Structural and stereochemical requirements of the spiroketal group of hippuristanol for antiproliferative activity

Article abstract of DOI:10.1016/j.bmcl.2010.03.093

Hippuristanol is a natural product that has recently been shown to inhibit eukaryotic translation initiation and tumor cell proliferation. To investigate the structure and activity relationship of hippuristanol, we synthesized a series of analogs by expan

Full text of DOI:10.1016/j.bmcl.2010.03.093

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3112–3115
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structural and stereochemical requirements of the spiroketal group of
hippuristanol for antiproliferative activity
a,
Wei Li a, Yongjun Dang b, Jun O. Liu b, , Biao Yu
*
*
a State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, 200032 Shanghai, China
b Department of Pharmacology and Department of Oncology, Johns Hopkins School of Medicine, 725 North Wolfe Street, Baltimore, 21205 MD, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Hippuristanol is a natural product that has recently been shown to inhibit eukaryotic translation initia-
tion and tumor cell proliferation. To investigate the structure and activity relationship of hippuristanol,
we synthesized a series of analogs by expanding the size of its F ring and determined their effects on
the proliferation of cancer cell lines. All changes to the F-ring of hippuristanol resulted in 3-fold to
>100-fold decrease in activity.
Received 2 March 2010
Revised 17 March 2010
Accepted 26 March 2010
Available online 30 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Eukaryotic translation initiation
Cancer
Inhibitor
Hippuristanol, a polyoxygenated steroid with potent cytotoxic-
ities against tumor cell lines, was discovered from the gorgonian
Isis hippuris.1 Recently, it was reported that this natural product ap-
peared to work through eukaryotic initiation factor (eIF)4A I and II,
an ATP-dependent RNA helicase, blocking its binding to mRNA
hence inhibiting translational initiation, making it the second small
molecule, after the marine natural product pateamine A, that mod-
ulate the function of eIF4A protein family.2 Given the critical role
of translation in cell proliferation, hippuristanol is considered a
promising lead for the development of anti-tumor agents. More-
over, translation is also necessary for viral infection, suggesting
that hippuristanol has potential as an antiviral agent.
Recently, we disclosed the first synthesis of hippuristanol using
the commercially available hydrocortisone as a starting material.3
A key step in the synthesis entailed the addition of 2,3-dihydrofu-
ran to a b-hydroxymethylketone precursor to construct the spirok-
etal functionality (Fig. 1). This chemistry rendered it possible to
attain several analogs with structural alteration at the F-ring of
hippuristanol. The preliminary structure and activity relationship
data suggested that besides the three hydroxyls at C3, C11 and
C20, the ‘R’ configuration at C22 and the three methyl groups on
the F ring were critical for activity. Herein, we report the synthesis
of a new series of analogs of hippuristanol with altered structures
and stereochemistry of the E and F rings and the determination of
their antiproliferative activity.
In our previous preliminary SAR study, we adopted a structural
‘contraction’ strategy by making analogs with the removal of a sub-
set or all of the methyl groups on the F-ring of hippuristanol in
addition to altering the stereochemistry at C22, C20 and C24.3 In
the present work, we decided to proceed, for most analogs, with
structural ‘expansion’, that is, increasing the ring size from five
to six, adding an extra methyl group or enlarging the methyl
groups to ethyl groups.
For the F-ring building blocks, we began with two commercially
available
a
,
a-dimethyl-c-butyrolactone 2 and
c-butyrolactone 3
(Scheme 1). Nucleophilic attack of the
c-butyrolactone derivatives
with the Grignard reagents (prepared from magnesium with iodo-
methane or bromoethane) in Et2O at 30 °C led to the corresponding
diols, which were then oxidized to 3,3,4,4-tetramethylbutyrolac-
tone 4 or 4,4-diethylbutyrolactone 5 with the required methyl or
ethyl groups by PCC, in 83% and 86% yield, respectively.3,4 Treat-
ment of the resulting lactones with DIBAL-H at ꢀ68 °C in CH2Cl2 of-
fered pairs of racemic acetals that were stable below 20 °C. Finally,
the acetals were dehydrated at high temperature (250 °C) without
any solvent to provide the desired 2,2,3,3-tetramethyl-2,3-dihy-
drofuran 6 and 2,2-diethyl-2,3-dihydrofuran 7 in 62% and 65%
yield, respectively.3,5
To prepare an F-ring analog lacking one of the methyl groups,
the commercial (ꢀ)-
D
-pantolactone 8 was chosen as the starting
-hydroxyl group at panto-
precursor (Scheme 2). Activation of the
a
lactone 8 with an Ms group in CH2Cl2, followed by reduction in the
presence of Zn and NaI, provided 3,3-dimethylbutyrolactone 9 in
86% yield.6 Subsequently, reduction and dehydration of 9 gave rise
* Corresponding authors. Fax: +86 21 64166128 (B.Y.).
