Synthesis of 2α-and 2β-substituted-14-epi-previtamin D 3 and their genomic activity

Article abstract of DOI:10.1016/j.tet.2010.05.028

2α-and 2α-Substituted analogs of 14-epi-previtamin D3 were synthesized and isolated after thermal isomerization of 14-epi-vitamin D3 triene at 80 °C.The VDR binding affinity and transactivation activity of osteocalcin promoter in HOS cells were tested, and the 2a-methyl-substituted analog was found to have greater genomic activity than 14-epi-previtamin D ₃.We found that modification at the C2 position of the seco-steroidal skeleton afforded interesting effects for biological genomic activity for the pre-vitamin D form as well as the natural vitamin D form.

Full text of DOI:10.1016/j.tet.2010.05.028

Tetrahedron 66 (2010) 5407e5423
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 2
a- and 2b-substituted-14-epi-previtamin D3 and their
genomic activity
,
,
Daisuke Sawada a, Tomoyuki Katayama a y, Yuya Tsukuda a, Nozomi Saito a y, Hiroshi Saito b,
Ken-ichiro Takagi b, Eiji Ochiai b, Seiichi Ishizuka b, Kazuya Takenouchi b, Atsushi Kittaka a
,
*
a Faculty of Pharmaceutical Sciences, Teikyo University, Midori-ku, Sagamihara, Kanagawa 252-5195, Japan
b Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., Hino, Tokyo 191-8512, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 April 2010
Received in revised form 8 May 2010
Accepted 10 May 2010
Available online 13 May 2010
2
a
- and 2
isomerization of 14-epi-vitamin D3 triene at 80 ꢀC. The VDR binding affinity and transactivation activity
of osteocalcin promoter in HOS cells were tested, and the 2 -methyl-substituted analog was found to
b-Substituted analogs of 14-epi-previtamin D3 were synthesized and isolated after thermal
a
have greater genomic activity than 14-epi-previtamin D3. We found that modification at the C2 position
of the seco-steroidal skeleton afforded interesting effects for biological genomic activity for the pre-
vitamin D form as well as the natural vitamin D form.
Keywords:
Vitamin D3
Ó 2010 Elsevier Ltd. All rights reserved.
14-epi-Previtamin D3
Osteocalcin
Vitamin D receptor
1. Introduction
previtamin D form (B) (Scheme 1). The biologically most active
metabolite of vitamin D3, 1
a,25(OH)2D3 (1), also contains 5e10% of
In our group, the systematic synthesis of vitamin D3 analogs
with C2-modifications has been initiated and a number of C2-
modified analogs with greater vitamin D receptor (VDR)-agonistic
its previtamin D form, 1
a
,25(OH)2preD3 (pre-1) at 37 ꢀC in similar
equilibrium.10 Most scientists have focused on the analogs of the
major vitamin D form for therapeutic evaluation rather than the
previtamin D form, because previtamin D3 is easily transformed to
vitamin D3 through thermal equilibrium and is almost impossible
to isolate in the pure form.10 While 1 is a ligand of the nucleic re-
ceptor (vitamin D receptor, VDR), regulates gene transcription, and
exhibits various biological responses as a hormone,11 pre-1 is
thought to be a weak ligand of VDR and a poor activator of the
above genomic actions,12 however, pre-1 has been studied as
a precursor of rapid responses,13 such as stimulation of intestinal
Ca2þ transport (transcaltachia),14 activation of PKC15 and MAP16
kinases, and so on, which are called non-genomic actions.
activity than the active vitamin D3, 1
,25(OH)2D3), have been successfully synthesized.1-5 We have also
synthesized highly potent VDR-antagonists, which belong to a
series of TEI-9647 analogs with C2 -functionalization as well as 24-
alkyl modification on the lactone ring.6 In particular, (23S,24S)-2
(3-hydroxypropoxy)-24-propylvitamin D3-26,23-lactone was
a,25-dihyrdoxyvitamin D3 (1,
1
a
a
a
-
found to exhibit approximately 850-fold greater antagonistic ac-
tivity (IC50¼7.4 pM) than the parent antagonist, TEI-9647
(IC50¼6.3 nM).7,8 The mechanism of the C2
a-effects on enhanced
VDR binding was explained by X-ray crystallographic analyses of
the VDR-ligand complexes.9 One of the important characteristics of
the vitamin D3 molecule is that vitamin D3 is present in thermal
equilibrium with previtamin D3 via [1,7]-sigmatropic hydrogen
shift. In this equilibrium, the 6-s-trans isomer, that is, the vitamin D
form (A), is more stable and major than the 6-cis isomer of the
Okamura et al. reported that the thermal equilibrium ratio be-
tween the vitamin D form (A) and previtamin D form (B) at 80 ꢀC
was reversed by epimerizing the CD-ring bridgehead hydrogen of
C14,17 that is to say, 14-epi-1
major and dominant over 14-epi-1
a
,25(OH)2preD3 (14-epi-pre-1) was
,25(OH)2D3 (14-epi-1), and 14-
a
epi-pre-1 is expected to be isolated stable as a single isomer at
room temperature. Therefore, we focused on the synthesis of 14-
epi-pre-1 analogs with A-ring modification, and aimed to identify
their more detailed biological properties and potential as thera-
peutic agents of the previtamin D3 skeleton. In this paper, we
present the details of the synthesis and biological evaluation of C2-
modified previtamin D3 analogs.
* Corresponding author. Tel./fax: þ81 42 685 3713; e-mail address: akittaka@
pharm.teikyo-u.ac.jp (A. Kittaka).
y
Present address: Faculty of Pharmaceutical Sciences, Hokkaido University,
Sapporo 060-0812, Japan.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.028

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D. Sawada et al. / Tetrahedron 66 (2010) 5407e5423
Scheme 1. Equilibrium between vitamin D3 and previtamin D3.
2. Results and discussion
2.1. Retrosynthetic analysis
Previously, we found that 2
14-epi-pre-1 should be prepared from 14-epi-1 by thermal
isomerization, so we planned to synthesize 14-epi-1 analogs as the
temporary first targets, and using their thermal isomerization, we
could obtain 14-epi-pre-1 analogs. This strategy would help to
understand the equilibrium between vitamin D3 and previtamin
D3. The 14-epi-1 analogs were divided into two fragments, CD-ring
and A-ring fragments, which should be coupled by the Roche
coupling method.21 The CD-ring fragment 2 should be obtained by
epimerization at H14 in Grundmann’s ketone derivative, which was
derived from vitamin D3.22 In the A-ring fragment, the phosphine
oxide 3aei could be synthesized from enyne 4aei, and they were
a
-alkyl and 2a-(u-hydroxyalkyl)
substitution afforded great improvements of VDR binding affinity
and the subsequent genomic actions.1-4 Also, it is well-known that
2
b
-hydroxypropoxy substitution afforded great improvement of
genomic activity.18 For the comprehensive study of the previtamin
D skeleton, we were interested in various 2 -substitutions and
stereochemistry of the 1-hydroxy group at the A-ring moiety. We
b
therefore decided to synthesize analogs with 2
a
- and 2
b-sub-
derived from methyl
stitutions (4aef), and from dimethyl
a
-
D
-glucoside through epoxide 5 for 2
a-sub-
stitutions (14-epi-pre-1ae1i) in this study (Scheme 2).19,20
D
-tartrate through epoxide 6
OTES
H
OH
H
Vitamin D3
H
OH
H
OH
O
2
R
H
H
HO
P(O)Ph2
HO
OH
14-epi-pre-1a: R = α−Me
R
14-epi-pre-1b: R = α−(CH2)3OH
14-epi-pre-1c: R = α−O(CH2)3OH
14-epi-pre-1d: R = α−Bu
TBSO
OTBS
R
4a~i
14-epi-1a~i
TBSO
OTBS
14-epi-pre-1e: R = α−Ph
R
14-epi-pre-1f: R = α−Bn
2α-substituted
2β-substituted
3a~i
14-epi-pre-1g: R = β−Me
14-epi-pre-1h: R = β−(CH2)3OH
14-epi-pre-1i: R = β−O(CH2)3OH
MeO
O
O
O
BnO
OBn
O
Ph
O
5
6
Dimethyl D-tartrate
Methyl α-
D-glucopyranoside
Scheme 2. Retrosynthetic analysis of 2-substituted 14-epi-1a,25(OH)2preD3.

D. Sawada et al. / Tetrahedron 66 (2010) 5407e5423
5409
for 2
groups at 2
reactions.2,23,24
b
-substitutions (4gei). Thus, we could introduce various alkyl
2.4. Synthesis of 2b-substituted A-ring fragments
a
- and 2 -positions by nucleophilic epoxide opening
b
2b
-Substituted A-ring fragments (3gei) were prepared from the
known epoxide 6 derived from dimethyl
D
-tartrate (Scheme 5).24,26
Using the nucleophilic epoxide opening reaction with compound 6,
three substitutions were introduced as follows: methyl cuprate
gave the methyl substitution; allylation by Grignard reaction fol-
lowed by hydroboration with 9-borabicyclo[3,3,1]nonane (9-BBN)
and subsequent H2O2 oxidation afforded the hydroxypropyl sub-
stitution; and propylene glycol and KOtBu gave hydroxypropoxy
substitution.24a,d After their primary alcohol was protected as tert-
butyldiphenylsilyl (TBDPS) ether (11gei), they were converted to
2.2. Synthesis of CD-ring fragment
The CD-ring fragment (2) was synthesized from the known
ketone, TES-protected 25-hydroxy Grundmann’s ketone (7)
(Scheme 3).22,25 According to the literature, epimerization of H14
was successfully conducted by NaOMe with recovery of the starting
material, which was easily separated by column chromatography.17
Thus, we were able to obtain the CD-ring fragment in short steps.
OTES
H
OTES
H
NaOMe
MeOH
H
H
O
7
2
O
conv. y. 93%
(7 : 2 = 1.2 : 1)
Scheme 3. Synthesis of the CD-ring fragment.
2.3. Synthesis of 2
a
-substituted A-ring fragments
bromide 12gei by the known procedure.27 Methanolysis of both
acetyl groups under basic conditions caused epoxide formation,
and the resultant hydroxy group was transformed into benzyl ester
13gei. The addition of (trimethylsilyl)acetylene to the epoxide us-
ing nBuLi was straightforward, and the generated secondary alcohol
was protected as tert-butyldimethylsilyl (TBS) ether, and removal of
2
a
-Substituted A-ring fragments (3aef) were prepared from the
known epoxide 5 derived from methyl -glucoside (Scheme
4).2,19,23 According to the literature, 5 was transformed to enyne
a-D
4aef, which had various alkyl groups at 2
a-position by nucleophilic
OH
MeO
O
(a)
O
(b)
refs. 2, 23
TBSO
OTBS
O
Ph
TBSO
OTBS
R
O
R
4a : R = Me
4b : R = (CH2)3OTBS
4c : R = O(CH2)3OTBS
4d : R = Bu
5
8a~f
4e : R = Ph
4f : R = Bn
OH
OH
P(O)Ph2
OTBS
I
(c)
(d)
TBSO
OTBS
TBSO
OTBS
TBSO
R
9a~f
R
10a~f
R
3a~f
Scheme 4. Synthesis of the A-ring fragments. Conditions: (a) nBuLi, (CH2O)n, THF, 91% for 8a, 92% for 8b, 89% for 8c, 91% for 8d, 81% for 8e, 94% for 8f; (b) Red-Al, Et2O, then I2, THF,
73% for 9a, 70% for 9b, 75% for 9c, 75% for 9d, 67% for 9e, 76% for 9f; (c) Pd(PPh3)4, Et3N, MeCN, 93% for 10a, 89% for 10b, 82% for 10c, 93% for 10d, 99% for 10e, 92% for 10f; (d) (i) NCS,
Me2S, CH2Cl2, (ii) PHPh2, nBuLi, THF, (iii) H2O2 aq, 77% for 3a, 74% for 3b, 76% for 3c, 76% for 3d, 39% for 3e, 83% for 3f.
epoxide opening reaction.2,23 Then, enyne 4aef reacted with nBuLi
and then (CH2O)n to give alcohol 8aef in good to excellent yield.
Then, hydroalumination and subsequent iodination of the alkyne
gave the vinyl iodide 9aef. Next, cyclization by Heck reaction
proceeded smoothly to afford a six-membered A-ring,24 whose
hydroxy group was converted into chloride with N-chlor-
osuccinimide (NCS). This allyl chloride was easily substituted by
Ph2PH and nBuLi, and the generated phosphine was oxidized to
the terminal trimethylsilyl (TMS) group and benzoyl group gave
alkyne 14gei. The primary alcohol was oxidized to aldehyde by
DMSO and SO3$pyridine complex (15gei), to which a vinyl group
was introduced to give a diastereomixture of alcohol 16gei. The
stereochemistry of the new hydroxy group is discussed below
(Scheme 6), and both isomers of 16g and the major isomer of 16h
and 16i were used for further transformation after separation by
column chromatography. The hydroxy group of 16gei was pro-
phosphine oxide 3aef. As above, we were able to prepare 2
a
-
tected by the TBS group, and we were able to synthesize 2
b-
substituted A-ring fragments in good overall yield.
substituted enyne 4gei. Similar transformation as Scheme 4 from

5410
D. Sawada et al. / Tetrahedron 66 (2010) 5407e5423
Scheme 5. Sythesis of the 2
b
-substituted A-ring fragments. Conditions. (a) for 11g MeLi, CuI, Et2O, 98%; (b) for 11h (i) allylmagnesium chloride, toluene, (ii) 9-BBN, THF, H2O2, NaOH,
(iii) TBDPSCl, imidazole, DMF, 90% (three steps); (c) for 11i (i) propylene glycol, KOtBu, (ii) TBDPSCl, imidazole, DMF, 92% (two steps); (d) Pd/C, H2, MeOH; (e) MeC(OMe)3, PPTS,
CH2Cl2; (f) AcBr, CH2Cl2, 60% for 12g, 52% for 12h, 55% for 12i (three steps); (g) K2CO3, MeOH; (h) BzCl, Et3N, CH2Cl2, 80% for 13g, 95% for 13h, 83% for 13i (two steps); (i) (tri-
methylsilyl)acetylene, nBuLi, BF3$OEt2, THF; (j) TBSOTf, iPr2EtN, CH2Cl2; (k) K2CO3, MeOH, 68% for 14g, 83% for 14h, 95% for 14i (three steps); (l) SO3$Py, Et3N, DMSO, 77% for 15g, 99%
for 15h, 95% for 15i; (m) vinylmagnesium chloride, THF, 93% (
97% for 4g , 99% for 4h , 99% for 4i
; (o) nBuLi, (CH2O)n, THF; (p) Red-Al, Et2O, then I2, THF; (q) Pd(PPh)4, Et3N, MeCN; (r) (i) NCS, Me2S, CH2Cl2, (ii) nBuLi, PHPh2, THF, then H2O2 aq,
49% for 3g , 57% for 3g , 27% for 3h , 28% for 3i (four steps).
a/b 46/47) for 16g, 95% (a/b 37/58) or 16h, 73% (a/b 15/58) for 16i (two steps); (n) TBSOTf, iPr2EtN, CH2Cl2, 100% for 4ga,
b
b
b
a
b
b
b
Scheme 6. Determination of the stereochemistry of the 1-hydroxy group of 16gei. Conditions. (a) TBAF, THF; (b) TBSOTf, iPr2EtN, CH2Cl2, 70% (two steps); (c) for 16g
b, TBAF, THF,
100%; (d) for 16h , PPTS, EtOH, 60%; (e) dimethoxypropane, PPTS, DMF, 70% for 18g , 90% for 18h
b
b
b.
enyne into phosphine oxide afforded the 2
fragment 3gei.
b
-substituted A-ring
of its 1-hydroxy group was found to be
major diastereomer of 16i was determined to have the 1
droxy group (16i ). For 16g and 16h, the TBS group of each major
diastereomer (16g and 16h ) was removed, and the resultant
1,3-dihydroxy groups was converted to acetonide 18g
28, which
is known, and 18h , respectively. Their NOE analyses are de-
scribed in Scheme 6, and the stereochemistry of the 1,3-dihy-
droxy groups is syn, that is, 18h also has the 1 ,3 -dihydroxy
groups. As above, we found that all of the major diastereomers of
16gei had the 1 -hydroxy group, and we continued further
synthesis with 3g , 3g , 3h , and 3i
a
-configuration, and the
b
-hy-
b
b
b
2.5. Determination of the stereochemistry of 1-hydroxy
group of 16gei
b
b
The minor diastereomer of 16i (16i
phosphine oxide 3i by the same strategy as shown in Scheme 4
followed by exchange of the protecting group from TBDPS to TBS,
and 3i was identical to the known compound reported by
Hatakeyama et al. (Scheme 6).24a Therefore, the stereochemistry
a) was converted to the
b
b b
a
b
a
a
b
b
b.

