Structural revisions of the reported A-ring phosphine oxide synthon for ED-71 (Eldecalcitol) and a new synthesis

Article abstract of DOI:10.1016/j.tet.2015.08.055

In a reported procedure for the synthesis of the ED-71 A-ring phosphine oxide, we discovered that unusual TBS transfer occurred from the 1α-position to the sterically more constrained 2β-position, and the subsequent Michael addition of ethyl acrylate predominated at the 1α-position. The X-ray analysis of a key intermediate confirmed our observations. We made a structural revision of the reported A-ring phosphine oxide synthon and ED-71. In addition, we provided the first stereoselective synthetic approach to ED-71 A-ring phosphine oxide applying the stereochemistry of d-mannitol.

Full text of DOI:10.1016/j.tet.2015.08.055

Tetrahedron 71 (2015) 8033e8040
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Structural revisions of the reported A-ring phosphine oxide synthon
for ED-71 (Eldecalcitol) and a new synthesis
*
Guo-Dong Zhao, Zhao-Peng Liu
Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University,
Jinan 250012, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 June 2015
Received in revised form 16 August 2015
Accepted 22 August 2015
Available online 24 August 2015
In a reported procedure for the synthesis of the ED-71 A-ring phosphine oxide, we discovered that
unusual TBS transfer occurred from the 1
a
-position to the sterically more constrained 2
b-position, and
the subsequent Michael addition of ethyl acrylate predominated at the 1
a
-position. The X-ray analysis of
a key intermediate confirmed our observations. We made a structural revision of the reported A-ring
phosphine oxide synthon and ED-71. In addition, we provided the first stereoselective synthetic ap-
proach to ED-71 A-ring phosphine oxide applying the stereochemistry of D-mannitol.
Keywords:
ED-71
Ó 2015 Elsevier Ltd. All rights reserved.
Eldecalcitol
A-ring phosphine oxide
TBS transfer
Michael addition
1a,25-Dihydroxyvitamin D3
1. Introduction
,25-Dihydroxyvitamin D3 [1,25(OH)2D3] is the hormonally
compared to the natural hormone.21e23 ED-71 is now used in the
name of Eldecalcitol in Japan for the treatment of patients with
osteoporosis.24,25
1
a
active form of vitamin D3. Apart from its classical roles on ho-
meostasis and bone metabolism, an entirely new facet of vitamin D
effects is increasingly being appreciated. As an important cell cycle
regulator, 1,25(OH)2D3 influences cell proliferation, differentiation
and apoptosis.1e5 The regulatory effects of vitamin D on both the
innate and adaptive immune responses may be a control point in
immunity to infection and chronic inflammatory diseases.6e10
These non-classical effects of vitamin D have now been recog-
ED-71 was prepared by the conventional linear steroidal ap-
proach from cholesterol or lithocholic acid,21,26 or by the conver-
gent Lythgoe27 or Trost28 coupling reactions of the CD-fragments
with the A ring synthons to build the conjugated triene system of
vitamin D3.29e33 The later approaches provide a versatile platform
for the preparation of diverse vitamin D analogs varying in the A-
ring, CD-ring, and/or side chains. As a continuous research for the
discovery of more selective 1,25(OH)2D3 derivatives, we are in-
terested in the construction of ED-71 related A-ring phosphine
nized as important components of vitamin
D physiology.
1,25(OH)2D3 and its derivatives have potential therapeutic appli-
cations for the treatment of hyperproliferative disorders (e.g.,
cancer and psoriasis), immune dysfunction, and endocrine dis-
orders.11e15 Therefore, extensive efforts have been made on the
structural modifications of the A-ring, C/D-rings, and/or the side
chain of 1,25(OH)2D3 to find more potent and selective vitamin D
analogs.16e20 The introduction of a 3-hydroxypropoxyl substituent
at the 2b-position of 1,25(OH)2D3 leads to the discovery of ED-71
that possesses higher binding affinity to the vitamin D-binding
protein and lower binding affinity to the vitamin D receptor (VDR)
oxide intermediates, applying the stereochemistry of D-mannitol.
2. Results and discussion
The known epoxide 1, which is readily available from D-man-
nitol,34 was reacted with the lithium acetylide, generated from
propargyl p-methoxybenzyl ether, in the presence of BF3 to give an
alcohol 2 in 61% yield (Scheme 1). Protection of the secondary
hydroxyl group by TBS ether formation and removal of the PMB
protective group with DDQ provided the propargylic alcohol 4 in
good yield. Hydroalumination of the acetylenic alcohol 4 with so-
dium bis(2-methoxyethoxy)aluminumhydride (Red-Al) and
quenching the resultant alkenyl-aluminum complex with iodine
gave the vinyl iodide 5 in 93% yield. We found that the addition of
* Corresponding author. E-mail address: liuzhaop@sdu.edu.cn (Z.-P. Liu).
http://dx.doi.org/10.1016/j.tet.2015.08.055
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

8034
G.-D. Zhao, Z.-P. Liu / Tetrahedron 71 (2015) 8033e8040
Scheme 1. A correction of the structure and former synthesis of the ‘A-ring phosphine oxide’ for ED-71.
alcohol 4 to Red-Al was crucial for the high yield conversion in this
step. Transformation of the vinyl iodide 5 to the exocyclic (Z)-diene
was achieved by Pd-catalyzed Heck cyclization. The structure of 6
was confirmed by comparison of its spectral data with that re-
ported for the same compound derived from the epoxide opening
of 1 with KCN followed by several transformations.32 Reaction of 6
with pivaloyl chloride in dichloromethane in the presence of pyr-
idine and DMAP gave the ester 7 in 98% yield. Treatment of 7 with
aqueous trifluoroacetic acid in dichloromethane followed by the
Reduction of diester 10 with LAH led to a diol 11, which can be
easily crystalized in n-heptane. X-ray analysis of 11 confirmed the
TBS migration. In a chair-like conformation, both the 1
hydroxypropoxy) and the 2 -t-butyldimethylsilyloxy substituents
occupy the less favored axial positions. The -hydroxyl group in 1
a-(3-
b
u
a-
position forms an intermolecular hydrogen bond with the allylic
oxygen, and the allylic oxygen also forms a hydrogen bond with the
1a
-(u
)-hydroxyl group in another molecule (Fig.1). These hydrogen
selective protection of the 1a-hydroxyl group as TBS ethers affor-
ded the secondary alcohol 933 in high yield.
A pivotal step in Takahashi’s synthesis of ED-71 A-ring phos-
phine oxide is the Michael addition of alcohol 9 with ethyl acrylate
in aqueous toluene under basic conditions.33 However, in TLC
monitoring the reaction process, we suspected that silyl migration
might occur, and the TBS group transferred from the less hindered
1a-position to the sterically more constrained 2b-position. Com-
parison of the data of the ED-71 A-ring phosphine oxide provided
by Takahashi33 with that reported by Kubodera30 indicated that
some chemical shifts in 1H and 13C NMR spectra were different, and
their specific rotations in chloroform solution were opposite (þ56.4
vs ꢀ16.3). In a parallel experiment without adding the ethyl acry-
late, a partially TBS migration was also observed. Silyl migrations
are well-known in carbohydrate and related chemistry.35,36
Therefore, under basic conditions, the 2b-hydroxyl group might
act as a nucleophile to attack on the silicon to form the five-
membered intermediate, and the subsequent Michael addition
occurs preferentially from the less sterically hindered trajectory
giving the migrated silyl ether 10 as the major product (Scheme 1).
