Synthesis of key fragments of amphidinolide Q - A cytotoxic 12-membered macrolide

Article abstract of DOI:10.3390/molecules16075422

β-Hydroxy aldehyde and alkyl ketone moieties were effectively synthesized as key intermediates of amphidinolide Q, a cytotoxic macrolide from the cultured dinoflagellate Amphidinium sp.. The asymmetric center of the former derivative was produced by Sharpless asymmetric epoxidation, followed by E-selective 1,4-addition to give the sp² methyl group. Derivatization of the L-ascorbic acid derivative by Evans asymmetric alkylation and Peterson olefination provided the latter intermediate. The coupling reaction of the segments was examined.

Full text of DOI:10.3390/molecules16075422

Molecules 2011, 16, 5422-5436; doi:10.3390/molecules16075422
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Key Fragments of Amphidinolide Q — A Cytotoxic
12-membered Macrolide
Kohei Kawa, Akihiro Hara, Yuichi Ishikawa and Shigeru Nishiyama *
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1,
Kohoku-ku, Yokohama 223-8522, Japan
* Author to whom correspondence should be addressed; E-Mail: nisiyama@chem.keio.ac.jp;
Tel.: +81 455631717, Fax: +81 455661717.
Received: 31 May 2011; in revised form: 20 June 2011 / Accepted: 22 June 2011 /
Published: 27 June 2011
Abstract: β-Hydroxy aldehyde and alkyl ketone moieties were effectively synthesized as
key intermediates of amphidinolide Q, a cytotoxic macrolide from the cultured
dinoflagellate Amphidinium sp.. The asymmetric center of the former derivative was
produced by Sharpless asymmetric epoxidation, followed by E-selective 1,4-addition to
give the sp2 methyl group. Derivatization of the L-ascorbic acid derivative by Evans
asymmetric alkylation and Peterson olefination provided the latter intermediate. The
coupling reaction of the segments was examined.
Keywords: amphidinolide Q; Amphidinium sp.; macrolide synthesis; cytotoxic marine
natural product
1. Introduction
Amphidinolide Q (1, Scheme 1) is a member of the cytotoxic macrolide family isolated from the
cultured dinoflagellate Amphidinium sp., and its absolute stereostructure was chemically determined
by Kobayashi and co-workers [1,2]. This macrolide exhibits potent cytotoxicity against L1210 murine
leukemia cells. Due to its low natural abundance, the detailed structure-activity relationship of 1 has
not been established. Although 1 was synthesized by Kobayashi’s group in 2009 [3], further increases
in synthetic efficiency and examination of related substances based on new synthetic approaches are

Molecules 2011, 16
5423
required to explain the detailed mode of action of 1 by structure-activity relationship studies, and to
develop new bioactive substances superior to the mother macrolide. We describe herein an efficient
method for synthesis of segments 2 and 3, which will be important intermediates for the construction
of 1.
2. Results and Discussion
As outlined in Scheme 1, retrosynthetic analysis showed that amphidinolide Q (1) could be obtained
by successive coupling of 2 and 3, with the former, carrying a stereogenic center and a tri-substituted
olefin, being produced from the known allyl alcohol 4 through E-selective 1,4-addition of a methyl
group at C3 and Sharpless asymmetric epoxidation. The alkyl ketone 3 carrying three stereogenic
centers could be obtained from the ascorbic acid derivative 5 through Evans asymmetric alkylation.
Scheme 1. Amphidinolide Q (1) and retrosynthetic analysis.
2.1. Synthesis of segment A (2)
The synthesis of 2 commenced with the conversion of 1,3-propanediol (6) into alcohol 4 (Scheme
2) [4]. Incorporation of the asymmetric center at C4 and carbon chain elongation were carried out by
Sharpless asymmetric epoxidation, followed by chlorination, alkynylation [5], and final p-methoxy-
benzyl (PMB) protection of the newly produced OH group under acidic conditions to avoid
unexpected removal of the tert-butyldiphenylsilyl (TBDPS) group. Further manipulation of 7 involved
introduction of a methoxycarbonyl group at the terminal of the alkynyl carbon to give 8, which upon
E-selective alkylation using a PhS group as an auxiliary [6], afforded the α,β-unsaturated ester 9. In
this case, the two-step procedure involving preparation of the vinyl sulfide, followed by exchange with
a methyl group must be used to afford the α,β-unsaturated ester 9 in good yield (Table 1). In the case
of direct methylation (path A), the desired compound 9 was obtained in low yield, even when the
reaction temperature was increased to 0 °C (entry 2). Although a number of reagent combinations to

Molecules 2011, 16
5424
control the properties of cuprates are known, the desired product was obtained in good yield in the
case of entry 5.
Deprotection and oxidation processes ultimately gave the β-hydroxyl aldehyde 2 (segment A) in
good overall yield.
Scheme 2. Synthesis of segment A (2).
1) Ti(O-iPr)4, (-)-DET,
t-BuOOH,CH2Cl2, -25 oC,
98%, >95%ee
2) PPh3, NaHCO3, CCl4, reflux,
ref.4
PMBO
4
OTBDPS
OTBDPS
86%
HO
OH
HO
3) n-BuLi, THF, -40 oC, 87%
4) 4-methoxybenzyl-
6
4
7
trichloroacetimidate,
TfOH, CH2Cl2, 0 oC, 90%
MeOCOCl, n-BuLi,
-78 oC, 99%
1) PhSH, NaOMe,
MeOH, rt, 93%
PMBO
OTBDPS
PMBO
OTBDPS
MeO2C
1) TBAF, AcOH, H2O,
THF, rt, 86%
2) PCC, celite,
2) CuI, MeMgBr, THF,
-30 oC, 87%
MeO2C
9
8
CH2Cl2, rt, 85%
PMBO
CHO
MeO2C
segment A (2)
Table 1. 1,4-Addition of methyl group at C3 position of compound 6.
PMBO
OTBDPS
PMBO
OTBDPS
path A
MeO2C
MeO2C
8
9
PhSH, NaOMe
MeOH, rt, 93%
path B
PMBO
OTBDPS
MeO2C
SPh
entry path
Cu reagent
(20 eq.)
alkylating agent
(39 eq.)
solvent
reaction
temperature
yields
9
8
-30 oC
1
2
18%
-
A
B
CuCN
CuCN
MeLi
MeLi
Et2O
Et2O
oC
-30 o
-30 oC
32%
-
0
3
4
CuCN
CuI
Et2O
Et2O
-
-
100%
71%
MeLi
MeLi
C
-30 o
-78 o
C
C
5
6
CuI
CuI
MeMgBr
MeMgBr
THF
THF
87%
33%
-
52%