D. Sawada et al. / Tetrahedron 66 (2010) 5407e5423
5411
2.6. Coupling reaction and isomerization
chick intestinal VDR30 and HOS cells31, respectively. The results are
summarized in Table 1 in comparison with the natural hormone 1
Using the CD- and A-ring fragments prepared above, we
attempted the coupling reaction under basic conditions using nBuLi
(Scheme 7).17,21 Small excess amounts of the A-ring fragment
worked well and we obtained the coupled product 19aei, although
some reactions resulted in low yield. At this point, isomerization to
the previtamin D form was seldom observed and small amounts of
the pre-form were present, probably because TBS groups at the A-
ring should have steric hindrance to reach the transition state for
the [1,7]-sigmatropic hydrogen shift between the vitamin D form
and 14-epi-1a,25(OH)2preD3 (14-epi-pre-1), which was synthe-
sized in a similar manner in our laboratory. The new compounds
showed lower activity than the natural hormone 1. Remarkably,
much lower activity was observed with the 2
regardless of the stereochemistry at 1-hydroxy group; however,
some 2 -substituted analogs showed higher activity than 14-epi-
pre-1. In particular, 14-epi-pre-1a, the 2 -methyl-substituted an-
b-substituted analogs
a
a
alog, showed a considerable increase in VDR binding affinity and
transactivation activity. It is worth noting that 14-epi-pre-1 analogs
Scheme 7. Coupling reaction and synthesis of 2-substituted 14-epi-1a,25(OH)2preD3.
and the previtamin D form. Then, all silyl groups in 19aei were
removed in one step with excess TBAF or HF/MeCN, and consider-
able amounts of deprotected compounds remained in the vitamin
D form (14-epi-1aei) under these reaction conditions. However,
once they were heated at 80 ꢀC in benzene, isomerization was
found to proceed smoothly by NMR observation. After 2 h, most of
the vitamin D form had been converted to the previtamin D form,
and isomerization seemed to reach thermal equilibrium, in which
the ratio of the compounds was about 5/95 (vitamin D/previtamin
D) based on 1H NMR studies.29 Using HPLC, the mixture of both
forms was separated, and we were able to obtain 14-epi-pre-1aei
as each pure form, which were used for further biological studies.
gain genomic activity, and 2-substitution on the A-ring seems to
have great effects on the biological actions of the previtamin D
form.
3. Conclusion
We synthesized the 2a- and 2b-substituted analogs of 14-epi-1
for the first time and were able to isolate these new analogs (14-
epi-pre-1aei) after thermal isomerization at 80 ꢀC. Using them, we
evaluated the VDR binding affinity and transactivation activity of
osteocalcin promoter in HOS cells, among which 2a-methyl-
substituted analog (14-epi-pre-1a) was found to have 17-fold
greater binding affinity for VDR and fourfold stronger trans-
activation activity than those of 14-epi-pre-1, respectively. It is
2.7. Biological evaluation
known that 6-s-cis-conformer analog of
1a,25-dihydrox-
The VDR binding affinity and osteocalcin promoter trans-
activation activity of the new compounds were evaluated using
ylumisterol3 shows non-genomic actions acting on genomic re-
sponses that are linked to cell differentiation, and the non-genomic

5412
D. Sawada et al. / Tetrahedron 66 (2010) 5407e5423
Table 1
Relative binding affinity for chick intestinal VDR and osteocalcin promoter transactivation activity in HOS cells of 2-substituted 14-epi-1a,25(OH)2preD3
Compound
VDRa
Osteocalcin transactivation activity (EC50 (nM))
1
100
0.5
8.4
1.4
0.03
0.46
0.12
0.69
0.95
5.77
0.88
30.2
1.34
9.12
1.01
1.24
14-epi-pre-1
14-epi-pre-1a
14-epi-pre-1b
14-epi-pre-1c
14-epi-pre-1d
14-epi-pre-1e
14-epi-pre-1f
14-epi-pre-1g
14-epi-pre-1g
14-epi-pre-1h
14-epi-pre-1i
0.17
0.27
< 0.03
0.03
0.08
0.08
a
b
b
0.18
0.01
b
a
The potency of 1 is normalized to 100.
19
pathway-mediated responses induced by 1 and 1
a
,25-dihydrox-
AcOEt¼20/1) to give 2 (5.5 g, 80%) as a colorless oil:[
0.01, CHCl3); IR (neat) 1711, 1236, 1213 cmꢁ1
CDCl3)
a]
þ35.1 (c
D
ylumisterol3 are able to be evaluated by using the NB4 cell (human
acute promyelocytic leukemia cell) differentiation system.32 Al-
though the non-genomic action of 14-epi-pre-1a was tested using
NB4 cells, the activity could not be observed so far (data not
shown). It was found that 2-modification afforded important ef-
fects on biological genomic activity for the previtamin D form as
well as the natural vitamin D form reported previously.1e4,23
;
1H NMR (400 MHz,
d
0.55 (dd, J¼7.6, 15.6 Hz, 6H), 0.9 (d, J¼7.3 Hz, 3H), 0.93 (t,
J¼8.1 Hz, 9H), 1.03 (s, 3H), 1.17 (s, 7H), 1.27e1.42 (m, 7H), 1.53e1.61
(m, 2H), 1.72e1.92 (m, 5H), 2.10e2.16 (m, 1H), 2.26e2.36 (m, 3H);
13C NMR (100 MHz, CDCl3)
d 7.2 (3C), 7.5 (3C), 19.5, 21.4, 21.6, 23.4,
28.1, 30.2, 30.3, 34.7, 36.4, 36.8, 40.5, 45.8, 49.0, 50.9, 58.7, 61.8, 73.7,
213.8; FABMS m/z 417 (MþNa)þ, HRFABMS calcd for C24H46NaO2Si,
417.3159, found 417.3136.
4. Experimental section
4.1. General
4.2.1. (5R,6S,7R)-5,7-Bis(tert-butyldimethylsilanyloxy)-6-methylnon-
8-en-2-yn-1-ol (8a). To a solution of 4a23b (1.06 g, 2.77 mmol) in
dry THF (9.2 mL) was added nBuLi (1.53 M hexane solution, 2.75 mL,
4.03 mmol) at ꢁ78 ꢀC and stirred for 1 h at the same temperature.
To the mixture was added paraformaldehyde (250 mg, 9.04 mmol)
at ꢁ78 ꢀC and stirred at the same temperature for 1 h. The mixture
was warmed up to room temperature over 2 h, and stirred at room
temperature for 2 h. To the mixture was added saturated NH4Cl
aqueous solution at 0 ꢀC, and extracted with Et2O. The organic layer
was washed with brine, dried over Na2SO4, and concentrated. The
1H and 13C NMR spectra were recorded on JEOL AL-400 NMR
(400 MHz) and ECP-600 NMR (600 MHz) spectrometers. 1H NMR
spectra were referenced with (CH3)4Si (
standard. 13C NMR spectra were referenced with deuterated solvent
77.0 ppm for CDCl3, and 128.0 ppm for C6D6). IR spectra were
d 0.00 ppm) as an internal
(d
recorded on JASCO FT-IR-800 Fourier Transform Infrared Spectro-
photometer. Low- and high resolution mass spectra were recorded
on a JEOL JMS-SX 102A mass spectrometer. FAB mass spectra were
measured using m-nitrobenzyl alcohol matrix. Optical rotations
were measured on a JASCO DIP-370 digital polarimeter. Column
chromatography was performed on silica gel 60 N (Kanto Chemical
residue was purified by flash column chromatography on silica gel
25
(hexane/AcOEt¼10/1) to give 8a (1.00 g, 91%) as a colorless oil: [
a
;
]
1DH
þ1.71 (c 3.69, CHCl3); IR (neat) 3331, 2340, 1644, 1253 cmꢁ1
NMR (400 MHz, CDCl3) d 0.03 (s, 3H), 0.05 (s, 3H), 0.07 (s, 3H), 0.08
(s, 3H), 0.89 (s, 9H), 0.75 (t, J¼10.0 Hz, 3H), 0.886 (s, 9H), 0.893 (s,
9H), 1.41 (t, J¼6.0 Hz, 1H), 1.86 (ddq, J¼10.5, 10.0, 3.5 Hz, 1H),
2.40e2.42 (m, 2H), 3.98e4.03 (m, 2H), 4.23 (dt, J¼6.0, 2.1 Hz, 2H),
5.08e5.15 (m, 2H), 5.73 (ddd, J¼18.0, 9.8, 7.3 Hz, 1H); 13C NMR
Co., Inc., 100e210 mm) or silica gel 60 (Merck, 0.040e0.063 mm).
Preparative thin layer chromatography was performed on silica gel
60 F254 (Merck, 0.5 mm). High performance liquid chromatography
(HPLC) was carried out on a SHIMADZU HPLC system consisting of
the following equipments: pump, LC-6AD; detector, SPD-10A; col-
umn, YMC-Pack ODS-A. All experiments were performed under
anhydrous conditions in an atmosphere of argon, unless otherwise
mentioned.
(100 MHz, CDCl3)
d
ꢁ4.5, ꢁ4.4, ꢁ3.9, ꢁ3.3, 9.6, 18.2, 18.3, 25.9 (3C),
26.0 (3C), 26.2, 43.8, 51.4, 70.7, 76.0, 80.1, 83.6, 115.6, 139.9; EI-LRMS
m/z 395 (MꢁOH)þ, 355, 343, 223, 171; EI-HRMS calcd for
C22H43O2Si2 (M-OH)þ 395.2802, found 395.2803.
4.2.2. (5R,6S,7R)-5,7-Bis(tert-butyldimethylsilanyloxy)-6-[3-(tert-
butyldimethylsilanyloxy)propyl]non-8-en-2-yn-1-ol (8b). In the
same procedure for 8a, 8b (330 mg, 92%) was obtained from 4b23c
(339 mg, 0.627 mmol), nBuLi (1.53 M hexane solution, 0.61 mL,
4.2. (1R,3aS,7aR)-1-[(R)-6-Triethylsilanyloxy-6-methylheptan-
2-yl]-7a-methylhexahydro-1H-inden-4(2H)-one (2)
To a solution of 725 (6.9 g, 17.4 mmol) in MeOH (35 mL) was
added NaOMe (2.4 g, 43.6 mmol) at 0 ꢀC and stirred at room tem-
perature for 3 h. After the reaction was quenched by aqueous NH4Cl
at 0 ꢀC, the mixture was extracted with AcOEt, washed with brine,
dried over Na2SO4, filtered, and concentrated. The residue was
purified by flush column chromatography on silica gel (hexane/
0.93 mmol), paraformaldehyde (60 mg, 1.20 mmol), and THF
24
(2.1 mL). Colorless oil; [
a
]
þ1.00 (c 3.31, CHCl3); IR (neat) 3441,
D
2226, 1642, 1254 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d 0.02 (s, 3H),
0.04 (s, 6H), 0.05 (s, 3H), 0.06 (s, 3H), 0.08 (s, 3H), 0.89 (s, 27H), 1.24
(m, 1H), 1.42 (m, 1H), 1.57e1.65 (m, 3H), 1.71 (ddt, J¼5.9, 5.7, 3.4 Hz,

D. Sawada et al. / Tetrahedron 66 (2010) 5407e5423
5413
1H), 2.41e2.44 (m, 2H), 3.56 (m, 2H), 4.01 (dt, J¼6.1, 3.4 Hz, 1H),
(400 MHz, CDCl3)
d
0.00 (s, 9H), 0.04 (s, 3H), 0.877 (s, 9H), 0.884 (s,
4.10 (dd, J¼6.7, 5.7 Hz, 1H), 4.22 (dt, J¼6.1, 2.1 Hz, 2H), 5.08 (dd,
J¼10.1, 1.0 Hz, 1H), 5.13 (dd, J¼17.2, 1.0 Hz, 1H), 5.83 (ddd, J¼17.2,
9H), 1.32 (t, J¼6.0 Hz, 1H), 2.18e2.25 (m, 2H), 2.33 (dd, J¼16.8,
6.4 Hz, 1H), 2.60 (dd, J¼14.3, 5.5 Hz, 1H), 2.66 (dd, J¼14.3, 7.1 Hz,
1H), 4.02 (ddd, J¼6.5, 6.4, 2.4 Hz, 1H), 4.14e4.19 (m, 3H), 5.06 (d,
J¼10.0 Hz, 1H), 5.14 (d, J¼17.2 Hz, 1H), 5.18 (ddd, J¼17.2, 10.0, 7.5 Hz,
10.1, 6.7 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
ꢁ5.2, ꢁ5.2, ꢁ4.6,
ꢁ4.3, ꢁ4.1, ꢁ3.5, 18.1, 18.2, 18.4, 22.2, 25.9 (3C), 26.0 (3C), 26.5 (3C),
32.5, 49.4, 51.3, 63.6, 71.5, 76.1, 80.0, 84.0, 115.4, 140.3; EI-LRMS m/z
553 (M-OH)þ, 513, 438, 381, 369, 171; EI-HRMS calcd for
C30H61O3Si3 (MꢁOH)þ 553.3928, found 553.3928.
1H), 7.11e7.24 (m, 5H); 13C NMR (100 MHz, CDCl3)
d
ꢁ4.6, ꢁ4.4,
ꢁ4.1, ꢁ3.5, 18.2, 18.3, 26.0 (3C), 26.0 (3C), 26.1, 32.1, 51.4, 51.6, 71.0,
75.9, 79.8, 84.3, 115.7, 125.5, 128.0 (2C), 129.2 (2C), 140.4, 142.1; EI-
LRMS m/z 431 (Mꢁ Bu)þ, 339, 287, 207; EI-HRMS calcd for
t
t
4.2.3. (5R,6S,7R)-5,7-Bis(tert-butyldimethylsilanyloxy)-6-[3-(tert-
butyldimethylsilanyloxy)propoxy]-non-8-en-2-yn-1-ol (8c). In the
same procedure for 8a, 8c (2.07 g, 89%) was obtained from 4c2
(2.31 g, 4.15 mmol), nBuLi (1.53 M hexane solution, 3.9 mL,
5.97 mmol), paraformaldehyde (424 mg, 14.1 mmol), and THF
C24H39O3Si2 (Mꢁ Bu)þ 431.2438, found 431.2455.
4.2.7. (2Z)-(5R,6S,7R)-5,7-Bis(tert-butyldimethylsilanyloxy)-3-iodo-
6-methylnona-2,8-dien-1-ol (9a). To
a solution of 8a (1.00 g,
2.43 mmol) in dry Et2O (25 mL) was added Red-AlÒ (65% toluene
solution, 1.73 mL, 5.76 mmol) at 0 ꢀC and stirred at room temper-
ature for 4 h. To the mixture was added ethyl acetate (0.41 mL,
4.20 mmol) at 0 ꢀC, and then cooled to ꢁ78 ꢀC and added I2 (1.28 g,
5.03 mmol) in THF (2 mL) and stirred at the same temperature for
30 min. The mixture was warmed up to room temperature over
1.5 h and stirred for 10 min. The mixture was diluted with Et2O,
added 10% Na2S2O3 aqueous solution and saturated NaHCO3
aqueous solution at 0 ꢀC, and the aqueous layer was extracted with
Et2O. The organic layer was washed with brine, dried over Na2SO4,
and concentrated. The residue was purified by flash column chro-
(13.1 mL). Colorless oil; [
a
]
25 þ0.42 (c 2.62, CHCl3); IR (neat) 3443,
D
2290,1644,1252 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
0.03 (s, 3H), 0.05
(s, 3H), 0.06 (s, 3H), 0.08 (s, 3H), 0.10 (s, 3H), 0.88 (s, 9H), 0.89 (s, 9H),
0.90 (s, 9H),1.54 (t, J¼6.1 Hz,1H),1.71e1.82 (m, 2H), 2.38 (ddt, J¼18.8,
6.4, 5.4 Hz, 1H), 2.53 (ddt, J¼16.8, 6.8, 5.7 Hz, 1H), 3.33 (dd, J¼5.5,
3.3 Hz, 1H), 3.59e3.76 (m, 4H), 3.84 (dt, J¼5.7, 5.5 Hz, 1H), 4.23 (m,
2H), 4.30 (m,1H), 5.12 (ddd, J¼10.3,1.7,1.0 Hz,1H), 5.22 (ddd, J¼17.3,
1.7, 1.2 Hz, 1H), 5.95 (ddd, J¼17.3, 10.3, 6.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3)
d
ꢁ5.2 (2C), ꢁ4.7, ꢁ4.3, ꢁ4.1, ꢁ4.0, 18.2, 18.3, 18.4,
24.4, 25.9, 27.0, 26.0, 33.5, 51.4, 60.6, 69.3, 71.8, 74.5, 79.8, 84.2, 85.1,
115.9, 138.7; EI-LRMS m/z 569 (M-OH)þ, 529, 415, 339, 327, 115; EI-
HRMS calcd for C30H61O4Si3 (MꢁOH)þ 569.3898, found 569.3888.
matography on silica gel (hexane/AcOEt¼10/1) to give 9a (985 mg,
24
62%) as a colorless oil: [
a
]
þ1.22 (c 2.38, CHCl3); IR (neat) 3328,
D
1644,1252, 675 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 0.03 (s, 3H), 0.06
4.2.4. (5R,6S,7R)-5,7-Bis(tert-butyldimethylsilanyloxy)-6-butylnon-
8-en-2-yn-1-ol (8d). In the same procedure for 8a, 8d (1.03 g, 91%)
was obtained from 4d23d (1.135 g, 2.50 mmol), nBuLi (1.57 M hexane
(s, 3H), 0.08 (s, 3H), 0.10 (s, 3H), 0.73 (d, J¼7.2 Hz, 3H), 0.88 (s, 9H),
0.89 (s, 9H), 1.51 (br s, 1H), 1.57 (ddq, J¼7.3, 7.2, 2.0 Hz, 1H),
2.69e2.70 (m, 2H), 3.98 (dd, J¼7.8, 7.3 Hz, 1H), 4.20 (d, J¼5.6 Hz,
2H), 4.32 (dt, J¼6.6, 2.0 Hz, 1H), 5.08e5.13 (m, 2H), 5.71 (ddd,
J¼17.8, 9.6, 7.8 Hz, 1H), 5.88 (t, J¼5.6 Hz, 1H); 13C NMR (100 MHz,
solution, 2.4 mL, 3.77 mmol), paraformaldehyde (226 mg,
20
7.52 mmol), and THF (8.3 mL). Colorless oil; [
a
]
D
þ1.46 (c 2.54,
CHCl3); IR (neat) 3347, 2957, 2228, 1253, 1074 cmꢁ1
;
1H NMR
CDCl3)
d
ꢁ4.3, ꢁ4.0, ꢁ3.4, ꢁ3.0, 9.5 (2C), 18.3, 18.3, 26.0 (3C), 26.2
(400 MHz, CDCl3) 0.00 (s, 3H), 0.03 (s, 3H), 0.04 (s, 3H), 0.07 (s,
d
(3C), 42.9, 50.9, 67.3, 70.1, 76.4, 116.0, 135.7, 140.7; EI-LRMS m/z 483
t
3H), 0.84e0.87 (m, 2H), 0.87 (s, 9H), 0.87 (s, 9H), 1.22e1.32 (m, 6H),
1.37 (dt, J¼6.0, 0.9 Hz, 1H), 1.68 (dd, J¼5.2, 3.8 Hz, 1H), 2.40e2.42
(m, 2H), 3.95 (ddd, J¼6.2, 6.2, 3.7 Hz, 1H), 4.10 (dd, J¼7.2, 6.5 Hz,
1H), 4.21 (dd, J¼2.0, 2.0 Hz, 1H), 4.22 (dd, J¼2.0, 2.0 Hz, 1H), 5.04
(dd, J¼10.1, 1.1 Hz, 1H), 5.83 (ddd, J¼17.3, 10.1, 7.2 Hz, 1H); 13C NMR
(Mꢁ Bu)þ, 415, 355, 241, 115; EI-HRMS calcd for C18H36IO3Si2
t
(Mꢁ Bu)þ 483.1248, found 483.1247.
4.2.8. (2Z)-(5R,6S,7R)-5,7-Bis(tert-butyldimethylsilanyloxy)-6-[3-
(tert-butyldimethylsilanyloxy)propyl]-3-iodonona-2,8-dien-1-ol
(9b). In the same procedure for 9a, 9b (1.01 g, 70%) was obtained
from 8b (1.19 g, 2.08 mmol), Red-AlÒ (65% toluene solution,
(100 MHz, CDCl3)
d
ꢁ4.6, ꢁ4.3, ꢁ4.1, ꢁ3.6, 14.1, 18.1, 23.2, 25.9 (3C),
25.9 (3C), 26.3, 31.5, 49.6, 51.4, 71.8, 75.8, 79.7, 84.4, 115.1, 140.4; EI-
LRMS m/z 397 (Mꢁ Bu)þ, 265, 131, 115; EI-HRMS calcd for
1.75 mL, 5.83 mmol), ethyl acetate (0.32 mL, 3.28 mmol), Et2O
t
t
25
C21H41O3Si2 (Mꢁ Bu)þ 397.2495, found 397.2582.
(25 mL), I2 (1.27 g, 4.99 mmol), and THF (2 mL). Colorless oil; [a]
D
þ1.89 (c 2.54, CHCl3); IR (neat) 3320,1644,1254, 671 cmꢁ1; 1H NMR
4.2.5. (5R,6S,7R)-5,7-Bis(tert-butyldimethylsilanyloxy)-6-phenylnon-
8-en-2-yn-1-ol (8e). In the same procedure for 8a, 8e (360 mg, 81
%) was obtained from 4e23e (470 mg, 1.0 mmol), nBuLi (1.56 M
(400 MHz, CDCl3) d 0.01 (s, 3H), 0.04 (s, 12H), 0.07 (s, 3H), 0.87 (s,
9H), 0.88 (s, 9H), 0.89 (s, 9H), 1.29e1.31 (m, 2H), 1.56e1.64 (m, 4H),
2.70 (dd, J¼7.2, 6.2 Hz, 2H), 3.57 (t, J¼6.4 Hz, 2H), 4.12e4.23 (m,
4H), 5.06 (dd, J¼10.3,1.2 Hz,1H), 5.13 (dd, J¼17.2,1.2 Hz,1H), 5.86 (t,
hexane solution 1.0 mL, 1.56 mmol), paraformaldehyde (95 mg,
21
3.1 mmol), and THF (3 mL). White amorphous solid; [
0.01, CHCl3); IR (neat) 3346, 1253, 1217 cmꢁ1
CDCl3) 0.04 (s, 3H), 0.06 (s, 3H), 0.10 (s, 6H), 0.86 (s, 9H), 0.92 (s,
a
]
ꢁ37.3 (c
J¼6.2 Hz, 1H), 5.88 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
ꢁ5.1 (2C),
D
;
1H NMR (400 MHz,
ꢁ4.5, ꢁ3.9, ꢁ3.6, ꢁ3.4,18.2,18.2,18.4,18.4, 22.4, 26.0 (3C), 26.1 (6C),
d
32.3, 49.5, 50.8, 63.5, 67.4, 71.4, 75.9, 107.6, 115.4, 136.1, 140.7; EI-
t
9H), 1.33 (s, 1H), 2.03 (ddd, J¼16.4, 9.5, 2.0 Hz, 1H), 2.28 (dt, J¼16.4,
2.2 Hz, 1H), 2.97 (dd, J¼2.4, 9.0 Hz, 1H), 4.27 (s, 2H), 4.47e4.53 (m,
2H), 4.86 (dd, J¼1.2, 10.3 Hz, 1H), 4.92 (dd, J¼17.1, 1.2 Hz, 1H), 5.53
(ddd, J¼17.1, 10.3, 8.8 Hz, 1H), 7.14e7.21 (m, 5H); 13C NMR
LRMS m/z 641 (Mꢁ Bu)þ 553, 509, 341, 283, 171; EI-HRMS calcd for
t
C26H54IO4Si3 (Mꢁ Bu)þ 641.2374, found 641.2363.
4.2.9. (2Z)-(5R,6S,7R)-5,7-Bis(tert-butyldimethylsilanyloxy)-6-[3-
(tert-butyldimethylsilanyloxy)propoxy]-3-iodonona-2,8-dien-1-ol
(9c). In the same procedure for 9a, 9c (1.88 g, 75%) was obtained
from 8c (2.07 g, 3.52 mmol), Red-AlÒ (65% toluene solution, 2.4 mL,
(100 MHz, CDCl3)
d
ꢁ4.2, ꢁ4.1, ꢁ4.0, ꢁ2.5, 14.2, 18.2, 18.3, 22.7, 25.9
(3C), 26.1 (2C), 26.3, 31.6, 51.4, 56.7, 69.7, 75.2, 80.6, 83.3, 117.0,
126.2,127.0, 131.2, 137.4,140.2; FABMS m/z 497 (MþNa)þ, HRFABMS
calcd for C27H47NaO3Si2 (MþNa)þ 497.2878, found 497.2855.
7.99 mmol), ethyl acetate (0.35 mL, 3.58 mmol), Et2O (35 mL), I2
25
(1.79 g, 7.06 mmol), and THF (10 mL). Colorless oil; [
4.46, CHCl3); IR (neat) 3331, 2930, 1254 cmꢁ1
CDCl3) 0.02 (s, 3H), 0.05 (s, 9H), 0.06 (s, 3H), 0.08 (s, 3H), 0.885 (s,
a
]
þ2.08 (c
D
4.2.6. (5R,6S,7R)-5,7-Bis(tert-butyldimethylsilanyloxy)-6-benzylnon-
8-en-2-yn-1-ol (8f). In the same procedure for 8a, 8f (1.18 g, 94%)
was obtained from 4f23e (1.18 g, 2.58 mmol), nBuLi (1.56 M hexane
;
1H NMR (400 MHz,
d
9H), 0.893 (s, 9H), 1.53 (t, J¼6.0 Hz, 1H), 1.78 (tt, J¼6.3, 6.3 Hz, 2H),
2.63 (dd, J¼14.2, 8.3 Hz, 1H), 2.78 (dd, J¼14.2, 4.3 Hz, 1H), 3.28 (dd,
J¼4.3, 3.1 Hz, 1H), 3.59 (dt, J¼9.3, 6.4 Hz, 1H), 3.66e3.77 (m, 3H),
4.06 (ddd, J¼8.3, 4.3, 3.8 Hz, 1H), 4.16 (m, 2H), 4.34 (dd, J¼7.3,
solution 2.5 mL, 3.90 mmol), paraformaldehyde (232 mg,
23
7.83 mmol), and THF (8.6 mL). Colorless oil; [
a
]
D
þ0.78 (c 2.15,
CHCl3); IR (neat) 3358, 2955, 2363, 1254, 1063 cmꢁ1 1H NMR
;