In fact, this silyl migration can happen easily, whether it is a TBS or
a more basic stable triisopropylsilyl (TIPS) group, and even under
less basic (aq K2CO3) conditions.
Fig. 1. ORTEP drawing of the crystal structure of diol 11.
binding may compensate the high energies required for its ‘axial-
rich’ conformation.
Treatment of diol 11 with N-chlorosuccinimide (NCS) in the
presence of dimethyl sulfide selectively converted the allylic

G.-D. Zhao, Z.-P. Liu / Tetrahedron 71 (2015) 8033e8040
8035
hydroxyl group into the allylic chloride. After the protection of the
-primary hydroxyl group through TBS ether formation, the allylic
step, and the diastereomeric separation of the 1
a
-isomer from its
u
1b
-epimer (3/2).30 Our approach provided the first stereoselective
chloride was transformed into the A-ring phosphine oxide 12 in
78% yield (3 steps from 11) by treatment with lithium diphenyl-
phosphide and subsequent hydrogen peroxide oxidation. The
spectral data of 12 are identical with that wrongly assigned ‘ED-71
A-ring phosphine oxide’.33 In the 2D HMBC (heteronuclear multiple
bond correlation) spectra of 12, the C1eH at 3.61 ppm shows long-
range correlations with C2 (74.7), C3 (70.4), and the neighbouring
construction of the ED-71 A-ring phosphine oxide applying the
stereochemistry of -mannitol. In addition, the 2 -alcohol 16 may
facilate the synthesis of a variety of 2-substituted 1,25(OH)2D3
analogs.
D
b
The CD-ring ketone 22 was prepared by the reaction of the
sulfonate 20, which is readily derived from VD2,37 with 4-bromo-2-
methylbutan-2-yl methoxymethyl ether,38 followed by the Oxone/
TEMPO oxidation.39 Convergent Lythgoe coupling reaction of
phosphine oxide 19 with the Grundmann’s ketone 22, and the
subsequent removal the MOM protecting groups completed the
synthesis of ED-71 (Scheme 3). Its spectral data are completely
identical to that reported by Kubodera.31 In the HMBC spectra of 23,
C1eH at 4.30 ppm showed correlation with C2 (85.4), C10 (144.2),
C19 (111.8); the C2eH at 3.24 with C3 (66.5), C10 (144.2), and the
methylene (65.5) in the 1a-(3-tert-butyl dimethylsiloxy)propoxy
substituent, while the C6eH (dH 5.32) correlates with C4 (40.3), C7
(31.3), C10 (141.4), and the C19eH (dH 5.09) with C1 (84.7), C5
(141.1).
Since the Takahashi’s approach33 did not lead to the ED-71 A-
ring phosphine oxide, we applied a new hydroxyl protective
strategy by using the methoxymethyl (MOM) group that is more
stable to basic hydrolysis. Attempts have been made to protect the
neighbouring methylene (68.2) in the 2
stituent; the C3eH (dH 4.25) with C1 (71.5), C5 (132.1); the C6eH
dH 6.33) with C7 (117.2), C8 (142.9), C10 (144.2); the C7eH (dH 6.02)
b-(3-hydroxy)propxy sub-
2
b
-hydroxyl by acyl groups, however, in the following TBS depro-
tection step (TBAF/THF), the acyl group (acetyl; benzoyl; pivaloyl)
migration to both the 1 - and 3 -positions was observed. As shown
in Scheme 2, THP protective group became the choice. After the
THP protection of the 2 -hydroxyl group, the TBS groups were re-
(
a
b
with C5 (132.1); and the C19eH (dH 5.49, 5.07) with C5 (132.1), C10
(144.2).
b
In a similar way, coupling the A-ring fragment 12 with the CD-
ring ketone 22 followed by the deprotection of TBS and MOM
groups furnished the ED-71 isomer 24. Its spectral data are in
agreement with the wrongly assigned ‘ED-71’ by Takahashi’s
group.33 Long-range correlations between the following protons
and carbons were observed in compound 24 by HMBC: C1eH (dH
3.83) and C2 (74.7), C3 (70.1), C5 (135.4), C10 (144.1), the neigh-
moved by the treatment with TBAF. The resulting diol was reacted
with MOMCl in dichloromethane to generate ether 15. Treatment of
15 with acetic acid in aqueous/THF solutions could selectively
remove the THP protective group. The Michael addition of 2b-al-
cohol 16 with ethyl acrylate in aqueous toluene under basic con-
ditions went smoothly to yield the ester 17. The diester 17 was
converted to the ED-71 A-ring phosphine oxide 19 via the ester
reduction, conversion of the allylic alcohol to chloride, protection
bouring methylene (67.2) in the 1a-(3-hydroxy)propoxy sub-
stituent; C2eH (dH 3.79) and C3 (70.1), C10 (144.1); C6eH (dH 6.33)
and C7 (118.7), C8 (143.1), C10 (144.1); C7eH (dH 6.05) and C5
(135.4); C19eH (5.33, 5.10) and C1 (84.9), C5 (135.4), C10 (144.1).
the
u-primary hydroxyl by MOM group, reaction with lithium
diphenylphosphide and subsequent oxidation. Long-range corre-
lations between the following protons and carbons were found in
compound 19 by HMBC: C1eH (dH 4.18) and C2 (81.8), C3 (73.2), C5
(139.6), C10 (141.6), C19 (116.0); C2eH (dH 3.44) and C10 (141.6), the
3. Conclusion
neighbouring methylene (67.4) in the 2
propxy substituent; C3eH (dH 3.96) and C4 (38.3), C5 (139.6); C6eH
dH 5.40) and C7 (31.1), C10 (141.6); C19eH (dH 5.33, 5.11) and C5
b-(3-methoxymethoxy)
In conclusion, unusual TBS migration from the 1a-to the 2b-
position was identified in a reported procedure for the synthesis of
ED-71 A-ring phosphine oxide. Therefore, a revision of its structure
was made. We also developed a new synthetic route to the ED-71
(
(139.6), C10 (141.6).
Scheme 2. A new synthetic route to the ED-71 A-ring synthon.
Kubodera’s group reported a correct synthesis of the ED-71 A-
ring phosphine oxide from a known C2-symmetrical epoxide via
several steps, including the regiospecific ring openging of epoxide
A-ring fragment by the careful selection of the proper hydroxyl
protective groups. Finally, ED-71 and its analog were prepared very
efficiently by the convergent Lythgoe approach. The application of
our discovery in the preparation of various ED-71 analogs with
to introduce the 2b-(3-hydroxypropoxy) substituent at the first

8036
G.-D. Zhao, Z.-P. Liu / Tetrahedron 71 (2015) 8033e8040
Scheme 3. Synthesis of ED-71 and its 1a-isomer.
modifications both in the A-ring and the vitamin D side chain are in
(s, 6H); 13C NMR (150 MHz, CDCl3)
d 159.3, 136.2, 129.7, 129.4, 118.4,
progress.