Molecules 2011, 16
5425
2.2. Synthesis of segment B (3)
Synthesis of alkyl ketone 3 was initiated by transformation of the ascorbic acid derivative 5 into
diol 10 by a known procedure [7] (Scheme 3).
Scheme 3. Synthesis of segment B (3).
1) NaIO4, CH2Cl2/H2O, rt,
then Ph3PCHCO2Me, rt
2) Raney Ni, H2, EtOH, rt
O
1) H2O2, K2CO3, H2O, rt
2) EtI, CH3CN, reflux
OH
O
HO2C
HO
HO
11
3) LiOH, THF/H2O, 0 oC
O
3) LiAlH4, THF, rt
87% in 3 steps
O
O
O
O
OH
O
82% in 3 steps
5
10
11
1) (R)-4-Benzyl-2-oxazolidinone
Et3N, PivCl, LiCl,, rt, 100%
2) LHMDS, MeI, THF,
-40 to -20 oC, 90%
1) PivCl, CH2Cl2,
pyr., rt, 98%
1) LiBH4, THF, MeOH, H2O, rt
2) BnBr, NaH, TBAI, DMF, rt,
90% in 2 steps
O
O
9
2) TBSCl, DMF,
imidazole, rt
BnO
OH
N
O
O
OH
3) TsOH-H2O, DMF/H2O
30 oC, 80 mm Hg, quant.
O
Bn
3) DIBAL, CH2Cl2,
-78 oC
13
12
97% in 2 steps
O
O
O
1) SO3-pyr., DMSO,
Et3N, CH2Cl2, rt
O
O
EtO P
EtO
BnO
OH
OTBS
BnO
N
N
O
O
2) 16, LiCl, DIPEA,
CH3CN, rt
OTBS
Bn
Bn
99% in 2 steps
14
15
16
1) LiBH4, THF,
1) H2, Rh-Al2O3, EtOAc, rt, 96%
2) LHMDS, -40 oC,
MeOH, H2O, rt, 93%
2) SO3-pyr., DMSO,
Et3N, CH2Cl2, rt
then MeI, -20 oC, THF, 77%
O
O
O
3) EtMgBr, THF, 0 oC,
13
89% in 2 steps
BnO
N
O
BnO
4) SO3-pyr., DMSO,
Et3N, CH2Cl2, rt, quant.
OTBS
Bn
OTBS
18
17
1) TMSCH2Li, THF,
-78 oC, 88%
1) Li, NH3,THF, -78 oC, 99%
2) SO3-pyr., DMSO, Et3N,
CH2Cl2, rt, 90%
2) NaH, THF,
reflux, 98%;
O
3) EtMgBr, THF, 0 oC, 80%
BnO
4) SO3-pyr., DMSO,
Et3N, CH2Cl2, rt, 84%.
OTBS
OTBS
19
segment B (3)
Compound 10 was subjected to oxidative cleavage of the vicinal diol, followed by immediate
Wittig reaction, hydrogenation, and hydrolysis to give 11. In particular, the second Wittig reaction was
carried out using crude aldehyde to avoid undesired epimerization of the asymmetric center at C11.

Molecules 2011, 16
5426
Selective asymmetric induction at C9 by the Evans protocol effected the desired introduction of a
methyl group to yield 12. Removal of the chiral auxiliary by LiBH4 and manipulation of protecting
groups in five steps gave the alcohol 14 via 13. After Parikh–Doering oxidation of 14, the aldehyde
generated was reacted with Horner–Wadsworth–Emmons reagent 16 [8] to yield 15, which on
hydrogenation followed by addition of a methyl group produced 17. After removal of the auxiliary by
LiBH4, an ethyl ketone function was constructed (compound 18), and the exo-methylene function was
introduced by Peterson olefination, followed by basic treatment, whereas other methods, such as the
Wittig and Petasis reactions did not produce the desired compound, probably due to the low reactivity
of the ethylketone moiety. Synthesis of segment B (3) was accomplished by Birch reduction, followed
by alkylation similar to that described the case of 18 and Parikh–Doering oxidation and
Grignard reaction.
The synthetic strategies used for both segments may enable the synthesis of analogs. The
stereogenic centers were introduced via asymmetric reactions, which can produce another enantiomer
by exchanging the auxiliary group or catalyst, with the exception of the C11 center: in this case the
opposite (R)-enantiomer would be produced using (R)-glyceraldehyde acetonide, derived from
D-mannitol [9].
Aldol coupling of both segments was attempted, as shown in Scheme 4. Whereas Lewis acidic
conditions such as method B [10] caused undesirable elimination of 2 and 20 [11] to give the
corresponding α,β,δ,γ-unsaturated ester, basic conditions (method A) provided 20, equipped with the
complete carbon framework, in moderate yield,. Detailed studies of the diastereomer distribution to
improve the coupling yields are currently in progress in our laboratory.
Scheme 4. Coupling attempts between 2 and 3 [12].
3. Experimental
General
All reactions were carried out under an argon atmosphere unless otherwise noted. When necessary,
solvents were dried prior to use. Dry THF, dry Et2O and dry CH2Cl2 were purchased from Kanto
Chemical Co., Inc. Optical rotations were measured on a JASCO P-2200 digital polarimeter with a
sodium (D line) lamp. IR spectra were recorded on a Jasco Model A-202 spectrophotometer. 1H-NMR
spectra and 13C-NMR spectra were obtained on JEOL JNM-EX270, JNM-GX400, JNM-α400,
JNM-AL400 and JNM-ECX400 spectrometers in deuterated solvent using tetramethylsilane as an
internal standard. Deuteriochloroform was used as a solvent, unless otherwise stated. Optical purity
was determined by HPLC using an OJ-H column. High-resolution mass spectra were obtained on a
Waters LCT Piemier XE (ESI) or JEOL JMS-700 (FAB). Preparative and analytical TLC were carried

