Asymmetric synthesis of a highly functionalized bicyclo[3.2.2]nonene derivative

Article abstract of DOI:10.3762/bjoc.9.74

The stereoselective Diels-Alder reaction between an optically active 1,4-dimethylcycloheptadiene and acrolein was effectively promoted by TBSOTf to produce a bicyclo[3.2.2]nonene derivative bearing two quaternary carbons. Seven additional transformations from the obtained bicycle delivered the C ₂-symmetric bicyclo[3.3.2]decene derivative, a key intermediate in our synthetic study of ryanodine.

Full text of DOI:10.3762/bjoc.9.74

Asymmetric synthesis of a highly functionalized
bicyclo[3.2.2]nonene derivative
Toshiki Tabuchi, Daisuke Urabe and Masayuki Inoue*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 655–663.
Graduate School of Pharmaceutical Sciences, The University of
Tokyo, Hongo, Bunkyo-ku, Tokyo 133-0033 Japan
doi:10.3762/bjoc.9.74
Received: 14 February 2013
Accepted: 14 March 2013
Published: 04 April 2013
Email:
Masayuki Inoue* - inoue@mol.f.u-tokyo.ac.jp
* Corresponding author
This article is part of the Thematic Series "Transition-metal and
organocatalysis in natural product synthesis".
Keywords:
asymmetric synthesis; C2-symmetry; catalysis; Diels–Alder reaction;
Lewis acid; natural product; quaternary carbon
Guest Editors: D. Y.-K. Chen and D. Ma
© 2013 Tabuchi et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The stereoselective Diels–Alder reaction between an optically active 1,4-dimethylcycloheptadiene and acrolein was effectively
promoted by TBSOTf to produce a bicyclo[3.2.2]nonene derivative bearing two quaternary carbons. Seven additional transforma-
tions from the obtained bicycle delivered the C2-symmetric bicyclo[3.3.2]decene derivative, a key intermediate in our synthetic
study of ryanodine.
Introduction
Ryanodine (Scheme 1) [1-3] is a potent modulator of the intra- tionalizations of these molecules minimized the total number of
cellular calcium release channels, known as ryanodine recep- steps.
tors [4,5]. Its complex architecture, including eight contiguous
tetrasubstituted carbons on the pentacyclic ABCDE-ring Bicyclo[3.3.2]decene 1 was prepared from C2-symmetric
system, has posed a formidable synthetic challenge. To date, the bicyclo[2.2.2]octene 2 through a ring-expansion reaction
only total synthesis of a compound in this class of natural prod- (Scheme 1) [11]. We reported the synthetic routes to racemic 2
ucts was reported by Deslongchamps, who constructed ryan- and enantiomerically pure 2 from 3 and 5, respectively. Specifi-
odol in 1979 [6-9]. Most recently, we reported the synthesis of cally, the dearomatizing Diels–Alder reaction between 2,5-
9-demethyl-10,15-dideoxyryanodol [10] by taking advantage of dimethylbenzene-1,4-diol (3) and maleic anhydride lead to the
the intrinsic C2-symmetry of the target molecule. In this syn- construction of bicyclo[2.2.2]octene 4, which was then trans-
thesis, C2-symmetric compounds such as bicyclo[3.3.2]decene formed into racemic 2 through electrolysis [11]. Alternatively,
1 were strategically designed, and application of pairwise func- the Diels–Alder reaction between 3,6-dimethyl-o-quinone
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Beilstein J. Org. Chem. 2013, 9, 655–663.
Scheme 1: Structure of ryanodine and the Diels–Alder reactions for construction of the potential intermediates of ryanodine.
monoacetal 5 and 1,1-diethoxyethylene provided construction of the two quaternary carbons by the intermolec-
bicyclo[2.2.2]octene 6, which was then converted to enan- ular Diels–Alder reaction of 1,4-disubstituted cycloheptadiene
tiopure 2 via an enzymatic kinetic resolution [12]. The derivatives has not been reported [13,14].
