Synthesis of C1-C9 domain of the nominal didemnaketal a

Article abstract of DOI:10.1002/cjoc.201500256

Based on chiral pool strategy, a synthesis of the C1-C9 domain of the proposed structure of didemnaketal A, a natural product with potent HIV-1 protease inhibitory activity, has been achieved. Key transformations are a Sharpless asymmetric dihydroxylation

Full text of DOI:10.1002/cjoc.201500256

FULL PAPER
DOI: 10.1002/cjoc.201500256
Synthesis of C1－C9 Domain of the Nominal Didemnaketal A
Shunji Zhang, Yong Shi,* and Weisheng Tian*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Based on chiral pool strategy, a synthesis of the C1－C9 domain of the proposed structure of didemnaketal A, a
natural product with potent HIV-1 protease inhibitory activity, has been achieved. Key transformations are a Shar-
pless asymmetric dihydroxylation and a chelation-controlled allylation.
Keywords didemnaketal, chiral pool, chelation-controlled allylation, natural products, Sharpless AD
Introduction
C10－C20 domain has been erroneously assigned.[6]
Despite their structural issues, didemnaketals posed
many challenges and opportunities for synthetic chem-
ists. To us, four methyl groups of 1 exhibited huge at-
traction because we have been focusing on the devel-
opment of chiral methyl building blocks for a long
time.[7] Herein, we report a synthesis of the C1－C9
domain (2) of the original didemnaketal A (1).
Didemnaketals are a seven-membered family of nat-
ural products, three of which were isolated from the
magenta ascidian Didemnum sp. by Faulkner and
co-workers,[1] and the others from marine ascridian spe-
cies belonging to the genus Didemnum by Youseff and
co-workers.[2] Didemnaketals A (1) and B showed potent
HIV-1 protease inhibitory activities (IC50 2－10 μmol/L)
presumably via a dissociative mechanism (Figure 1).
Experimental
OH
21
Methyl (4R)-5-(benzyloxy)-4-methyl-2-((methyl-
sulfonyl)-oxy)pentanoate (6)
20
O
O
Me
Me
Me
O
To a solution of 4 (5.2 g, 20.6 mmol) in dry DCM
(40 mL) under argon were added Et3N (8.9 mL, 62
mmol) and MsCl (2.4 mL, 31 mmol) at 0 ℃. The reac-
tion mixture was stirred for 1 h, quenched with diluted
HCl solution, and extracted with DCM. The combined
organic extracts were washed with brine, dried over
Na2SO4, concentrated under reduced pressure, and puri-
fied by column chromatography on silica gel (petroleum
ether/EtOAc: 10/1) to give 6 (6.20 g, 18.8 mmol, 91%,
inseparable mixture of epimers) as a colorless liquid. 1H
NMR (CDCl3, 400 MHz) δ: 7.37－7.26 (m, 5H), 5.14
(dd, J＝18.0, 4.0 Hz, 1H), 4.49 (s, 2H), 3.77 (s, 3H),
3.46－3.34 (m, 2H), 3.13 (s, 3H), 2.16－1.99 (m, 2H),
1.78－1.69 (m, 1H), 1.02 (d, J＝8.8 Hz, 3H); IR (KBr)
ν: 2961, 1755, 1361, 1177, 1101, 959, 741, 699 cm−1;
MS (EI, m/z) (%): 209 ([M−BnOCH2]＋) (1), 330 (M＋)
(3); HRMS-EI: M＋ calcd for C15H22O6S: 330.1137,
found 330.1140.
Me
O
Me
Me
11
Me
Me
O
10
9
O
O
Me
O
AcO
6
1
OMe
O
Me
Me
O
didemnaketal A (1)
Figure 1 The structure of didemnaketal A (1).
The densely functionalized structures and interesting
biological activities of didemnaketals have stimulated
several groups to pursue the chemical synthesis.[3] The
Tu group has accomplished the synthesis of the pro-
posed didemnaketal A in 2012 and the Fuwa group the
nominal didemnaketal B in 2013.[4] Both groups re-
ported disagreement of NMR spectroscopic data be-
tween the synthetic samples and the natural ones, and
therefore, devoting much effort on disclosing the real
structures through synthesis.[5] Recently, the Fuwa group
revised the structure of didemnaketal B by total synthe-
sis, pointing out that the absolute configuration of its
Methyl (4R)-5-(benzyloxy)-2-bromo-4-methylpenta-
noate (8)
A solution of 6 (9.90 g, 30 mmol) and LiBr•H2O (9.5
g, 90.5 mmol) in acetone (150 mL) was heated at reflux
for 18 h. The mixture was concentrated in vacuo, added
*
E-mail: shiong81@sioc.ac.cn; wstian@sioc.ac.cn
Received March 30, 2015; accepted May 6, 2015; published online June 12, 2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500256 or from the author.