Molecules 2011, 16
5427
out on silica gel plate (Kieselgel 60 F254, E. Merck AG., Germany) using UV light and/or 5%
molybdophosphoric acid in ethanol for detection. Kanto silica 60N (spherical, neutral, 105–210 μm)
was used for column chromatography.
(R)-tert-Butyl(3-(4-methoxybenzyloxy)pent-4-ynyloxy)diphenylsilane (7). To a suspension of Ti(OiPr)4
(4.28 mL, 14.6 mmol) and MS4A (4.9 g) in CH2Cl2 (100 mL) was added (-)-DET (3.32 mL,
19.5 mmol) at −25 °C. To the mixture were added 4 (3.31 g, 9.73 mmol) and t-BuOOH (3.17 mL,
29.2 mmol); the solution was stirred overnight. The reaction was quenched by L-(+)-tartaric acid
(12.4 g, 82.6 mmol) aqueous and iron (II) sulfate heptahydrate (12.2 g, 43.9 mmol). The mixture was
extracted with Et2O, and the organic extracts were dried (Na2SO4), and concentrated in vacuo. The
crude product was purified by silica gel column chromatography using hexane-ethyl acetate (3:1) to
give an alcohol (3.38 g, 98%, 95% ee) as a colorless oil: [α]23D +14.7 (c 1.00, CHCl3); IR (film) 3437,
3048, 1428, 1110, 936, 822 cm−1; 1H-NMR (400 MHz) δ 1.06 (9H, s), 1.81 (2H, td, J = 12.1, 6.0 Hz),
2.98 (1H, td, J = 4.7. 2.5 Hz), 3.13 (1H, td, J = 6.0, 2.5 Hz), 3.63 (1H, m), 3.80 (2H, m), 3.91 (1H, m),
13
7.40 (6H, m), 7.66 (4H, m); C-NMR (100 MHz) δ 19.2, 26.8, 34.8, 53.7, 58.5, 60.7, 61.6, 127.7,
129.7, 133.6, 135.5. ESI-MS: calcd for C21H29O3Si 357.1886 (M+H)+, found, m/z 357.1897.
A stirred mixture of the alcohol (3.38 g, 9.49 mmol), PPh3 (7.47 g, 28.5 mmol), and NaHCO3
(0.80 g, 9.5 mmol) in CCl4 (100 mL) was refluxed under argon atmosphere overnight. After
completion of the reaction, CCl4 was removed under reduced pressure, and the residue was purified by
silica gel column chromatography (hexane-ethyl acetate 40:1) to furnish an epoxy chloride (3.04 g,
86%) as a colorless oil: [α]23D +12.9 (c 1.00, CHCl3); IR (film) 3049, 1428, 1111, 939, 822 cm−1; 1H-
NMR (400 MHz) δ 1.06 (9H, s), 1.81 (2H, td, J = 11.2, 5.6 Hz), 3.07 (2H, m), 3.56 (2H, m), 3.80 (2H,
m), 7.41 (6H, m), 7.66 (4H, m); 13C-NMR (100 MHz) δ 19.2, 26.8, 34.7, 44.7, 56.7, 57.3, 60.5, 127.7,
129.7, 133.5, 135.5. ESI-MS: calcd for C21H28O2SiCl 375.1547 (M+H)+, found, m/z 375.1539.
To a stirred solution of the epoxy chloride (0.23 g, 0.63 mmol) in dry THF (7 mL) was added n-
BuLi (2.4 mL, 1.6 M solution in n-hexane, 3.79 mmol) dropwise at −40 °C under argon atmosphere;
and the mixture was stirred for an additional 2 h. The mixture was quenched with saturated aqueous
NH4Cl, and the mixture was extracted with ethyl acetate. The organic extracts were dried (Na2SO4),
and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-
ethyl acetate 7:1) to give an alcohol (0.18 g, 87%) as a colorless oil: [α]23D +3.67 (c 1.00, CHCl3); IR
1
(film) 3422, 3304, 3071, 1428, 1111, 823 cm−1; H-NMR (400 MHz) δ 1.06 (9H, s), 1.92 (1H, tdd,
J = 14.0, 6.3, 3.6 Hz), 2.05 (1H, tdd, J = 14.0, 8.0, 4.3 Hz), 2.48 (1H, d, J = 5.8 Hz), 3.34 (1H, d,
J = 5.8 Hz), 3.85 (1H, ddd, J = 12.0, 6.3, 4.3 Hz), 4.07 (1H, ddd, J = 12.0, 8.0, 3.6 Hz), 4.71 (1H, m),
13
7.42 (6H, m), 7.69 (4H, m); C-NMR (100 MHz) δ 19.0, 26.8, 38.5, 61.5, 61.7, 73.0, 84.4, 127.8,
129.9, 132.8, 135.6. ESI-MS: calcd for C21H27O2Si 339.1780 (M+H)+, found, m/z 339.1775.
To a solution of the alcohol (0.10 g, 0.30 mmol) in anhydrous CH2Cl2 (7 mL) were added
4-methoxybenzyl trichloroacetimidate (0.493 g, 1.74 mmol) and TfOH (cat.) at 0 ºC, and the mixture
was stirred overnight. The reaction was quenched with saturated aqueous NH4Cl, and extracted with
ethyl acetate. The organic extracts were dried (Na2SO4), and concentrated in vacuo. The residue was
purified by silica gel column chromatography (hexane-ethyl acetate 7:1) to give 7 (0.12 g, 90%) as a
1
colorless oil: [α]23 +45.1 (c 1.02, CHCl3); IR (film) 3286, 1514, 1249, 1111, 823 cm−1; H-NMR
D
(400 MHz) δ 0.94 (9H, s), 1.91 (2H, m), 2.36 (1H, d, J = 2.1 Hz), 3.72 (5H, m), 4.34 (2H, m), 4.66 (1H,

Molecules 2011, 16
5428
d, J = 11.2 Hz), 6.77 (2H, m), 7.20 (2H, m), 7.31 (6H, m), 7.56 (4H, m); 13C-NMR (100 MHz) δ 19.2,
26.8, 38.7, 55.2, 59.7, 65.0, 70.3, 73.8, 83.0, 113.8, 127.6, 129.6, 133.7, 135.5, 159.2. ESI-MS: calcd
for C29H34O3SiK 497.1914 (M+K)+, found, m/z 497.1911.
(R)-Metyl-6-(tert-Butyldiphenylsilyloxy)-4-(4-methoxybenzyloxy)hex-2-ynoate (8). To a solution of 7
(50.8 mg, 0.11 mmol) in THF (1.5 mL) was added dropwise n-BuLi (0.3 mL, 1.6 M solution in
hexane, 0.48 mmol) at −78 °C, and the mixture was stirred at the same temperature for 1 h. Methyl
chloroformate (0.09 mL, 1.11 mmol) was added dropwise to the mixture; the resulting mixture was
stirred at 0 °C for 2.5 h. After being quenched with saturated aqueous NH4Cl, the mixture extracted
with ethyl acetate. The organic layer was dried (Na2SO4), and concentrated in vacuo. The residue was
purified by silica gel column chromatography (hexane-ethyl acetate 9:1) to give 8 (56.4 mg, 99%) as a
1
colorless oil: [α]23 +59.8 (c 0.99, CHCl3); IR (film) 3071, 2233, 1719, 1249, 1111 cm−1; H-NMR
D
(400 MHz) δ 1.00 (9H, s), 2.01 (2H, ddd, J = 12.7, 7.6, 6.0 Hz), 3.79 (8H, m), 4.43 (1H, d,
J = 11.2 Hz), 4.55 (1H, d, J = 7.6, 6.0 Hz), 4.74 (1H, d, J = 11.2 Hz), 6.86 (2H, m), 7.26 (2H, m), 7.37
13
(6H, m), 7.60 (4H, m); C-NMR (100 MHz) δ 19.1, 26.7, 38.0, 52.8, 55.2, 59.3, 64.7, 71.0, 86.9,
113.8, 127.7, 129.2, 129.6, 129.7, 133.5, 135.5, 153.7, 159.4. ESI-MS: calcd for C31H36O5SiK
555.1969 (M+K)+, found, m/z 555.1970.
(R,E)-Methyl 6-(tert-butyldiphenylsilyloxy)-4-(4-methoxybenzyloxy)-3-methylhex-2-enoate (9). To a
solution of 8 (90.8 mg, 0.18 mmol) in MeOH was added PhSH (36 μL, 0.35 mmol) and NaOMe (0.18
mL, 0.02 mmol) at room temperature. After being stirred at the same temperature for 3 h, the reaction
mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography
(hexane- ethyl acetate 9:1) to give a methyl ester (102.1 mg, 93%) as a colorless oil: [α]23 -91.3 (c
D
1.0, CHCl3); IR (film) 1705, 1513, 1248, 1110 cm−1; 1H-NMR (400 MHz) δ 0.93 (9H, s), 1.63 (1H, m),
2.02 (1H, m), 3.46 (1H, m), 3.50 (1H, m), 3.77 (3H, s), 3.79 (3H, s), 3.96 (1H, dd, J = 2.5, 9.9 Hz),
4.04 (1H, d, J = 10.8 Hz), 4.46 (1H, d, J = 10.8 Hz), 6.35 (1H, s), 6.79 (2H, m), 7.07 (2H, m), 7.21
(3H, m), 7.34 (4H, m), 7.43 (4H, m), 7.53 (4H, m); 13C-NMR (100 MHz) δ 19.1, 26.8, 39.8, 51.4, 55.3,
60.2, 70.7, 75.3, 113.8, 111.6, 113.7, 127.5, 129.2, 129.3, 129.5, 135.3, 135.5, 159.2, 160.5, 166.8.
ESI-MS: calcd for C37H42O5SiSNa 649.2420 (M+Na)+, found, m/z 649.2440.
To a suspension of CuI (0.62 g, 3.2 mmol) in THF was added MeMgBr (6.7 mL, 0.95 M in THF,
6.3 mmol) at −78 °C; the solution was warmed to −30 °C and stirred for 1.5 h. The solution was cooled
to −78 °C, and the methyl ester (0.10 g, 0.16 mmol) was added. The reaction mixture was stirred at
−30 °C for 1 h, then quenched with saturated aqueous NH4Cl and NH4OH. The reaction mixture was
extracted with ethyl acetate, and the organic layer was dried (Na2SO4) and concentrated in vacuo. The
residue was purified by silica gel column chromatography (benzene-hexane 7:1) to give 9 (75 mg,
87%) as a colorless oil: [α]23D +64.0 (c 0.50, CHCl3); IR (film) 1720, 1428, 1249, 1111, 822 cm−1; 1H-
NMR (400 MHz) δ 0.96 (9H, s), 1.69 (2H, m), 2.05 (3H, d, J = 1.0 Hz), 3.64 (8H, m), 3.99 (1H, t,
J = 6.6 Hz), 4.08 (1H, d, J = 11.2 Hz), 4.34 (1H, d, J = 11.2 Hz), 5.86 (1H, s), 6.77 (2H, m), 7.12
13
(2H, m), 7.31 (6H, m), 7.56 (4H, m); C-NMR (100 MHz) δ 14.3, 19.2, 26.8, 37.2, 51.0, 55.2, 59.9,
70.6, 80.2, 113.8, 116.4, 127.6, 129.4, 129.6, 130.1, 133.7, 135.5, 158.9, 159.2, 167.0. ESI-MS: calcd
for C32H40O5SiNa 555.2543 (M+Na)+, found, m/z 555.2530.