Diels–Alder reaction was effectively employed in both of these
syntheses for construction of the two quaternary carbons at the Results and Discussion
C1 and C5 positions of ryanodine (highlighted in gray). The synthesis of optically active 7 began from crotyl chloride
However, the current route to (+)-2 from racemic 6 generated (Scheme 2). The carbon chain extension of crotyl chloride by
the unnecessary antipode. Therefore, development of an alter- treatment with acetylacetone and K2CO3 [15], followed by the
native asymmetric route to 1 was planned to further improve the addition of vinylmagnesium bromide [16], provided 9. The
overall practicality. Here we report an asymmetric Diels–Alder bromoetherification of tertiary alcohol 9 by using NBS led to
reaction for simultaneous installation of the C1- and C5-stereo- tetrahydrofuran 10 as a diastereomeric mixture. Next, the base-
centers using the optically active cycloheptadiene derivative 7, induced elimination of HBr converted 10 to diene 11, which
and its derivatization into bicyclo[3.3.2]decene 1.
underwent the Claisen rearrangement at 170 °C to give rise to
heptenone 12 [17-21]. The more thermodynamically stable silyl
We assumed that the C4-stereocenter of optically active seven- enol ether 13 was regioselectively formed from 12 under
membered diene 7 would permit the requisite stereoselective Holton’s conditions [22], and DDQ-mediated oxidation of 13
Diels–Alder reaction (Scheme 1). Namely, the reaction between resulted in the formation of α,β-unsaturated ketone 14. Asym-
7 and acrolein was expected to stereoselectively introduce the metric reduction of ketone 14 was in turn realized by applying a
C1, C5 and C12 stereocenters to afford bicyclo[3.2.2]nonene 8. stoichiometric amount of (R)-CBS and BH3·SMe2 to produce
The C11-aldehyde of 8 was then to be utilized as a handle for 15 (82% ee) [23]. The absolute configuration of C4 was deter-
the ring expansion to access 1. To the best of our knowledge, mined as S by the modified Mosher method after acylation of
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Scheme 2: Asymmetric synthesis of 7 and determination of the absolute configuration at C4 of 15 by the modified Mosher method. The numbers are
differences in 1H chemical shifts between 16a and 16b (Δδ = δ16a − δ16b).
15 using (R)- and (S)-MTPACl [24]. Finally, the hydroxy group pected bicyclo[2.2.2]octene skeletons 17a and 17b as a 2.9:1
of 15 was protected as its TBS ether to afford 7.
mixture. Under these conditions, BF3·OEt2-promoted elimina-
tion of the allylic siloxy group in 7 generated triene 18, which
We then explored the Diels–Alder reaction between 7 and then isomerized into 19 via a 6π-electrocyclic reaction. Diene
acrolein to construct the bicyclo[3.2.2]nonene structure 19, which appeared to be more reactive than the original diene
(Scheme 3). The Diels–Alder reaction under thermal conditions 7, then underwent the Diels–Alder reaction to provide 17a and
(100 °C) induced the decomposition of diene 7, and only the 17b.
starting material was recovered after 10 h (26%). Because of the
low reactivity of 7, we applied a Lewis acid to facilitate the Formation of 17a and 17b in Scheme 3 confirmed that selec-
reaction. However, the reaction of 7 and acrolein in the pres- tive activation of acrolein in the presence of the Lewis-basic
ence of BF3·OEt2 (50 mol %) led to formation of the unex- allylic oxygen was a prerequisite to the successful formation
Scheme 3: Generation of 17 through the 6π-electrocyclic reaction and the Diels–Alder reaction.
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Beilstein J. Org. Chem. 2013, 9, 655–663.
of 8. We anticipated that bulky trialkylsilyl triflates would func- stereoisomeric transition states, and leave only TS-A and TS-B,
tion as such chemoselective Lewis acids, because the activation which in fact correspond to the generated adducts 8 and 20, res-
of the TBS-connected oxygen of 7 by the silyl triflate would pectively. TS-A would be preferred over TS-B due to the unfa-
cause highly unfavorable steric interactions. Indeed, the cyclo- vorable interaction of the two proximal TBS groups in TS-B,
addition between 7 and acrolein proceeded even at −78 °C by allowing formation of 8 as the major compound.