E-mail addresses: joliu@jhu.edu (J.O. Liu), byu@mail.sioc.ac.cn (B. Yu).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.03.093

W. Li et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3112–3115
3113
OH
O
O
HO
BzO
OH
11
OH
O
BzO
Hydrocortisone
OH
1
OH
OH
O F
O
24
OH
20
H+
22
11
E
CD
O
O
B
A
16
3
OH
OH
22-epi-Hippuristanol
Hippuristanol
Figure 1. Hippuristanol and its synthetic strategy.
R1
O
sulted in the corresponding 5-lithio-2,3-dihydrofuran, which were
then added to ketone 1 at 0 °C to provide mainly the required 20b-
OH adducts. Otherwise, low temperature (ꢀ68 °C) led mainly to
R1
R1
R1
R2
R2
R1
R2
R2
R1 = Me, R2 = Me
R1
c-d
a-b
O
O
O
the adducts with 20a-OH configuration, which we previously
O
6
found dramatically decreased the antiproliferative activity. The
crude products with 20b-OH were acidified directly with the addi-
tion of 5% HCl to open the 2,3-dihydrofuran ring to introduce the
side chain with a 22-carbonyl and a 25-hydroxyl groups.7 Cycliza-
tion of the resulting intermediate containing 16-hydroxyl, 22-car-
bonyl and 25-hydroxyl substituents was then achieved to provide
the desired 22-spiro-ketal functionalities. Subsequent deprotection
of the remaining Bz groups with LiAlH4 furnished the desired ana-
logs 11a/11b, 12a/12b, 13a/13b in satisfactory yields.3,8 Analog 14
4
R1 = Me, R2 = Me
7 R1 = H, R2 = Et
2
R1 = Me
3 R1 = H
5 R1 = H, R2 = Et
Scheme 1. Reagents and conditions: (a) MeMgI or EtMgBr, Et2O, 30 °C; (b) PCC,
CH2Cl2, rt, 83% (for 4, two steps) and 86% (for 5, two steps); (c) DIBAL-H, CH2Cl2,
ꢀ68 °C; (d) Al2O3, 250 °C, 62% (for 6, two steps) and 65% (for 7, two steps).
OH
a, b
c, d
O
with 20a-OH were also found in a 17% yield. We note that the
O
O
O
O
epimerization of 22-spiro-ketal could still be observed under acid
conditions, suggesting that substitutions in the F ring did not
influence the epimerization significantly.
9
8
10
Scheme 2. Reagents and conditions: (a) MsCl, Et3N, DMAP, CH2Cl2, rt; (b) Zn, NaI,
DME, reflux, 86% (for two steps); (c) DIBAL-H, CH2Cl2, ꢀ68 °C; (d) Al2O3, 200 °C, 60%
(for two steps).
Generally, ketals with six-membered rings are more difficult to
epimerize, compared to five-membered rings. Thus, the same pro-
cedure used for the preparation of analogs with five-membered F
rings was employed on the commercial 3,4-dihydropyran 15 with
1 to synthesize analogs 19a/19b with six-membered F rings in
good yields (Scheme 4).3,7 To obtain ring-expansion analogs with
methyl substitutions, the commercially available ketone 16 was
converted to lactone 17 using Baeyer–Villiger rearrangement in
67% yield.9 Subsequent reduction and dehydration of lactone 17
to the corresponding 3,3-dimethyl-2,3-dihydrofuran 10 in 60%
yield.