Chin. J. Chem. 2015, 33, 663—668
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FULL PAPER
water, extracted with ethyl acetate for three times. The
combined organic extracts were washed with brine,
dried over Na2SO4, concentrated in vacuo, and purified
on silica gel (petroleum ether/EtOAc: 10/1) to give
bromide 8 (8.93 g, 28 mmol, 95%, inseparable mixture
174.0, 137.9, 128.5 (2C), 127.8, 127.7 (2C), 74.8, 73.4,
73.2, 71.8, 52.7, 37.0, 13.3; IR (KBr) ν: 3400, 2959,
1742, 1455, 1216, 1142, 1097, 1048, 738, 699 cm−1; MS
(EI, m/z) (%): 268 (M+) (1); HRMS-EI: M＋ calcd for
C14H20O5: 268.1311, found 268.1310.
1
of epimers) as a colorless liquid. H NMR (CDCl3, 400
(1R,2S)-3-(Benzyloxy)-1-((R)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)-2-methylpropan-1-ol (11)
MHz) δ: 7.38－7.26 (m, 5H), 4.48 (s, 2H), 4.45－4.37
(m, 1H), 3.75 (s, 3H), 3.39－3.27 (m, 2H), 2.29－1.87
(m, 3H), 0.98 or 0.94 (d, J＝12.4 Hz, 3H); IR (KBr) ν:
2957, 2858, 1743, 1455, 1438, 1158, 1099, 738, 699
cm−1; MS (EI, m/z) (%): 193 ([M−BnOCH2]＋ ) (6);
HRMS-EI: M＋ calcd for C14H19O3Br: 314.0515, found
314.0518.
A solution of 10 (500 mg, 1.9 mmol) in THF (20 mL)
was treated with LiAlH4 (90 mg, 2.3 mmol, added at 0
℃) at room temperature under argon for 12 h. The reac-
tion was quenched with diluted HCl solution, extracted
with ethyl acetate, dried over Na2SO4, and concentrated
under reduced pressure. The crude was dissolved in dry
acetone (30 mL) and treated with TsOH•H2O (35 mg,
0.19 mmol) at ambient temperature for 10 h before be-
ing quenched with a saturated aqueous solution of Na-
HCO3. The mixture was extracted with ethyl acetate for
three times, the combined organic layers were washed
with brine, dried over Na2SO4, concentrated in vacuo,
and purified on silica gel (petroleum ether/EtOAc: 5/1)
to afford 11 (300 mg, 1.1 mmol, 57%) as a colorless oil.
Methyl (R,E)-5-(benzyloxy)-4-methylpent-2-enoate
(7)
A solution of bromide 8 (17.3 g, 55 mmol) in dry
HMPA (40 mL) was stirred at 100 ℃ for 4 h. Removal
of the solvent and purification through column chroma-
tography on silica gel (petroleum ether/EtOAc: 15/1)
afforded alkene 7 (8.47 g, 36 mmol, 66%, known com-
28
pound[8]) as a colorless oil. [α]D ＋14.6 (c 1.38,
24
1
CHCl3); 1H NMR (CDCl3, 400 MHz) δ: 7.37－7.26 (m,
5H), 7.00－6.93 (dd, J＝21.2, 8.0 Hz, 1H), 5.90－5.85
(d, J＝21.2 Hz, 1H), 4.51 (2H), 3.73 (s, 3H), 2.73－2.60
(m, 1H), 1.10－1.08 (d, J＝8.8 Hz, 3H); IR (KBr) ν:
3066, 3032, 2952, 2858, 1724, 1659, 1497, 1455, 1436,
1359, 1315, 1274, 1196, 1180, 1154, 1099, 1029, 985,
918, 862, 738, 699 cm−1; MS (EI, m/z) (%): 113
([M−BnOCH2]＋) (8), 219 (M＋) (1). For compound 9
[α]D ＋20.4 (c 1.21, CHCl3); H NMR (CDCl3, 400
MHz) δ: 7.36－7.26 (m, 5H), 4.49 (s, 2H), 4.02－3.98
(m, 1H), 3.92－3.88 (m, 1H), 3.77－3.72 (m, 1H), 3.64
－3.58 (m, 1H), 3.42 (d, J＝5.6 Hz, 2H), 2.09－2.07 (m,
1H), 2.00－1.94 (m, 1H), 1.40 (s, 3H), 1.39 (s, 3H),
1.03 (d, J＝6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ:
138.2, 128.4 (2C), 127.7, 127.6 (2C), 108.5, 79.4, 78.6,
73.2, 73.1, 62.9, 36.2, 27.2, 27.2, 12.7; IR (KBr) ν: 3449,
2985, 2934, 1455, 1370, 1247, 1215, 1103, 1054, 738,
699 cm−1; MS (EI, m/z) (%): 265 ([M−Me]＋ ) (5);
HRMS-EI: [M−Me]＋ calcd for C15H21O4: 265.1440,
found 265.1443.