5414
D. Sawada et al. / Tetrahedron 66 (2010) 5407e5423
3.1 Hz, 1H), 5.12 (d, J¼17.4 Hz, 1H), 5.21 (d, J¼10.2 Hz, 1H), 5.87 (t,
J¼5.9 Hz, 1H), 5.94 (ddd, J¼17.4, 10.4, 7.3 Hz, 1H); 13C NMR
1.23 mmol) at 0 ꢀC and stirred at 90 ꢀC for 1 h. The mixture was
cooled to room temperature, and concentrated. The residue was
(100 MHz, CDCl3)
d
ꢁ5.2 (2C), ꢁ4.7, ꢁ4.3, ꢁ4.1, ꢁ4.0, 18.2, 18.3, 24.4,
purified by flash column chromatography on silica gel (hexane/
25
25.9 (3C), 26.0 (3C), 26.0 (3C), 26.1, 33.5, 51.5, 60.6, 69.3, 71.8, 74.6,
AcOEt¼12/1) to give 10a (633 mg, 82%) as a white powder: [
a
;
]
1DH
t
79.8, 84.2, 85.1, 115.9, 138.7; EI-LRMS m/z 657 (Mꢁ Bu)þ, 639, 525,
þ0.53 (c 2.85, CHCl3); IR (neat) 3353, 2953, 1458, 1254 cmꢁ1
t
467, 397; EI-HRMS calcd for C26H54IO5Si3 (Mꢁ Bu)þ 657.2324,
NMR (400 MHz, CDCl3) d 0.03 (s, 3H), 0.05 (s, 6H), 0.06 (s, 3H), 0.88
found 657.2323.
(s, 18H), 0.92 (d, J¼6.9 Hz, 3H), 1.13 (t, J¼5.7 Hz, 1H), 1.83 (ddq,
J¼6.9, 6.9, 3.7 Hz, 1H), 2.11 (dd, J¼13.5, 7.0 Hz, 1H), 2.48 (dd, J¼10.5,
3.6 Hz, 1H), 3.82 (ddd, J¼7.0, 6.9, 3.6 Hz, 1H), 4.20 (dd, J¼6.3, 5.7 Hz,
2H), 4.31 (d, J¼3.7 Hz, 1H), 4.77 (d, J¼1.5 Hz, 1H), 5.13 (d, J¼1.5 Hz,
4.2.10. (2Z)-(5R,6S,7R)-5,7-Bis(tert-butyldimethylsilanyloxy)-3-iodo-
6-butylnona-2,8-dien-1-ol (9d). In the same procedure for 9a, 9d
(992 mg, 75%) was obtained from 8d (1.03 g, 2.27 mmol), Red-AlÒ
(65% toluene solution, 1.71 mL, 5.70 mmol), ethyl acetate (0.40 mL,
4.06 mmol), Et2O (23 mL), I2 (1.15 g, 4.56 mmol), and THF (8 mL).
1H), 5.51 (t, J¼6.3 Hz, 1H); 13C NMR (100 MHz, CDCl3)
ꢁ5.0, ꢁ4.8,
d
ꢁ4.5, ꢁ4.4, 13.0, 18.1, 18.3, 25.8 (3C), 25.9 (3C), 42.9, 45.5, 59.7, 72.0,
75.1, 111.7, 126.2, 139.5, 146.5; EI-LRMS m/z 412 (M)þ, 394, 381, 355,
337, 223, 183; EI-HRMS calcd for C22H44O3Si2 (M)þ 412.2829, found
412.2815. Anal. Calcd for C22H44O3Si2: C, 64.01; H, 10.75. Found: C,
64.01; H, 10.42.
Colorless oil; [
a
]
22 þ2.56 (c 2.15, CHCl3); IR (neat) 3326, 2950, 1644,
D
1470, 1254, 1074 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
0.00 (s, 3H),
0.020 (s, 3H), 0.023 (s, 3H), 0.04 (s, 3H), 0.85 (s, 9H), 0.86 (s, 9H),
0.85e0.89 (m, 2H), 1.21e1.29 (m, 6H), 1.43 (t, J¼5.9 Hz, 1H), 1.61 (m,
1H), 2.64 (dd, J¼14.1, 4.4 Hz, 1H), 2.71 (dd, J¼14.1, 7.4 Hz, 1H), 4.07
(ddd, J¼7.4, 4.4, 3.0 Hz, 1H), 4.14e4.20 (m, 3H), 5.03 (dd, J¼10.0,
1.3 Hz, 1H), 5.10 (dd, J¼17.3, 1.4 Hz, 1H), 5.83 (t, J¼5.8 Hz, 1H), 5.88
4.2.14. (Z)-2-[(3S,4S,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-4-{3-
(tert-butyldimethylsilanyloxy)propyl}-2-methylenecyclohexylidene]
ethanol (10b). In the same procedure for 10a, 10b (404 mg, 89%)
was obtained from 9b (609 mg, 0.87 mmol), Pd(PPh3)4 (106 mg,
(ddd, J¼17.3, 10.0, 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
ꢁ4.6,
ꢁ3.9, ꢁ3.6, ꢁ3.5, 14.1, 18.1, 18.2, 23.1, 26.0, 26.0 (3C), 26.0 (3C), 31.1,
49.8, 50.8, 67.3, 71.4, 75.7,107.8,115.2, 136.1,140.8; EI-LRMS m/z 525
0.092 mmol), Et3N (1.21 mL, 8.68 mmol), and MeCN (44 mL). Col-
24
orless oil; [
a
]
ꢁ2.90 (c 1.69, CHCl3); IR (neat) 3322, 2955, 1640,
D
t
(Mꢁ Bu)þ, 509, 341, 283, 209; EI-HRMS calcd for C21H42IO3Si2
1472, 1254 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 0.02 (s, 3H), 0.04 (s,
t
(Mꢁ Bu)þ 525.1718, found 525.1724.
6H), 0.05 (s, 6H), 0.06 (s, 3H), 0.88e0.89 (m, 27H), 1.21e1.32 (m,
2H), 1.43e1.66 (m, 4H), 2.11 (dd, J¼13.7, 6.3 Hz, 1H), 2.46 (dd,
J¼13.7, 3.6 Hz, 1H), 3.58 (t, J¼6.2 Hz, 2H), 3.92 (d, J¼6.3 Hz, 1H),
4.20 (d, J¼6.8 Hz, 2H), 4.43 (d, J¼2.9 Hz, 1H), 4.76 (s, 1H), 5.14 (s,
4.2.11. (2Z)-(5R,6S,7R)-5,7-Bis(tert-butyldimethylsilanyloxy)-3-iodo-
6-phenylnona-2,8-dien-1-ol (9e). In the same procedure for 9a, 9e
(89 mg, 67%) was obtained from 8e (130 mg, 0.27 mmol), Red-AlÒ
1H), 5.50 (t, J¼6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
ꢁ5.2 (2C),
(65% toluene solution, 0.2 mL, 0.68 mmol), ethyl acetate (40
mL,
ꢁ5.0, ꢁ4.7, ꢁ4.5, ꢁ4.4,18.1,18.3, 18.4, 22.2, 25.9 (3C), 25.9 (3C), 26.1
(3C), 31.2, 42.6, 50.7, 59.7, 63.6, 70.3, 73.0, 111.5, 126.1, 139.3, 146.5;
EI-LRMS m/z 570 (M)þ, 552, 513, 423, 381, 289; EI-HRMS calcd for
C30H62O4Si3 (M)þ 570.3956, found 570.3964.
0.44 mmol), Et2O (3 mL), I2 (270 mg, 1.1 mmol), and THF (1 mL).
21
Colorless oil; [
a
]
þ10.7 (c 0.009, CHCl3); IR (neat) 3356, 2928,
D
1732, 1462, 1253 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d 0.03 (s, 3H),
0.09 (s, 6H), 0.19 (s, 3H), 0.90 (s, 9H), 0.93 (s, 9H), 1.23e1.26 (m, 1H),
2.38 (dd, J¼13.9, 9.3 Hz, 1H), 2.45e2.50 (m, 1H), 2.59 (dd, J¼9.3,
2.0 Hz, 1H), 4.15e4.24 (m, 2H), 4.46 (t, J¼9.0 Hz, 1H), 4.74e4.82 (m,
3H), 5.45 (ddd, J¼19.0, 10.3, 9.0 Hz 1H), 5.74 (t, J¼5.9 Hz, 1H),
4.2.15. (Z)-2-[(3R,4S,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-4-{3-
(tert-butyldimethylsilanyloxy)propoxy}-2-methylenecyclohexylidene]
ethanol (10c). In the same procedure for 10a, 10c (633 mg, 82%)
was obtained from 9c (936 mg, 1.31 mmol), Pd(PPh3)4 (153 mg,
7.15e7.18 (m, 5H); 13C NMR (100 MHz, CDCl3)
d
ꢁ4.2, ꢁ3.9, ꢁ3.8,
ꢁ2.5, 18.1, 18.2, 25.9 (3C), 26.2 (3C), 50.4, 55.7, 67.1, 69.6, 75.4, 105.3,
0.132 mmol), Et3N (1.82 mL, 13.1 mmol), and MeCN (33 mL).
25
116.6, 126.2, 127.1 (2C), 131.2 (2C), 136.0, 137.5, 140.4; EI-LRMS m/z
Colorless oil; [
a
]
ꢁ3.03 (c 2.85, CHCl3); IR (neat) 3346, 2955,
D
t
t
602 (Mꢁ Bu)þ; EI-HRMS calcd for C27H47IO3Si2 (Mꢁ Bu)þ 602.2113,
1645, 1253 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 0.03 (s, 6H), 0.05
found 602.2102.
(s, 3H), 0.07 (s, 6H), 0.08 (s, 3H), 0.88 (s, 9H), 0.88 (s, 9H), 0.89 (s,
9H), 1.12 (m, 1H), 1.76 (m, 2H), 2.07 (dd, J¼13.4, 5.2 Hz, 1H), 2.56
(d, J¼13.4 Hz, 1H), 3.28 (m, 1H), 3.58e3.79 (m, 4H), 4.01 (dd,
J¼5.2, 5.0 Hz, 1H), 4.19 (dd, J¼6.2, 5.9 Hz, 2H), 4.42 (s, 1H), 4.62 (s,
1H), 5.22 (s, 1H), 5.50 (dd, J¼6.7, 6.2 Hz, 1H); 13C NMR (100 MHz,
4.2.12. (2Z)-(5R,6S,7R)-5,7-Bis(tert-butyldimethylsilanyloxy)-3-iodo-
6-benzylnona-2,8-dien-1-ol (9f). In the same procedure for 9a, 9f
(1.13 g, 76%) was obtained from 8f (1.18 g, 2.42 mmol), Red-AlÒ (65%
toluene solution, 1.8 mL, 6.00 mmol), ethyl acetate (0.38 mL,
3.89 mmol), Et2O (25 mL), I2 (1.22 g, 4.88 mmol), and THF (4 mL).
CDCl3)
d
ꢁ5.2, ꢁ5.0, ꢁ4.7 (2C), ꢁ4.5, ꢁ4.4, 18.1, 18.3, 18.4, 22.2,
25.9 (3C), 25.9 (3C), 26.1 (3C), 31.2, 50.7, 59.7, 63.6, 70.3, 72.9,
111.4, 126.1, 139.4, 146.5; EI-LRMS m/z 586 (M)þ, 543, 529, 453,
397, 339; EI-HRMS calcd for C30H62O5Si3 (M)þ 586.3905, found
586.3890.
Colorless oil; [
a
]
21 þ2.46 (c 2.15, CHCl3); IR (neat) 3329, 2955, 1645,
D
1471, 1254, 1063 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
ꢁ0.08 (s, 3H),
ꢁ0.06 (s, 3H), 0.02 (s, 3H), 0.06 (s, 3H), 0.86 (s, 9H), 0.90 (s, 9H), 1.31
(t, J¼6.1 Hz, 1H), 2.02 (m, 1H), 2.49 (dd, J¼14.1, 5.5 Hz, 1H), 2.56 (dd,
J¼14.2, 9.5 Hz, 1H), 2.60 (dd, J¼14.1, 7.2 Hz, 1H), 2.75 (dd, J¼14.2,
3.9 Hz,1H), 4.00e4.11 (m, 3H), 4.22 (ddd, J¼7.3, 5.1, 0.5 Hz,1H), 5.08
(dd, J¼10.2, 1.6 Hz, 1H), 5.17 (ddd, J¼17.2, 1.6, 0.5 Hz, 1H), 5.40 (t,
J¼5.7 Hz, 1H), 5.90 (ddd, J¼17.2, 10.2, 7.3 Hz, 1H), 7.15 (m, 1H),
4.2.16. (Z)-2-[(3S,4S,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-4-bu-
tyl-2-methylenecyclohexylidene]ethanol (10d). In the same pro-
cedure for 10a, 10d (723 mg, 93%) was obtained from 9d (992 mg,
1.70 mmol), Pd(PPh3)4 (199 mg, 0.172 mmol), Et3N (2.4 mL,
21
7.20e7.26 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
ꢁ4.5, ꢁ4.2, ꢁ3.7,
17.2 mmol), and MeCN (43 mL). Colorless oil; [
a]
ꢁ0.98 (c 1.54,
D
ꢁ3.5, 18.2, 18.3, 26.1 (3C), 26.1 (3C), 31.9, 50.4, 51.8, 67.2, 70.6, 75.8,
CHCl3); IR (neat) 3329, 2955, 1640, 1472, 1254, 1088 cmꢁ1; 1H NMR
(400 MHz, CDCl3) 0.00 (s, 3H), 0.027 (s, 3H), 0.030 (s, 3H), 0.04 (s,
106.8, 115.8, 125.7, 128.1 (2C), 129.4 (2C), 136.4, 140.4, 142.0; EI-
d
LRMS m/z 559 (Mꢁ Bu)þ, 541, 415, 245; EI-HRMS calcd for
3H), 0.86 (s, 18H), 0.86e0.89 (m, 2H), 1.13e1.30 (m, 6H), 1.42 (m,
1H), 1.59 (m, 1H), 2.09 (dd, J¼13.7, 6.6 Hz, 1H), 2.45 (dd, J¼13.7,
3.6 Hz, 1H), 3.90 (ddd, J¼6.6, 6.6, 3.6 Hz, 1H), 4.18 (br d, J¼6.8 Hz,
1H), 4.39 (br d, J¼3.4 Hz, 1H), 4.74 (d, J¼1.6 Hz, 1H), 5.12 (d,
J¼1.6 Hz, 1H), 5.48 (t, J¼6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
t
C24H40IO3Si2 (Mꢁ Bu)þ 559.1560, found 559.1153.
t
4.2.13. (Z)-2-[(3S,4S,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-4-
methyl-2-methylenecyclohexylidene]ethanol (10a). To a solution of
Pd(PPh3)4 (135 mg, 0.119 mmol) in dry MeCN (19 mL) were added
9a (632 mg, 1.17 mmol) in dry MeCN (10 mL) and Et3N (1.63 mL,
d
ꢁ5.0, ꢁ4.8, ꢁ4.5, ꢁ4.4, 14.1 (2C), 18.1, 18.3, 23.0, 25.4, 25.8 (3C),
25.9 (3C), 29.9, 50.7, 59.6, 70.2, 72.9, 111.4, 126.1, 139.3, 146.7; EI-