the action of TMSOTf (50 mol %) in toluene to afford the
bicyclo[3.2.2]nonene 8 and 20 along with a small amount of
two other isomers 21ab (Table 1, entry 1). Among the various
silyl triflates used (Table 1, entries 1–3), TBSOTf was found to
be superior to TMSOTf or TIPSOTf in terms of the combined
yield. Alteration of the amount of TBSOTf from 50 mol %
(Table 1, entry 2) to 200 mol % (Table 1, entry 4) and change of
the solvent from toluene (Table 1, entry 4) to CH2Cl2 (Table 1,
entry 5) increased the yield of the adducts. It is particularly
worthy of note that the use of 2,6-di-tert-butylpyridine in
combination with 200 mol % of TBSOTf effectively inhibited
the Lewis-acid-promoted elimination of the C4-oxy group, and
that the ratio of 8 to 20 was improved from 1.6:1 to 3.4:1 by
replacement of the solvent (Table 1, entries 4 and 5). Thus, we
developed an effective method for synthesis of the requisite
stereoisomer 8 by applying a TBSOTf-promoted Diels–Alder
reaction [25,26]. Most importantly, the C4-stereocenter behaved
as the control element to introduce the two quaternary carbons
(C1 and 5) and the C12-stereocenter.
Scheme 4: Rationale of the stereoselectivity of the Diels–Alder reac-
tion.
The selective formation of 8 out of eight possible isomers is
rationalized in Scheme 4. The endo-type transition states would
be favored over their exo-type counterparts, and acrolein would
approach from the bottom face of 7 to avoid steric interactions Having synthesized the optically active 8, the next task was the
with the axially oriented C2- and C4-hydrogen atoms on the top preparation of C2-symmetric bicyclo[3.3.2]decene 1 from 8
face [27]. These considerations eliminate six out of the eight (Scheme 5). The silyl enol ether formation of aldehyde 8
Table 1: Optimization of the Diels–Alder reaction.a
entry
silyl triflate (R)
solvent
yieldb
ratioc (8/20/21ab)
1
2
TMS (50 mol %)
TBS (50 mol %)
TIPS (50 mol %)
TBS (200 mol %)
TBS (200 mol %)
toluene
toluene
toluene
toluene
CH2Cl2
31%
59%
47%
69%
88%
1.9:1:0.6
1.8:1:0.5
1.9:1:0.4
1.6:1:0.4
3.4:1:0.5
3
4d
5d
aReaction was performed at 0.5 M. bCombined yield of 8, 20 and two other isomers 21a/21b. cRatio was determined by 1H NMR analysis. d2,6-Di-
tert-butylpyridine (200 mol %) was added as a buffer.
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Beilstein J. Org. Chem. 2013, 9, 655–663.
Scheme 5: Synthesis of C2-symmetric 1.
afforded 22 as a single stereoisomer, and the obtained 22 was performed by using E. Merck Silica gel 60 F254 precoated
oxidized with DMDO to provide α-hydroxy aldehyde 23 as a plates. Flash column chromatography was performed by using
diastereomeric mixture (dr = 2.8:1). Compound 23 then reacted 40–50 µm Silica Gel 60N (Kanto Chemical Co., Inc.),
with benzyl hydroxylamine to produce oxime 24, LiAlH4-treat- 40–63 µm Silicagel 60 (Merck) or 32–53 µm Silica-gel
ment of which led to 25. The regioselective ring expansion of BW-300 (Fuji Silysia Chemical Ltd.). Melting points were
seven-membered 25 was induced by treatment with NaNO2 in measured on a Yanaco MP-J3 micro melting-point apparatus
acetic acid [28,29], resulting in the formation of eight- and are uncorrected. Optical rotations were recorded on a
membered 27 through the intermediary of 26. Finally, the desi- JASCO DIP-1000 Digital Polarimeter. Infrared (IR) spectra
lylation of 27 with TBAF and the subsequent oxidation of the were recorded on a JASCO FT/IR-4100 spectrometer. 1H and
resultant hydroxy group delivered the symmetric diketone 1 in 13C NMR spectra were recorded on JEOL JNM-ECX-500,
optically active form.