1
(mixture of isomers): H NMR (CDCl3, 400 MHz) δ:
7.34－7.25 (m, 5H), 5.65 (t, J＝9.2 Hz, 1H), 4.45 (s,
2H), 3.94 (s, 2H), 3.69 (s, 3H), 3.12 (d, J＝10 Hz, 2H),
1.70 (s, 3H); IR (KBr) ν: 2952, 2856, 1741, 1454, 1436,
1202, 1166, 1072, 738, 699 cm−1; MS (EI, m/z) (%): 234
(M＋) (5); HRMS-EI: M＋ calcd for C14H18O3: 234.1256,
found 234.1254.
(R)-4-((1R,2S)-3-(Benzyloxy)-1-(methoxymethoxy)-2-
methylpropyl)-2,2-dimethyl-1,3-dioxolane (12)
To a solution of 11 (7.2 g, 25.7 mmol) and i-Pr2NEt
(18 mL, 103 mmol) in dry DCM (100 mL) was added
MOMCl (7.7 mL, 102 mmol) at 0 ℃. The mixture was
stirred at ambient temperature for 12 h, then quenched
with a saturated aqueous solution of NH4Cl and concen-
trated. The residue was extracted with ethyl acetate for
three times, and the combined organic layers were
washed with brine, dried over Na2SO4, and concentrated.
Column chromatography on silica gel (petroleum
ether/EtOAc: 9/1) afforded 12 (8.12 g, 25 mmol, 98%)
as a colorless oil. [α]D ＋16.7 (c 1.08, CHCl3); H
NMR (CDCl3, 400 MHz) δ: 7.36－7.26 (m, 5H), 4.64 (s,
2H), 4.50 (s, 2H), 4.09－4.05 (m, 1H), 3.89 (dd, J＝8.4,
4.8 Hz, 1H), 3.65 (dd, J＝10.8, 3.6 Hz, 1H), 3.58 (dd,
J＝10.4, 2.8 Hz, 1H), 3.47－3.38 (m, 2H), 3.34 (s, 3H),
2.02－1.96 (m, 1H), 1.40 (s, 6H), 1.02 (d, J＝6.8 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ: 138.4, 128.4 (2C),
127.6 (3C), 108.8, 96.6, 78.9, 77.8, 73.1, 73.1, 68.6,
55.3, 35.9, 27.1, 27.1, 12.2; IR (KBr) ν: 2985, 2933,
2885, 1455, 1369, 1214, 1109, 1043, 919, 738, 699 cm−1;
MS (EI, m/z) (%): 309 ([M−Me]＋ ) (5); HRMS-EI:
Methyl (2S,3R,4S)-5-(benzyloxy)-2,3-dihydroxy-4-
methylpentanoate (10)
A suspension of K3Fe(CN)6 (15.5 g, 47 mmol),
(DHQD)2PHAL (0.12 g, 0.15 mmol), K2CO3 (47 mmol),
MeSO2NH2 (1.5 g, 15.8 mmol) and 7 (3.66 g, 15.6
mmol) in t-BuOH (30 mL)/water (20 mL) was added a
solution of OsO4 in water (7.9 mL, 1.0 mg/mL, 0.2
mol%) at 0 ℃. The reaction was warmed to ambient
temperature and stirred for 12 h before Na2SO3 was
added. The mixture was extracted with ethyl acetate for
three times; the extracts were combined, washed with
brine, dried over Na2SO4, concentrated in vacuo, and
purified on silica gel (petroleum ether/EtOAc: 2/1) to
24
1
1
afford diol 10 (3.6 g, 13 mmol, 86%, d.r.＞19/1 by H
27
NMR) as a colorless liquid. [α]D ＋6.8 (c 1.16,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ: 7.40－7.27 (m,
5H), 4.51 (s, 2H), 4.32－4.31 (d, J＝2.8 Hz, 1H), 3.90
(dd, J＝8.0, 2.8 Hz, 1H), 3.81 (s, 3H), 3.54 (d, J＝3.6
Hz, 1H), 3.52 (s, 1H), 3.09 (s, 2H), 2.19－2.05 (m, 1H),
1.06 (d, J＝9.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ:
664
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Chin. J. Chem. 2015, 33, 663—668

Synthesis of C1－C9 Domain of the Nominal Didemnaketal A
＋
[M−Me]
calcd for C17H25O5: 309.1702, found
mL) and treated with MgBr2•Et2O (630 mg, 2.4 mmol)
and Bu3SnCH2CHCH2 (0.50 mL, 1.6 mmol) at ambient
temperature for 12 h. The mixture was quenched with a
saturated aqueous solution of NaHCO3, extracted with
ethyl acetate for three times. The combined organic lay-
ers were washed with brine, dried over Na2SO4, concen-
trated in vacuo, and purified on silica gel (petroleum
ether/EtOAc: 8/1) to afford 14 (180 mg, 0.66 mmol,
309.1703.