D. Sawada et al. / Tetrahedron 66 (2010) 5407e5423
5415
LRMS m/z 454 (M)þ, 436, 397, 379, 265, 223; EI-HRMS calcd for
14.8, 6.6 Hz,1H), 3.41 (ddd, J¼14.8,13.8, 7.3 Hz,1H), 3.76 (dd, J¼11.3,
4.9 Hz, 1H), 4.33 (d, J¼3.7 Hz, 2H), 4.78 (s, 1H), 5.10 (s, 1H), 5.31 (dd,
J¼7.3, 6.6 Hz, 1H), 7.43e7.54 (m, 6H), 7.67e7.75 (m, 4H); 13C NMR
C25H50O3Si2 (M)þ 454.3298, found 454.3291.
4.2.17. (Z)-2-[(3S,4S,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-2-
methylene-4-phenylcyclohexylidene]ethanol (10e). In the same
procedure for 10a, 10e (77 mg, 99%) was obtained from 9e (89 mg,
(100 MHz, CDCl3)
d
ꢁ5.0, ꢁ4.8, ꢁ4.53, ꢁ4.50, 12.3, 18.1, 18.3, 25.9
(6C), 30.9, 31.6, 42.6, 45.4, 72.3, 72.3, 74.3, 111.5, 111.5, 114.3, 114.4,
128.4, 128.5, 130.9, 131.0, 131.6, 131.6, 141.1, 141.2, 145.9, 145.9; EI-
LRMS m/z 596 (M)þ, 539, 449, 263, 210; EI-HRMS calcd for
C34H53O3PSi2 (M)þ 596.3271, found 596.3284.
0.15 mmol), Pd(PPh3)4 (17 mg, 15
and MeCN (4 mL). Colorless oil; [
(neat) 3323, 2955, 1638, 1254 cmꢁ1
mmol), Et3N (0.2 mL, 1.5 mmol),
22
a
]
þ32.6 (c 0.007, CHCl3); IR
D
;
1H NMR (400 MHz, CDCl3)
d
ꢁ0.05 (s, 3H), ꢁ0.02 (s, 3H), ꢁ0.01 (s, 3H), 0.01 (s, 3H), 0.64 (s, 9H),
4.2.20. (Z)-[2-{(3S,4S,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-2-
methylene-4-(3-(tert-butyldimethylsilanyloxy)propyl)cyclo-
hexylidene}ethyl]diphenylphosphine oxide (3b). In the same
procedure for 3a, 3b (698 mg, 74%) was obtained from 10b
(715 mg, 1.25 mmol), NCS (340 mg, 2.54 mmol), CH2Cl2 (13 mL),
dimethylsulfide (0.19 mL, 2.59 mmol), Ph2PH (0.36 mL,
2.07 mmol), THF (7 mL), nBuLi (1.53 M hexane solution, 1.0 mL,
0.84 (s, 9H), 2.28 (t, J¼12.6 Hz, 1H), 2.66 (dd, J¼4.9, 12.6 Hz, 1H),
2.85 (dd, J¼2.7, 9.5 Hz, 1H), 4.08e4.21 (m, 2H), 4.25e4.31 (m, 2H),
4.41e4.46 (m, 1H), 4.83 (t, J¼1.6 Hz 1H), 5.13 (s, 1H), 5.65 (t,
J¼6.8 Hz, 1H), 7.14e7.25 (m, 5H); 13C NMR (100 MHz, CDCl3)
ꢁ5.5,
d
ꢁ5.0, ꢁ4.5, ꢁ3.9, 17.9, 18.1, 25.6 (3C), 25.9 (3C), 45.6, 58.4, 59.9, 69.5,
77.3, 113.0, 125.2, 126.2, 126.7, 127.5, 128.1, 129.0, 129.8, 138.8, 140.3,
146.9; FABMS m/z 492 (MþNa)þ, HRFABMS calcd for C27H46NaO3Si2
(MþNa)þ 497.2878, found 497.2860.
1.53 mmol), 35% H2O2 aqueous solution (9 mL), and CH2Cl2
27
(3.4 mL). Amorphous solid; [
a
]
þ0.16 (c 1.92, CHCl3); IR (neat)
D
2955, 1634, 1255, 1183 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
ꢁ0.05
4.2.18. (Z)-2-[(3S,4S,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-4-
benzyl-2-methylenecyclohexylidene]ethanol (10f). In the same pro-
cedure for 10a, 10f (824 mg, 92%) was obtained from 9f (1.13 g,
(s, 3H), ꢁ0.02 (s, 3H), ꢁ0.01 (s, 3H), 0.01 (s, 6H), 0.02 (s, 3H), 0.80
(s, 9H), 0.85 (s, 9H), 0.87 (s, 9H), 1.13 (br s, 1H), 1.45e1.65 (m, 2H),
2.05 (m, 1H), 2.39 (m, 1H), 3.12 (ddd, J¼16.0, 14.9, 6.8 Hz, 1H),
3.38 (ddd, J¼14.9, 14.8, 8.8 Hz, 1H), 3.54 (t, J¼6.1 Hz, 2H), 3.86
(ddd, J¼4.7, 4.7, 4.7 Hz, 1H), 4.41 (d, J¼2.3 Hz, 1H), 4.73 (s, 1H),
5.09 (s, 1H), 5.29 (dd, J¼14.1, 6.8 Hz, 1H), 7.42e7.52 (m, 6H),
1.84 mmol), Pd(PPh3)4 (218 mg, 0.189 mmol), Et3N (2.6 mL,
22
18.7 mmol), and MeCN (36 mL). Colorless oil; [
a]
D
ꢁ3.84 (c 1.54,
CHCl3); IR (neat) 3333, 2955, 1638, 1254, 1094 cmꢁ1
;
1H NMR
ꢁ0.10 (s, 3H), ꢁ0.09 (s, 3H), 0.02 (s, 3H), 0.04 (s,
(400 MHz, CDCl3)
d
7.65e7.72 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
ꢁ5.2 (2C), ꢁ5.0,
3H), 0.81 (s, 9H), 0.92 (s, 9H), 1.15 (br s, 1H), 2.10 (dd, J¼13.7, 4.6 Hz,
1H), 2.10 (m,1H), 2.43 (dd, J¼14.2, 9.2 Hz, 1H), 2.57 (d, J¼13.7 Hz, 1H),
2.88(dd, J¼14.2, 6.2 Hz,1H), 3.81 (dd, J¼4.8, 4.6 Hz,1H), 4.15e4.26(m,
2H), 4.46 (d, J¼2.7 Hz, 1H), 4.79 (s, 1H), 5.18 (s, 1H), 5.49 (t, J¼6.7 Hz,
1H), 7.11e7.17 (m, 3H), 7.24e7.26 (m, 2H); 13C NMR (100 MHz, CDCl3)
ꢁ4.8, ꢁ4.6, ꢁ4.5, 18.0, 18.3, 18.4, 21.8, 25.9 (5C), 26.0 (1C), 30.9,
31.3, 31.6, 50.7, 58.0, 63.6, 70.3, 71.3, 72.6, 72.6, 111.1, 113.3, 114.3,
114.4, 128.4, 128.5, 130.9, 130.9, 130.9, 131.0, 131.6, 133.5, 138.5,
141.0. 146.1; EI-LRMS m/z 754 (M)þ, 697, 622, 565, 490, 433, 201;
EI-HRMS calcd for C42H71O4PSi3 (M)þ 754.4398, found 754.4413.
d
ꢁ4.94, ꢁ4.92, ꢁ4.7, ꢁ4.5, 18.0, 18.4, 25.8 (3C), 26.0 (3C), 31.4, 41.4,
52.4, 59.7, 70.0, 72.1, 111.4, 125.7, 126.4, 128.2 (2C), 128.7 (2C), 139.2,
141.0,146.1; EI-LRMS m/z 488 (M)þ, 470, 431, 413, 299; EI-HRMS calcd
for C28H48O3Si2 (M)þ 488.3142, found 488.3149.
4.2.21. (Z)-[2-{(3R,4S,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-2-
methylene-4-(3-(tert-butyldimethylsilanyloxy)propoxy)cyclohexy-
lidene}ethyl]diphenylphosphine oxide (3c). In the same procedure
for 3a, 3c (1.20 g, 66%) was obtained from 10c (1.33 g, 2.27 mmol),
NCS (701 mg, 5.25 mmol), CH2Cl2 (18 mL), dimethylsulfide (0.42 mL,
5.45 mmol), Ph2PH (0.62 mL, 3.56 mmol), THF (13 mL), nBuLi (1.53 M
4.2.19. (Z)-[2-{(3S,4S,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-2-
methylene-4-methylcyclohexylidene}ethyl]diphenylphosphine oxide
(3a). To a solution of NCS (169 mg, 1.23 mmol) in dry CH2Cl2 (3 mL)
was added dimethylsulfide (0.10 mL, 1.26 mmol) at 0 ꢀC, and stirred
at the same temperature for 15 min. To the mixture was added 10a
(251 mg, 0.2 mmol) in dry CH2Cl2 (3 mL) at e16 ꢀC and stirred for
1.5 h at the same temperature. The mixture was warmed up to 0 ꢀC,
added water at the same temperature, and extracted with CH2Cl2.
The organic layer was washed with brine, dried over Na2SO4, and
concentrated. The residue was purified by short column chroma-
tography on silica gel (hexane/AcOEt/TEA¼100/10/1) to give
a crude product. To a solution of Ph2PH (0.21 mL, 1.21 mmol) in dry
THF (25 mL) was added nBuLi (1.53 M hexane solution, 0.58 mL,
0.887 mmol) at 0 ꢀC and stirred for 10 min at the same tempera-
ture. To another flask charged with the crude product in dry THF
(2 mL) was added the above lithium diphenylphosphide solution at
ꢁ78 ꢀC and stirred at the same temperature for 10 min. To the
mixture was added water at ꢁ78 ꢀC and warmed up to 0 ꢀC. The
resulting mixture was concentrated, and the residue was dissolved
in CH2Cl2 (2.1 mL). To the mixture was added 35% H2O2 aqueous
solution (5.1 mL) at 0 ꢀC. After stirring for 1.5 h at 0 ꢀC, to the
mixture was added water at the same temperature and extracted
with CH2Cl2. The organic layer was washed with 2 N Na2SO3
aqueous solution, and brine, dried over Na2SO4, and concentrated.
The residue was purified by flash column chromatography on silica
hexane solution, 1.0 mL, 1.53 mmol), 35% H2O2 aqueous solution
27
(16 mL), and CH2Cl2 (6 mL). Amorphous solid; [
CHCl3); IR (neat) 2955, 1644, 1256, 1186 cmꢁ1
CDCl3)
a
]
ꢁ1.05 (c 3.62,
D
;
1H NMR (400 MHz,
d
ꢁ0.04 (s, 3H), 0.00 (s, 9H), 0.01 (s, 3H), 0.04 (s, 3H), 0.80 (s,
9H), 0.85 (s, 9H), 0.88 (s, 9H), 1.71 (tt, J¼6.7, 6.7 Hz, 2H), 2.02 (m, 1H),
2.49 (m, 1H), 3.14 (ddd, J¼15.5, 14.9, 6.3 Hz, 1H), 3.25 (m, 1H), 3.36
(ddd, J¼14.9, 14.0, 8.2 Hz, 1H), 3.44e3.52 (m, 4H), 3.92 (ddd, J¼4.2,
4.2, 4.2 Hz,1H), 4.37 (s,1H), 4.76 (s, 1H), 5.16 (s, 1H), 5.32 (dd, J¼15.5,
8.2 Hz,1H), 7.41e7.51 (m, 6H), 7.64e7.73 (m, 4H); 13C NMR (100 MHz,
CDCl3)
d
ꢁ5.3, ꢁ5.2, ꢁ4.9, ꢁ4.8 (2C), ꢁ4.7, 18.1, 18.3, 18.4, 25.8 (3C),
25.9 (3C), 26.0 (3C), 31.0, 31.7, 33.6, 60.3, 68.5, 69.9, 73.3, 84.3, 111.6,
114.7, 114.8, 128.4, 128.4, 128.5, 130.9, 130.9, 131.0, 131.0, 131.6, 133.1,
140.4, 140.6, 144.9, 144.9; EI-LRMS m/z 770 (M)þ, 713, 581, 523, 449,
201; EI-HRMS calcd for C42H71O5PSi3 (M)þ 770.4347, found 770.4341.
4.2.22. (Z)-[2-{(3S,4S,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-4-
butyl-2-methylenecyclohexylidene}ethyl]diphenylphosphine
oxide
(3d). In the same procedure for 3a, 3d (776 mg, 76%) was obtained
from 10d (723 mg, 1.59 mmol), NCS (429 mg, 3.21 mmol), CH2Cl2
(17 mL), dimethylsulfide (0.26 mL, 3.54 mmol), Ph2PH (0.55 mL,
3.16 mmol), THF (5 mL), nBuLi (1.57 M hexane solution, 1.51 mL,
2.37 mmol), 35% H2O2 aqueous solution (10 mL), and CH2Cl2 (5 mL).
Amorphous solid; [
a
]
26 ꢁ0.39 (c 2.08, CHCl3); IR (neat) 2955, 2226,
gel (hexane/AcOEt¼3/2) to give 3a (213 mg, 77% in three steps) as
1254, 1182, 1080 cmꢁD1
;
1H NMR (400 MHz, CDCl3)
d
ꢁ0.05 (s, 3H),
25
an amorphous solid: [
a
]
þ0.22 (c 3.69, CHCl3); IR (neat) 2924,
ꢁ0.02 (s, 3H), ꢁ0.01 (s, 3H), 0.02 (s, 3H), 0.80 (s, 9H), 0.83e0.88 (m,
3H), 0.88 (s, 9H), 1.10 (m, 1H), 1.23e1.24 (m, 4H), 1.44 (m, 1H), 1.63
(m, 1H), 2.04 (m, 1H), 2.39 (m, 1H), 3.12 (ddd, J¼16.0, 15.5, 7.0 Hz,
1H), 3.39 (ddd, J¼15.5,14.9, 8.3 Hz,1H), 3.85 (ddd, J¼9.3, 3.6, 3.6 Hz,
D
1458, 1377, 1091 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
0.00 (s, 6H), 0.01 (s, 3H), 0.38 (m, 1H), 1.85 (m, 1H), 2.06 (ddd,
d
ꢁ0.32 (s, 3H),
J¼13.6, 5.6, 4.9 Hz, 1H), 2.43 (d, J¼13.6 Hz, 1H), 3.13 (ddd, J¼15.8,