With the F-ring precursors in hand, we synthesized their corre-
sponding hippuristanol analogs using similar chemistry as that for
the synthesis of hippuristanol (Scheme 3).3 Treatment of the three
2,3-dihydrofuran derivatives prepared above with t-BuLi in THF re-
HO
O
HO
O
O
HO
HO
a,b,c
a,b,c
O
O
H
OH
H
1
H
H
H
H
HO
O
7
HO
O
10
H
H
12a
12b
a,b,c
13a (22
13b (22
S
R
) (31%)
) (51%)
(22
(22
R
) (44%)
S
) (13%)
O
6
HO
O
O
O
HO
HO
H
20
HO
20
O
H
H
+
H
H
H
H
HO
HO
11a
11b
(22
R
) (47%)
) (16%)
H
14
(17%)
(22
S
Scheme 3. Reagents and conditions: (a) t-BuLi, THF, 0 °C; (b) 0.1 M HCl, THF, rt; (c) LiAlH4, THF, 40 °C.

3114
W. Li et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3112–3115
HO
Table 1 (continued)
O
O
Compd
Structures
IC50
>10
(lM)
HO
H
O
a,b,c
H
OH
OH
O
13a
13b
H
H
1
19a (22S) (27%)
19b (22R) (33%)
O
15
O
O
HO
O
OH
e-f
d
>10
>10
a,b,c
O
O
O
O
O
18
17
16
HO
O
O
HO
14
HO
O
H
OH
OH
O
H
H
20a (22R) (3%)
20b (22S) (7%)
19a
19b
1.6
HO
H
O
Scheme 4. Reagents and conditions: (a) t-BuLi, THF, 0 °C; (b) 0.1 M HCl, THF, rt; (c)
LiAlH4, THF, 40 °C; (d) 30% H2O2, (CF3CO)2O, rt, 67%; (e) DIBAL-H, CH2Cl2, ꢀ68 °C; (f)
Al2O3, 200 °C, 37% (two steps).
O
>10
O
provided 2,2-dimethyl-3,4-dihydropyran precursor 18. However,
the same procedure employed on 2,2-dimethyl-3,4-dihydropyran
with ketone 1 offered the desired 20a/20b in only 3% and 7% yield,
respectively, for the 6-lithio-2,2-dimethyl-3,4-dihydropyran (pre-
pared from 2,2-dimethyl-3,4-dihydropyran with t-BuLi in THF)
OH
OH
O
20a
20b
0.6
4.9
O
mainly caused the elimination of 16b-OH to result in a
a,b-unsat-
O
O
urated ketone, instead of the expected 20b-OH adduct. Despite the
low yields, sufficient amount of each analog was obtained upon
scaling up the reaction to enable their evaluation in cell prolifera-
tion assays. However, the final congeners with the six-membered F
rings (19 and 20) could still epimerize at 22-spiro-ketal upon acidic
treatment.
We determined the activity of the new analogs in HeLa cell pro-
liferation assay using incorporation of [3H]thymidine as a readout
(Table 1).3 In the previous study, it was found that R stereochem-
istry at C22 is essential for activity. The same stereochemical
requirement at C22 is seen in the new series of analogs among sev-
eral pairs of diastereomers that differ only in the stereochemistry
at C22. Thus, analogs 11a and 12a are both significantly more ac-
tive than 11b and 12b. The same stereochemical requirement also
applies to the analogs with six-membered F rings with analogs 19a
and 20a being much more active than 19b and 20b. For the substit-
uents on the F ring, replacement of the gem-dimethyl3 with gem-
diethyl substituents led to a 10-fold decrease in activity (12a). To-
gether with the previous observation that an analog that lacks the
two methyl group is inactive,3 these results suggest that the gem-
dimethyl substitution is optimal for activity. It is interesting to
note that the analogs with expanded six-membered F rings re-
tained antiproliferative activity. In particular, 19a whose counter-
part with five-membered F ring is inactive,3 is moderately active.
This may be due to the potential compensation of the missing
gem-dimethyl groups by the methylene carbon inserted into the
F ring, partially compensating for the lost hydrophobic interaction
with the binding pocket in eIF4A. Restoration of the gem-dimethyl
group in 19a led to further enhancement of the activity (20a). To-
gether, these results helped to further define the boundary for fu-
ture design and synthesis of analogs of hippuristanol with
improved stability and high biological activity as leads for develop-
ing anticancer and antiviral agents.