(2S,3R)-3-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-
(methoxymethoxy)-2-methylpropan-1-ol (13)
A reaction flask containing 12 (1.7 g, 5.2 mmol),
Pd/C (5%, 400 mg), and MeOH (40 mL) was evacuated
and back-filled with hydrogen (1 atm). The reaction
mixture was stirred at ambient temperature under hy-
drogen for 12 h and then filtered over a plug of silica gel
topped with Celite (MeOH eluent). The filtrate was
concentrated and purified by flash column chromatog-
raphy on silica gel (petroleum ether/EtOAc: 5/1) to give
1
24
81%, d.r.＞19/1 by H NMR) as a colorless oil. [α]D
＋20.2 (c 1.36, CHCl3); 1H NMR (CDCl3, 400 MHz) δ:
5.90－5.80 (m, 1H), 5.16 (d, J＝6.0 Hz, 1H), 5.13 (s,
1H), 4.66 (s, 2H), 4.17－4.14 (m, 1H), 4.08－4.03 (m,
1H), 3.64－3.62 (m, 3H), 3.37 (s, 3H), 2.44－2.39 (m,
2H), 2.25－2.18 (m, 1H), 1.81－1.77 (m, 1H), 1.41 (s,
6H), 1.01 (d, J＝6.8 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ: 134.9, 118.0, 109.1, 96.7, 78.0, 77.1, 73.4, 68.3,
55.3, 39.7, 38.2, 27.1, 27.0, 10.7; IR (KBr) ν: 3492,
2985, 2935, 1380, 1370, 1244, 1215, 1042, 918 cm−1;
MS (EI, m/z) (%): 259 ([M−Me]＋ ) (1); HRMS-EI:
[M−Me]+ calcd for C13H23O5: 259.1545, found
259.1546.
24
13 (1.2 g, 5.1 mmol, 98%) as a colorless oil. [α]D
＋18.0 (c 1.31, CHCl3); 1H NMR (CDCl3, 400 MHz) δ:
4.67 (s, 2H), 4.12－4.06 (m, 1H), 3.95 (dd, J＝8.0, 4.0
Hz, 1H), 3.66－3.65 (m, 4H), 3.38 (s, 3H), 2.18 (s, 1H),
1.96－1.87 (m, 1H), 1.41 (s, 3H), 1.40 (s, 3H), 1.02 (d,
J＝6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 109.0,
96.8, 80.4, 77.3, 68.7, 66.3, 55.5, 37.3, 27.2, 27.2, 11.7;
IR (KBr) ν: 3446, 2935, 2887, 1380, 1371, 1251, 1215,
1153, 1042, 1109 cm−1; MS (EI, m/z) (%): 219
([M−Me]+) (17); HRMS-EI: [M−Me]+ calcd for
C10H19O5: 219.1232, found 219.1231.
(4S,5S,6R)-4-Allyl-6-((R)-2,2-dimethyl-1,3-dioxolan-
4-yl)-2,2,5-trimethyl-1,3-dioxane (15)
A solution of 14 (700 mg, 1.8 mmol) in MeOH (80
mL) was treated with aqueous HCl solution (4 N, 80 mL)
at room temperature for 2 h. The mixture was concen-
trated and dissolved with acetone (100 mL) and treated
with TsOH-H2O (200 mg) at room temperature for 12 h.