113.8, 109.3, 82.1, 81.7, 78.92, 78.89, 71.1, 70.1, 57.2, 55.2, 26.9, 23.9;
HRMS (ESI) m/z calcd for C20H26O5 [MþNa]þ 369.1672, found
369.1667.
4. Experimental section
4.1. General information
4.2.2. [3R-(3a,4b,5b)]-5-(tert-Butyldimethylsilyloxy)-3,4-
isopropylidenedioxy-9-(p-methoxyphenylmethoxy)non-1-en-7-yne
(3). A mixture of alcohol 2 (490 mg,1.41 mmol), imidazole (340 mg,
4.99 mmol) and TBSCl (610 mg, 4.05 mmol) in DCM (3 mL) was
stirred at rt for 24 h. The reaction was quenched by the addition of
the saturated NaHCO3 aqueous solution, and the whole was
extracted with DCM. The organic layer was washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by silica gel column chromatography
(hexane/EtOAc, 50:1) to give compound 3 (589 mg, 90%) as a col-
1H, 13C NMR spectra and 2D HMBC were recorded on Bruker-400
or Bruker-600 NMR spectrometers. 1H spectra were recorded rel-
ative to CDCl3 (7.26 ppm) or TMS (0.00 ppm) as internal standard,
and 13C NMR spectra were recorded relative to CDCl3 (77.0 ppm).
High resolution mass spectra (HRMS) were performed on Agilent
6520 QTOF instrument by electrospray ionization (ESI). Optical
rotations were recorded on a JASCO DIP-370 digital polarimeter.
Ultra violet (UV) spectra were performed on TU-1901 spectropho-
tometer (Purkinje General Co., Ltd). Melting points were de-
termined on X-6 micro-melting point apparatus (Beijing Tech. Co.,
Ltd) without correction. Column chromatography was performed
on silica gel (200e300 mesh). All experiments were performed
under a dry N2 atmosphere, unless otherwise noted. THF and tol-
uene were distilled from sodium, and DCM was distilled from CaH2
before use.
orless oil. 1H NMR (400 MHz, CDCl3)
d 7.26e7.29 (m, 2H), 6.86e6.89
(m, 2H), 5.88 (ddd, J¼6.8, 10.4, 17.2 Hz, 1H), 5.39 (dt, J¼1.2, 17.2 Hz,
1H), 5.22 (d, J¼1.2, 10.4 Hz, 1H), 4.51 (s, 2H), 4.45e4.48 (t, J¼7.2 Hz,
1H), 4.12e4.13 (t, J¼2.4 Hz, 2H), 3.97e4.02 (m, 2H), 3.81 (s, 3H),
2.41e2.54 (m, 2H), 1.42 (s, 3H), 1.41 (s, 3H), 0.91 (s, 9H), 0.12 (s, 3H),
0.11 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 159.4,136.9,129.71,129.67,
118.0, 113.8, 108.9, 83.0, 82.0, 78.3, 78.2, 71.0, 70.8, 57.3, 55.3, 27.1,
27.0, 25.9, 24.8, 18.1, e4.4, e4.5; HRMS (ESI) m/z calcd for
4.2. Detailed procedure
C
26H40O5Si [MþNa]þ 483.2537, found 483.2536.
4.2.1. [3R-(3
yphenylmethoxy)non-1-en-7-yn-5-ol (2). To
a
,4
b
,5
b
)]-3,4-Isopropylidenedioxy-9-(p-methox-
solution of p-
4.2.3. [7R-(5b,6b,7a)]-5-(tert-Butyldimethylsilyloxy)-6,7-
a
isopropylidenedioxynon-8-en-2-yn-1-ol (4). A solution of com-
pound 3 (182 mg, 0.395 mmol), H2O (0.2 mL) and DDQ (134 mg,
0.59 mmol) in DCM (2 mL) was stirred at 0 ꢁC for 14 h. The reaction
was diluted with DCM and filtered through Celite. The organic layer
was washed with brine, dried over anhydrous Na2SO4, filtered, and
evaporated in vacuo. The residue was purified by silica gel column
chromatography (hexane/EtOAc,10:1) to give compound 4 (121 mg,
methoxybenzyl 2-propynyl ether (16.8 g, 95.3 mmol) in THF
(60 mL) was added n-BuLi (2.5 M solution in n-hexane, 38.0 mL,
95.0 mmol) at ꢀ78 ꢁC under nitrogen, and the mixture was stirred
for another 20 min. BF3$OEt2 (12.0 mL, 97.2 mmol) and a solution of
compound 1 (3.10 g, 18.2 mmol) in THF (10 mL) were added suc-
cessively at the same temperature, and the mixture was stirred for
another 4 h. The reaction was quenched by the addition of the
saturated NaHCO3 aqueous solution, and the whole was extracted
with ethyl acetate. The organic layer was washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (hexane/
EtOAc, 10:1) to give alcohol 2 (3.84 g, 61%) as a light yellow oil. 1H
90%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
d
5.87 (ddd, J¼6.8,
10.4, 17.2 Hz, 1H), 5.38 (dt, J¼1.2, 17.2 Hz, 1H), 5.23 (dt, J¼1.2,
10.4 Hz, 1H), 4.43 (t, J¼6.8 Hz, 1H), 4.25 (t, J¼2.0 Hz, 1H), 4.23 (t,
J¼2.0 Hz, 1H), 3.91e4.00 (m, 2H), 2.43e2.47 (m, 2H), 1.42 (s, 3H),
1.41 (s, 3H), 0.91 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d 136.8, 118.1, 109.0, 82.6, 82.0, 80.5, 78.2, 70.7,
NMR (600 MHz, CDCl3)
d
7.26 (d, J¼8.8 Hz, 2H), 6.87 (d, J¼8.8 Hz,
51.4, 27.1, 27.0, 25.8, 24.7, 18.1, e4.4, e4.5; HRMS (ESI) m/z calcd for
C
2H), 5.88 (ddd, J¼6.8, 10.4, 17.2 Hz, 1H), 5.42 (d, J¼17.2 Hz, 1H), 5.25
(d, J¼10.4 Hz, 1H), 4.51 (s, 2H), 4.44 (t, J¼7.6 Hz, 1H), 4.14 (d,
J¼2.0 Hz, 1H), 4.13 (d, J¼2.0 Hz, 1H), 3.90e3.96 (m, 1H), 3.83e3.85
(m, 1H), 3.80 (s, 3H), 2.54e2.57 (m, 2H), 2.24 (d, J¼4.4 Hz, 1H) 1.43
18H32O4Si [MþNa]þ 363.1962, found 363.1965.