JNM-ECA-500, or JNM-ECS-400 spectrometers. Chemical
shifts were reported in parts per million (ppm) on the δ scale
relative to CHCl3 (δ 7.26 for 1H NMR), CDCl3 (δ 77.0 for
Conclusion
In summary, we developed a synthetic route to the optically 13C NMR), C6D5H (δ 7.16 for 1H NMR), C6D6 (δ 128.0 for
active seven-membered 7 and established the TBSOTf- 13C NMR), CO(CD3)(CD2H) (δ 2.05 for 1H NMR) as internal
promoted stereoselective Diels–Alder reaction between 7 and references. Signal patterns are indicated as s, singlet; d, doublet;
acrolein to construct highly functionalized bicyclo[3.2.2]nonene t, triplet; q, quartet, m, multiplet. The numbering of the com-
8 bearing two quaternary carbons. Seven additional transforma- pounds corresponds to that of the natural products. High-resolu-
tions of 8, including the ring expansion of the seven-membered tion mass spectra were measured on Bruker microTOFII.
ring to an eight-membered ring, delivered C2-symmetric
bicyclo[3.3.2]decene 1, which is the key intermediate in our TMS-enol ether 13: Methylmagnesium bromide (3.0 M in
synthetic studies of ryanodine.
Et2O, 8.5 mL, 26 mmol) was added to a solution of iPr2NH
(3.9 mL, 28 mmol) in Et2O (170 mL) at 0 °C. The mixture was
stirred at room temperature for 19 h, and cooled to −78 °C.
Experimental
General: All reactions sensitive to air or moisture were carried Then, a solution of 12 [3.5 g as a 5.7:1 mixture of 12 (23 mmol)
out under argon or nitrogen atmosphere in dry, freshly distilled and Et2O] in Et2O (60 mL), TMSCl (9.1 mL, 72 mmol), Et3N
solvents under anhydrous conditions, unless otherwise noted. (11.3 mL, 81 mmol), and HMPA (2.0 mL, 11 mmol) were
All other reagents were used as supplied unless otherwise successively added to the mixture. The reaction mixture was
stated. Analytical thin-layer chromatography (TLC) was stirred at room temperature for 18 h and cooled to 0 °C. Phos-
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Beilstein J. Org. Chem. 2013, 9, 655–663.
phate buffer (pH 7, 100 mL) was added, and the resultant solu- after the esterification with (S)-MTPACl; yellow oil; [α]D20
tion was extracted with Et2O (150 mL × 3). The combined −402 (c 0.995, CHCl3); IR (neat) νmax: 3336, 2965, 2920, 2880,
organic layers were washed with H2O (30 mL) and brine 1434, 1056, 1013 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.54
(200 mL), dried over Na2SO4, filtered, and concentrated. The (1H, br s, OH), 1.75 (1H, dddd, J = 13.7, 11.9, 2.8, 2.8 Hz,
residue was purified by flash column chromatography (silica gel H3a), 1.85 (3H, s, H17 or 20), 1.95 (3H, s, H17 or 20),
200 g, pentane only) to afford silyl enol ether 13 (3.3 g, 2.00–2.15 (2H, m, H2a and 3b), 2.32–2.39 (1H, br dd, J = 16.5,
16 mmol) and its regioisomer (344 mg, 1.64 mmol) in 70% and 11.9 Hz, H2b), 4.20 (1H, m, H4), 5.52 (1H, br d, J = 7.8 Hz,
7% yield, respectively. The synthesized silyl enol ether 13 was H14 or 15), 5.61 (1H, d, J = 7.8 Hz, H14 or 15); 13C NMR
immediately subjected to the next reaction: colorless oil; (125 MHz, C6D6) δ 24.0, 26.6, 29.2, 33.2, 72.4, 120.7, 122.6,
1H NMR (500 MHz, C6D6) δ 0.17 (9H, s, CH3 of TMS), 1.61 140.2, 142.9; HRMS–ESI (m/z): [M + Na]+ calcd for
(3H, d, J = 1.2 Hz, H17), 1.73 (3H, s, H20), 2.05 (2H, t, J = C9H14ONa, 161.0937; found, 161.0934.