5416
D. Sawada et al. / Tetrahedron 66 (2010) 5407e5423
1H), 4.40 (d, J¼3.7 Hz, 1H), 4.74 (s, 1H), 5.09 (s, 1H), 5.29 (ddd,
J¼15.3, 8.3, 7.0 Hz, 1H), 7.42e7.52 (m, 6H), 7.65e7.72 (m, 4H); 13C
bottom vessel using vacuum pump to give a residue, which was
suspended in toluene (5 mL). To the solution was added 6 (700 mg,
2.46 mmol) in toluene (5 mL) and the mixture was stirred for 3 h at
room temperature. The reaction was quenched by aqueous NH4Cl at
0 ꢀC, and the mixture was extracted with AcOEt, washed with brine,
dried over Na2SO4, filtered, and concentrated. The residue was puri-
fied by flash column chromatography on silica gel (hexane/
AcOEt¼10/1 to 8/1) to give a colorless oil (800 mg,100%). To a solution
of the compound obtained above (595 mg,1.82 mmol) inTHF (10 mL)
was added 9-BBN (8.02 mL, 0.5 M THF solution, 4 mmol), and the
mixture was stirred for 3 h at room temperature. Then, the mixture
was cooled to 0 ꢀC, and aqueous 35% H2O2 (1 mL) and aqueous 15%
NaOH (1 mL) were added to the mixture, which was stirred for 1 h.
The reaction was quenched by aqueous Na2S2O3 and aqueous NH4Cl
at0 ꢀC, and themixturewasextracted withAcOEt, washedwithbrine,
dried over Na2SO4, filtered, and concentrated. The residue was puri-
fied by flash column chromatography on silica gel (hexane/AcOEt¼1/
1 to 1/2) to give a colorless oil (630 mg, 100%).To a solution of the
compound obtained above (105 mg, 0.305 mmol) in DMF (1.5 mL)
NMR (100 MHz, CDCl3)
d
ꢁ5.5, ꢁ5.3, ꢁ5.0, ꢁ4.9, 13.6, 17.6, 17.7, 22.5,
24.5, 25.4 (6C), 25.5, 25.6, 50.2, 69.8, 113.8, 113.9, 127.9, 128.0, 130.3,
130.3, 130.4, 130.4, 131.1, 131.8, 132.1, 132.8, 133.1, 140.4, 140.5, 145.7,
145.7; EI-LRMS m/z 638 (M)þ, 581, 437, 201; EI-HRMS calcd for
C37H59O3PSi2 (M)þ 638.3740, found 638.3748.
4.2.23. (Z)-[2-{(3S,4S,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-2-
methylene-4-phenylcyclohexylidene}ethyl]diphenylphosphine oxide
(3e). In the same procedure for 3a, 3e (77 mg, 39%) was obtained
from 10e (135 mg, 0.28 mmol), NCS (114 mg, 0.85 mmol), CH2Cl2
(4 mL), dimethylsulfide (70 mL, 0.94 mmol), Ph2PH (56 mL,
0.3 mmol), THF (1 mL), nBuLi (1.57 M hexane solution, 0.1 mL,
0.16 mmol), 35% H2O2 aqueous solution (0.16 mL), and CH2Cl2
23
(1 mL). Amorphous solid; [
a
]
þ66.2 (c 0.009, CHCl3); IR (neat)
1472, 1437, 1391, 1362 cmꢁ1; 1DH NMR (400 MHz, CDCl3)
d
ꢁ0.46 (s,
3H), ꢁ0.22 (s, 3H), ꢁ0.16 (s, 3H), ꢁ0.04 (s, 3H), 0.61 (s, 9H), 0.79 (s,
9H), 2.24e2.32 (m,1H), 2.61 (dd, J¼13.2, 4.7 Hz,1H), 2.84 (dd, J¼9.2,
3.0 Hz, 1H), 3.04e3.12 (m, 1H), 3.50 (dt, J¼14.4, 10.5, Hz, 1H), 4.24
(d, J¼3.0 Hz, 1H), 4.36 (dt, J¼9.2, 4.7 Hz, 1H), 4.82 (d, J¼2.1 Hz, 1H),
5.03 (s, 1H), 5.41 (t, J¼5.0 Hz, 1H), 7.13e7.22 (m, 5H), 7.44e7.58 (m,
6H), 7.65e7.70 (m, 2H), 7.76e7.80 (m, 2H); 13C NMR (100 MHz,
were added imidazole (42 mg, 0.61 mmol) and TBDPSCl (95 mL,
0.366 mmol), and the mixture was stirred for 1 h at room tempera-
ture. The reaction was quenched by aqueous NH4Cl at 0 ꢀC, and the
mixture was extracted with AcOEt, washed with brine, dried over
Na2SO4, filtered, and concentrated. The residue was purified by flash
column chromatography on silica gel (hexane/AcOEt¼30/1) to give
CDCl3)
d
ꢁ5.4, ꢁ5.0, ꢁ4.4, ꢁ3.9, 14.3, 17.8, 18.1, 25.6 (3C), 25.8, 25.9
(3C), 31.2, 45.5, 58.3, 69.9, 77.0, 77.2, 112.9, 126.2, 127.5, 128.5, 128.6,
129.8, 130.7, 130.8, 131.0, 131.2, 131.7, 131.8, 132.7, 140.3, 140.8, 146.5,
146.5; FABMS m/z 659 (MþH)þ, HRFABMS calcd for C39H55O3PSi2
(MþH)þ 659.3525, found 659.3506.
11h (169 mg, 95% in three steps) as a colorless oil: [
a
]
22 þ5.1 (c 0.69,
D
CHCl3); IR (neat) 3069, 2930, 2859, 1109, 737, 700 cmꢁ1
;
1H NMR
(400 MHz, CDCl3) d 1.92e1.96 (m, 1H), 2.22e2.32 (m, 2H), 3.06 (br s,
1H), 3.56e3.66 (m, 4H), 3.93 (dd, J¼11.2, 5.6 Hz,1H), 4.49 (s, 2H), 4.57
4.2.24. (Z)-[2-{(3S,4S,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-4-
benzyl-2-methylenecyclohexylidene}ethyl]diphenylphosphine oxide
(3f). In the same procedure for 3a, 3f (947 mg, 83%) was obtained
from 10f (723 mg, 1.59 mmol), NCS (824 mg, 1.69 mmol), CH2Cl2
(17 mL), dimethylsulfide (0.27 mL, 3.68 mmol), Ph2PH (0.54 mL,
3.10 mmol), THF (13 mL), nBuLi (1.57 M hexane solution, 1.50 mL,
2.36 mmol), 35% H2O2 aqueous solution (5 mL), and CH2Cl2 (2 mL).
(s, 2H), 5.04e5.10 (m, 2H), 5.77e5.84 (m,1H), 7.29e7.39 (m,10H); 13C
NMR (100 MHz, CDCl3)
d 19.2, 24.6, 26.9, 30.2, 40.4, 64.0, 70.4, 72.2,
72.9, 73.3, 73.3, 127.5, 127.5, 127.6, 127.6, 128.3, 129.4, 133.9, 135.4,
138.0, 138.0; FABMS m/z 605 (MþNa)þ, HRFABMS calcd for
C37H46NaO4Si 605.3063, found 605.3061.
4.2.27. (4R,5R)-5-(Benzyloxymethyl)-12,12-dimethyl-1,11,11-tri-
phenyl-2,6,10-trioxa-11-silatridecan-4-ol (11i). To a solution of 6
(100 mg, 0.35 mmol) in propylene glycol (1 mL) was added KOtBu
(119 mg, 1.06 mmol) and stirred at 100 ꢀC for 2.5 h. The reaction
was quenched by aqueous NH4Cl at 0 ꢀC, and the mixture was
extracted with AcOEt, washed with brine, dried over Na2SO4, fil-
tered, and concentrated. The residue was purified by flash column
chromatography on silica gel (hexane/AcOEt¼1/1) to give a color-
less oil (123 mg, 97%). To a solution of the compound obtained
above (120 mg, 0.33 mmol) in DMF (1 mL) were added imidazole
Amorphous solid; [
a
]
23 ꢁ2.02 (c 5.31, CHCl3); IR (neat) 2955, 1638,
D
1593, 1254, 1173, 1078 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
ꢁ0.22 (s,
3H), ꢁ0.17 (s, 3H), 0.00 (s, 3H), 0.04 (s, 3H), 0.71 (s, 9H), 0.92 (s, 9H),
2.03e2.15 (m, 2H), 2.27 (dd, J¼13.1, 11,8 Hz, 1H), 2.53 (d, J¼13.9 Hz,
1H), 2.91 (dd, J¼13.1, 5.0 Hz, 1H), 3.18 (ddd, J¼16.1, 14.9, 6.6 Hz, 1H),
3.38 (ddd, J¼14.9, 13.7, 8.0 Hz, 1H), 3.71 (m, 1H), 4.48 (d, J¼2.2 Hz,
1H), 4.83 (s, 1H), 5.19 (s, 1H), 5.32 (ddd, J¼14.2, 8.0, 6.6 Hz, 1H),
7.07e7.15 (m, 3H), 7.21e7.24 (m, 2H), 7.42e7.52 (m, 6H), 7.67e7.77
(m, 4H); 13C NMR (100 MHz, CDCl3)
d
ꢁ5.0, ꢁ5.0, ꢁ4.9, ꢁ4.5, 18.0,
18.3, 25.8 (3C), 25.9 (3C), 30.9, 31.2, 31.6, 52.5, 68.9, 71.7, 111.0,
114.5, 114.6, 125.6, 128.2 (2C), 128.4 (2C), 128.5 (2C), 128.7 (2C),
130.8, 130.9, 130.9, 131.0, 131.7, 140.8, 140.9, 141.0, 145.6, 145.7; EI-
LRMS m/z 672 (M)þ, 616, 483, 449; EI-HRMS calcd for C40H57O3PSi2
(M)þ 672.3584, found 672.3581.
(45 mg, 0.66 mmol) and TBDPSCl (104 mL, 0.40 mmol), and the
mixture was stirred for 1 h at room temperature. The reaction was
quenched by aqueous NH4Cl at 0 ꢀC, and the mixture was extracted
with AcOEt, washed with brine, dried over Na2SO4, filtered, and
concentrated. The residue was purified by flash column chroma-
tography on silica gel (hexane/AcOEt¼10/1 to 6/1) to give 11i
25
4.2.25. (2S,3S)-1,4-Bis(benzyloxy)-3-methylbutan-2-ol
(11g). To
(189 mg, 92% in two steps) as a colorless oil: [
a
]
þ7.7 (c 6.54,
D
a solution of CuI (398 mg, 2.09 mmol) in Et2O (5 mL) was added
MeLi (1.14 M Et2O solution, 3.66 mL, 4.17 mmol) at ꢁ40 ꢀC and
stirred for 40 min at 0 ꢀC. After the mixture was cooled to ꢁ78 ꢀC, 6
(396 mg, 1.39 mmol) in Et2O (2 mL) was added, and the whole
mixture was gradually warmed up to 0 ꢀC over 2 h. After stirring for
further 1 h at 0 ꢀC, the reaction was quenched by aqueous NH4Cl at
0 ꢀC, the mixture was extracted with AcOEt, washed with brine,
dried over Na2SO4, filtered, and concentrated. The residue was
purified by flash column chromatography on silica gel (hexane/
AcOEt¼10/1 to 8/1) to give 11g (409 mg, 98%) as a colorless oil.26b
CHCl3); IR (neat) 3453, 2930, 2859, 1111, 737, 702 cmꢁ1
(400 MHz, CDCl3)
3.48 (m, 1H), 3.55e3.62 (m, 4H), 3.66e3.75 (m, 4H), 3.92 (m, 1H),
4.49 (s, 2H), 4.50 (d, J¼11.2 Hz, 1H), 4.53 (d, J¼11.2 Hz, 1H),
7.27e7.40 (m, 16H), 7.64e7.66 (m, 4H); 13C NMR (100 MHz, CDCl3)
;
1H NMR
d
1.04 (s, 9H), 1.78 (m, 2H), 2.60 (d, J¼5.1 Hz, 1H),
d
19.0, 19.2, 26.6, 26.9, 33.0, 60.8, 67.3, 69.7, 70.6, 71.1, 73.3, 73.4,
78.8, 127.4, 127.5, 127.5, 127.5, 127.6, 128.2, 128.2, 129.4, 129.4, 133.7,
134.7, 135.2, 135.4, 137.9, 138.0; EI-LRMS m/z 598 (M)þ, 575, 507; EI-
HRMS calcd for C37H46O5Si 598.3115, found 598.3109.
4.2.28. (2S,3S)-4-Bromo-2-methylbutane-1,3-diyl diethanoate (12g).
To a solution of 11g (400 mg, 1.33 mmol) in THF (8 mL) was added
Pd on carbon (20 mg), and the mixture was stirred under H2 at-
mosphere for 10 h. The reaction was filtered and concentrated to
4.2.26. (2S,3S)-1-(Benzyloxy)-3-(benzyloxymethyl)-6-(tert-butyldi-
phenylsilanyloxy)hexan-2-ol
(11h). Allylmagnesium
chloride
(6.15 mL, 2.0 M THF solution, 12 mmol) was evaporated in a round