Molecules 2011, 16
5429
(R,E)-Methyl 4-(4-methoxybenzyloxy)-3-methyl-6-oxohex-2-enoate (segment A, 2). To a solution of 9
(0.33 g, 0.62 mmol) in THF (6 mL) was added reagent (TBAF-AcOH-H2O= 1:1:5 0.1 M in THF,
0.3 mmol) at room temperature; the mixture was stirred at the same temperature overnight. After the
addition of cold water, the mixture was extracted with Et2O. The organic layer was dried (Na2SO4) and
concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl
acetate 1:1) to give an alcohol (0.16 g, 88%) as a colorless oil: [α]23D +68.7 (c 0.99, CHCl3); IR (film)
1
3429, 1718, 1654, 1613, 1513, 1156, 1035 cm−1; H-NMR (270 MHz) δ 1.84 (2H, m), 2.15 (3H, d,
J = 1.3 Hz), 3.73 (5H, m), 3.81 (3H, s), 3.98 (1H, dd, J = 9.1, 3.8 Hz), 4.20 (1H, d, J = 11.2 Hz), 4.48
13
(1H, d, J = 11.2 Hz), 5.95 (1H, s), 6.89 (2H, m), 7.23 (2H, m); C-NMR (67.5 MHz) δ 14.4, 29.7,
36.3, 51.1, 55.2, 60.4, 70.6, 82.03, 113.9, 116.6, 128.3, 129.5, 129.6, 157.7, 159.4, 166.8. ESI-MS:
calcd for C16H22O5Na 317.1365 (M+Na)+, found, m/z 317.1363.
To a mixture of PCC (35 mg, 0.16 mmol) and Celite in CH2Cl2 (2 mL) was added the alcohol
(31.7 mg, 0.11 mmol) at 0 °C; the mixture was stirred at room temperature for 30 min. After
concentration of the reaction mixture, the residue was purified by silica gel column chromatography
(Et2O-hexane 2:1) to give segment A (26.7 mg, 85%) as a colorless oil: [α]23D +28.9 (c 0.91, CHCl3);
1
IR (film) 1720, 1655, 1612, 1513, 1248, 1034 cm−1; H-NMR (270 MHz, C6D6) δ 1.90 (1H, ddd,
J = 1.1, 3.6, 16.6 Hz), 2.14 (3H, m), 2.34 (1H, ddd, J = 2.5, 9.2, 16.6 Hz), 3.38 (3H, s), 3.53 (3H, s),
4.05 (1H, m), 4.07 (1H, d, J = 11.2 Hz), 4.32 (1H, d, J = 11.2 Hz), 6.09 (1H, m), 6.84 (2H, m), 7.18
(2H, m), 9.38 (1H, dd, J = 1.1, 2.5 Hz); 13C-NMR (67.5 MHz, C6D6) δ 14.3, 47.5, 50.7, 54.7, 70.7,
77.6, 78.2, 114.1, 117.4, 129.7, 130.0, 156.6, 166.3, 198.3. ESI-MS: calcd for 293.1389 (M+H)+,
found, m/z 293.1402.
(R)-3-(2,2-Dimethyl-1,3-dioxolan-4-yl)propanoic acid (11). To a solution of NaIO4 (3.78 g, 17.7 mmol)
in CH2Cl2 (60 mL) and H2O (30 mL) was added 10 (1.91 g, 11.8 mmol) at 0 °C; the mixture was
stirred at room temperature for 1.5 h. After the addition of Ph3PCHCO2Me (7.89 g, 23.6 mmol) at 0
°C, the mixture was stirred at room temperature overnight. The organic layer was separated and the
aqueous layer was extracted with CHCl3 three times. The combined organic layers were washed with
brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column
chromatography (hexane-ethyl acetate 3:1) to give an α,β-unsaturated ester (1.84 g, 84%, E:Z = 1:3) as
a colorless oil.
The ester (1.02 g, 5.48 mmol) was dissolved in EtOH (55 mL) in the presence of Raney Ni W-4.
The mixture was stirred at room temperature under hydrogen atmosphere overnight. After filtration,
the filtrate was concentrated at 110 °C to afford the corresponding ester as a crude oil. To a solution of
the ester in THF (17 mL) was added 1.5 M LiOH aqueous (17 mL) at 0 °C. The mixture was stirred at
0 °C for 3 h. The mixture was acidified to pH 4 with 10% aqueous citric acid and extracted with ethyl
acetate three times. The combined organic layers were washed with brine, dried (Na2SO4), and
concentrated in vacuo to give 11 (0.935 g, 98%) as a colorless oil: [α]23 +1.2 (c 1.00, CHCl3); IR
D
(film) 2987, 1712, 1215, 1154, 1073 cm−1; 1H-NMR (270 MHz) δ 1.35 (3H, s), 1.42 (3H, s), 1.89 (2H,
m), 2.51 (2H, m), 3.57 (1H, dd, J = 6.5, 7.8 Hz), 4.06 (1H, dd, J = 5.9, 7.8 Hz), 4.14 (1H, m);
13C- NMR (67.5 MHz) δ 25.6, 26.9, 28.5, 30.2, 68.9, 74.7, 109.1, 178.9. ESI-MS: calcd for C8H15O4
175.0970 (M+H)+, found, m/z 175.0968.