After being quenched with a saturated solution of Na-
HCO3, the mixture was concentrated to remove acetone
and extracted with ethyl acetate for three times. The
combined organic extracts were washed with brine,
dried over Na2SO4, concentrated in vacuo, and purified
on silica gel to afford a diol (178 mg, 0.8 mmol, 43%).
Diol was treated with PPTS (20 mg) in DMP/DCM (10
mL/10 mL) at room temperature for 12 h. The solution
was concentrated and purified on silica gel (petroleum
ether/EtOAc: 12/1－8/1) to afford 15 (154 mg, 0.57
(2R,3R)-3-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-
(methoxymethoxy)-2-methylpropanal (3)
To a solution of 13 (180 mg, 0.77 mmol) in DCM
(20 mL) were added NaHCO3 (260 mg, 3.1 mmol) and
Dess-Martin reagent (500 mg, 1.2 mmol) at 0 ℃. The
mixture was stirred for 1 h and quenched with a satu-
rated aqueous solution of Na2S2O3 and separated. The
aqueous layer was extracted with DCM twice. The
combined organic layers were washed with brine, dried
over Na2SO4, concentrated in vacuo, and purified on
silica gel (petroleum ether/EtOAc: 12/1) to afford alde-
hyde 3 (120 mg, 0.52 mmol, 67%) as a colorless oil.
25
1
[α]D ＋12.6 (c 1.08, CHCl3); H NMR (CDCl3, 400
MHz) δ: 9.74 (s, 1H), 4.65 (s, 2H), 4.27 (dd, J＝8.0, 4.4
Hz, 1H), 4.09－4.00 (m, 1H), 3.68 (d, J＝5.2 Hz, 2H),
3.37 (s, 3H), 2.66－2.59 (m, 1H), 1.41 (s, 3H), 1.40 (s,
3H), 1.22 (d, J＝7.2 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ: 202.8, 109.7, 96.9, 77.4, 68.2, 55.5, 48.2, 27.1,
27.1, 8.6; IR (KBr) ν: 2986, 2937, 1728, 1458, 1371,
1216, 1153, 1111, 1043, 919 cm−1; MS (EI, m/z) (%):
217 ([M−Me]＋) (5); HRMS-EI: [M−Me]＋ calcd for
C10H17O5: 217.1076, found 217.1070.
26
mmol, 74%) as a colorless oil. [α]D ＋27.3 (c 1.39,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ: 5.93－5.82 (m,
1H), 5.09 (s, 1H), 5.06 (d, J＝1.2 Hz, 1H), 4.51－4.45
(m, 1H), 4.09 (dd, J＝12.0, 5.6 Hz, 1H), 3.63 (dd, J＝
9.2, 8.4 Hz, 2H), 3.37 (dd, J＝12.0, 10.4 Hz, 1H), 2.35
－2.24 (m, 2H), 1.78－1.68 (m, 1H), 1.41 (s, 3H), 1.36
(s, 6H), 1.32 (s, 3H), 1.02 (d, J＝6.8 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ: 134.3, 117.4, 107.4, 100.5, 84.5,
76.7, 71.7, 65.5, 43.0, 38.3, 27.3, 26.9, 25.8, 24.01, 15.1;
IR (KBr) ν: 2988, 2934, 1374, 1255, 1212, 1061, 1034,
912, 836 cm−1; MS (EI, m/z) (%): 255 ([M−Me]+) (12);
HRMS-EI: [M−Me]+ calcd for C14H23O4: 255.1596,
found 255.1595.