Table 1
Antiproliferative activity of hippuristanol analogs10
Compd
Structures
IC50 (lM)
OH
O
24
Hip
0.07
20
22
O
OH
O
11a
11b
0.2
2.2
O
OH
O
O
OH
OH
O
12a
12b
3.6
Acknowledgments
O
We thank Professor Carlos Jiménez of the Universidade de A
Coruña (Spain) for providing NMR spectra of the authentic hippu-
ristanol and 22-epi-hippuristanol. Financial support from the Na-
tional Natural Science Foundation of China (20728202 and
20621062) and the Chinese Academy of Sciences (KJCX2-YW-
H08) is gratefully acknowledged.
>10
O
O

W. Li et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3112–3115
3115
499.33924. Compound 11b: ½a D27
ꢁ
ꢀ16.1 (c 0.31, CHCl3); 1H NMR (400 MHz,
References and notes
CDCl3): d 4.44ꢀ4.39 (m, 1H), 4.30 (br s, 1H), 4.05 (br s, 1H), 2.44 (d, J = 14.4 Hz,
1H), 2.16ꢀ2.12 (m, 1H), 2.07ꢀ2.01 (m, 1H), 1.37 (s, 3H), 1.31 (s, 3H), 1.20 (s,
3H), 1.08 (s, 3H), 1.04 (s, 3H), 1.03 (s, 3H), 0.93 (s, 3H), 0.81ꢀ0.77 (m, 1H); 13C
NMR (100 MHz, CDCl3): d 117.4, 85.5, 82.7, 78.7, 67.7, 66.2, 66.0, 57.77, 57.75,
48.5, 46.9, 41.8, 41.5, 39.5, 35.8, 34.9, 31.9, 31.8, 31.3, 29.9, 28.2, 27.4, 27.2,
24.6, 24.3, 23.8, 23.7, 18.5, 13.7; HR-ESIMS calcd for C29H48O5Na [M+Na]+
1. (a) Higa, T.; Tanaka, J.-I.; Tsukitani, Y.; Kikuchi, H. Chem. Lett. 1981, 1647; (b)
Rao, C. B.; Ramana, K. V.; Rao, D. V.; Fahy, E.; Faulkner, D. J. J. Nat. Prod. 1988, 51,
954; (c) Gonzalez, N.; Barral, M. A.; Rodriguez, J.; Jimenez, C. Tetrahedron 2001,
57, 3487.
2. (a) Bordeleau, M.-E.; Mori, A.; Oberer, M.; Lindqvist, L.; Chard, L. S.; Higa, T.;
Wagner, G. J.; Belsham, G.; Tanaka, J.; Pelletier, J. Nat. Chem. Biol. 2006, 2, 213;
(b) Lindqvist, L.; Oberer, M.; Reibarkh, M.; Cencic, R.; Bordeleau, M.-E.; Voqt, E.;
Marintchev, A.; Tanaka, J.; Fagotto, F.; Altmann, M.; Wagner, G.; Pelletier, J. PLoS
One 2008, 3, e1583; (c) Low, W. K.; Dang, Y.; Schneider-Poetsch, T.; Shi, Z.; Choi,
N. S.; Merrick, W. C.; Romo, D.; Liu, J. O. Mol. Cell 2005, 20, 709; (d) Bordeleau,
M.-E.; Matthews, J.; Wojnar, J. M.; Lindqvist, L.; Novac, O.; Jankowsky, E.;
Sonenberg, N.; Northcote, P.; Teesdale-Spittle, P.; Pelletier, J. Proc. Natl. Acad.
Sci. U.S.A. 2005, 102, 10460; (e) Clardy, J. ACS Chem. Biol. 2006, 1, 17; (f) Pestova,
T. V.; Hellen, C. U. Nat. Chem. Biol. 2006, 2, 176.
499.33940, found 499.33975. Compound 12a: ½a D28
ꢁ
+38.0 (c 0.52, CHCl3); 1H
NMR (400 MHz, CDCl3): d 4.36ꢀ4.30 (m, 2H), 4.05 (br s, 1H), 3.08 (s, 1H),
2.23ꢀ2.19 (m, 1H), 2.08ꢀ2.01 (m, 1H), 1.42 (s, 3H), 1.31 (s, 3H), 1.04 (s, 3H),
0.89 (t, J = 7.6 Hz, 3H), 0.84 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
116.1, 88.5, 80.6, 78.9, 68.3, 66.6, 66.4, 58.4, 57.4, 49.9, 42.3, 40.1, 36.5, 35.5,
34.3, 33.5, 33.3, 32.7, 32.1, 31.8, 30.4, 29.8, 28.8, 28.6, 28.1, 18.5, 14.2, 8.9, 8.8;
HR-ESIMS calcd for C29H48O5Na [M+Na]+ 499.33940, found 499.34072.