6.3 Hz, H2ab), 2.31–2.35 (2H, m, H3ab), 2.60 (2H, d, J =
5.7 Hz, H14ab), 5.53 (1H, tq, J = 5.7, 1.2 Hz, H15); 13C NMR Diene 7: The mixture of 15 (259 mg, 1.88 mmol), imidazole
(125 MHz, C6D6) δ 1.2, 19.3, 25.8, 30.9, 31.7, 32.8, 114.7, (300 mg, 4.41 mmol) and TBSCl (330 mg, 2.19 mmol) in DMF
123.3, 137.4, 146.4. The regioisomer of 13: colorless oil; (6.0 mL) was stirred for 8.5 h at room temperature and cooled
1H NMR (400 MHz, C6D6) δ 0.18 (9H, s, CH3 of TMS), 1.19 to 0 °C. H2O (10 mL) was added to the reaction mixture, and
(3H, d, J = 6.9 Hz, H20), 1.67 (3H, br s, H17), 2.00 (1H, ddd, J the resultant solution was stirred for 30 min. The mixture was
= 14.6, 7.3, 7.3 Hz, H14a), 2.23–2.27 (1H, m, H14b), 2.32–2.40 extracted with EtOAc (6 mL × 3). The combined organic layers
(1H, m, H5), 2.46 (1H, dd, J = 17.9, 6.4 Hz, H2a), 2.62 (1H, dd, were dried over Na2SO4, filtered and concentrated. The residue
J = 17.9, 5.5 Hz, H2b), 4.95 (1H, dd, J = 6.4, 5.5 Hz, H3), 5.49 was purified by flash column chromatography (silica gel 5 g,
(1H, br ddq, J = 7.3, 7.3, 1.4 Hz, H15).
hexane/EtOAc 1:0 to 100:1) to afford 7 (404 mg, 1.60 mmol) in
85% yield; colorless oil; [α]D20 −247 (c 1.04, CHCl3); IR (neat)
Diene 14: DDQ (7.1 g, 31 mmol) was added to a solution of 13 νmax: 2956, 2928, 2856, 1472, 1436, 1253 cm−1; 1H NMR
(3.3 g 16 mmol) and 2,6-lutidine (5.4 mL, 46 mmol) in benzene (400 MHz, CDCl3) δ 0.085 (3H, s, CH3 of TBS), 0.093 (3H, s,
(30 mL) at 0 °C. The reaction mixture was stirred at room CH3 of TBS), 0.91 (9H, s, t-Bu of TBS), 1.75 (1H, dddd, J =
temperature for 20 min and filtered through a short column of 13.3, 10.5, 2.3, 2.3 Hz, H3a), 1.83 (3H, s, H17), 1.85 (3H, s,
Al2O3 with Et2O. The filtrate was concentrated. The residue H20), 1.92–2.00 (1H, dddd, J = 13.3, 8.7, 6.4, 2.3 Hz, H3b),
was purified by flash column chromatography (silica gel 120 g, 2.04 (1H, ddd, J = 16.5, 8.7, 2.3 Hz, H2a), 2.40 (1H, br dd, J =
pentane/Et2O 10:1 to 5:1) to afford diene 14 (1.5 g, 11 mmol) in 16.5, 10.5 Hz, H2b), 4.22 (1H, br d, J = 6.4 Hz, H4), 5.50 (1H,
69% yield: yellow oil; IR (neat) νmax: 2949, 1656, 1595, 1431, d, J = 7.8 Hz, H15), 5.54, (1H, d, J = 7.8 Hz, H14); 13C NMR
1377 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.92 (3H, s, H20), (100 MHz, CDCl3) δ −4.3, −4.1, 18.5, 24.0, 26.2, 26.9, 30.0,
1.98 (3H, s, H17), 2.29 (2H, t, J = 6.3 Hz, H2ab), 2.64 (2H, t, J 34.9, 73.4, 120.5, 121.5, 141.4, 143.2; HRMS–ESI (m/z): [M +
= 6.3 Hz, H3ab), 5.80 (1H, d, J = 8.0 Hz, H15), 6.51 (1H, d, J = Na]+ calcd for C15H28OSiNa, 275.1802; found, 275.1801.