D. Sawada et al. / Tetrahedron 66 (2010) 5407e5423
5417
give a crude product, which was dissolved in CH2Cl2 (5 mL). To the
filtered, and concentrated. The residue was purified by flash col-
umn chromatography on silica gel (hexane/AcOEt¼10/1) to give
solution was added trimethyl orthoacetate (208 mL,1.73 mmol), and
PPTS (3.3 mg, 0.0133 mmol) at 0 ꢀC, and the mixture was stirred at
room temperature for 30 min. The reaction was concentrated, and
the residue was dissolved in CH2Cl2 (4 mL). To the solution was
13g (432 mg, 80% in two steps) as a colorless oil: [
a
]
24 ꢁ9.0 (c 2.85,
D
CHCl3); IR (neat) 2970, 1721, 1275, 1113, 711 cmꢁ1
;
1H NMR
(400 MHz, CDCl3)
d
1.02 (d, J¼7.1 Hz, 3H), 1.75e1.83 (m, 1H), 2.50
added acetyl bromide (118
mL, 1.6 mmol), and the mixture was
(dd, J¼4.9, 2.7 Hz, 1H), 2.69 (dd, J¼4.9, 4.2 Hz, 1H), 2.85e2.90 (m,
stirred at room temperature for 1 h. The reaction was quenched by
aqueous NH4Cl at 0 ꢀC, and the mixture was extracted with AcOEt,
washed with brine, dried over Na2SO4, filtered, and concentrated.
The residue was purified by flash column chromatography on silica
gel (hexane/AcOEt¼6/1 to 4/1) to give 12g (213 mg, 60% in three
1H), 4.30 (d, J¼5.7 Hz, 2H), 7.35e7.42 (m, 2H), 7.46e7.50 (m, 1H),
8.00e8.02 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 12.7, 35.8, 45.2,
53.6, 66.7, 128.0, 129.2, 129.9, 132.6, 166.0; FABMS m/z 207 (MþH)þ,
HRFABMS calcd for C12H15O3 207.1021, found 207.1028.
steps) as a colorless oil: [
a
]
24 ꢁ29.9 (c 1.38, CHCl3); IR (neat) 2975,
4.2.32. (S)-5-(tert-Butyldiphenylsilanyloxy)-2-[(S)-oxiran-2-yl]pen-
tyl benzoate (13h). In the same procedure for 13g, 12h (28 mg,
0.051 mmol), K2CO3 (17 mg, 0.122 mmol), MeOH (3 mL) gave a col-
orless oil (19 mg, 96%). The compound obtained above (270 mg,
0.70 mmol), CH2Cl2 (5 mL), triethylamine (0.196 mL, 1.40 mmol),
1742, 1373, 1240, 1038 cmꢁD1
; d 1.01 (d,
1H NMR (400 MHz, CDCl3)
J¼7.1 Hz, 3H), 2.05 (s, 3H), 2.12 (s, 3H), 2.26e2.35 (m, 1H), 3.50 (dd,
J¼11.4, 5.3 Hz, 1H), 3.64 (dd, J¼11.4, 3.7 Hz, 1H), 4.02 (dd, J¼11.2,
4.8 Hz, 1H), 4.09 (dd, J¼11.2, 5.4 Hz, 1H), 4.93e4.98 (m, 1H); 13C
NMR (100 MHz, CDCl3)
d
13.6, 20.9, 20.9, 33.0, 34.9, 65.0, 72.9, 170.1,
and benzoyl chloride (122
95% in two steps) as a colorless oil: [
(neat) 2932, 1721, 1273, 1111, 706 cmꢁ1; 1H NMR (400 MHz, CDCl3)
mL, 1.05 mmol) afforded 13h (339 mg,
170.8; FABMS m/z 267 (MþH)þ, HRFABMS calcd for C9H1579BrO4
a
]
ꢁ2.9 (c 1.08, CHCl3); IR
22
D
267.0232, found 267.0254.
d
1.10 (s, 9H),1.62e1.71 (m, 5H), 2.58 (m,1H), 2.83 (dd, J¼4.6, 4.4 Hz,
4.2.29. (2S,3S)-4-Bromo-2-[3-(tert-butyldiphenylsilanyloxy)propyl]
butane-1,3-diyl diethanoate (12h). In the same procedure for 12g,
11h (52 mg, 0.089 mmol), Pd on carbon (16 mg), H2, THF (5 mL)
gave a colorless oil (19 mg, 96%). The compound obtained above
1H), 2.95e2.98 (m, 1H), 3.73e3.74 (m, 2H), 4.43e4.50 (m, 2H),
7.39e7.48 (m, 8H), 7.56 (m, 1H), 7.70e7.72 (m, 4H), 8.07e8.10 (m,
2H); 13C NMR (100 MHz, CDCl3)
d 19.1, 24.7, 26.8, 29.9, 41.1, 46.5,
53.2, 63.6, 65.5, 127.5, 127.8, 128.2, 129.4, 129.8, 130.0, 132.7, 133.6,
133.4, 166.2; FABMS m/z 489 (MþH)þ, HRFABMS calcd for
C30H37O4Si 489.2461, found 489.2448.
(37 mg, 0.092 mmol), CH2Cl2 (1 mL), trimethyl orthoacetate (33
0.276 mmol), and then PPTS (1 mg, 0.013 mmol), acetyl bromide
(8 L, 0.11 mmol), and CH2Cl2 (1 mL) afforded 12h (30 mg, 52% in
three steps) as a colorless oil: [
2932, 1744, 1372, 1236, 1111 cmꢁ1; 1H NMR (400 MHz, CDCl3)
mL,
m
22
a
]
þ8.7 (c 0.77, CHCl3); IR (neat)
4.2.33. (S)-2-[3-(tert-Butyldiphenylsilanyloxy)propoxy]-2-[(R)-ox-
iran-2-yl]ethyl benzoate (13i). In the same procedure for 13g, 12i
(440 mg, 0.778 mmol), K2CO3 (269 mg, 1.95 mmol), MeOH (3 mL)
gave a colorless oil (309 mg, 99%). The compound obtained above
(68 mg, 0.17 mmol), CH2Cl2 (2.5 mL), triethylamine (0.047 mL,
D
d
1.03
(s, 9H), 1.3e1.45 (m, 2H), 1.56e1.61 (m, 2H), 2.02 (s, 2H), 2.07 (s,
1H), 2.13 (m, 1H), 3.49 (dd, J¼11.2, 5.9 Hz, 1H), 3.55 (dd, J¼11.2,
4.4 Hz, 1H), 3.65 (t, J¼5.9 Hz, 2H), 4.05 (dd, J¼11.7, 5.1 Hz, 1H), 4.14
(dd, J¼11.7, 4.6 Hz, 1H), 5.05 (m, 1H), 7.34e7.43 (m, 6H), 7.62e7.65
0.34 mmol) and benzoyl chloride (30
mL, 2.55 mmol) afforded 13i
(m, 4H); 13C NMR (100 MHz, CDCl3)
d
19.2, 20.8, 20.8, 20.9, 20.9,
(72 mg, 83% in two steps) as a colorless oil: [
a]
22 þ0.3 (c 1.54, CHCl3);
D
24.0, 26.9, 29.6, 32.7, 39.5, 62.5, 63.4, 72.3, 127.5, 129.5,133.6, 135.4,
169.9, 170.6; FABMS m/z 573 (MþNa)þ, HRFABMS calcd for
C27H3779BrNaO5Si 571.1491, found 571.1490.
IR (neat) 2930,1725,1273,1111, 706 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.09 (s, 9H),1.86 (m, 2H), 2.80 (dd, J¼5.4, 2.4 Hz,1H), 2.83 (dd, J¼5.4,
3.9 Hz, 1H), 3.10 (m, 1H), 3.54 (m, 1H), 3.70e3.83 (m, 4H), 4.45 (dd,
J¼11.7, 5.9 Hz, 1H), 4.55 (dd, J¼11.7, 3.9 Hz, 1H), 7.38e7.40 (m, 8H),
7.56 (m, 1H), 7.68e7.71 (m, 4H), 8.07e8.10 (m, 2H); 13C NMR
4.2.30. (2S,3S)-4-Bromo-2-[3-(tert-butyldiphenylsilanyloxy)pro-
poxy]butane-1,3-diyl diethanoate (12i). In the same procedure for
12g, 11i (185 mg, 0.309 mmol), Pd on carbon (24 mg), H2, MeOH
(5 mL) gave a colorless oil (98 mg, 76%). The compound obtained
above (585 mg, 1.40 mmol), CH2Cl2 (6 mL), trimethyl orthoacetate
(100 MHz, CDCl3)
d 19.2, 19.6, 26.9, 33.0, 45.2, 51.0, 60.4, 64.6, 67.4,
77.0, 127.5, 127.5, 127.5, 127.6, 128.3, 129.5, 129.5, 129.6, 129.6, 129.8,
132.9, 133.7, 135.4, 160.1; FABMS m/z 527 (MþNa)þ, HRFABMS calcd
for C30H36NaO5Si 527.2230, found 527.2227.
(508
mL, 4.20 mmol), and then PPTS (3.5 mg, 0.014 mmol), trie-
thylamine (2
m
L, 0.014 mmol), acetyl bromide (155 L, 2.1 mmol),
m
4.2.34. (2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-methylhex-5-yn-
1-ol (14g). To a solution of trimethylsilylacetylene (0.823 mL,
5.83 mmol) in THF (5 mL) was added nBuLi (1.56 M hexane solution,
3.43 mL, 5.36 mmol) at ꢁ78 ꢀC and stirred at the same temperature
for 30 min. To the mixture were added 13g (480 mg, 2.33 mmol) in
and CH2Cl2 (6 mL) afforded 12i (578 mg, 55% in three steps) as
a colorless oil: [
a]
22 ꢁ3.9 (c 0.46, CHCl3); IR (neat) 2930, 2361, 1748,
D
1238, 1111 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.03 (s, 9H), 1.79 (m,
2H), 2.01 (s, 3H), 2.07 (s, 3H), 3.60e3.80 (m, 6H), 4.09 (dd, J¼12.2,
4.2 Hz, 1H), 4.26 (dd, J¼12.2, 3.2 Hz, 1H), 4.98 (m, 1H), 7.34e7.41 (m,
THF (3 mL) and BF3$Et2O (325
m
L, 2.56 mmol) at ꢁ78 ꢀC, and the
6H), 7.63e7.65 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
14.2, 19.1, 20.7,
whole mixture was gradually warmed to ꢁ30 ꢀC over 2.5 h. After the
reaction was quenched by aqueous NaHCO3 at 0 ꢀC, the mixture was
extracted with AcOEt, washed with brine, dried over Na2SO4, fil-
tered, and concentrated. The residue was purified by flash column
chromatography on silica gel (hexane/AcOEt¼15/1 to 10/1) to give
a colorless oil (564 mg, 80%). To a solution of the compound obtained
above (540 mg, 1.77 mmol) in CH2Cl2 (5 mL) were added N,N-dii-
20.8, 26.8, 32.1, 32.8, 60.2, 60.4, 61.6, 67.5, 70.4, 76.4, 127.5, 129.4,
133.6, 135.3, 169.4, 170.4; FABMS m/z 587 (MþNa)þ, HRFABMS calcd
for C27H3779BrNaO6Si 587.1441, found 587.1448.
4.2.31. (S)-2-[(S)-Oxiran-2-yl]propyl benzoate (13g). To a solution of
12g (700 mg, 2.62 mmol) in MeOH (7 mL) was added K2CO3 (1.09 g,
7.86 mmol) at 0 ꢀC and stirred at room temperature for 2.5 h. After
the reaction was quenched by aqueous NH4Cl at 0 ꢀC, the mixture
was extracted with AcOEt, washed with brine, dried over Na2SO4,
filtered, and concentrated to give a crude product, which was dis-
solved in CH2Cl2 (11 mL). To the solution was added triethylamine
sopropylethylamine (462 mL, 2.66 mmol) and TBSOTf (508 mL,
2.21 mmol) at 0 ꢀC and stirred at room temperature for 1 h. After the
reaction was quenched by aqueous NaHCO3 at 0 ꢀC, the mixture was
extracted with AcOEt, washed with brine, dried over Na2SO4, fil-
tered, and concentrated. The residue was purified by flash column
chromatography on silica gel (hexane/AcOEt¼100/1 to 50/1) to give
a colorless oil (672 mg, 90%). To a solution of the compound obtained
above (630 mg, 1.50 mmol) in MeOH (5 mL) was added K2CO3
(624 mg, 4.50 mmol) at 0 ꢀC and stirred at room temperature for
(1.1 mL, 7.86 mmol) and benzoyl chloride (608 mL, 5.24 mmol), and
the mixture was stirred at room temperature for 4 h. The reaction
was quenched by aqueous NaHCO3 at 0 ꢀC, and the mixture was
extracted with AcOEt, washed with brine, dried over Na2SO4,

5418
D. Sawada et al. / Tetrahedron 66 (2010) 5407e5423
16 h. After the reaction was quenched by aqueous NH4Cl at 0 ꢀC, the
mixture was extracted with AcOEt, washed with brine, dried over
Na2SO4, filtered, and concentrated. The residue was purified by flash
column chromatography on silica gel (hexane/AcOEt¼20/1 to 15/1)
1.69, CHCl3); IR (neat) 3312, 2932, 2859, 1711, 1256, 1103, 837,
777 cmꢁ1 1H NMR (400 MHz, CDCl3)
0.04 (s, 3H), 0.05 (s, 3H),
;
d
0.85 (s, 9H), 1.09 (d, J¼7.1 Hz, 3H), 2.00e2.02 (m, 1H), 2.40 (ddd,
J¼16.8, 5.1, 2.9 Hz, 1H), 2.47 (ddd, J¼16.8, 7.1, 2.7 Hz, 1H), 2.68e2.73
(m, 1H), 3.99e4.04 (m, 1H), 9.79 (d, J¼2.2 Hz, 1H); 13C NMR
to give 14g (344 mg, 68% in three steps) as a colorless oil: [
a
]
24 ꢁ30.1
D
(c 1.62, CHCl3); IR (neat) 3314, 2932,1256,1084,1030, 837, 777 cmꢁ1
;
(100 MHz, CDCl3)
d
ꢁ4.9, ꢁ4.4, 10.7, 18.0, 25.5, 25.6, 50.6, 71.3, 72.3,
1H NMR (400 MHz, CDCl3)
d
0.06 (s, 3H), 0.07 (s, 3H), 0.85 (s, 9H),
80.0, 203.9; FABMS m/z 263 (MþNa)þ, HRFABMS calcd for
0.98 (d, J¼7.1 Hz, 3H), 1.95e2.00 (m, 2H), 2.39 (ddd, J¼17.1, 4.9,
2.7 Hz,1H), 2.43 (ddd, J¼17.1, 7.3, 2.4 Hz,1H), 2.66 (br s,1H), 3.55 (dd,
J¼11.2, 5.1 Hz, 1H), 3.74 (dd, J¼11.2, 4.2 Hz, 1H), 3.78e3.80 (m, 1H);
C13H24NaO2Si 263.1522, found 263.1530.
4.2.38. (2R,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[3-(tert-butyldi-
phenylsilanyloxy)propyl]hex-5-ynal (15h). In the same procedure
for 15g, 15h (216 mg, 99 %) was obtained from 14h (250 mg,
13C NMR (100 MHz, CDCl3)
d
ꢁ4.9, ꢁ4.5, 14.5, 17.9, 25.3, 25.7, 38.3,
64.5, 70.4, 75.0, 80.8; FABMS m/z 244 (MþH)þ, HRFABMS calcd for
C13H26O2Si 243.1780, found 243.1780.
0.476 mmol), DMSO (3 mL), triethylamine (0.93 mL, 6.66 mmol)
22
and SO3$Py (531 mg, 3.33 mmol). Colorless oil; [
a
]
D
ꢁ19.1 (c 1.38,
4.2.35. (2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[3-(tert-butyldi-
phenylsilanyloxy)propyl]hex-5-yn-1-ol (14h). In the same pro-
cedure for 14g, 13h (320 mg, 0.655 mmol), trimethylsilylacetylene
CHCl3); IR (neat) 3312, 2932, 2859, 1725, 1256, 1111, 837, 704 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
0.11 (s, 3H), 0.13 (s, 3H), 0.90 (s, 9H),
1.07 (s, 9H), 1.54e1.68 (m, 3H), 1.89e1.97 (m, 1H), 2.02 (dd, J¼2.7,
2.4 Hz, 1H), 2.41e2.53 (m, 2H), 2.57e2.60 (m, 1H), 3.70 (t,
J¼5.9 Hz, 2H), 4.05e4.10 (m, 1H), 7.38e7.46 (m, 6H), 7.68e7.70 (m,
(231
0.965 mL, 1.51 mmol), BF3$Et2O (91
oil (386 mg. 100%). Then, the compound obtained above (370 mg,
0.63 mmol), CH2Cl2 (4 mL), N,N-diisopropylethylamine (165 L,
0.945 mmol) and TBSOTf (181 L, 0.79 mmol) gave a colorless oil
m
L, 1.64 mmol), THF (5 mL), nBuLi (1.56 M hexane solution,
mL, 0.72 mmol) gave a colorless
4H), 9.77 (d, J¼3.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
ꢁ4.8,
m
ꢁ4.3, 18.0, 19.2, 22.9, 25.7, 26.0, 26.9, 30.2, 55.7, 63.4, 71.3, 71.3,
72.1, 80.1, 127.5, 129.5, 133.7, 133.7, 135.4, 204.3; FABMS m/z 545
(MþNa)þ, HRFABMS calcd for C31H46NaO3Si2 545.2831, found
545.2836.
m
(397 mg, 90%). Then, the compound obtained above (380 mg,
0.542 mmol), MeOH (5 mL), K2CO3 (225 mg, 1.63 mmol) afforded
22
14h (263 mg, 83% in three steps) as a colorless oil: [
a]
þ0.78 (c
D
1.15, CHCl3); IR (neat) 3312, 2932, 1256, 1109, 837, 777, 702 cmꢁ1
;
4.2.39. (2R,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[3-(tert-butyldi-
phenylsilyloxy)propoxy]hex-5-ynal (15i). In the same procedure for
15g, 15i (114 mg, 95 %) was obtained from 14i (120 mg,
1H NMR (400 MHz, CDCl3)
d
0.12 (s, 3H), 0.14 (s, 3H), 0.90 (s, 9H),
1.07 (s, 9H), 1.48e1.55 (m, 1H), 1.61e1.73 (m, 3H), 1.77e1.84 (m, 1H),
1.98 (dd, J¼2.7, 2.7 Hz, 1H), 2.46 (ddd, J¼16.8, 4.9, 2.7 Hz, 1H), 2.57
(ddd, J¼16.8, 8.6, 2.7 Hz, 1H), 2.63 (br s, 1H), 3.64 (dd, J¼11.5, 4.6 Hz,
1H), 3.70e3.73 (m, 2H), 3.92e4.01 (m, 2H), 7.37e7.43 (m, 6H),
0.222 mmol), DMSO (3 mL), triethylamine (309 mL, 2.22 mmol) and
SO3$Py (177 mg, 1.11 mmol). Colorless oil; [
a]
22 þ8.6 (c 1.0, CHCl3);
D
IR (neat) 3312, 2930, 2857, 1736, 1256, 1111, 839, 779, 702 cmꢁ1; 1H
7.68e7.70 (m, 4H); 13C NMR (100 MHz, CDCl3)
19.2, 25.2, 25.7, 26.9, 30.3, 42.4, 62.0, 63.9, 70.7, 70.7, 74.9, 80.7,
127.5, 129.4, 129.4, 133.9, 133.9, 135.5; FABMS m/z 525 (MþH)þ,
HRFABMS calcd for C31H48O3Si2 525.3220, found 525.3228.
d
ꢁ4.8, ꢁ4.4, 17.9,
NMR (400 MHz, CDCl3) d 0.05 (s, 3H), 0.07 (s, 3H), 0.85 (s, 9H), 1.03
(s, 9H), 1.85 (m, 2H), 1.98 (dd, J¼2.6, 2.6 Hz, 1H), 2.40 (ddd, J¼13.2,
5.4, 2.6 Hz, 1H), 2.48 (ddd, J¼13.2, 7.1, 2.6 Hz, 1H), 3.71 (t, J¼6.1 Hz,
2H), 3.74 (m, 1H), 3.77 (t, J¼5.9 Hz, 2H), 4.07 (m, 1H), 7.35e7.41 (m,
6H), 7.63e7.66 (m, 4H), 9.64 (d, J¼2.0 Hz, 1H); 13C NMR (100 MHz,
4.2.36. (2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[3-(tert-butyldi-
phenylsilanyloxy)propoxy]hex-5-yn-1-ol (14i). In the same pro-
cedure for 14g, 13i (650 mg, 1.29 mmol), trimethylsilylacetylene
CDCl3)
d
ꢁ4.8, ꢁ4.6, 18.0, 19.3, 23.9, 25.7, 26.9, 32.9, 60.4, 68.0, 71.2,
72.5, 80.2, 85.9, 127.6, 129.5, 129.5, 133.7, 133.7, 135.4, 203.2; FABMS
m/z 561 (MþNa)þ, HRFABMS calcd for C31H46NaO4Si2 561.2832,
found 561.2837.
(455
1.90 mL, 3.0 mmol), BF3$Et2O (180
oil (700 mg, 100%). Then, the compound obtained above (740 mg,
1.29 mmol), CH2Cl2 (5 mL), N,N-diisopropylethylamine (337 L,
1.94 mmol) and TBSOTf (370 L, 1.61 mmol) gave a colorless oil
m
L, 3.22 mmol), THF (13 mL), nBuLi (1.56 M hexane solution,
mL, 1.42 mmol) gave a colorless
4.2.40. (4S,5R)-5-(tert-Butyldimethylsilanyloxy)-4-methyloct-1-en-
7-yn-3-ol (16g). To a solution of 15g (450 mg, 1.87 mmol) in THF
(12 mL) was added vinylmagnesium chloride (1.44 M THF solution,
3.9 mL, 5.61 mmol) at ꢁ78 ꢀC and the whole mixture was gradually
warmed to ꢁ30 ꢀC over 1.5 h. The reaction was quenched by
aqueous NH4Cl at 0 ꢀC, and the mixture was extracted with AcOEt,
washed with brine, dried over Na2SO4, filtered, and concentrated.
The residue was purified by flash column chromatography on silica
m
m
(880 mg, 95%). Then, the compound obtained above (860 mg,
1.20 mmol), MeOH (5 mL), K2CO3 (497 mg, 3.60 mmol) afforded 14i
22
(700 mg, 95% in three steps) as a colorless oil: [
a
]
ꢁ11.6 (c 0.31,
D
CHCl3); IR (neat) 3312, 2930, 2361, 1256, 1111, 837, 777, 702 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
0.13 (s, 3H), 0.15 (s, 3H), 0.94 (s, 9H),
1.10 (s, 9H), 1.84 (m, 2H), 1.99 (dd, J¼2.6, 2.6 Hz, 1H), 2.30 (br s, 1H),
2.45 (ddd, J¼11.2, 5.6, 2.6 Hz, 1H), 2.52 (ddd, J¼11.2, 4.6, 2.6 Hz, 1H),
3.51 (m, 1H), 3.71e3.83 (m, 6H), 3.92 (m, 1H), 7.38e7.44 (m, 6H),
gel (hexane/AcOEt¼50/1 to 30/1) to give 16g
a (230 mg, 46%) and
24
16g
b
(235 mg, 47%) as each colorless oil. Compound 16g
a
: [
;
a
]
1DH
ꢁ24.2 (c 0.69, CHCl3); IR (neat) 3310, 2934, 1468, 1256 cmꢁ1
7.70e7.72 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
ꢁ4.8, ꢁ4.6, 18.0,
NMR (400 MHz, CDCl3) d 0.11 (s, 3H), 0.12 (s, 3H), 0.89 (s, 9H), 0.95
19.2, 24.1, 25.8, 26.9, 32.9, 60.7, 67.1, 70.4, 70.4, 80.9, 81.1, 127.5,
129.5, 133.6,133.6,135.4; FABMS m/z 563 (MþNa)þ, HRFABMS calcd
for C31H48NaO4Si2 563.2989, found 563.2994.
(d, J¼7.1 Hz, 3H), 1.94e2.01 (m, 2H), 2.46 (ddd, J¼17.1, 4.9, 2.7 Hz,
1H), 2.57 (ddd, J¼17.1, 8.3, 2.7 Hz,1H), 3.90e3.93 (m, 1H), 4.59e4.61
(m, 1H), 5.12e5.15 (m, 1H), 5.25e5.31 (m, 1H), 5.81 (ddd, J¼17.1,
10.5, 4.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
ꢁ4.9, ꢁ4.4, 10.9, 17.9,
4.2.37. (2R,3R)-3-(tert-Butyldimethylsilanyloxy)-2-methylhex-5-
ynal (15g). To a solution of 14g (310 mg, 1.28 mmol) in DMSO
(7 mL) was added triethylamine (2.50 mL, 17.9 mmol) and SO3$Py
(1.43 g, 8.96 mmol) at 0 ꢀC and stirred at room temperature for 4 h.
The reaction was quenched by aqueous NH4Cl at 0 ꢀC, and the
mixture was extracted with AcOEt, washed with brine, dried over
Na2SO4, filtered, and concentrated. The residue was purified by
flash column chromatography on silica gel (hexane/AcOEt¼100/1
25.3, 25.8, 39.9, 70.8, 71.0, 75.6, 80.3, 114.3, 139.5; FABMS m/z 269
(MþH)þ, HRFABMS calcd for C15H28O2Si 269.1937, found 269.1927.
Compound 16g
b
: [
a]
24 ꢁ33.2 (c 0.69, CHCl3); IR (neat) 3310, 2934,
D
1479, 1267 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
0.10 (s, 3H), 0.12 (s,
3H), 0.86 (d, J¼7.1 Hz, 3H), 0.90 (s, 9H),1.93e1.99 (m, 2H), 2.36 (ddd,
J¼16.9, 5.4, 2.7 Hz, 1H), 2.53 (ddd, J¼16.9, 5.9, 2.4 Hz, 1H),
3.88e3.95 (m, 1H), 4.08 (dd, J¼7.1, 7.1 Hz, 1H), 5.13e5.16 (m, 1H),
5.23e5.27 (m, 1H), 5.83e5.92 (m, 1H); 13C NMR (100 MHz, CDCl3)
to 50/1) to give 15g (237 mg, 77%) as a colorless oil: [
a
]
24 ꢁ48.7 (c
d
ꢁ4.7, ꢁ4.3, 13.1, 18.1, 25.1, 25.8, 42.9, 70.3, 74.1, 75.5, 81.5, 115.6,
D