Compound 12b: ½a D28
ꢁ
ꢀ17.7 (c 0.29, CHCl3); 1H NMR (400 MHz, CDCl3): d 4.42
(dd, J = 12.8, 7.2 Hz, 1H), 4.31 (br s, 1H), 4.05 (br s, 1H), 2.18ꢀ2.14 (m, 1H), 1.35
(s, 3H), 1.32 (s, 3H), 1.03 (s, 3H), 0.84 (t, J = 7.6 Hz, 6H); 13C NMR (100 MHz,
CDCl3): d 120.6, 87.9, 82.7, 78.9, 68.1, 66.4, 66.2, 58.4, 58.1, 48.9, 42.1, 39.9,
36.3, 35.3, 32.7, 32.4, 31.9, 31.8, 31.4, 30.3, 30.2, 28.7, 27.9, 26.8, 19.7, 14.2, 8.7,
8.4; HR-ESIMS calcd for C29H48O5Na [M+Na]+ 499.33940, found 499.34087.
3. Li, W.; Dang, Y.; Liu, J. O.; Yu, B. Chem. Eur. J. 2009, 15, 10356.
4. (a) Barua, N. C.; Schmidt, R. R. Synthesis 1986, 891; (b) Martin, D. D.; Marcos, I.
S.; Basabe, P.; Romero, R. E.; Moro, R. F.; Lumeras, W.; Rodríguez, L.; Urones, J.
G. Synthesis 2001, 1013; (c) Baklan, V. F.; Antipenkova, L. S.; Zakharchenko, L. I.;
Fesenko, T. E.; Kukhar, V. P. Russ. J. Org. Chem. 1984, 20, 1212; (d) Fukuzawa, S.-
I.; Sumimoto, N.; Fujinami, T.; Sakai, S. J. Org. Chem. 1990, 55, 1628.
5. (a) Botteghi, C.; Consiglio, G.; Ceccarelli, G.; Stefani, A. J. Org. Chem. 1972, 37,
1835; (b) Paquette, L. A.; Lanter, J. C.; Johnston, J. N. J. Org. Chem. 1997, 62, 1702;
(c) Hennessy, A. J.; Connolly, D. J.; Malone, Y. M.; Guiry, P. J. Tetrahedron Lett.
2000, 41, 7757.
6. (a) Akbutina, F. A.; Sadretdinov, I. F.; Vasil’eva, E. V.; Miftakhov, M. S. Russ. J.
Org. Chem. 2001, 37, 695; (b) Ueki, T.; Kinoshita, T. Org. Biomol. Chem. 2004, 2,
2777; (c) Doyle, M. P.; Dyatkin, A. B. J. Org. Chem. 1995, 60, 3035.
7. (a) Szendi, Z.; Sweet, F. Steroids 1991, 56, 458; (b) Hedtmann, U.; Klintz, R.;
Hobert, K.; Frelek, J.; Vlahov, I.; Welzel, P. Tetrahedron 1991, 47, 3753; (c)
Hobert, U.; Hedtmann, K.; Klintz, R.; Welzel, P.; Frelek, J.; Strangmann-
Diekmann, M.; Klöne, A.; Pongs, O. Angew. Chem., Int. Ed. Engl. 1989, 28, 1515.