8.0 Hz, H14); 13C NMR (100 MHz, CDCl3) δ 20.4, 26.5, 28.1,
41.7, 122.4, 136.0, 137.0, 150.0, 201.3; HRMS–ESI (m/z): [M + Cycloadduct 8 and 20: TBSOTf (530 μL, 2.3 mmol) was
Na]+ calcd for C9H12ONa, 159.0780; found, 159.0778.
added to a solution of 7 (297 mg, 1.18 mmol), acrolein (390 μL,
5.8 mmol) and 2,6-di-tert-butylpyridine (530 μL, 2.3 mmol) in
Diene 15: BH3·SMe2 (220 μL, 2.3 mmol) was added to a solu- CH2Cl2 (2.4 mL) at −78 °C. The reaction mixture was stirred
tion of (R)-2-Me-CBS-oxazaborolidine (1.0 M in toluene, for 15 min at −78 °C, and then saturated aqueous NaHCO3
2.3 mL, 2.3 mmol) in THF (6 mL) at 0 °C. The solution was (3 mL) was added. The resultant mixture was extracted with
stirred for 30 min at 0 °C and cooled to −78 °C. Then a solu- EtOAc (5 mL × 3). The combined organic layers were dried
tion of diene 14 (265 mg, 1.94 mmol) in THF (3 mL) was added over Na2SO4, filtered and concentrated. The residue was puri-
at −78 °C. The reaction mixture was warmed to 0 °C over fied by flash column chromatography (silica gel 12 g, hexane/
15 min, and H2O (10 mL) was added. The resultant solution CH2Cl2 4:1 to 3:1) to afford pure 20 (23 mg, 75 μmol), a mix-
was extracted with Et2O (6 mL × 3). The combined organic ture of 20, 21a, 21b and 8 (215 mg, 0.67 mmol), and pure 8
layers were washed with brine (5 mL), dried over Na2SO4, (87 mg, 0.29 mmol) in 88% combined yield. 8: colorless oil;
filtered and concentrated. The residue was purified by flash [α]D20 +25.6 (c 1.13, CHCl3); IR (neat) νmax: 2954, 2930, 1724,
column chromatography (silica gel 5 g, pentane/Et2O 20:1 to 1253, 1070 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.02 (6H, s,
5:1) to afford 15 (261 mg, 1.89 mmol) in 97% yield. The enan- CH3 of TBS × 2), 0.88 (9H, s, t-Bu of TBS), 1.02 (3H, s, H17
tiopurity of 15 was determined as 82% ee by comparison of the or 20), 1.03 (3H, s, H17 or 20), 1.21 (1H, dd, J = 14.6, 4.1 Hz,
integrations of the H14 peak at 5.78 and 5.72 ppm on 1H NMR H6a), 1.42 (1H, ddd, J = 13.7, 5.5, 5.0 Hz, H2a), 1.56 (1H, ddd,
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Beilstein J. Org. Chem. 2013, 9, 655–663.
J = 13.7, 11.5, 5.0 Hz, H2b), 1.72 (1H, dddd, J = 14.6, 11.5, 0.73, CHCl3); IR (neat) νmax: 3522, 2954, 2929, 2856, 1455,
9.2, 5.5 Hz, H3a), 1.84 (1H, dddd, J = 14.6, 5.0, 5.0, 5.0 Hz, 1363, 1254, 1067 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.006