Molecules 2011, 16
5430
(R)-4-Benzyl-3-((R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropanoyl)oxazolidin-2-one (12).
To a solution of 11 (6.10 g, 35.0 mmol) in THF (325 mL) were added Et3N (15.0 mL, 0.190 mol)
and PivCl (6.40 mL, 52.5 mmol) at 0 °C. After 2 h, LiCl (7.42 g, 175 mmol) and (R)-4-benzyl-2-
oxazolidinone (9.30 g, 52.5 mmol) were added to the reaction mixture, and then the mixture was
stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous
NH4Cl at 0 °C, then the resulting slurry was extracted with ethyl acetate three times. The combined
organic layers were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was
purified by silica gel column chromatography (hexane-ethyl acetate 3:1) to give an amide (10.8 g,
92%) as a colorless oil: [α]24 -42.4 (c 1.01, CHCl3); IR (film) 2984, 1782, 1690, 1382, 1212, 1054
D
cm−1; 1H-NMR (400 MHz) δ 1.35 (3H, s), 1.42 (3H, s), 1.96 (2H, m), 2.78 (1H, dd, J = 9.8, 13.2 Hz),
3.07 (2H, t, J = 7.8 Hz), 3.30 (1H, dd, J = 3.4, 13.2 Hz), 3.60 (1H, dd, J = 6.8, 7.8 Hz), 4.08 (1H, dd,
13
J = 5.9, 7.8 Hz), 4.64 (3H, m), 4.67 (1H, m), 7.27 (5H, m); C-NMR (100 MHz) δ 25.7, 27.0, 28.2,
32.0, 37.9, 55.1, 66.2, 69.2, 74.9, 108.9, 127.2, 128.8, 129.3, 135.1, 153.3, 172.5, 180.1. ESI-MS:
calcd for C18H23NO5Na 356.1474 (M+Na)+, found, m/z 356.1489.
To a solution of LHMDS (73.0 mL, 1.0 M solution in THF, 73.0 mmol) was added the amide
(12.2 g, 36.5 mmol) in THF (400 mL) at −40 °C. After 1.5 h, MeI (22.7 mL, 0.365 mol) was added to
the reaction mixture. The mixture was stirred at −20 °C for 4 h. The reaction was quenched by the
addition of saturated aqueous NH4Cl at 0 °C, then the resulting slurry was extracted with ethyl acetate
three times. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated in
vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 3:1) to
give 12 (10.8 g, 85%) as a white needles: m.p. 93–93.5 °C (ethyl acetate); [α]24 -65.4 (c 1.00,
D
CHCl3); IR (film) 2983, 1780, 1697, 1381, 1213, 1159, 1085, 1053 cm−1; 1H-NMR (400 MHz) δ 1.26
(3H, d, J = 7.3 Hz), 1.30 (3H, s), 1.36 (3H, s), 1.66 (1H, ddd, J = 4.4, 5.4, 13.7 Hz), 2.05 (1H, ddd,
J = 8.8, 8.3, 13.7 Hz), 2.79 (1H, dd, J = 9.8, 13.2 Hz), 3.26 (1H, dd, J = 3.4, 13.2 Hz), 3.50 (1H, dd,
J = 7.3, 7.8 Hz), 4.01 (1H, m), 4.03 (1H, dd, J = 5.4, 7.8 Hz), 4.17 (3H, m), 4.67 (1H, m), 7.28 (5H,
13
m); C- NMR (100 MHz) δ 18.2, 25.7, 26.9, 34.7, 38.0, 38.1, 55.4, 66.0, 69.5, 74.2, 108.9, 127.2,
128.8, 129.3, 153.2, 176.9, 180.1. ESI-MS: calcd for C19H26NO5Na (M+Na)+ 348.1811, found, m/z
348.1805.
(2R,4R)-5-(Benzyloxy)-4-methylpentane-1,2-diol (13). To a solution of 12 (7.44 g, 21.4 mmol) in THF-
MeOH-H2O (4:4:1), (220 mL) was added LiBH4 (2.1 g, 86 mmol) at 0 °C. The mixture was stirred at
room temperature for 2.5 h. The reaction was quenched by the addition of saturated aqueous NH4Cl at
0 °C, then the resulting slurry was extracted with Et2O three times. The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel
chromatography (hexane-ethyl acetate (1:1)) to give an alcohol. To a solution of the alcohol in DMF
(220 mL) was added BnBr (8 mL, 64.3 mmol), TBAI (3.2 g, 8.57 mmol) and NaH (3.1 g, 64.3 mmol)
at 0 °C. The mixture was stirred at room temperature overnight. The reaction was quenched by the
addition of saturated aqueous NH4Cl at 0 °C, then the resulting slurry was extracted with Et2O three
times. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated in
vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 10:1) to
give an acetonide (5.09 g, 90%) as a colorless oil: [α]24D -11.5 (c 1.03, CHCl3); IR (film) 2984, 1454,
1368, 1213, 1098, 1061 cm−1; 1H-NMR (400 MHz) δ 0.91 (3H, d, J = 6.8 Hz), 1.29 (7H, m), 1.71 (1H,