D. Sawada et al. / Tetrahedron 66 (2010) 5407e5423
5419
139.4; FABMS m/z 269 (MþH)þ, HRFABMS calcd for C15H28O2Si
procedure for 4g
pounds below, 16h
amine (50 L, 0.285 mmol), and TBSOTf (55
CH2Cl2 (2.5 mL). Colorless oil; [
2932,1256,1100 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 0.04 (s, 3H), 0.05
a
, 4h
b
b
(126 mg, 99%) was obtained from the com-
269.1937, found 269.1935.
(105 mg, 0.190 mmol), N,N-diisopropylethyl-
L, 0.356 mmol) in
ꢁ4.3 (c 0.92, CHCl3); IR (neat)
m
m
22
4.2.41. (4S,5R)-5-(tert-Butyldimethylsilanyloxy)-4-[3-(tert-butyldi-
phenylsilanyloxy)propyl]oct-1-en-7-yn-3-ol (16h). In the same pro-
a]
D
cedure for 16g, 16h
obtained from 15h (200 mg, 0.38 mmol), THF (3 mL), vinyl-
magnesium chloride (1.44 M THF solution, 1.33 mL, 1.90 mmol).
b
(123 mg, 58%) and 16h
a
(37 mg, 37%) were
(s, 3H), 0.06 (s, 3H), 0.12 (s, 3H), 0.91 (s, 9H), 0.92 (s, 9H), 1.07 (s, 9H),
1.35e1.45 (m, 2H),1.62e1.72 (m, 3H),1.94 (dd, J¼2.7, 2.4 Hz,1H), 2.31
(ddd, J¼16.8, 7.6, 2.4 Hz,1H), 2.55(ddd, J¼16.8, 4.3, 2.7 Hz,1H), 3.66 (t,
J¼6.6 Hz, 2H), 4.06 (m, 1H), 4.26 (m, 1H), 5.11 (m, 1H), 5.18 (m, 1H),
5.82e5.89 (m, 1H), 7.37e7.44 (m, 6H), 7.68e7.71 (m, 4H); 13C NMR
Colorless oil (16h
b
); [
a
]
D
22 ꢁ9.2 (c 1.46, CHCl3); IR (neat) 3320, 2932,
1256, 1100 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
0.10 (s, 3H), 0.14 (s,
3H), 0.90 (s, 9H), 1.06 (s, 9H), 1.44e1.55 (m, 2H), 1.77 (m, 1H),
1.65e1.73 (m, 2H), 2.00 (dd, J¼2.7, 2.4 Hz, 1H), 2.54 (ddd, J¼16.9,
4.9, 2.4 Hz, 1H), 2.62 (ddd, J¼16.9, 9.0, 2.7 Hz, 1H), 3.65e3.68 (m,
2H), 4.06e4.11 (m, 1H), 4.69 (m, 1H), 5.15 (m, 1H), 5.36 (m, 1H),
5.77e5.85 (m, 1H), 7.36e7.45 (m, 6H), 7.67e7.69 (m, 4H); 13C NMR
(100 MHz, CDCl3)
d
ꢁ4.8, ꢁ4.5, ꢁ4.2, ꢁ4.1, 18.1, 18.2, 19.3, 21.7, 24.3,
26.0, 26.0, 27.0, 31.8, 49.9, 64.4, 69.5, 69.5, 71.0, 73.7, 73.7, 83.0, 114.6,
127.5,129.4,129.4,134.0,134.1,135.5,140.2; FABMS m/z 687(MþNa)þ,
HRFABMS calcd for C39H64NaO3Si3 687.4061, found 687.4084.
(100 MHz, CDCl3)
d
ꢁ4.8, ꢁ4.3, 17.9, 19.2, 20.4, 25.5, 25.8, 26.9, 30.9,
4.2.46. (3S,4R,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-4-[3-(tert-
butyldimethylsilanyloxy)propoxy]oct-1-en-7-yne (4ib). In the same
44.6, 63.8, 70.8, 71.1, 73.3, 80.3, 114.3, 127.5, 129.4, 133.8, 133.9,
135.5, 139.3; FABMS m/z 573 (MþNa)þ, HRFABMS calcd for
procedure for 4g
compounds below, 16i
thylamine (106
in CH2Cl2 (5 mL). Colorless oil; [
2945, 1261, 1102 cmꢁ1
a
, 4i
b
(273 mg, 99%) was obtained from the
(230 mg, 0.406 mmol), N,N-diisopropyle-
22
C33H50O3NaSi2 573.3196, found 573.3209. Colorless oil (16h
a
); [a
]
b
D
ꢁ8.8 (c 0.75, CHCl3); IR (neat) 3320, 2932,1256,1100 cmꢁ1; 1H NMR
mL, 0.609 mmol), and TBSOTf (112 mL, 0.487 mmol)
(400 MHz, CDCl3)
d
0.10 (s, 3H), 0.15 (s, 3H), 0.90 (s, 9H), 1.06 (s, 9H),
a
]
D
22 ꢁ0.07 (c 1.38, CHCl3); IR (neat)
1.43e1.53 (m, 2H), 1.65e1.70 (m, 2H), 1.79 (m, 1H), 2.00 (dd, J¼2.7,
2.7 Hz,1H), 2.52 (ddd, J¼16.9, 4.9, 2.7 Hz,1H), 2.62 (ddd, J¼16.9, 9.0,
2.7 Hz, 1H), 3.55 (br s, 1H), 3.66e3.69 (m, 2H), 4.10 (m, 1H), 4.69 (m,
1H), 5.15 (m, 1H), 5.36 (m, 1H), 5.78e5.86 (m, 1H), 7.37e7.43 (m,
;
1H NMR (400 MHz, CDCl3)
d
0.01 (s, 3H),
0.04 (s, 3H), 0.05 (s, 3H), 0.08 (s, 3H), 0.88 (s, 9H), 0.90 (s, 9H), 1.03
(s, 9H), 1.78 (m, 2H), 1.90 (t, J¼2.6 Hz, 1H), 2.40 (ddd, J¼11.2, 3.7,
2.7 Hz,1H), 2.48 (ddd, J¼11.2, 5.6, 2.7 Hz,1H), 3.36 (dd, J¼5.1, 4.6 Hz,
1H), 3.72 (m, 2H), 3.80 (m, 1H), 3.84 (m, 1H), 4.25 (m, 1H), 5.09 (m,
1H), 5.21 (m, 1H), 5.83 (ddd, J¼16.9, 10.5, 6.4 Hz, 1H), 7.34e7.40 (m,
6H), 7.67e7.69 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
ꢁ4.8, ꢁ4.8,
17.9, 19.2, 20.4, 25.5, 25.8, 26.9, 30.9, 44.6, 63.8, 70.7, 70.8, 71.1, 71.1,
73.3, 80.3, 114.3,114.4,127.5, 129.4, 133.8, 133.9, 135.5, 139.3; FABMS
m/z 573 (MþNa)þ, HRFABMS calcd for C33H50NaO3Si2 573.3196,
found: 573.3217.
6H), 7.64e7.67 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
ꢁ4.7, ꢁ4.4,
ꢁ4.3, ꢁ4.2, 18.1, 19.2, 19.3, 23.2, 25.9, 26.0, 26.0, 26.9, 33.5, 61.3,
69.6, 69.8, 70.9, 74.3, 82.1, 85.6, 115.9, 127.5, 127.5, 129.4, 134.0,
135.5, 138.0; FABMS m/z 703 (MþNa)þ, HRFABMS calcd for
C39H64NaO4Si3 703.4010, found 703.4014.
4.2.42. (4S,5R)-5-(tert-Butyldimethylsilanyloxy)-4-[3-(tert-butyldi-
phenylsilanyloxy)propoxy]oct-1-en-7-yn-3-ol (16i). In the same
procedure for 16g, 16i
obtained from 15i (420 mg, 0.78 mmol), THF (5 mL), vinyl-
b
(256 mg, 58%) and 16i
a
(67 mg, 15%) were
4.2.47. (Z)-[2-{(3S,4R,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-2-
methylene-4-methylcyclohexylidene}ethyl]diphenylphosphine Oxide
magnesium chloride (1.44 M THF solution, 2.71 mL, 3.5 mmol).
(3ga). To a solution of 4ga (340 mg, 0.888 mmol) in dry THF
Colorless oil 16i
b
: [a
]
22 ꢁ11.2 (c 4.92, CHCl3); IR (neat) 3320, 2945,
(20 mL) was added nBuLi (1.57 M hexane solution, 0.85 mL,
1.33 mmol) at ꢁ78 ꢀC and stirred for 1 h at the same temperature.
To the mixture was added paraformaldehyde (89 mg, 2.66 mmol) at
ꢁ78 ꢀC and stirred at the same temperature for 1 h. The mixture
was warmed up to room temperature over 2 h, and stirred at room
temperature for 2 h. To the mixture was added saturated NH4Cl
aqueous solution at 0 ꢀC, and extracted with Et2O. The organic layer
was washed with brine, dried over Na2SO4, and concentrated. The
residue was purified by flash column chromatography on silica gel
(hexane/AcOEt¼10/1) to give a colorless oil (345 mg, 94%). To a so-
lution of the compound obtained above (340 mg, 0.824 mmol) in
dry Et2O (5 mL) was added Red-AlÒ (65% toluene solution, 0.74 mL,
2.47 mmol) at 0 ꢀC and stirred at room temperature for 4 h. To the
mixture was added ethyl acetate (0.5 mL) at 0 ꢀC, and then cooled to
ꢁ78 ꢀC and added I2 (627 mg, 2.47 mmol) in THF (1 mL) and stirred
at the same temperature for 30 min. The mixture was warmed up to
room temperature over 1.5 h and stirred for 10 min. To the mixture
was diluted with Et2O, added 10% Na2S2O3 aqueous solution and
saturated NaHCO3 aqueous solution at 0 ꢀC, and the aqueous layer
was extracted with Et2O. The organic layer was washed with brine,
dried over Na2SO4, and concentrated. The residue was purified by
flash column chromatography on silica gel (hexane/AcOEt¼10/1) to
give a colorless oil (272 mg, 61%). To a solution of Pd(PPh3)4 (27 mg,
0.023 mmol) in dry MeCN (4 mL) was added the compound
obtained above (250 mg, 0.462 mmol) in dry MeCN (1 mL) and Et3N
(0.77 mL, 0.554 mmol) at 0 ꢀC and stirred at 90 ꢀC for 1 h. The
mixture was cooled to room temperature, and concentrated. The
residue was purified by flash column chromatography on silica gel
(hexane/AcOEt¼12/1) to give a colorless oil (185 mg, 97%). To a so-
lution of NCS (549 mg, 4.11 mmol) in dry CH2Cl2 (5 mL) was added
D
1261, 1102 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
0.08 (s, 3H), 0.12 (s,
3H), 0.89 (s, 9H), 1.05 (s, 9H), 1.74 (m, 2H), 1.97 (t, J¼2.7 Hz, 1H), 2.50
(dd, J¼5.1, 2.7 Hz, 1H), 3.43 (dd, J¼5.6, 5.4 Hz, 1H), 3.70e3.82 (m,
4H), 3.88 (m, 1H), 5.17 (m, 1H), 5.35 (m, 1H), 5.98 (ddd, J¼17.3, 10.7,
5.6 Hz, 1H), 7.35e7.42 (m, 6H), 7.65e7.67 (m, 4H); 13C NMR
(100 MHz, CDCl3)
d
ꢁ4.6, ꢁ4.3, 18.1, 19.2, 24.2, 25.9, 26.9, 33.0, 60.7,
68.9, 70.5, 72.2, 73.3, 81.2, 83.7, 116.0, 127.5, 129.5, 133.7, 133.7,
135.5, 135.5, 137.2; FABMS m/z 589 (MþNa)þ, HRFABMS calcd for
C33H50NaO4Si2 589.3146, found 589.3146.
4.2.43. (3R,4R,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-4-methyl-
oct-1-en-7-yne (4g
CH2Cl2 (6 mL) were added N,N-diisopropylethylamine (263
1.52 mmol) and TBSOTf (290
L, 1.26 mmol) at 0 ꢀC and stirred at
a
). To a solution of 16g
a
(270 mg, 1.01 mmol) in
mL,
m
room temperature for 1 h. After the reaction was quenched by
aqueous NaHCO3 at 0 ꢀC, the mixture was extracted with AcOEt,
washed with brine, dried over Na2SO4, filtered, and concentrated.
The residue was purified by flash column chromatography on silica
gel (hexane/AcOEt¼100/1 to 50/1) to give 4g
a
28 (385 mg, 100%) as
a colorless oil.
4.2.44. (3S,4R,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-4-methyl-
oct-1-en-7-yne (4g ). In the same procedure for 4g
4gb28
(415 mg, 97%) was obtained from the compounds below, 16g
(300 mg, 1.12 mmol), N,N-diisopropylethylamine (293 L,
1.68 mmol), and TBSOTf (321 L, 1.40 mmol) in CH2Cl2 (6 mL).
b
a,
b
m
m
4.2.45. (3S,4R,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-4-[3-(tert-
butyldimethylsilanyloxy)propyl]oct-1-en-7-yne (4h ). In the same
b