(1R,2S,3S)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-
(methoxymethoxy)-2-methylhex-5-en-3-ol (14)
To a solution of 13 (190 mg, 0.8 mmol) in
DMSO/DCM (10 mL/10 mL) were added Et3N (0.61
mL, 4.2 mmol) and SO3•py complex (400 mg, 2.5 mmol)
at 0 ℃. The mixture was stirred for 1 h and quenched
with an aqueous NH4Cl solution and extracted with
ether for three times. The combined extracts were
washed with a saturated aqueous solution of NaHCO3
and brine, dried over Na2SO4, and concentrated to give
aldehyde 3. The crude 3 was dissolved in dry DCM (15
(5R,6R,7S)-7-Allyl-5-((R)-2,2-dimethyl-1,3-dioxolan-
4-yl)-6,9,9,10,10-pentamethyl-2,4,8-trioxa-9-silaunde-
cane (16)
To a solution of 14 (170 mg, 0.60 mmol) in dry DMF
(5 mL) were added imidazole (180 mg, 2.6 mmol) and
TBSCl (200 mg, 1.3 mmol). The reaction was stirred at
Chin. J. Chem. 2015, 33, 663—668
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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665

Zhang, Shi & Tian
FULL PAPER
room temperature for 12 h, then quenched with water
and extracted with ether for three times. The combined
organic layers were washed with brine, dried over
Na2SO4, concentrated in vacuo, and purified on silica
gel (petroleum ether/EtOAc: 12/1) to afford 16 (200 mg,
4.66 (s, 2H), 4.04 (dd, J＝8.4, 1.6 Hz, 1H), 3.96－3.91
(m, 1H), 3.81－3.77 (m, 1H), 3.74 (s, 3H), 3.63－3.55
(m, 2H), 3.38 (s, 3H), 2.42－2.39 (m, 2H), 1.85 (s, 3H),
1.73－1.66 (m, 1H), 1.39 (s, 3H), 1.38 (s, 3H), 0.90 (d,
J＝9.6 Hz, 1H), 0.89 (s, 9H), 0.07 (s, 3H), 0.4 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ: 168.6, 139.2, 128.8,
109.2, 96.9, 77.8, 73.6, 68.6, 55.5, 51.8, 39.9, 33.4, 27.3,
27.3, 25.9 (3C), 18.2, 12.8, 8.7, −4.3, −4.6; IR (KBr) ν:
2986, 2931, 1717, 1472, 1463, 1436, 1379, 1370, 1253,
1046, 836, cm−1; MS (ESI, m/z): 483.4 ([M＋Na]＋);
HRMS-ESI: [M＋Na]＋ calcd for C23H44O7Si: 483.2749,
found 483.2761.
25
0.52 mmol, 83%) as a colorless oil. [α]D ＋48.3 (c
1
1.18, CHCl3); H NMR (CDCl3, 400 MHz) δ: 5.93－
5.82 (m, 1H), 5.08 (d, J＝5.2 mmol, 1H), 5.05 (s, 1H),
4.66 (s, 2H), 4.09 (dd, J＝9.6, 2.0 Hz, 1H), 3.96－3.91
(m, 1H), 3.72－3.68 (m, 1H), 3.63－3.54 (m, 2H), 3.37
(s, 3H), 2.37－2.23 (m, 2H), 1.68－1.58 (m, 1H), 1.39
(s, 3H), 1.38 (s, 3H), 0.90 (s, 9H), 0.89 (d, J＝6.0 Hz,
3H), 0.07 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ: 134.6,
117.2, 109.1, 96.8, 77.6, 77.4, 73.4, 68.7, 55.5, 39.1,
38.6, 27.3, 27.3, 26.0 (3C), 18.29, 9.1, −4.1, −4.7; IR
(KBr) ν: 2931, 2888, 1473, 1463, 1379, 1369, 1256,
1046, 913, 837, 776 cm−1; MS (EI, m/z) (%): 373
([M−Me] ＋ ) (1); HRMS-EI: [M−Me] ＋ calcd for
C19H37O5Si: 373.2410, found 373.2412.
Results and Discussion
To exclude the use of CrO3 in Marker degradation,
we have developed a green oxidation which enabled us
to obtain potassium salt 5 on multikilogram scale as side
product.[9] Compound 5 is a versatile compound and
could easily be transformed into a series of 4C－6C
chiral pool molecules including 4 on a 100 g scale.[10]
From 4 we started our synthesis of 2, as shown in Figure
2 the synthetic plan. The C2－C3 (Z)-double bond was
to be introduced through a Horner–Wadsworth–Emmons
(HWE) olefination and the C4－C5 bond through a
chelation-controlled allylation of aldehyde 3. The de-
sired chiral vicinal diol in 3 was to be introduced by
Sharpless asymmetric dihydroxylation of C2－C3 dou-
ble bond derived from 4 by dehydration.