4.2.4. [7R-(Z,5
b,6b,7a)]-5-(tert-Butyldimethylsilyloxy)-6,7-
isopropylidenedioxy-3-iodonon-2,8-dien-1-ol (5). To a solution of

G.-D. Zhao, Z.-P. Liu / Tetrahedron 71 (2015) 8033e8040
8037
Red-Al (3.6 M solution in toluene, 6.80 mL, 24.5 mmol) in THF
(6.5 mL) was added compound 4 (2.48 g, 7.28 mmol) in THF
(13.5 mL) dropwise at 0 ꢁC. The mixture was stirred at 0 ꢁC for 3 h,
quenched by ethyl acetate (2.48 mL, 25.2 mmol) and cooled to
ꢀ50 ꢁC. Then a solution of iodine (4.87 g, 19.2 mmol) in THF
(6.8 mL) was added dropwise, and the suspension was stirred for
another 3 h. The reaction was quenched by the addition of the
saturated Na2S2O3 and NaHCO3 aqueous solution, and the whole
was extracted with ethyl acetate. The organic layer was washed
with brine, dried over anhydrous Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel column chroma-
tography (hexane/EtOAc, 15:1) to give compound 5 (3.16 g, 93%) as
solution (14 mL) were added and vigorously stirred at rt for 16.5 h.
The mixture was partitioned between water and ethyl acetate. The
organic layer was washed with brine, dried over anhydrous Na2SO4,
filtered, and evaporated in vacuo. The residue was purified by silica
gel column chromatography (hexane/DCM, 1:1) to give compound
10 (608 mg, 81%) as a colorless oil. The 1H NMR spectral data are in
agreement with that reported for the wrongly stated ‘2b-’
derivative.33
4.2.10. [3R-(1Z,3
(3-hydroxypropoxy)-2-methylenecyclohexylidene]ethanol
a
,4
b
,5
b
)]-2-[4,5-Bis(tert-butyldimethylsilyloxy)-3-
(11). To
a solution of diester 10 (14.2 mg, 0.0237 mmol) in THF (0.5 mL) was
added LAH (6.50 mg, 0.171 mmol) at 0 ꢁC under nitrogen, and the
mixture was stirred for 1.5 h. The reaction was quenched by the
addition of diluted HCl (0.2 mol/L, 10 mL) aqueous solution, and the
whole was extracted by ethyl acetate. The organic layer was washed
with saturated NaHCO3 aqueous solution and brine, dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (hexane/EtOAc,
1:1) to give diol 11 (8.60 mg, 77%) as white crystal. Mp 96e98 ꢁC;
the 1H NMR spectral data are identical with that reported for the
a colorless oil. 1H NMR (400 MHz, CDCl3)
d
5.89 (t, J¼5.6 Hz, 1H),
5.81 (ddd, J¼7.6, 10.4, 17.6 Hz, 1H), 5.41 (dt, J¼1.2, 17.2 Hz, 1H), 5.28
(d, J¼10.0 Hz,1H), 4.37 (t, J¼8.0 Hz,1H), 4.16e4.20 (m, 3H), 3.77 (dd,
J¼2.0, 8.4 Hz, 1H), 2.63e2.72 (m, 2H), 1.43 (s, 3H), 1.40 (s, 3H), 0.89
(s, 9H), 0.11 (br s, 3H), 0.08 (br s, 3H); 13C NMR (100 MHz, CDCl3)
d
137.2, 136.6, 119.2, 109.0, 105.5, 82.8, 77.8, 69.6, 67.3, 49.4, 27.0,
26.9, 26.0, 18.1, e4.0, e4.1; HRMS (ESI) m/z calcd for C18H33O4SiI
[MþNa]þ 491.1085, found 491.1081.
4.2.5. [3R-(1Z,3
a
,4
b
,5
b
)]-2-(5-tert-Butyldimethylsilyloxy-3,4-
wrongly stated ‘2
b
-’ derivative (43) in Ref. 33.
isopropylidenedioxy-2-methylenecyclohexylidene)ethanol (6). A so-
lution of compound 5 (3.88 g, 8.28 mmol), PdCl2(PPh3)2 (378 mg,
0.54 mmol) and Et3N (6.5 mL, 46.6 mmol) in MeCN (130 mL) was
refluxed for 4 h. The mixture was evaporated and diluted with ethyl
acetate. The organic layer was washed with brine, dried over an-
hydrous Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (hexane/EtOAc,
10:1) to give compound 6 (2.67 g, 95%) as a light yellow oil. The 1H
NMR spectral data are identical with that reported by Takahashi’
group.32
4.2.11. [3R-(1Z,3
a
,4 ,5 )]-[2-[4,5-Bis(tert-butyldimethylsilyloxy)-3-
b b
[ 3 - ( t e r t - b u t y l d i m e t h y l s i l y l o x y ) p r o p o x y ] - 2 -
methylenecyclohexylidene]ethyl] diphenylphosphine oxide (12). A
solution of NCS (219 mg, 1.64 mmol) and dimethyl sulfide (270 mL,
3.69 mmol) in DCM (4.5 mL) was stirred at 0 ꢁC for 25 min. Then
compound 11 (125 mg, 0.264 mmol) in DCM (2.5 mL) was added
dropwise, and the mixture was stirred at 0 ꢁC for 1 h. The whole
was quenched by the addition of the saturated NaHCO3 aqueous
solution, and the whole was extracted with ethyl acetate. The or-
ganic layer was washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo to give the unstable crude allyl
chloride, which was used for the next step without purification.
A solution of the above allyl chloride (0.264 mmol), imidazole
(77.5 mg, 1.14 mmol) and TBSCl (117 mg, 0.776 mmol) in DCM
(2 mL) was stirred at 0 ꢁC for 1 h. The reaction was quenched by the
addition of the saturated NaHCO3 aqueous solution, and the whole
was extracted with DCM. The organic layer was washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
The residue was purified (less than 10 min) by flash silica gel col-
umn chromatography (hexane/EtOAc, 50:1) to give the unstable
crude compound as a light yellow oil, which was put into the next
step without purification.
4.2.6. [3R-(1Z,3a,4b,5b)]-2-(5-tert-Butyldimethylsilyloxy-3,4-
isopropylidenedioxy-2-methylenecyclohexylidene)ethyl trimethylace-
tate (7). This compound was obtained in a yield of 98% according to
a similar reported procedure33 by the use of alcohol 6 (102 mg,
0.30 mmol), pyridine (320 mL, 3.96 mmol), PivCl (160 mL,1.30 mmol)
and DMAP (4.0 mg, 0.0327 mmol) in DCM (1 mL). The 1H NMR
spectral data are identical with that reported by Takahashi’ group.33
4.2.7. [3R-(1Z,3
dihydroxy-2-methylenecyclohexylidene)ethyl trimethylacetate (8). A
suspension of H2O (400 L), CF3CO2H (800 L) and compound 7
a,4b,5b)]-2-(5-tert-Butyldimethylsilyloxy-3,4-
m
m
(1.17 g, 2.76 mmol) in DCM (20.8 mL) was stirred at ꢀ10 ꢁC for 1 h.
The reaction was quenched by the addition of the saturated
NaHCO3 aqueous solution, and the whole was extracted with DCM.