Molecules 2011, 16
5431
ddd, J = 5.8, 8.3, 13.7 Hz), 1.89 (1H, m), 3.24 (2H, m), 3.42 (1H, t, J = 7.8 Hz), 3.97 (1H, dd, J = 7.8,
13
5.8 Hz), 4.12 (1H, tt, J = 7.8, 5.8 Hz), 4.43 (2H, s), 7.26 (5H, m); C-NMR (100 MHz) δ 17.1, 25.8,
27.1, 30.7, 37.8, 69.9, 72.9, 74.2, 108.5, 127.4, 127.5, 128.3, 138.6. ESI-MS: calcd for C16H25O3
265.1804 (M+H)+, found, m/z 265.1803.
To a solution of the acetonide (0.73 g, 2.8 mmol) in DMF (30 mL) were added TsOH·H2O (1.6 g,
8.3 mmol) and H2O (10 mL) at 0 °C; the mixture was stirred at 30 ºC under 80 mmHg for 3 h. After
the addition of saturated aqueous NH4Cl, the mixture was extracted with Et2O. The organic layer was
dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column
chromatography (hexane-ethyl acetate 1:1) to give 13 (0.66 g, quant.) as a colorless oil: [α]24D +16.0 (c
0.99, CHCl3); IR (film) 3375, 1454, 1363, 1074 cm−1; 1H-NMR (400 MHz) δ 0.87 (3H, d, J = 6.8 Hz),
1.39 (2H,m), 1.93 (2H, m), 3.22 (1H, m), 3.37 (2H, m), 3.52 (2H, m), 3.70 (1H, m), 4.47 (2H, s), 7.24
13
(5H, m); C- NMR (100 MHz) δ 18.2, 31.8, 39.6, 67.4, 71.0, 73.3, 76.6, 127.7, 127.8, 128.5, 137.6.
ESI-MS: calcd for C13H20O3Na 247.1310 (M+Na)+, found, m/z 247.1309.
(2R,4R)-5-(Benzyloxy)-2-(tert-butyldimethylsilyloxy)-4-methylpentan-1-ol (14). To a solution of 13
(3.39 g, 15.1 mmol) in CH2Cl2 (75 mL) and pyridine (75 mL) was added PivCl (2.8 mL, 22.7 mmol) at
0 °C; the mixture was stirred at room temperature for 1.5 h. The reaction was quenched with saturated
aqueous NH4Cl, and the mixture was extracted with Et2O. The organic layer was dried (Na2SO4), and
concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl
acetate 4:1) to give an alcohol (4.57 g, 98%) as a colorless oil: [α]24D +10.7 (c 1.01, CHCl3); IR (film)
1
3442, 1730, 1455, 1285, 1164, 1097 cm−1; H-NMR (400 MHz) δ 0.88 (3H, d, J = 7.3 Hz), 1.15
(9H, s), 1.33 (1H, ddd, J = 14.4, 6.8, 2.9 Hz), 1.46 (1H, m), 1.95 (1H, m), 2.98 (1H, br), 3.22 (1H, dd,
J = 9.8, 6.3 Hz), 3.32 (1H, dd, J = 9.8, 5.4 Hz), 3.84 (1H, m), 3.96 (2H, m), 4.46 (2H, s), 7.26
(5H, m); 13C-NMR (100 MHz) δ 17.7, 27.2, 31.2, 38.8, 39.0, 68.8, 73.1, 76.2, 127.7, 128.3, 128.4,
138.0, 178.6. ESI-MS: calcd for C18H28O4Na 331.1885 (M+Na)+, found, m/z 331.1880.
To a solution of the alcohol (4.57 g, 14.8 mmol) in DMF (150 mL) were added imidazole (3.03 g,
44.5 mmol) and TBSCl (6.7 g, 44.5 mmol) at 0 °C; the mixture was stirred at room temperature
overnight. After the addition of saturated aqueous NH4Cl, the mixture was extracted with Et2O. The
organic layer dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column
chromatography (hexane-ethyl acetate 7:1) to give a silyl ether (6.31 g, quant.) as a colorless oil:
1
[α]24 +10.6 (c 1.02, CHCl3); IR (film) 1733, 1160, 836 cm−1; H-NMR (400 MHz) δ 0.09 (6H, s),
D
0.88 (9H, s), 0.94 (3H, m), 1.20 (9H, s), 1.28 (1H, m), 1.63 (1H, ddd, J = 4.5, 7.9, 13.7 Hz), 1.97 (1H,
m), 3.27 (1H, dd, J = 6.1, 9.2 Hz), 3.33 (1H, dd, J = 6.1, 9.2 Hz), 3.97 (3H, m), 4.50 (2H, s), 7.34
13
(5H, m); C- NMR (100 MHz) δ –4.7, –4.4, 17.1, 18.0, 25.5, 25.8, 27.1, 27.2, 29.5, 38.7, 38.8, 68.1,
68.4, 76.2, 127.3, 127.4, 128.3, 138.7, 178.5. ESI-MS: calcd for C24H42O4SiNa 445.2750 (M+Na)+,
found, m/z 445.2747.
To a solution of the silyl ether (11.7 mg, 27.7 μmol) in CH2Cl2 (0.3 mL) was added DIBAL-H
(0.08 mL, 1.03 M in n-hexane, 83.1 μmol) at −78 °C. After being stirred for 1 h then the reaction was
quenched by potassium-sodium tartrate aqueous. The mixture was extracted with CHCl3, dried
(Na2SO4), and concentrated in vacuo. The crude product was purified by silica gel column
chromatography using hexane-ethyl acetate (5:1) to give 14 (9.1 mg, 97%) as a colorless oil: [α]24
-
D
2.3 (c 0.97, CHCl3); IR (film) 3437, 2857, 836 cm−1; 1H-NMR (400 MHz) δ 0.08 (6H, s), 0.90 (9H, s),

Molecules 2011, 16
5432
0.95 (3H, m), 1.29 (2H, m), 1.66 (1H, m), 1.90 (1H, m), 3.29 (2H, m), 3.45 (1H, dd, J = 4.9, 11.0 Hz),
3.58 (1H, dd, J = 4.9, 11.0 Hz), 3.88 (1H, m), 4.49 (2H, s), 7.33 (5H, m); 13C-NMR (100 MHz) δ –4.5,
–4.4, 17.7, 18.1, 25.8, 29.6, 38.2, 66.6, 70.8, 73.0, 76.1, 127.4, 127.5, 128.3, 138.5. ESI-MS: calcd for
C19H34O3SiNa 361.2175 (M+Na)+, found, m/z 361.2168.
(R)-4-Benzyl-3-((4R,6R,E)-7-(benzyloxy)-6-methyl-4-(tert-butyldimethylsilyloxy)hept-2-enoyl)oxazol-
idin-2-one (15). To a solution of 14 (4.39 g, 13 mmol) in CH2Cl2 (65 mL) and DMSO
(65 mL) were added Et3N (5.4 mL, 39 mmol) and SO3-pyridine (6.2 g, 39 mmol) complex at 0 °C.
After 2 h, the reaction was quenched with saturated aqueous NH4Cl, and the mixture was partitioned
between Et2O and H2O. The organic layer was dried (Na2SO4), and concentrated in vacuo. The residue
was purified by silica gel column chromatography (hexane-ethyl acetate 6:1) to give an aldehyde
(4.3 g, 99%) as a colorless oil.
To a suspension of LiCl (0.09 g, 2.2 mmol) in anhydrous CH3CN (8 mL) were added 16 (0.29 g,
0.81 mmol), DIPEA (0.3 mL, 1.65 mmol), and the aldehyde (0.18 g, 0.55 mmol) at room temperature;
the mixture was stirred at room temperature for overnight. The reaction was quenched with saturated
aqueous NH4Cl, and the mixture was partitioned between Et2O and H2O. The organic layer was dried
(Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography
(hexane-ethyl acetate 6:1) to give 15 (0.33 g, quant.) as a colorless oil: [α]24D -23.1 (c 1.02, CHCl3); IR
1
(film) 1782, 1683, 1639, 1352, 1207, 1100, 836 cm−1; H-NMR (400 MHz) δ 0.07 (6H, s), 0.93
(9H, s), 0.99 (3H, d, J = 6.8 Hz), 1.35 (1H, ddd, J = 4.9, 8.8, 13.7 Hz), 1.75 (1H, ddd, J = 4.9, 8.8, 13.7
Hz), 2.02 (1H, m), 2.81 (1H, dd, J = 9.8, 13.7 Hz), 3.32 (3H, m), 4.19 (2H, m), 4.50 (3H, m), 4.73 (1H,
13
ddd, J = 3.4, 6.8, 12.7 Hz), 7.37 (12H, m); C-NMR (100 MHz) δ –5.0, –4.3, 17.3, 18.1, 25.8, 29.7,
37.9, 41.6, 55.3, 66.1, 70.2, 72.9, 76.0, 77.3, 118.7, 127.3, 127.4, 127.5, 128.3, 128.9, 129.5, 135.3,
138.6, 153.2, 153.6, 165.0. ESI-MS: calcd for C31H43NO5SiNa 560.2808 (M+Na)+, found, m/z
560.2808.
(R)-4-Benzyl-3-((2R,4R,6R)-7-(benzyloxy)-2,6-dimethyl-4-(tert-butyldimethylsilyloxy)heptanoyl)oxazol
-idin-2-one (17). To a solution of 15 (6.21 g, 11.6 mmol) in ethyl acetate (120 mL) was added Rh-
Al2O3 (cat.) at room temperature under hydrogen atmosphere; the mixture was stirred for 2 h. The
reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column
chromatography (hexane-ethyl acetate 6:1) to give an amide (5.99 g, 96%) as a colorless oil: [α]24
D
-23.6 (c 0.99, CHCl3); IR (film) 1784, 1701, 1210, 835 cm−1; H-NMR (400 MHz,) δ 0.07 (6H, d,
1
J = 4.9 Hz), 0.90 (9H, s), 0.97 (3H, d, J = 6.5 Hz), 1.26 (1H, ddd, J = 5.4, 8.1, 13.7 Hz), 1.62 (1H, ddd,
J = 5.4, 7.2, 13.7 Hz), 1.88 (3H, m), 2.76 (1H, dd, J = 9.6, 13.7 Hz), 2.92 (1H, ddd, J = 5.4, 9.6,
17.3 Hz), 3.05 (1H, ddd, J = 5.4, 9.6, 17.3 Hz), 3.31 (3H, m), 3.89 (1H, tt, J = 5.4, 11.7 Hz), 4.17 (2H, m),
13
4.50 (2H, s), 4.66 (1H, ddd, J = 3.4, 7.2, 13.0 Hz), 7.34 (10H, m); C-NMR (100 MHz) δ –4.5,
–4.4, 17.6, 18.0, 25.9, 29.8, 31.5, 31.7, 37.9, 41.3, 55.1, 66.1, 69.2, 72.8, 76.1, 127.4, 127.5, 128.2,
128.3, 128.9, 129.4, 135.3, 153.4, 173.4. ESI-MS: calcd for C31H45NO5SiNa 562.2965 (M+Na)+,
found, m/z 562.2962.
To a solution of LHMDS (47 mL, 1.0 M in THF, 47 mmol) in THF (100 mL) was added the amide
(5.07 g, 9.4 mmol) at −40 °C. After being stirred at same temperature for 2 h, MeI (12 mL, 0.19 mol)
was added and the resultant mixture stirred at −20 °C for 0.5 h. After the addition of saturated aqueous