8. Procedure for the synthesis of analogs 12a and 12b: To a solution of 2,2-
Compound 13a: ½a D27
ꢁ
+42.8 (c 0.44, CHCl3); 1H NMR (400 MHz, CDCl3): d
4.38ꢀ4.30 (m, 2H), 4.05 (br s, 1H), 3.78 (d, J = 8.0 Hz, 1H), 3.53 (d, J = 8.0 Hz,
1H), 3.10 (s, 1H), 2.22ꢀ2.18 (m, 1H), 2.07ꢀ2.01 (m, 1H), 1.38 (s, 3H), 1.30 (s,
3H), 1.21 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H), 0.80ꢀ0.76 (m, 1H); 13C NMR
(100 MHz, CDCl3): d 117.3, 80.7, 80.5, 79.8, 68.1, 66.4, 65.6, 58.3, 57.1, 49.8,
47.5, 42.1, 39.9, 37.9, 36.3, 35.2, 34.1, 32.5, 31.6, 30.1, 29.1, 28.6, 27.9, 27.1,
26.3, 18.4, 14.1; HR-ESIMS calcd for C27H44O5Na [M+Na]+ 471.30810, found
471.30893. Compound 13b: ½a D27
ꢁ
ꢀ42.0 (c 0.83, CHCl3); 1H NMR (400 MHz,
CDCl3): d 4.43ꢀ4.38 (m, 1H), 4.31 (br s, 1H), 4.05 (br s, 1H), 3.64 (d, J = 7.2 Hz,
1H), 3.51 (d, J = 8.0 Hz, 1H), 2.20ꢀ2.14 (m, 2H), 2.09ꢀ2.02 (m, 1H), 1.98ꢀ1.88
(m, 1H), 1.37 (s, 3H), 1.32 (s, 3H), 1.14 (s, 3H), 1.05 (s, 3H), 1.03 (s, 3H),
0.81ꢀ0.78 (m, 1H); 13C NMR (100 MHz, CDCl3): d 121.1, 82.7, 79.8, 79.4, 68.0,
66.6, 66.3, 58.3, 58.1, 48.7, 46.4, 42.0, 39.8, 37.9, 36.2, 35.2, 32.3, 31.76, 31.75,
30.3, 28.6, 27.8, 27.7, 26.9, 26.0, 19.0, 14.1; HR-ESIMS calcd for C27H44O5Na
[M+Na]+ 471.30810, found 471.30901. Compound 14: a 2D7
½ ꢁ ꢀ36.8 (c 0.32,
diethyl-2,3-dihydrofuran 7 (200 lL, 1.46 mmol) in anhydrous THF (3 mL) was
CHCl3); 1H NMR (400 MHz, CDCl3): d 4.60ꢀ4.55 (m, 1H), 4.42 (s, 1H), 4.31 (br s,
1H), 4.04 (br s, 1H), 2.22ꢀ2.18 (m, 1H), 2.12ꢀ2.08 (m, 1H), 1.43 (s, 3H), 1.24 (s,
3H), 1.12 (s, 3H), 1.11 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H), 0.95 (s, 3H), 0.82ꢀ0.78
(m, 1H); 13C NMR (100 MHz, CDCl3): d 114.9, 85.6, 80.1, 79.7, 69.7, 67.7, 65.9,
58.2, 57.6, 47.8, 47.6, 42.8, 39.9, 39.4, 35.8, 34.8, 31.7, 31.4, 30.2, 28.2, 27.4,
24.3, 24.0, 23.8, 23.7, 23.0, 17.8, 13.9; HR-ESIMS calcd for C29H48O5Na [M+Na]+
added t-BuLi (1.5 M in pentane, 1.3 mL, 1.95 mmol) at ꢀ68 °C. The reaction was
allowed to warm to 0 °C and the stirring continued for another 15 min at rt. The
mixture was cooled to 0 °C again and ketone
1 (91 mg, 0.16 mmol) in
anhydrous THF (1 mL) was added. After stirring for 1 h, the reaction was
quenched with H2O. The resulting mixture was diluted with EtOAc (30 mL),
and washed with brine. The organic layer was dried, filtered, and concentrated.
The residue was dissolve in THF (4 mL) and 0.1 M HCl (1 mL). After stirring for
2 h, the mixture was diluted with EtOAc (30 mL), washed with brine, dried, and
concentrated. The crude product was dissolved in anhydrous THF (2 mL), and
LiAlH4 (33 mg, 0.87 mmol) was added. After stirring for 20 min at 40 °C, the
reaction was quenched with H2O slowly. To the resulting mixture was added
EtOAc (10 mL), NaHCO3 (1 g) and Na2SO4 (1 g), and the stirring continued for
another 3 h. The mixture was then filtered and concentrated to give a residue,
which was purified by silica gel column chromatography (petroleum ether–
EtOAc, 2:1) to afford analogs 12a (34 mg, 44%) and 12b (10 mg, 13%).