The organic layer was washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by silica gel column chromatography (hexane/EtOAc, 3:1) to
give compound 8 (1.0 g, 94%) as a colorless oil. The 1H NMR spectral
data are identical with that reported by Takahashi’ group.33
To a solution of the above compound (0.264 mmol) and
diphenylphosphine (300 mL, 1.72 mmol) in DCM (1 mL) was added
LHMDS (1.80 mL, 1 mol/L in THF, 1.80 mmol) at ꢀ78 ꢁC under ni-
trogen, and the mixture was allowed to warm to rt gradually for 5 h.
Then water (1.5 mL) and H2O2 (6.5 mL, 30% in water) were added
successively, and the mixture was stirred at rt for another 2 h. The
reaction was quenched by the addition of the saturated Na2SO3
aqueous solution, and the whole was extracted with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by silica gel column chromatography (hexane/EtOAc, 5:1) to
give compound 12 (160 mg, 78% for three steps) as a colorless oil.
The 1H NMR spectral data are identical with that reported for the
4.2.8. [3R-(1Z,3
hydroxy-2-methylenecyclohexylidene]ethyl
a
,4
b
,5
b
)]-2-[3,5-Bis(tert-butyldimethylsilyloxy)-4-
trimethylacetate
(9). This compound was obtained in a yield of 98% according to
a similar procedure33 by the use of alcohol 8 (427 mg, 1.11 mmol),
imidazole (333 mg, 4.89 mmol) and TBSCl (528 mg, 3.50 mmol) in
DCM (3 mL). The 1H NMR spectral data are identical with that re-
ported by Takahashi’ group.33
wrongly stated ‘2
b
-’ derivative (44) in Ref. 33.
4.2.12. [3R-(1Z,3
a
,4b,5b)]-2-[3,5-Bis(tert-butyldimethylsilyloxy)-4-
4.2.9. [3R-(1Z,3
(ethoxycarbonyl)ethoxy]-2-methylenecyclohexylidene]ethyl
thylacetate (10). Compound 9 (626 mg, 1.25 mmol) was dissolved
in toluene (38 mL). Ethyl acrylate (3.40 mL, 31.3 mmol), 25%
Me4NOH aqueous solution (0.9 mL) and 50% NaOH aqueous
a
,4
b
,5
b
)]-2-[4,5-Bis(tert-butyldimethylsilyloxy)-3-[2-
trime-
(2-tetrahydropyranyloxy)-2-methylenecyclohexylidene]ethyl trime-
thylacetate (13). A mixture of compound 9 (500 mg, 1.0 mmol),
DHP (848 mg, 10.1 mmol) and PPTS (47.0 mg, 0.187 mmol) in DCM
(3 mL) was stirred at rt for 36 h. The reaction was quenched by the
addition of the saturated NaHCO3 aqueous solution, and the whole

8038
G.-D. Zhao, Z.-P. Liu / Tetrahedron 71 (2015) 8033e8040
was extracted with DCM. The organic layer was washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by silica gel column chromatography
(hexane/EtOAc, 50:1) to give compound 13 (566 mg, 97%) as a col-
(12 mL) and THF (6 mL) was stirred at 40 ꢁC for 14 h. The reaction
was quenched by the addition of the NaOH aqueous solution
(2.6 mol/L,150 mL), and the whole was extracted with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by silica gel column chromatography (hexane/EtOAc, 3:1) to
give compound 16 (279 mg, 93%) as a colorless oil. 1H NMR
orless oil. 1H NMR (400 MHz, CDCl3)
d
5.49 (t, J¼7.2 Hz, 1H), 5.25 (br
s, 1H), 4.93 (d, J¼1.2 Hz, 1H), 4.89 (t, J¼3.2 Hz, 1H), 4.59 (d, J¼7.2 Hz,
2H), 4.27 (d, J¼5.2 Hz, 1H), 4.21e4.24 (m, 1H), 3.91e3.97 (m, 1H),
3.72 (d, J¼3.6 Hz, 1H), 3.46e3.50 (m, 1H), 2.50 (t, J¼10.8 Hz, 1H),
2.19 (dd, J¼4.0, 12.8 Hz, 1H), 1.41e1.87 (m, 6H), 1.19 (s, 9H), 0.88 (s,
9H), 0.86 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H);
(400 MHz, CDCl3)
d
5.57 (t, J¼7.2 Hz, 1H), 5.41 (br s, 1H), 5.09 (br s,
1H), 4.62e4.75 (m, 6H), 4.21 (d, J¼6.0 Hz, 1H), 4.05e4.07 (m, 1H),
3.86 (d, J¼3.2 Hz, 1H), 3.41 (s, 6H), 2.58 (dd, J¼7.6, 13.6 Hz, 1H), 2.39
13C NMR (100 MHz, CDCl3)
d
178.5, 144.2, 141.1, 121.7, 115.4, 98.6,
(d, J¼13.2 Hz, 1H), 1.20 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d 178.3,
79.3, 75.2, 68.7, 62.3, 61.8, 40.4, 38.6, 30.5, 27.2, 25.8, 25.7, 25.6, 19.5,
18.1, e4.6, e4.8, e4.86, e4.88; HRMS (ESI) m/z calcd for C31H58O6Si2
[MþNa]þ 605.3664, found 605.3668.
140.9, 139.7, 123.0, 116.7, 96.1, 95.2, 79.5, 75.6, 73.2, 61.4, 55.7, 55.6,
38.6, 37.5, 27.2; HRMS (ESI) m/z calcd for C18H30O7 [MþNa]þ
381.1884, found 381.1884.
4 . 2 .13 . [ 3 R - ( 1 Z , 3
a
, 4
b
, 5
b
) ] - 2 - [ 3 , 5 - D i h y d r o x y - 4 - ( 2 -
4.2.16. [3R-(1Z,3a,4b,5b)]-2-[4-[2-(Ethoxycarbonyl)ethoxy]-3,5-
tetrahydropyranyloxy)-2-methylenecyclohexylidene]ethyl trimethy-
lacetate (14). A mixture of compound 13 (566 mg, 0.971 mmol) and
TBAF (2.73 g, 10.4 mmol) in THF (11 mL) was stirred at 70 ꢁC for 5 h.