Molecules 2011, 16
5433
NH4Cl, the mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), and
concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl
acetate 9:1) to give 17 (4.03 g, 77%) as a colorless oil: [α]24 -41.5 (c 1.00, CHCl3); IR (film) 1783,
D
1697, 1455, 1386, 1209, 836 cm−1; 1H-NMR (400 MHz) δ 0.05 (6H, d, J = 14.6 Hz), 0.90 (9H, s), 1.02
(3H, d, J = 6.1 Hz), 1.32 (4H, m), 1.58 (2H, m), 1.98 (1H, ddd, J = 6.7, 13.2, 19.7 Hz), 2.11 (1H, m),
2.80 (1H, dd, J = 10.1, 13.2 Hz), 3.34 (3H, m), 3.84 (2H, m), 4.18 (2H, m), 4.55 (2H, s), 4.67 (1H, m),
13
7.33 (10H, m); C-NMR (100 MHz) δ –4.7, –4.3, 17.9, 18.0, 18.6, 25.8, 29.9, 34.3, 37.9, 40.7, 41.6,
55.3, 65.9, 68.7, 72.9, 76.0, 127.3, 127.5, 128.2, 128.9, 129.4, 135.3, 138.8, 152.8, 176.8. ESI-MS:
calcd for C32H48NO5Si 554.3302 (M+H)+, found, m/z 554.3292.
(4R,6R,8R)-9-(Benzyloxy)-4,8-dimethyl-6-(tert-butyldimethylsilyloxy)nonan-3-one (18). To a solution
of 17 (4.7 g, 8.49 mmol) in THF-MeOH-H2O (4:4:1, 90 mL) was added LiBH4 (0.82 g, 34 mmol) at
0 °C; the mixture was stirred at room temperature for 1 h. After the addition of saturated aqueous
NH4Cl, the mixture was extracted with Et2O. The organic layer was dried (Na2SO4), and concentrated
in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 5:1) to
give an alcohol (3.02 g, 93%) as a yellow oil: [α]24D +9.1 (c 1.00, CHCl3); IR (film) 1459, 1255, 1049,
835 cm−1; 1H-NMR (400 MHz) δ 0.08 (6H, d, J = 3.6 Hz), 0.87 (3H, d, J = 7.2 Hz), 0.90 (9H, s), 0.95
(3H, d, J = 7.2 Hz), 1.38 (1H, ddd, J = 6.3, 7.2, 13.7 Hz), 1.55 (4H, m), 1.86 (2H, m), 3.26 (2H, m),
13
3.33 (1H, m), 3.44 (1H, m), 3.98 (1H, tt, J = 4.5, 11.4 Hz), 4.49 (2H, s), 7.33 (5H, m); C-NMR
(100 MHz) δ –4.6, –4.4, 17.8, 18.0, 18.3, 25.8, 30.0, 31.8, 40.6, 42.6, 69.3, 73.0, 76.2, 127.4, 127.5,
128.3, 138.6. ESI-MS: calcd for C22H41O3Si 381.2825 (M+H)+, found, m/z 381.2821.
To a solution of the alcohol (2.5 mg, 6.6 μmol) in CH2Cl2 (0.05 mL) and DMSO (0.05 mL) were
added Et3N (3 μL, 19.7 μmol) and SO3-pyridine (3 mg, 19.7 μmol) complex at 0 °C. After 1.5 h, the
reaction was quenched with saturated aqueous NH4Cl, and the mixture was partitioned between Et2O
and H2O. The organic layer was dried (Na2SO4), and concentrated in vacuo. The residue was purified
by PLC (hexane-ethyl acetate 3:1) to give an aldehyde as a colorless oil.
To a solution of the aldehyde in THF (0.1 mL) was added EtMgBr (0.02 mL, 1.0 M in THF,
19.7 μmol) at 0 °C; the mixture was stirred at the same temperature for 15 min. The reaction mixture
was quenched with saturated aqueous NH4Cl, and extracted with CH2Cl2. The organic layer was dried
(Na2SO4), and concentrated in vacuo. The residue was purified by PLC (hexane-ethyl acetate (5:1)) to
give an alcohol as a colorless oil.
To a solution of the alcohol in CH2Cl2 (0.05 mL) and DMSO (0.05 mL) were added Et3N (3 μL,
19.7 μmol) and SO3-pyridine (3 mg, 19.7 μmol) complex at 0 °C. After 4 h, the reaction was quenched
with saturated aqueous NH4Cl, and the mixture was partitioned between Et2O and H2O. The organic
layer was dried (Na2SO4), and concentrated in vacuo. The residue was purified by PLC (hexane-ethyl
acetate (5:1) to give 18 (2.5 mg 89% in 3 steps) as a colorless oil: [α]24 +1.1 (c 0.98, CHCl3); IR
D
(film) 1714, 1459, 1255, 1099, 835 cm−1; 1H-NMR (400 MHz) δ 0.02 (6H, d, J = 6.7 Hz), 0.87 (9H, s),
0.95 (3H, d, J = 7.2 Hz), 1.05 (6H, m), 1.22 (1H, m), 1.35 (1H, m), 1.57 (1H, m), 1.93 (1H, m), 2.46
(2H, m), 2.66 (qt, 1H, J = 7.2, 13.7 Hz), 3.26 (1H, dd, J = 6.1, 8.8 Hz), 3.33 (1H, dd, J = 6.1, 8.8 Hz),
13
3.75 (1H, tt, J = 5.8, 12.1 Hz), 4.50 (2H, s), 7.33 (5H, m); C-NMR (100 MHz) δ –4.34, –4.30, 7.8,
17.5, 17.7, 18.1, 25.9, 29.8, 34.2, 40.6, 41.4, 42.3, 68.8, 75.9, 127.4, 127.5, 128.3, 138.8, 214.7.
ESI-MS: calcd for C24H43O3Si 407.2981 (M+H)+, found, m/z 407.2982.