H3b), 2.34 (1H, dd, J = 14.6, 9.6 Hz, H6b), 2.57 (1H, ddd, J = (3H, s, CH3 of TBS), 0.012 (3H, s, CH3 of TBS), 0.88 (9H, s,
9.6, 5.5, 4.1 Hz, H12), 3.38 (1H, dd, J = 9.2, 5.0 Hz, H4), 5.76 t-Bu of TBS), 0.98 (3H, s, H17 or 20), 1.02 (3H, s, H17 or 20),
(1H, d, J = 9.2 Hz, H14), 5.81 (1H, d, J = 9.2 Hz, H15), 9.29 1.33 (1H, d, J = 16.1 Hz, H6a), 1.36–1.57 (3H, m, H2ab and
(1H, d, J = 5.5 Hz, CHO); 13C NMR (100 MHz, CDCl3) δ −4.8, 3a), 1.85 (1H, dddd, J = 14.9, 5.8, 5.8, 5.8 Hz, H3b), 2.81 (1H,
−4.2, 18.1, 25.9, 26.7, 27.0, 29.2, 34.5, 35.3, 40.2, 40.4, 56.5, d, J = 16.1 Hz, H6b), 2.94 (1H, s, OH), 3.40 (1H, dd, J = 6.3,
71.7, 138.1, 138.3, 204.4; HRMS–ESI (m/z): [M + Na]+ calcd 5.8 Hz, H4), 5.13 (2H, s, OCH2Ph), 5.73 (1H, d, J = 9.2 Hz,
for C18H32O2SiNa, 331.2064; found, 331.2063. 20: IR (neat) H14 or 15), 5.79 (1H, d, J = 9.2 Hz, H14 or 15), 7.30–7.39 (5H,
νmax: 2954, 2930, 2856, 1724, 1253, 1070 cm−1; 1H NMR m, aromatic), 7.71 (1H, s, CHNOBn); 13C NMR (125 MHz,
(400 MHz, CDCl3) δ 0.02 (6H, s, CH3 of TBS × 2), 0.88 (9H, s, CDCl3) δ −4.8, −4.3, 18.1, 23.3, 25.9, 27.0, 32.6, 33.9, 39.7,
t-Bu of TBS), 1.02 (3H, s, CH3CCHCHO), 1.06 (3H, s, 42.6, 42.9, 71.0, 76.3, 78.0, 128.0, 128.42, 128.44, 137.1, 137.3,
CH3CCH2), 1.34 (1H, ddd, J = 13.7, 6.0, 3.7 Hz, 138.4, 152.8; HRMS–ESI (m/z): [M + Na]+ calcd for
CCHAHBCH2), 1.52–1.59 (2H, m, CCHAHBCH2 and C25H39NO3SiNa, 452.2591; found, 452.2589. 24b: IR (neat)
CCHAHBCHCHO), 1.70–1.87 (2H, m, CCH2CH2CH(OTBS)), νmax: 3525, 3025, 2955, 2928, 2856 cm−1; 1H NMR (400 MHz,
1.91 (1H, dd, J = 14.7, 10.1 Hz, CCHAHBCHCHO), 2.97 (1H, CDCl3) δ 0.01 (3H, s, CH3 of TBS), 0.02 (3H, s, CH3 of TBS),
ddd, J = 10.1, 5.0, 5.0 Hz, CHCHO), 3.32 (1H, dd, J = 9.2, 0.83 (3H, s, H17), 0.88 (9H, s, t-Bu of TBS), 0.95 (3H, s, H20),
5.5 Hz, CH(OTBS)), 5.55 (1H, d, J = 9.2 Hz, CCH=CHCCH2), 1.33–1.42 (1H, m, H2a), 1.50 (1H, d, J = 15.1 Hz, H6a),
5.97 (1H, d, J = 9.2 Hz, CCH=CHCCH2), 9.37 (1H, d, J = 1.80–1.88 (2H, m, H2b and 3a), 1.96–2.07 (1H, m, H3b), 2.44
5.0 Hz, CHO); 13C NMR (125 MHz, CDCl3) δ −4.8, −4.2, 18.1, (1H, d, J = 15.1 Hz, H6b), 3.42 (1H, dd, J = 8.2, 6.0 Hz, H4),
24.1, 25.9, 29.7, 33.8, 34.1, 34.6, 38.0, 41.8, 50.6, 73.5, 134.1, 3.48 (1H, s, OH), 5.06 (2H, s, OCH2Ph), 5.62 (1H, d, J =
142.4, 204.3; HRMS–ESI (m/z): [M + Na]+ calcd for 9.6 Hz, H14), 5.65 (1H, d, J = 9.6 Hz, H15), 7.27–7.35 (5H, m,
C18H32O2SiNa, 331.2064; found, 331.2057.