The reaction was quenched by the addition of the saturated
NaHCO3 aqueous solution, and the whole was extracted with ethyl
acetate. The organic layer was washed with brine, dried over an-
hydrous Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (hexane/EtOAc,
50:1) to give compound 14 (314 mg, 91%) as a white solid. 1H NMR
bis(methoxymethoxy)-2-methylenecyclohexylidene]ethyl trimethyla-
cetate (17). A mixture of compound 16 (94.0 mg, 0.262 mmol),
ethyl acrylate (300 mL, 2.76 mmol), Me4NOH (25% in H2O, 0.08 mL)
and NaOH (50% in H2O, 0.6 mL) in toluene (1.5 mL) was stirred
vigorously at rt for 20 h. The suspension was partitioned between
water and EtOAc. The organic layer was washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (hexane/
EtOAc, 4:1) to give compound 17 (97.2 mg, 81%) as a colorless oil. 1H
(400 MHz, CDCl3)
d
5.50e5.65 (m, 1H), 5.52 (br s, 1Hꢂ6/11), 5.38 (br
NMR (400 MHz, CDCl3)
d
5.54 (t, J¼7.2 Hz, 1H), 5.34 (br s, 1H), 5.06
s, 1Hꢂ5/11), 5.00 (br s, 1Hꢂ6/11), 4.95 (br s, 1Hꢂ5/11), 4.81 (dd,
J¼8.4, 12.4 Hz, 1Hꢂ5/11), 4.62e4.65 (m, 2H), 4.42 (dd, J¼6.0,
12.0 Hz, 1Hꢂ6/11), 4.31 (d, J¼7.6 Hz, 1Hꢂ6/11), 4.28 (d, J¼6.8 Hz,
1Hꢂ5/11), 4.14 (br s,1H), 4.02 (d, J¼11.6 Hz,1Hꢂ6/11), 3.95e3.98 (d,
J¼10.8 Hz, 1Hꢂ5/11), 3.71 (dd, J¼2.8, 6.4 Hz, 1Hꢂ6/11), 3.49e3.58
(m, 1H), 3.29 (d, J¼6.0 Hz, 1Hꢂ5/11), 2.45e2.53 (m, 1H), 2.39 (br s,
1H), 1.72e1.93 (m, 2H), 1.42e1.62 (m, 4H), 1.17 (s, 9Hꢂ6/11), 1.16 (s,
(d, J¼1.2 Hz, 1H), 4.55e4.72 (m, 6H), 4.25 (d, J¼5.6 Hz, 1H), 4.10 (q,
J¼7.2 Hz, 2H), 4.03e4.06 (m, 1H), 3.85e3.93 (m, 2H), 3.61 (dd,
J¼2.4, 5.6 Hz, 1H), 3.38 (s, 3H), 3.36 (s, 3H), 2.56e2.64 (m, 3H), 2.32
(dd, J¼4.0, 13.2 Hz, 1H), 1.22 (t, J¼7.2 Hz, 3H), 1.18 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 178.4, 171.5, 140.9, 139.9, 122.8, 117.6, 95.7, 94.8,
81.0, 77.3, 73.8, 66.4, 61.5, 60.4, 55.7, 55.4, 38.6, 37.5, 35.5, 27.2, 14.2;
HRMS (ESI) m/z calcd for C23H38O9 [MþNa]þ 481.2408, found
481.2408.
9Hꢂ5/11); 13C NMR (100 MHz, CDCl3)
d 178.8, 178.5, 143.2, 143.1,
140.4, 139.7, 123.2, 122.6, 114.6, 112.9, 101.6, 100.6, 85.3, 83.7, 73.1,
70.9, 68.7, 68.1, 64.93, 64.88, 61.6, 61.5, 40.0, 39.8, 38.70, 38.65, 31.5,
31.3, 27.2, 27.1, 25.0, 24.9, 21.0, 20.8; HRMS (ESI) m/z calcd for
4.2.17. [3R-(1Z,3a,4b,5b)]-2-[4-(3-Hydroxypropoxy)-3,5-bis-(me-
thoxymethoxy)-2-methylenecyclohexylidene]ethanol (18). To a solu-
tion of compound 17 (674 mg,1.47 mmol) in THF (15 mL) was added
LAH (162 mg, 4.26 mmol) in portions, and the mixture was stirred
at 0 ꢁC for 30 min. The reaction was quenched by the addition of
cold water, and the whole was extracted by ethyl acetate. The or-
ganic layer was washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (EtOAc) to give compound 18
C
19H30O6 [MþNa]þ 377.1935, found 377.1939.
4.2.14. [3R-(1Z,3a,4b,5b)]-2-[4-(2-Tetrahydropyranyloxy)-3,5-
bis(methoxymethoxy)-2-methylenecyclohexylidene]ethyl trimethyla-
cetate (15). A mixture of compound 14 (389 mg, 1.10 mmol), DIPEA
(4.40 mL, 26.6 mmol) and MOMCl (1.68 mL, 22.1 mmol) in DCM
(3 mL) was refluxed for 6 h. The reaction was quenched by the
addition of diluted HCl aqueous solution (0.2 mol/L, 10 mL), and the
whole was extracted with DCM. The organic layer was washed with
saturated NaHCO3 aqueous solution and brine, dried over anhy-
drous Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by silica gel column chromatography (hexane/EtOAc, 50:1)
to give compound 15 (401 mg, 83%) as a colorless oil. 1H NMR
(480 mg, 98%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
d 5.63 (t,
J¼6.0 Hz, 1H), 5.32 (br s, 1H), 5.04 (br s, 1H), 4.71 (br s, 2H), 4.64 (d,
J¼6.4 Hz, 1H), 4.56 (d, J¼6.0 Hz, 1H), 4.24e4.29 (m, 2H), 4.06e4.15
(m, 2H), 3.67e3.85 (m, 5H), 3.39 (s, 3H), 3.36 (s, 3H), 2.56 (t,
J¼11.2 Hz, 1H), 2.37 (d, J¼12.8 Hz, 1H), 1.81 (br s, 2H); 13C NMR
(100 MHz, CDCl3)
d 140.8, 137.0, 128.2, 118.3, 95.5, 94.4, 80.4, 77.4,
(400 MHz, CDCl3)
d
5.51e5.59 (m, 1H), 5.37 (br s, 1Hꢂ2/5), 5.33 (br
73.8, 70.1, 61.7, 59.4, 55.7, 55.5, 37.3, 32.1; HRMS (ESI) m/z calcd for
C
s, 1Hꢂ3/5), 5.10 (d, J¼1.2 Hz, 1Hꢂ2/5), 5.03 (br s, 1Hꢂ3/5),
4.87e4.92 (m, 1H), 4.80e4.81 (m, 1H), 4.56e4.72 (m, 5H),
4.26e4.29 (m, 1H), 3.85e4.12 (m, 3H), 3.43e3.54 (m, 1H), 3.38 (br s,
3Hꢂ3/5), 3.37 (br s, 3Hꢂ3/5), 3.36 (br s, 3Hꢂ2/5), 3.34 (br s, 3Hꢂ2/
5), 2.61e2.67 (m, 1H), 2.37 (br s, 1Hꢂ3/5), 2.34 (br s, 1Hꢂ2/5),
16H28O7 [MþNa]þ 355.1727, found 355.1720.
4.2.18. [3R-(1Z,3a,4b,5b)]-[2-[3,5-Bis(methoxymethoxy)-4-[3-(me-
thoxymethoxy)propoxy]-2-methylenecyclohexylidene]ethyl] diphe-
nylphosphine oxide (19). A solution of NCS (202 mg, 1.51 mmol) and
dimethyl sulfide (160 mL, 2.19 mmol) in DCM (8 mL) was stirred at
1.48e1.88 (m, 6H), 1.18 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
178.3,
141.9, 140.8, 140.3, 140.1, 122.7, 122.6, 118.3, 115.9, 98.6, 98.5, 95.6,
95.5, 95.4, 94.5, 93.6, 78.5, 77.4, 76.5, 74.2, 73.5, 62.2, 62.1, 61.5, 55.9,
55.6, 55.43, 55.42, 38.6, 38.2, 37.3, 30.9, 30.6, 27.2, 25.5, 25.4, 19.4,
19.2; HRMS (ESI) m/z calcd for C23H38O8 [MþNa]þ 465.2459, found
465.2461.
