8, 32.5, 32.6, 38.1, 38.7, 41.4, 55.7,
64.2, 68.6, 72.8, 76.2, 76.6, 82.1, 95.3, 127.5, 129.4, 133.9, 135.5,
178.5 ppm. MS (ESI): m/z = 665 [M + Na]+. HRMS (ESI): calcd.
for C37H62NO7Si [M + NH4]+ 660.4290; found 660.4305.
Acknowledgments
A. S. R and B. M. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi for a research fellowship.
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Received: August 16, 2012
Published Online: October 29, 2012
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