(3S,4R,5R)-3-((tert-Butyldimethylsilyl)oxy)-5-((R)-
2,2-dimethyl-1,3-dioxolan-4-yl)-5-(methoxymethoxy)-
4-methylpentanal (17)
A solution of 16 (575 mg, 1.48 mml) in MeOH/DCM
(50 mL/50 mL) was treated with ozone at −78 ℃ until
the blue color sustained. To the mixture were added
Et3N (0.32 mL, 2.2 mmol) and Me2S (3.3 mL, 44.7
mmol). The solution was stirred at ambient temperature
for 5 h and concentrated and purified on silica gel (pe-
troleum ether/EtOAc: 15/1) to give aldehyde 17 (570
26
mg, 1.46 mmol, 99%) as a colorless oil. [α]D ＋18.8
HWE reaction
1
OMOM
(c 1.18, CHCl3); H NMR (CDCl3, 400 MHz) δ: 9.83
TBSO
OMOM
9
O
3
(dd, J＝2.8, 1.6 Hz, 1H), 4.65 (s, 2H), 4.21 (dd, J＝10.8,
6.0 Hz, 1H), 3.98－3.92 (m, 2H), 3.65－3.57 (m, 2H),
3.37 (s, 3H), 2.69－2.54 (m, 2H), 1.89－1.81 (m, 1H),
1.38 (s, 3H), 1.36 (s, 3H), 0.96 (d, J＝7.2 Hz, 3H), 0.88
(s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13CNMR (CDCl3, 100
MHz) δ: 202.4, 109.4, 96.9, 78.0, 77.3, 70.9, 68.4, 55.5,
47.9, 40.4, 27.2, 27.2, 25.9 (3C), 18.1, 8.0, −4.5, −4.6;
IR (KBr) ν: 2932, 2888, 1728, 1473, 1463, 1380, 1370,
1254, 1046, 838, 777 cm−1; MS (EI, m/z) (%): 375
([M−Me] ＋ ) (1); HRMS-EI: [M−Me] ＋ calcd for
C18H35O6Si: 375.2203, found 375.2207.
6
O
O
5
4
7
MeO
1
8
O
2
O
O
Me
Me
3
chelation-controlled allylation
Sharpless
C1-C9 domain (2)
asymmetric
dihydroxylation
O
3
ref. 8
(R)
2
4
(R) CO2K
1
OMe
HO
BnO
100 g scale
OH
OH
5
4
Figure 2 A retrosynthetic analysis of C1－C9 domain (2).
Methyl (5S,6R,7R,E)-5-((tert-butyldimethylsilyl)oxy)-
7-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-7-(methoxy-
methoxy)-2,6-dimethylhept-2-enoate (2)
To implement the dehydration of 4, as depicted in
Scheme 1, its exposed hydroxyl group was first
transformed into mesylate 6 in excellent yield, however,
elimination of 6 did not proceed to afford 7, even under
harsh condition. Then we prepared bromide 8, by
heating 6 with lithium bromide in acetone at reflux for
18 h, and put it through several typical conditions.
Treatment of 8 with DBU in DMF at 80 ℃ delivered
completely 9, a deconjugated product of 7. After much
optimization, we found that treating 8 with exact one
equivalent of NaHCO3 in HMPA at 100 ℃ for 4 h
afforded the desired 7 in good yield without forming 9.
Under the standard condition of Sharpless asymmetric
dihydroxylation,[11] diol 10 was prepared from 7 in high
A solution of 18 (690 mg, 3.1 mmol) in dry DME
(10 mL) was treated with n-BuLi (1.0 mL, 2.4 mol/L in
hexane, 2.4 mmol) at 0 ℃ for 10 min, then a solution
of 17 (480 mg, 1.23 mmol) in DME (10 mL) was added.
The resulting mixture was stirred at room temperature
for 30 min and quenched with a saturated solution of
NH4Cl and extracted with ethyl acetate for three times.
The combined organic layers were washed with brine,
dried over Na2SO4, concentrated, and purified on silica
gel (petroleum ether/EtOAc: 10/1) to give 2 (550 mg,
26
1
1.19 mmol, 97%). [α]D ＋34.4 (c 1.10, CHCl3); H
NMR (CDCl3, 400 MHz) δ: 6.90 (t, J＝8.0 Hz, 1H),
666
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© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2015, 33, 663—668

Synthesis of C1－C9 Domain of the Nominal Didemnaketal A
1
yield and stereoselectivity (86%, d.r.＞19∶1 by H
NMR).
free hydroxyl in 14 was protected as TBS ether and the
terminal double bond was cleaved with ozone to give
aldehyde 17 in high yield. HWE reaction of 17 with
phosphonate 18 delivered α,β-unsaturated ester 2 effec-
tively (97% yield, E/Z: 5/1). The major isomer was iso-
lated by flash column chromatography and its geometry
of the C2－C3 double bond was confirmed to be E by
an NOE experiment.