0 ꢁC for 20 min. Then compound 18 (158 mg, 0.475 mmol) in DCM
(3 mL) was added dropwise, and the mixture was stirred at 0 ꢁC for
30 min. The reaction was quenched by the addition of cold water,
and the whole was extracted by DCM. The organic layer was
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo to give the unstable crude allyl chloride,
which was used for the next reaction without purification.
4.2.15. [3R-(1Z,3a,4b,5b)]-2-[4-Hydroxy-3,5-bis(methoxymethoxy)-
2-methylenecyclohexylidene]ethyl trimethylacetate (16). A mixture
of compound 15 (369 mg, 0.834 mmol) in water (3 mL), AcOH
A mixture of the above allyl chloride (0.475 mmol), DIPEA
(470
mL, 2.84 mmol) and MOMCl (180 mL, 2.37 mmol) in DCM

G.-D. Zhao, Z.-P. Liu / Tetrahedron 71 (2015) 8033e8040
8039
(1.5 mL) was stirred at rt for 3 h. The reaction was quenched by the
addition of diluted HCl (0.2 mol/L, 2.5 mL) aqueous solution, and
the whole was extracted by DCM. The organic layer was washed
with saturated NaHCO3 aqueous solution and brine, dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue
was purified (less than 10 min) by flash silica gel column chroma-
tography (hexane/EtOAc, 3:1) to give the unstable crude compound
as a light yellow oil, which was put into the next step immediately.
To a solution of the above compound (0.475 mmol) and diphe-
0.125 mmol) dropwise, and the mixture was stirred for another
10 min. A solution of compound 22 (24.0 mg, 0.074 mmol) in THF
(0.5 mL) was added, and the mixture was stirred for another 4 h.
The reaction was quenched by the addition of cold water, and the
whole was extracted by ethyl acetate. The organic layer was washed
with brine, dried over anhydrous Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel column chroma-
tography (hexane/EtOAc, 3:1) to give the protected ED-71 (30 mg,
61%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
d 6.32 (d,
nylphosphine (210
m
L,1.21 mmol) in DCM (2 mL) was added LHMDS
J¼11.2 Hz, 1H), 5.99 (d, J¼11.2 Hz, 1H), 5.37 (br s, 1H), 5.17 (br s, 1H),
4.70e4.74 (m, 5H), 4.58e4.60 (m, 3H), 4.26 (d, J¼5.6 Hz, 1H),
4.06e4.08 (m, 1H), 3.66e3.73 (m, 2H), 3.59e3.62 (m, 3H), 3.39 (s,
3H), 3.38 (s, 3H), 3.36 (s, 3H), 3.35 (s, 3H), 2.80 (d, J¼12.4 Hz, 1H),
2.62e2.68 (m, 1H), 2.34 (dd, J¼3.2, 12.8 Hz, 1H), 1.90e2.00 (m, 2H),
1.85e1.89 (m, 3H), 1.60e1.70 (m, 3H), 0.98e1.53 (m, 12H), 1.21 (s,
6H), 0.91 (d, J¼6.0 Hz, 3H), 0.51 (s, 3H); 13C NMR (100 MHz, CDCl3)
(1.20 mL, 1 mol/L in THF, 1.20 mmol) at ꢀ78 ꢁC under nitrogen, and
the mixture was allowed to warm to room temperature gradually
for 3 h. Then water (0.5 mL) and H2O2 (10 mL, 30% in water) were
added successively, and the mixture was stirred at rt for another
13 h. The reaction was quenched by the addition of saturated
Na2SO3 aqueous solution, and the whole was extracted by DCM.
The organic layer was washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by silica gel column chromatography (EtOAc/MeOH, 20:1) to
give compound 19 (206 mg, 77% for three steps) as a colorless oil. 1H
d
142.7, 141.7, 133.0, 124.1, 117.8, 117.2, 96.5, 95.5, 94.4, 91.0, 80.7,
76.4, 74.1, 67.4, 64.8, 56.6, 56.3, 55.6, 55.4, 55.12, 55.07, 45.9, 42.3,
40.5, 38.1, 36.4, 36.1, 30.5, 29.0, 27.7, 26.4, 26.3, 23.5, 22.2, 20.5, 18.8,
11.9; HRMS (ESI) m/z calcd for C38H66O9 [MþNa]þ 689.4599, found
689.4600.
NMR (400 MHz, CDCl3) d 7.67e7.73 (m, 4H), 7.44e7.52 (m, 6H), 5.40
(dd, J¼7.2, 15.2 Hz, 1H), 5.33 (br s, 1H), 5.11 (br s, 1H), 4.56e4.80 (m,
6H), 4.18 (d, J¼6.8 Hz, 1H), 3.96e3.99 (m, 1H), 3.56e3.70 (m, 4H),
3.13e3.46 (m, 3H), 3.36 (s, 3H), 3.32 (s, 3H), 3.28 (s, 3H), 2.49e2.54
(m, 1H), 2.21 (d, J¼13.2 Hz, 1H), 1.81e1.85 (m, 2H); 13C NMR
To a stirred solution of the protected ED-71 (200 mg, 0.30 mmol)
in methanol (10 mL), CSA (718 mg, 3.09 mmol) was added. The
mixture was stirred at rt for 66 h. The reaction was quenched by the
addition of saturated NaHCO3 aqueous solution, and the whole was
extracted by ethyl acetate. The organic layer was washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel column chromatog-
raphy (DCM/MeOH, 30:1) to give compound ED-71 (100 mg, 68%)
as a light yellow foam. Mp 126e128 ꢁC; 13C NMR (100 MHz, CDCl3)
(100 MHz, CDCl3)
d
141.6, 139.6, 139.5, 133.0 (d, JC,P¼40.0 Hz), 132.1
(d, JC,P¼40.0 Hz), 131.72, 131.70, 131.0, 130.94, 130.91, 130.85, 128.6,
128.5, 116.3, 116.2, 116.0, 96.4, 95.4, 95.3, 81.8, 77.3, 73.2, 67.4, 64.7,
55.7, 55.3, 55.1, 38.3, 31.1 (d, JC,P¼70.0 Hz), 30.4; HRMS (ESI) m/z
calcd for C30H41O8P [MþH]þ 561.2612, found 561.2619.
d
144.2, 142.9, 132.1, 124.9, 117.2, 111.8, 85.4, 71.5, 71.1, 68.2, 66.5,
4.2.19. (1R,2S,6R,7R)-7-[(R)-6-(Methoxymethoxy)-6-methylheptan-
61.1, 56.5, 56.4, 45.9, 44.4, 40.5, 36.4, 36.1, 31.8, 29.3, 29.2, 29.1, 27.6,
2-yl]-6-methylbicyclo[4.3.0]nonan-2-ol (21). To stirred magnesium
23.7, 22.3, 20.8, 18.8, 11.9; UV (EtOH)
l
¼264 nm; HRMS (ESI) m/z
turnings (470 mg, 19.3 mmol),
a
solution of 4-bromo-2-
calcd for C30H50O5 [MþNa]þ 513.3550, found 513.3549. The 1H NMR
spectral data are identical with that reported by Kubodera’s
group.31
methylbutan-2-yl methoxymethyl ether (1.60 g, 7.58 mmol) in
THF (6 mL) was added dropwise at rt under nitrogen, and the
mixture was stirred for 1 h. The resulting Grignard reagent was
added to a suspension of compound 20 (110 mg, 0.30 mmol) and
CuBrꢃMe2S (62.0 mg, 0.302 mmol) in THF (3 mL) at ꢀ20 ꢁC, and the
mixture was stirred at 0 ꢁC for 18 h. The reaction was quenched by
the addition of diluted aqueous HCl (0.2 mol/L, 20 mL) solution, and
the whole was extracted by ethyl acetate. The organic layer was
washed with saturated NaHCO3 aqueous solution and brine, dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (hexane/
EtOAc, 10:1) to give compound 21 (52.2 mg, 53%) as a colorless oil.