aromatic), 7.39 (1H, s, CHNOBn); 13C NMR (100 MHz,
CDCl3) δ −4.8, −4.1, 18.1, 23.5, 25.9, 26.7, 34.3, 34.9, 41.4,
Oxime 24: TMSOTf (220 μL, 1.2 mmol) was added to a solu- 41.5, 42.3, 71.6, 76.2, 78.1, 127.9, 128.3, 128.4, 137.2, 137.6,
tion of 8 (122 mg, 0.395 mmol) and Et3N (330 μL, 2.4 mmol) 138.3, 156.2; HRMS–ESI (m/z): [M + Na]+ calcd for
in CH2Cl2 (2.0 mL) at 0 °C. The reaction mixture was stirred at C25H39NO3SiNa, 452.2591; found, 452.2580.
room temperature for 15 h and cooled to 0 °C. Phosphate buffer
(pH 7, 5 mL) was added, and the resultant mixture was Ketone 27: LiAlH4 (2.0 M in THF, 380 μL, 0.76 mmol) was
extracted with EtOAc (6 mL × 3). The combined organic layers added to a solution of oxime 24 (110 mg, 0.256 mmol, a 2.8:1
were dried over Na2SO4, filtered and concentrated. The residue diastereomixture of 24a and 24b) in THF at 0 °C. The reaction
was passed through a short column (silica gel 100 mg, hexane/ mixture was stirred at 0 °C for 10 min, at room temperature for
EtOAc 2:1) to afford the crude TMS enol ether 22, which was 2.5 h, and at 40 °C for 2 h. After additional LiAlH4 (2.0 M in
used in the next reaction without further purification. DMDO THF, 380 μL, 0.76 mmol) was added, the reaction mixture was
(58 mM in acetone, 6.8 mL, 0.39 mmol) was added to a solu- stirred at 50 °C for a further 3.5 h. LiAlH4 (2.0 M in THF,
tion of the above crude TMS enol ether 22 in CH2Cl2 (1.0 mL). 380 μL, 0.76 mmol) was added again, and the reaction mixture
The reaction mixture was stirred for 10 min at 0 °C, and then was stirred for a further 1 h. After the reaction mixture was
isoprene (39 μL, 0.39 mmol) was added. The resultant solution cooled to 0 °C, H2O (87 μL) was added. The resultant solution
was concentrated. The residue was roughly purified by flash was stirred for 1 h at room temperature, and then 15% aqueous
column chromatography (silica gel 24 g, hexane/EtOAc 1:0 to NaOH (87 μL) and H2O (260 μL) were added. The solution was
10:1) to afford hydroxy aldehyde 23 (93 mg) as a diastereomix- stirred for 9 h. The resultant mixture was filtered through a pad
ture (2.8:1), which was used in the next reaction without further of Celite with THF (30 mL), and the filtrate was concentrated to
purification. A mixture of the above crude 23, BnONH2·HCl afford amino alcohol 25, which was used in the next reaction
(135 mg, 0.846 mmol), and MS4Å (93 mg) in THF (3.0 mL) without further purification. A solution of NaNO2 (141 mg,
was stirred at room temperature for 22 h. The reaction mixture 2.04 mmol) in H2O (1.3 mL) was added to a solution of the
was filtered through a pad of Celite with EtOAc (15 mL), and above crude amino alcohol 25 in H2O (3.8 mL) and AcOH
the filtrate was concentrated. The residue was purified by flash (1.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for
column chromatography (silica gel 15g, hexane/toluene 2:1 to 3 h, and then saturated aqueous NaHCO3 (30 mL) was added.
0:1 then hexane/CH2Cl2 1:1 to 1:3) to afford oxime 24a (81 mg, The resultant mixture was extracted with EtOAc (8 mL × 4).
0.19 mmol) and 24b (29 mg, 67 μmol) in 48% and 17% yield, The combined organic layers were dried over Na2SO4, filtered
respectively, over three steps. 24a: colorless oil: [α]D20 +60 (c and concentrated. The residue was purified by flash column
661

Beilstein J. Org. Chem. 2013, 9, 655–663.
chromatography (silica gel 18 g, hexane/CH2Cl2 3:1 to 0:1) to (JSPS) to M.I. and a Grant-in-Aid for Young Scientists (B)
afford ketone 27 (20 mg, 65 μmol) in 25% yield over two steps: (JSPS) to D.U.
colorless oil; [α]D20 +134 (c 0.165, CHCl3); IR (neat) νmax:
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This research was financially supported by the Funding
Program for Next Generation World-Leading Researchers
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