We then set out to prepare aldehyde 3. Ester 10 was
reduced with LiAlH4 and the resulting triol was pro-
tected as acetonide selectively to give 11, the more
thermodynamically stable isopropylidene derivative, in
57% yield. The exposed secondary hydroxyl group in 11
was protected as a MOM ether to form a chelation site
we needed later. The benzyl ether was removed by cata-
lytic hydrogenation and the exposed hydroxyl group
was oxidized with Dess-Martin periodinane to afford
aldehyde 3 in moderate yield.
Scheme 2
OMOM
O
OMOM
O
OH
TBSO
a
c
13
O
O
O
Scheme 1
14
16
b
d
CO2Me
OMs
CO2Me
CO2Me
a
13C NMR δ
C1: 100.49
C2: 24.02
C3: 25.80
BnO
BnO
3
BnO
4
2
9
TBSO
OMOM
6
b
O
O
1
c
+
O
O
CO2Me
d
O
BnO
BnO
O
17
Br
15
7
e
8
e
TBSO
OMOM
OH
OH
MeO2C
MeO2C
f
PO(OEt)2
18
CO2Me
O
BnO
BnO
O
O
H
O
OH
11
2
10
OMOM
NOEs
g
OMOM
Conditions and reagents: (a) SO3•py, DMSO, Et3N, CH2Cl2, 0 ℃, 1 h;
then MgBr2•Et2O, Bu3SnCH2CHCH2, CH2Cl2, r.t., 12 h, 81%, d.r.＞19∶1
by NMR; (b) MeOH, 4 N HCl, r.t., 2 h, concentration, acetone, TsOH, r.t.,
12 h, 43%, then DMP, PPTS, CH2Cl2, r.t., 12 h, 74%; (c) TBSCl, imida-
zole, DMF, r.t., 12 h, 83%; (d) O3, MeOH, CH2Cl2, −78 ºC, then Et3N,
Me2S, r.t., 5 h, 99%; (e) 18, n-BuLi, DME, 0 ℃, 10 min, 17, 97%, E/Z:
5/1.
h
i
HO
3
O
O
O
O
12
13
Conditions and reagents: (a) MsCl, Et3N, CH2Cl2, 0 ℃, 1 h, 91%; (b)
LiBr, Li2CO3, DMF, 120 ℃, 8 h; (c) LiBr, acetone, reflux, 18 h, 95%; (d)
NaHCO3, HMPA, 100 ℃, 4 h, 66%; (e) K3Fe(CN)6, K2CO3, OsO4,
(DHQD)2PHAL, MeSO2NH2, t-BuOH/H2O, 0 ℃ to r.t., 12 h, 86%, d.r.＞
19∶1 by NMR; (f) LiAlH4, THF, 0 ℃ to r.t., 12 h; then TsOH•H2O, ace-
tone, r.t., 10 h, 57%; (g) MOMCl, i-Pr2NEt, CH2Cl2, 0 ºC to r.t., 12 h, 98%;
(h) H2, Pd/C, MeOH, r.t., 12 h, 98%; (i) Dess-Martin periodinane, Na-
HCO3, CH2Cl2, 0 ℃, 1 h, 67%.
Conclusions
The C1－C9 domain 2 of the nominal didemnaketal
A was synthesized from α-OH ester 4, a chiral pool
molecule which passed its methyl on to the target, in 12
steps with an overall yield of 14%. Both key reactions,
the introduction of the 7,8-syn-diol through Sharpless
asymmetric dihydroxylation and the C4-OH through
chelation-controlled allylation, proceeded with high
yields and stereoselectivities. Currently, developing
more and useful chiral pool molecules from 5 and ap-
plying them in the syntheses of natural products are on-
going in this laboratory.
To minimize the possible α-epimerization and
β-elimination, 3 was used without purification to give
better result, as in Scheme 2. Allylation of crude 3, with
allyltributyltin in the presence of magnesium bromide
etherate in CH2Cl2 at room temperature, gave 14 in high
yield and stereochemical control.[12] To confirm the ste-
reochemistry of the newly generated hydroxyl in 14, we
prepared diacetonide 15 and analyzed its 13C NMR
spectroscopy. The chemical shift of the acetal carbon in
the 1,3-dioxolane appearing at δ 100.5 and the methyl
groups at δ 24.0 and 25.8 suggested the presence of
anti-1,3-diol.[13] The allylation step was therefore con-
firmed to be chelation-controlled. As both chirality at α-
and β-positions induced the same stereochemical out-
come under chelation conformation, the stereochemical
control was reinforced to give 14 as the sole product.
To prepare for the forthcoming HWE olefination, the
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Chin. J. Chem. 2015, 33, 663—668