The 1H NMR spectral data are identical with that reported by Kit-
taka’s group.40
4.2.22. (1a,2b,3b,5Z,7E)-1-(3-Hydroxypropoxy)-9,10-secocholesta-
5,7,10(19)-triene-2,3,25-triol (24). To a cooled solution of com-
pound 12 (73.4 mg, 0.0952 mmol) in THF (0.5 mL) at ꢀ78 ꢁC under
nitrogen was added n-BuLi (2.5 M in hexane, 40.0 mL, 0.10 mmol)
dropwise, and the mixture was stirred for another 10 min. Then
a solution of compound 22 (34.0 mg, 0.105 mmol) in THF (0.5 mL)
was added by cannula, and the mixture was stirred for another 10 h.
The reaction was quenched by the addition of cold water, and the
whole was extracted by ethyl acetate. The organic layer was washed
with brine, dried over anhydrous Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel column chroma-
tography (hexane/EtOAc, 70:1) to give the silyl ether (46.5 mg, 56%)
4.2.20. (1R,6R,7R)-7-[(R)-6-(Methoxymethoxy)-6-methylheptan-2-
yl]-6-methylbicyclo[4.3.0]nonan-2-one (22). A solution of com-
pound 21 (224 mg, 0.686 mmol), TBAB (50.0 mg, 0.155 mmol),
TEMPO (34.0 mg, 0.218 mmol) and Oxone (556 mg, 1.59 mmol) in
DCM (20 mL) was stirred at rt for 6 h. The reaction was quenched by
the addition of saturated NaHCO3 aqueous solution, and the whole
was extracted with DCM. The organic layer was washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by silica gel column chromatography
(hexane/EtOAc, 10:1) to give compound 22 (200 mg, 90%) as a pale
yellow oil. The 1H NMR spectral data are identical with that re-
ported by Kittaka’s group.40
as a colorless oil. 1H NMR (400 MHz, CDCl3)
d
6.25 (d, J¼11.2 Hz,1H),
5.99 (d, J¼11.2 Hz, 1H), 5.17 (d, J¼2.0 Hz, 1H), 5.11 (d, J¼2.0 Hz, 1H),
4.70 (s, 2H), 4.02 (ddd, J¼2.4, 4.4, 10.8 Hz, 1H), 3.86 (br s, 1H),
3.54e3.70 (m, 3H), 3.31e3.46 (m, 2H), 3.37 (s, 3H), 2.81 (d,
J¼12.4 Hz, 1H), 2.57 (t, J¼11.2 Hz, 1H), 2.09 (dd, J¼4.4, 12.4 Hz, 1H),
1.83e2.04 (m, 3H), 1.62e1.71 (m, 5H), 1.00e1.56 (m, 12H), 1.21 (s,
6H), 0.92 (d, J¼6.4 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H), 0.85 (s, 9H),
0.52 (s, 3H), 0.08 (s, 6H), 0.07 (s, 3H), 0.06 (s, 3H), 0.040 (s, 3H),
0.037 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 142.4, 141.6, 134.6, 123.2,
117.6, 91.0, 84.7, 76.4, 74.6, 70.3, 64.6, 60.4, 56.5, 56.2, 55.1, 45.8,
42.2, 40.6, 40.2, 36.4, 36.1, 33.0, 28.9, 27.7, 26.41, 26.35, 26.1, 26.0,
25.8, 23.4, 22.3, 20.5, 18.8, 18.4, 18.3, 18.2, 12.0, e4.3, e4.4, e4.5,
e4.8, e5.31, e5.33; HRMS (ESI) m/z calcd for C50H96O6Si3 [MþNa]þ
899.6407, found 899.6410.
4.2.21. (1a,2b,3b,5Z,7E)-2-(3-Hydroxypropoxy)-9,10-secocholesta-
5,7,10(19)-triene-1,3,25-triol (23; ED-71). To a cooled solution of
To a solution of the above silyl ether (57.6 mg, 0.0656 mmol) in
methanol (4 mL) was added CSA (280 mg, 1.21 mmol). After stirring
at rt for 6 h, saturated NaHCO3 aqueous solution was added, and the
compound 19 (70.0 mg, 0.125 mmol) in THF (0.5 mL) at ꢀ78 ꢁC
under nitrogen was added n-BuLi (2.5 M in hexane, 50.0
mL,

8040
G.-D. Zhao, Z.-P. Liu / Tetrahedron 71 (2015) 8033e8040
8. Cutolo, M.; Paolino, S.; Sulli, A.; Smith, V.; Pizzorni, C.; Se-riolo, B. Ann. N. Y.
Acad. Sci. 2014, 1317, 39.
9. Cantorna, M. T.; McDaniel, K.; Bora, S.; Chen, J.; James, J. Exp. Biol. Med. 2014,
mixture was extracted by ethyl acetate. The organic layer was
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by silica gel column
chromatography (DCM/MeOH, 15:1) to give compound 24 (23 mg,
239, 1524.
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D. W.; Donahue, T. R.; Masamune, A.; Shimosegawa, T.; Apte, M. V.; Wilson, J. S.;
Ng, B.; Lau, S. L.; Gunton, J. E.; Wahl, G. M.; Hunter, T.; Drebin, J. A.; O’Dwyer, P.
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71%) as a colorless oil. [
l
found 513.3550. The 1H NMR spectral data are identical with that
a
]
25þ63.3 (c 0.15, MeOH); UV (EtOH)
D
¼267 nm; HRMS (ESI) m/z calcd for C30H50O5 [MþNa]þ 513.3550,
reported for the wrongly assigned ‘ED-71’ in Ref. 33.
Acknowledgements
Partially financial support from the Shandong Provincial Natural
Science Foundation (key project, ZR2011CZ001) is gratefully
acknowledged.
ꢀ
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Supplementary data
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Supplementary data (Synthesis of compound 1 from D-mannitol,
spectroscopic data (1H, 13C NMR and HMBC), HRMS for the key
compounds, and the crystal parameters of compound 11 are
available free of charge via the internet at. Crystallographic data for
compound 11 in this paper have been deposited with the Cam-
bridge Crystallographic Data Center as CCDCe1401159.) associated
with this article can be found in the online version, at http://
dx.doi.org/10.1016/j.tet.2015.08.055.
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