Molecules 2011, 16
5434
((2R,4S,6R)-1-(Benzyloxy)-2,6-dimethyl-7-methylenenonan-4-yloxy)(tert-butyl)dimethylsilane (19). To
a solution of ethyl ketone 18 (60.0 mg, 0.12 mmol) in THF (1 mL) was added (trimethylsilylmethyl)
lithium (0.5 mL, 1.0 M in pentane, 0.5 mmol) at −78 °C; the mixture was stirred at the same
temperature for 20 min. The reaction mixture was quenched with saturated aqueous NH4Cl, and
extracted with ethyl acetate. The organic layer was dried (Na2SO4), and concentrated in vacuo. The
residue was purified by PLC (hexane-ethyl acetate 9:1) to give an alcohol as a colorless oil.
To a solution of the alcohol in THF (2 mL) was added NaH (60% dispersion in mineral oil, 50 mg,
0.1 mmol) at room temperature; the mixture was stirred at reflux temperature overnight. The reaction
was quenched with saturated aqueous NH4Cl, and the mixture was extracted with ethyl acetate. The
organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by PLC
(hexane-ethyl acetate 9:1) to give 19 as a colorless oil (48 mg, 86% in 2 steps): [α]24 +17.8 (c 1.01,
D
1
CHCl3); IR (film) 2958, 1642, 1460, 1254, 1097, 835 cm−1; H-NMR (400 MHz) δ 0.05 (6H, s), 0.89
(9H, s), 0.95 (3H, d, J = 6.5 Hz), 1.02 (6H, m), 1.24 (1H, m), 1.46 (2H, m), 1.61 (1H, m), 1.99
(3H, m), 2.19 (1H, m), 3.23 (1H, dd, J = 6.5, 9.1 Hz), 3.34 (1H, dd, J = 6.5, 9.1 Hz), 3.77 (1H, m), 4.50
13
(2H, s), 4.72 (2H, dd, J = 1.5, 11.9 Hz), 7.33 (5H, m); C-NMR (100 MHz) δ –4.2, –4.1, 12.4, 17.4,
18.1, 20.3, 26.0, 26.2, 29.7, 36.8, 41.3, 44.2, 69.0, 72.8, 76.3, 106.4, 127.4, 127.5, 128.3, 138.8, 156.3.
ESI-MS: calcd for C25H45O2Si 405.3189 (M+H)+, found, m/z 405.3181.
(4R,6S,8R)-6-(tert-Butyldimethylsilyloxy)-4,8-dimethyl-9-methyleneundecan-3-one (segment B, 3). To
a solution of lithium (12.4 mg, 1.9 mmol) in liquid NH3 (10 mL) was added 19 (46.4 mg,
0.11 mmol) in dry THF (3 mL) at −78 °C. The reaction mixture was stirred for 15 min at the same
temperature; and quenched with solid NH4Cl. The mixture was extracted with ethyl acetate, and the
organic layer was dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel
column chromatography (hexane-ethyl acetate 5:1) to give an alcohol (35.6 mg, 99%) as a colorless
1
oil: [α]24 +36.4 (c 0.98, CHCl3); IR (film) 3346, 2959, 1643, 1461, 1254, 1046, 835 cm−1; H-NMR
D
(400 MHz) δ 0.06 (6H, d, J = 1.6 Hz), 0.89 (9H, s), 0.93 (3H, d, J = 6.3 Hz), 1.02 (6H, m), 1.27 (1H,
ddd, J = 3.7, 8.5, 13.9 Hz), 1.46 (2H, m), 1.59 (1H, m), 1.81 (1H, ttd, J = 2.2, 6.3, 13.0 Hz), 2.00 (2H,
m), 2.16 (1H, qt, J = 6.3, 7.0 Hz), 3.45 (2H, dd, J = 4.5, 6.3 Hz), 3.76 (1H, m), 4.72 (2H, ddd, J = 1.6,
2.9, 11.9 Hz); 13C-NMR (100 MHz) δ –4.2, –4.0, 12.4, 17.0, 18.1, 20.1, 25.8, 25.9, 26.3, 32.3,
36.9, 40.8, 44.4, 68.8, 69.3, 106.4, 156.3. ESI-MS: calcd for C18H39O2Si 315.2719 (M+H)+, found,
m/z 315.2717.
To a solution of the alcohol (0.35 g, 1.10 mmol) in CH2Cl2 (6 mL) and DMSO (6 mL) were added
Et3N (0.5 mL, 3.29 mmol) and SO3-pyridine (0.52 g, 3.29 mmol) complex at 0 °C. After 1 h, the
reaction was quenched with saturated aqueous NH4Cl, and the mixture was partitioned between Et2O
and H2O. The organic layer was dried (Na2SO4), and concentrated in vacuo. The residue was purified
by silica gel column chromatography (hexane-ethyl acetate 7:1) to give an aldehyde as a colorless oil.
To a solution of the aldehyde in THF (10 mL) was added EtMgBr (3 mL, 1.0 M in THF, 2.95
mmol) at 0 °C; the mixture was stirred at the same temperature for 30 min. The reaction was quenched
with saturated aqueous NH4Cl, and the mixture was extracted with CH2Cl2. The organic layer was
dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column
chromatography (hexane-ethyl acetate (9:1)) to give an alcohol as a colorless oil.

Molecules 2011, 16
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To a solution of the alcohol in CH2Cl2 (4 mL) and DMSO (4 mL) were added Et3N (0.32 mL,
2.34 mmol) and SO3-pyridine (0.4 g, 2.34 mmol) complex at 0 °C. After 40 min, the reaction was
quenched with saturated aqueous NH4Cl, and the mixture was partitioned between Et2O and H2O. The
organic layer was dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel
column chromatography (hexane-ethyl acetate 11:1) to give segment B (0.22 g 60% in 3 steps) as a
colorless oil.: [α]24 +11.7 (c 0.99, CHCl3); IR (film) 2960, 1716, 1643, 1461, 1255, 1101, 835 cm−1;
D
1H-NMR (400 MHz) δ 0.06 (6H, d, J = 3.8 Hz), 0.89 (9H, s), 1.02 (12H, m), 1.38 (2H, m), 1.55 (1H,
ddd, J = 6.7, 7.0, 13.5 Hz), 1.74 (1H, ddd, J = 5.2, 7.0, 13.5 Hz), 1.97 (2H, m), 2.16 (1H, dd, J = 7.0,
14.0 Hz), 2.47 (2H, q, J = 7.0 Hz), 2.73 (1H, qt, J = 7.0, 14.0 Hz), 3.66 (1H, m), 4.70 (2H, m);
13C- NMR (100 MHz) δ –4.3, –4.1, 7.9, 12.3, 16.4, 18.1, 20.3, 25.9, 26.2, 34.2, 36.8, 40.1, 41.8,
44.0, 68.7, 77.3, 106.6, 156.0, 215.2. ESI-MS: calcd for C20H39O2Si 339.2719 (M+H)+, found, m/z
339.2689.
4. Conclusions
In conclusion, this study reports the efficient synthesis of promising segments 2 and 3 for
the construction of amphidinolide Q (1). Both routes provided good yields and availability for
analog synthesis.
Acknowledgement
This work was financially supported by High-Tech Research Center Project for Private Universities
Matching Fund (2006-2011) and by The Science Research Promotion Fund from the Promotion and
Mutual Aid Corporation for Private Schools of Japan from MEXT.
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Sample Availability: Available from the authors.
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