499.33940, found 499.33963. Compound 19a: ½a D27
ꢁ
+11.4 (c 0.70, CHCl3); 1H
NMR (400 MHz, CDCl3): d 4.4 (dd, J = 15.2, 7.6 Hz, 1H), 4.30 (br s, 1H), 4.05 (br s,
1H), 3.98ꢀ3.92 (m, 1H), 3.76ꢀ3.72 (m, 1H), 3.29 (s, 1H), 2.22ꢀ2.18 (m, 1H),
2.09ꢀ2.03 (m, 1H), 1.32 (s, 3H), 1.25 (s, 3H), 1.03 (s, 3H), 0.80ꢀ0.77 (m, 1H);
13C NMR (100 MHz, CDCl3): d 105.0, 81.4, 81.0, 68.1, 66.5, 66.4, 61.8, 58.3, 57.1,
50.0, 42.4, 40.0, 36.3, 35.3, 33.8, 32.6, 31.6, 30.21, 30.18, 28.7, 27.9, 27.4, 24.9,
20.1, 18.5, 14.1; HR-MALDI calcd for C26H42O5Na [M+Na]+ 457.2924, found
457.2933. Compound 19b: ½a D27
ꢁ
ꢀ34.3 (c 0.94, CHCl3); 1H NMR (400 MHz,
CDCl30): d 4.38ꢀ4.33 (m, 1H), 4.30 (br s, 1H), 4.05 (br s, 1H), 3.79ꢀ3.72 (m, 1H),
3.60ꢀ3.56 (m, 1H), 2.18ꢀ2.14 (m, 1H), 2.09ꢀ2.03 (m, 1H), 1.34 (s, 3H), 1.31 (s,
3H), 1.03 (s, 3H), 0.81ꢀ0.77 (m, 1H); 13C NMR (100 MHz, CDCl3): d 110.2, 83.5,
79.2, 68.0, 66.8, 66.4, 61.1, 58.5, 58.0, 48.7, 42.0, 39.9, 36.3, 35.3, 32.3, 31.8,
31.2, 30.2, 28.6, 28.1, 27.9, 26.5, 25.1, 19.9, 19.7, 14.1; HR-MALDI calcd for
C26H42O5Na [M+Na]+ 457.2924, found 457.2928. Compound 20a: 1H NMR
(400 MHz, CDCl3): d 4.35ꢀ4.29 (m, 2H), 4.05 (br s, 1H), 3.50 (s, 1H), 2.23ꢀ2.19
(m, 1H), 1.39 (s, 3H), 1.38 (s, 3H), 1.24 (s, 3H), 1.20 (s, 3H), 1.04 (s, 3H),
0.80ꢀ0.77 (m, 1H). Compound 20b: 1H NMR (300 MHz, CDCl3): d 4.36 (dd,
J = 17.6, 10.0 Hz, 1H), 4.30 (br s, 1H), 4.05 (br s, 1H), 2.18ꢀ2.12 (m, 2H), 1.32
(s, 3H), 1.29 (s, 3H), 1.26 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H), 0.81ꢀ0.77 (m, 1H).
9. (a) Lane, K. J.; Pinder, A. R. J. Org. Chem. 1982, 47, 3171; (b) Kaneda, K.; Ueno, S.;
Imanaka, T. Chem. Commun. (Cambridge, U.K.) 1994, 797.
10. Analytical data for the analogs 11a/11b, 12a/12b, 13a/13b, 14, 19a/19b, 20a/
20b. Compound 11a: ½a D28
ꢁ
+39.9 (c 0.87, CHCl3); 1H NMR (400 MHz, CDCl3): d
4.32ꢀ4.27 (m, 2H), 4.05 (br s, 1H), 3.10 (s, 1H), 2.21ꢀ2.17 (m, 1H), 2.16ꢀ2.12
(m, 1H), 2.06ꢀ2.00 (m, 1H), 1.39 (s, 3H), 1.29 (s, 3H), 1.21 (s, 3H), 1.12 (s, 3H),
1.08 (s, 3H), 1.03(s, 3H), 0.94 (s, 3H), 0.80ꢀ0.76 (m, 1H); 13C NMR (100 MHz,
CDCl3): d 113.7, 86.2, 79.8, 78.8, 67.7, 66.0, 65.4, 57.8, 56.7, 49.3, 47.4, 41.7,
41.6, 39.5, 35.9, 34.9, 33.8, 32.1, 31.2, 29.8, 28.4, 28.2, 27.5, 25.2, 24.1, 23.9,
23.8, 18.2, 13.6; HR-ESIMS calcd for C29H48O5Na [M+Na]+ 499.33940, found