5420
D. Sawada et al. / Tetrahedron 66 (2010) 5407e5423
dimethylsulfide (0.30 mL, 4.11 mmol) at 0 ꢀC, and stirred at the
same temperature for 15 min. To the mixture was added the com-
pound obtained above (170 mg, 0.411 mmol) in dry CH2Cl2 (2 mL) at
e16 ꢀC and stirred for 1.5 h at the same temperature. The mixture
was warmed up to 0 ꢀC, added water at the same temperature, and
extracted with CH2Cl2. The organic layer was washed with brine,
dried over Na2SO4, and concentrated. The residue was purified by
short column chromatography on silica gel (hexane/AcOEt/
TEA¼100/10/1) to give a crude product of allyl chloride. To a solu-
tion of Ph2PH (0.215 mL, 1.23 mmol) in dry THF (5 mL) was added
nBuLi (1.57 M hexane solution, 0.785 mL, 1.23 mmol) at 0 ꢀC and
stirred for 10 min at the same temperature. To another flask charged
the crude allyl chloride in dry THF (2 mL) was added the above
lithium diphenylphosphide solution at ꢁ78 ꢀC and stirred at the
same temperature for 10 min. To the mixture was added water at
ꢁ78 ꢀC and warmed up to 0 ꢀC. The resulting mixture was con-
centrated, and the residue was dissolved in CH2Cl2 (2 mL). To the
mixture was added 35% H2O2 aqueous solution (2 mL) at 0 ꢀC. After
stirring for 1.5 h at 0 ꢀC, to the mixture was added water at the same
temperature and extracted with CH2Cl2. The organic layer was
washed with 2 N Na2SO3 aqueous solution, and brine, dried over
Na2SO4, and concentrated. The residue was purified by flash column
cyclohexylidene}ethyl]diphenylphosphine Oxide (3h
b). In the same
procedure for 3g , 4h
a
b
(205 mg, 0.308 mmol), nBuLi (1.57 M hexane
solution, 0.29 mL, 0.462 mmol), THF (4 mL), and paraformaldehyde
(31 mg, 0.924 mmol) gave a colorless oil (212 mg, 93%). Then, the
compound obtained above (103 mg, 0.148 mmol), Et2O (3 mL), Red-
AlÒ (65% toluene solution, 0.133 mL, 0.444 mmol), ethyl acetate
(0.3 mL), I2 (112 mg, 0.444 mmol), and THF (1 mL) gave a colorless
oil (63 mg, 52%). Then, Pd(PPh3)4 (4.6 mg, 0.00395 mmol), MeCN
(4 mL), the compound obtained above (65 mg, 0.079 mmol), and
Et3N (0.013 mL, 0.095 mmol) gave a colorless oil (56 mg, 100%).
Then, NCS (92 mg, 0.69 mmol), CH2Cl2 (3 mL), dimethylsulfide
(0.051 mL, 0.69 mmol), the compound obtained above (48 mg,
0.069 mmol), Ph2PH (0.038 mL, 0.207 mmol), THF (3 mL), nBuLi
(1.57 M hexane solution, 0.132 mL, 0.207 mmol), and 35% H2O2
aqueous solution (0.5 mL) afforded 3h
b
(45 mg, 27% in four steps) as
22
an amorphous solid; [
a]
D
þ19.1 (c 1.92, CHCl3); IR (neat) 2950,
1644,1250,1190 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
0.01 (s, 6H), 0.01
(s, 6H), 0.85 (s, 9H), 0.91 (s, 9H), 1.02 (s, 9H), 1.34e1.36 (m, 2H),
1.65e1.80 (m, 2H), 1.86 (m, 1H), 2.09 (dd, J¼13.2, 4.6 Hz, 1H), 2.23
(m, 1H), 3.13e3.33 (m, 2H), 3.57e3.60 (m, 3H), 3.76 (m, 1H), 4.82 (s,
1H), 5.26 (s, 1H), 5.41e5.47 (m, 1H), 7.32e7.54 (m, 12H), 7.64e7.74
(m, 8H); 13C NMR (100 MHz, CDCl3)
d
ꢁ5.0, ꢁ5.0, ꢁ4.7, ꢁ4.7, 18.2,
chromatography on silica gel (hexane/AcOEt¼3/2) to give 3g
a
18.4, 18.4, 19.2, 25.9, 25.9, 26.9, 29.7, 31.2, 31.9, 34.0, 41.6, 49.6, 64.9,
71.0, 73.6, 111.6, 114.9, 114.9, 127.4, 128.3, 128.4, 128.5, 128.6, 129.3,
130.9, 131.0, 131.1, 131.2, 131.7, 131.8, 134.2, 135.5, 140.4, 140.5, 144.6,
144.6; FABMS m/z 901 (MþNa)þ, HRFABMS calcd for
C52H75NaO4PSi3 901.4608, found 901.4622.
24
(216 mg, 49% in four steps) as an amorphous solid: [
5.77, CHCl3); IR (neat) 2920, 1466, 1370, 1085 cmꢁ1
(400 MHz, CDCl3)
a
]
ꢁ14.5 (c
D
;
1H NMR
d
ꢁ0.06 (s, 3H), ꢁ0.05 (s, 3H), ꢁ0.02 (s, 3H), 0.02
(s, 3H), 0.82 (s, 9H), 0.88 (s, 9H), 0.91 (d, J¼7.1 Hz, 3H), 1.70e1.74 (m,
1H), 2.22 (m, 2H), 3.10e3.19 (m, 1H), 3.29e3.38 (m, 1H), 3.97 (m,
2H), 4.72 (m, 1H), 5.09 (m, 1H), 5.25e5.30 (m, 1H), 7.42e7.46 (m,
4.2.50. (Z)-[2-{(3S,4R,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-
2-methylene-4-(3-(tert-butyldimethylsilanyloxy)propoxy)cyclo-
6H), 7.67e7.70 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
ꢁ4.9, ꢁ4.9,
ꢁ4.4,13.6,14.1,18.1, 22.6, 25.8, 30.9, 31.5, 43.5, 45.7, 70.9, 75.4,110.9,
114.2, 114.3, 128.3, 128.4, 130.8, 130.9, 131.5, 131.6, 132.1, 133.1, 133.2,
141.3, 141.4, 146.8; FABMS m/z 597 (MþH)þ, HRFABMS calcd for
C34H54O3PSi2 597.3349, found 597.3372.
hexylidene}ethyl]diphenylphosphine Oxide (3i
b). In the same
procedure for 3g , 4i
a
b
(270 mg, 0.396 mmol), nBuLi (1.57 M hexane
solution, 0.38 mL, 0.594 mmol), THF (4.5 mL), and paraformaldehyde
(45 mg, 1.19 mmol) gave a colorless oil (255 mg, 90%). Then, the
compound obtained above (255 mg, 0.359 mmol), Et2O (4 mL), Red-
AlÒ (65% toluene solution, 0.323 mL, 1.08 mmol), ethyl acetate
(0.4 mL), I2 (273 mg, 1.08 mmol), and THF (1 mL) gave a colorless oil
(142 mg, 47%). Then, Pd(PPh3)4 (9.2 mg, 0.008 mmol), MeCN (4.5 mL),
the compound obtained above (133 mg, 0.158 mmol), and Et3N
(0.027 mL, 0.19 mmol) gave a colorless oil (106 mg, 94%). Then, NCS
(107 mg, 0.8 mmol), CH2Cl2 (3 mL), dimethylsulfide (0.059 mL,
0.8 mmol), thecompoundobtainedabove(57 mg, 0.08 mmol), Ph2PH
(0.042 mL, 0.24 mmol), THF (3.5 mL), nBuLi (1.57 M hexane solution,
4.2.48. (Z)-[2-{(3R,4R,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-2-
methylene-4-methylcyclohexylidene}ethyl]diphenylphosphine Oxide
(3gb). In the same procedure for 3ga, 4gb (330 mg, 0.862 mmol),
nBuLi (1.57 M hexane solution, 0.82 mL, 1.29 mmol), THF (20 mL),
and paraformaldehyde (86 mg, 2.58 mmol) gave a colorless oil
(344 mg, 93%). Then, the compound obtained above (330 mg,
0.80 mmol), Et2O (5 mL), Red-AlÒ (65% toluene solution, 0.72 mL,
2.40 mmol), ethyl acetate (0.5 mL), I2 (609 mg, 2.40 mmol), and THF
(2 mL) gave a colorless oil (319 mg, 74%). Then, Pd(PPh3)4 (32 mg,
0.027 mmol), MeCN (5 mL), the compound obtained above
(300 mg, 0.555 mmol), and Et3N (0.093 mL, 0.666 mmol) gave
a colorless oil (219 mg, 95%). Then, NCS (645 mg, 4.83 mmol),
CH2Cl2 (13 mL), dimethylsulfide (0.355 mL, 4.83 mmol), the com-
pound obtained above (200 mg, 0.483 mmol), Ph2PH (0.252 mL,
1.44 mmol), THF (8 mL), nBuLi (1.57 M hexane solution, 0.92 mL,
0.153 mL, 0.24 mmol), and 35% H2O2 aqueous solution (0.5 mL)
22
afforded 3ib (51 mg, 28% in four steps) as an amorphous solid; [a]
D
þ32.7 (c 0.62, CHCl3); IR (neat) 2945, 1649,1261, 1190 cmꢁ1; 1H NMR
(400 MHz, CDCl3)
d
ꢁ0.03 (s, 3H), ꢁ0.01 (s, 3H), 0.03 (s, 6H), 0.84 (s,
9H), 0.89 (s, 9H),1.00 (s, 9H),1.80 (m, 2H), 2.04 (dd, J¼12.7, 3.9 Hz,1H),
2.53 (m, 1H), 3.13 (m, 1H), 3.30 (m, 1H), 3.41 (m, 2H), 3.59 (m, 1H),
3.68e3.78 (m, 4H), 4.77 (br s, 1H), 5.24 (br s, 1H), 5.47 (m, 1H),
7.30e7.50 (m, 12H), 7.61e7.73 (m, 8H); 13C NMR (100 MHz, CDCl3)
1.44 mmol), and 35% H2O2 aqueous solution (2 mL) afforded 3g
b
24
(250 mg, 57% in four steps) as an amorphous solid; [
2.85, CHCl3); IR (neat) 2934, 1468, 1379, 1099 cmꢁ1
(400 MHz, CDCl3)
a
]
þ63.6 (c
d
ꢁ4.9, ꢁ4.7, ꢁ4.6,18.2,18.3,19.2, 25.9, 26.9, 31.2, 31.9, 33.6, 40.6, 61.6,
D
;
1H NMR
70.5, 71.5, 73.5, 84.3,112.0,115.2,115.3,127.4,128.3,128.4,128.5,128.6,
129.3, 130.9, 131.0, 131.0, 131.1, 131.6, 131.8, 134.0, 135.4, 140.2, 140.3,
143.4; FABMS m/z 917 (MþNa)þ, HRFABMS calcd for C52H75NaO5PSi3,
917.4557, found 917.4559.
d
0.01 (s, 6H), 0.01 (s, 6H), 0.75 (d, J¼6.8 Hz, 3H),
0.86 (s, 9H), 0.91 (s, 9H), 2.01e2.10 (m, 2H), 2.22e2.29 (m, 1H),
3.15e3.21 (m, 1H), 3.26e3.32 (m, 1H), 3.51e3.54 (m, 1H), 3.69 (m,
1H), 4.84 (m, 1H), 5.27 (m, 1H), 5.42e5.47 (m, 1H), 7.45e7.54 (m,
6H), 7.65e7.74 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
ꢁ5.0, ꢁ4.9,
4.2.51. 14-epi-1a,25-Dihydroxy-2a-methylprevitamin D3 (14-epi-
ꢁ4.8, ꢁ4.7, 5.0, 18.2, 18.3, 25.9, 29.7, 31.1, 31.8, 40.7, 44.2, 60.2, 70.4,
70.4, 72.9, 72.9, 111.5, 114.9, 115.0, 128.3, 128.4, 128.5, 128.6, 130.9,
131.0, 131.1, 131.2, 131.7, 131.8, 140.5, 140.6, 144.2, 144.2, 169.2;
FABMS m/z 597 (MþH)þ, HRFABMS calcd for C34H54O3PSi2
597.3349, found 597.3358.
pre-1a). To a solution of 3a (166 mg, 0.273 mmol) in THF (2 mL)
was added nBuLi (1.58 M hexane solution, 0.19 mL, 0.30 mmol) at
ꢁ78 ꢀC and stirred at the same temperature for 15 min. To the
mixture was added 217 (72 mg, 0.18 mmol) in THF (1.7 mL) at
ꢁ78 ꢀC and stirred at the same temperature for 1 h. The reaction
mixture was allowed to warm to room temperature and stirred for
1 h. After the reaction was quenched by aqueous NH4Cl at 0 ꢀC, the
mixture was extracted with AcOEt, washed with brine, dried over
4.2.49. (Z)-[2-{(3R,4R,5R)-3,5-Bis(tert-butyldimethylsilanyloxy)-2-
methylene-4-(3-(tert-butyldimethylsilanyloxy)propyl)

D. Sawada et al. / Tetrahedron 66 (2010) 5407e5423
5421
Na2SO4, filtered, and concentrated. The residue was purified by
flash column chromatography on silica gel (hexane/AcOEt¼10/1) to
give coupling products (62 mg, 44%) as a colorless oil. Then, to the
solution of the products (60 mg, 0.051 mmol) in MeCN (5 mL) was
added 10% solution of HF in MeCN (5 mL) at 0 ꢀC and stirred at room
temperature for 9 h. The aqueous layer was extracted with AcOEt,
washed with brine, dried over Na2SO4, and concentrated. The res-
idue was purified by flash column chromatography on silica gel
(hexane/AcOEt¼1/1) to give a mixture of 14-epi-1a and 14-epi-pre-
1a. The mixture were dissolved in benzene (2 mL) and stirred at
80 ꢀC for 1 h. The solution was cooled to room temperature, and
concentrated to give a crude product, which was purified by re-
solution, 0.31 mL, 0.487 mmol), and THF (9 mL) gave coupling
products (58 mg, 24%), and the compound obtained above (58 mg,
0.070 mmol), TBAF (1.0 M THF solution, 1.4 mL, 1.40 mmol), and
THF (7 mL) afforded 14-epi-pre-1d (32 mg, 96%) as a colorless oil:
[a
]
18 ꢁ17.7 (c 1.15, CHCl3); UV (EtOH) lmax 248.0 nm, lmin 234.5 nm;
D
IR (neat) 3376, 2955, 1641 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
0.90e0.95 (m, 10H), 1.15 (m, 1H), 1.22e1.86 (m, 30H), 1.96e2.04
(m, 4H), 2.57 (dd, J¼16.8, 4.9 Hz, 1H), 3.73 (ddd, J¼9.5, 9.5, 5.1 Hz,
1H), 4.40 (br s, 1H), 5.64 (t, J¼3.3 Hz, 1H), 5.78 (d, J¼12.9 Hz, 1H),
5.82 (d, J¼12.9 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 14.2, 17.8, 19.6,
20.9, 21.8, 22.9, 23.2, 25.9, 28.8, 29.1, 29.3, 29.5, 29.6 33.9, 34.1, 35.8,
38.8, 41.1, 44.3, 46.7, 51.1, 51.8, 67.5, 71.1, 71.3, 125.6, 127.4, 130.4,
130.8, 132.8, 138.7; EI-LRMS m/z 472 (M)þ, 436, 418, 267, 155; EI-
HRMS calcd for C31H52O3 472.3916, found 472.3939.
versed-phase recycle HPLC (MeCN/H2O¼90/10) for biological assay
22
to give 14-epi-pre-1a (13 mg, 39%) as a colorless oil: [
a]
e11.6 (c
D
1.61, CHCl3); UV (EtOH) lmax 252.5 nm, lmin 229.5 nm; IR (neat)
3374, 2961, 1456, 1375 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
0.84 (s,
4.2.55. 14-epi-1
a,25-Dihydroxy-2a-phenylprevitamin D3 (14-epi-
3H), 0.87 (d, J¼6.4 Hz, 3H), 0.99e1.98 (m, 34H), 2.50 (dd, J¼16.8,
5.1 Hz, 1H), 3.65 (dt, J¼10.0, 5.5 Hz, 1H), 3.87 (d, J¼2.0 Hz, 1H), 5.58
(d, J¼3.4 Hz, 1H), 5.71 (d, J¼13.1 Hz, 1H), 5.75 (d, J¼13.1 Hz, 1H); 13C
pre-1e). In the same procedure for 14-epi-pre-1a, 3e (44.0 mg, 67
mmol), 2 (18 mg, 44
m
mol), nBuLi (1.57 M hexane solution, 50
mL, 80
mmol), and THF (1.2 mL) gave coupling products (3 mg, 9%), and the
NMR (100 MHz, CDCl3)
d
12.8, 17.6, 19.6, 20.9, 21.8, 22.9, 28.6, 29.1,
compound obtained above (3 mg, 0.0035 mmol), TBAF (1.0 M THF
29.5, 29.6, 33.9, 34.1, 35.7, 38.4, 41.1, 41.7, 44.3, 51.0, 51.8, 68.2, 71.1,
74.5, 125.6, 127.4, 130.4, 130.8, 132.7, 138.7; EI-LRMS m/z 430 (M)þ,
412, 396, 374, 350, 169; EI-HRMS calcd for C28H46O3 430.3446,
found 430.3430.
solution, 70
(1.0 mg, 81%) as a colorless oil:
mL, 70 mmol), and THF (0.7 mL) afforded 14-epi-pre-1e
[
a
]
D
23ꢁ37.9 (c 0.092, CHCl3); UV
(EtOH) lmax 251.0 nm, lmin 229.0 nm; IR (neat) 3374, 1730, 1466,
1375, 1251 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 0.12 (s, 3H),
0.83ꢁ2.34 (m, 32H), 2.86 (dd, J¼ 3.4, 11.5 Hz, H), 4.07ꢁ4.12 (m, H),
4.43 (ddd, J¼ 5.5, 10.3, 10.3 Hz, H), 5.32 (s, H), 5.71 (s, H), 5.77ꢁ5.79
(m, H), 5.83 (d, J¼ 6.6 Hz, 2H), 7.33e7.40 (m, 5H); 13C NMR (100
4.2.52. 14-epi-1a,25-Dihydroxy-2a-(3-hydroxypropyl)previtamin D3
(14-epi-pre-1b). In the same procedure for 14-epi-pre-1a, 3b
(501 mg, 0.663 mmol), 2 (178 mg 0.452 mmol), nBuLi (1.53 M hex-
ane solution, 0.46 mL, 0.727 mmol), and THF (13 mL) gave coupling
products (219 mg, 52%), and the compound obtained above (14 mg,
0.015 mmol), 10% solution of conc. HF in MeCN (5 mL), MeCN
(5 mL), and benzene (2 mL) afforded 14-epi-pre-1b (3.0 mg, 41%) as
MHz, CDCl3)
d
ꢁ0.2 (2C), 13.9, 17.6, 22.5, 22.7, 28.9, 29.1, 29.3, 29.4,
29.5, 29.5, 31.7 (3C), 33.7, 40.8, 44.1, 51.0, 55.1, 64.7, 70.8, 73.8, 76.6,
76.7, 77.1, 77.1, 77.2, 122.3, 128.8 (2C), 129.3, 131.0; EI-LRMS m/z 515
(M)þ, EI-HRMS calcd for C33H48O3 515.3501, found 515.3481.
a colorless oil: [
a]
22 ꢁ4.63 (c 1.23, CHCl3); UV (EtOH) lmax 251.0 nm,
4.2.56. 14-epi-1a,25-Dihydroxy-2a-benzylprevitamin D3 (14-epi-
D
lmin 226.5 nm; IR (neat) 3358, 2928,1458,1377,1215 cmꢁ1; 1H NMR
pre-1f). In the same procedure for 14-epi-pre-1a, 3f (330 mg,
0.490 mmol), 2 (129 mg, 0.326 mmol), nBuLi (1.57 M hexane solu-
tion, 0.34 mL, 0.534 mmol), and THF (13 mL) gave coupling prod-
ucts (162 mg, 59%), and the compound obtained above (89 mg,
(400 MHz, CDCl3)
d
0.90 (s, 3H), 0.94 (d, J¼6.3 Hz, 3H),1.11e2.05 (m,
34H), 2.52e2.57 (m, 2H), 3.11 (br s, 1H), 3.69 (m, 1H), 4.01 (d,
J¼3.4 Hz, 1H), 5.63 (t, J¼3.3 Hz, 1H), 5.71 (d, J¼13.6 Hz, 1H), 5.81 (d,
J¼13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
17.8, 19.6, 20.6, 21.6,
0.105 mmol), TBAF (1.0 M THF solution, 2.1 mL, 2.1 mmol), and THF
23
22.6, 23.0, 28.5, 29.0, 29.3, 29.7, 29.8, 33.8, 34.1, 35.7, 38.9, 41.3, 44.4,
46.8, 50.8, 50.9, 62.7, 67.1, 71.2, 71.5, 125.7, 127.4, 130.3, 131.1, 132.9,
138.9; EI-LRMS m/z 457 (M-OH)þ, 438, 420, 379, 145, 59; EI-HRMS
calcd for C30H49O3 (M-OH)þ 457.3682, found 457.3686.
(9.6 mL) afforded 14-epi-pre-1f (49 mg, 92%) as a colorless oil: [a]
D
ꢁ21.1 (c 8.08, CHCl3); UV (EtOH) lmax 251.5 nm, lmin 227.0 nm; IR
(neat) 3387, 2951, 1636, 1603 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
0.89 (s, 3H), 0.95 (d, J¼6.4 Hz, 3H), 1.06e1.56 (m, 21H), 1.78e1.89
(m, 4H), 1.99e2.08 (m, 5H), 2.64 (dd, J¼16.9, 4.6 Hz, 1H), 2.75 (dd,
J¼13.5,11.1 Hz,1H), 3.20 (dd, J¼13.5, 4.5 Hz,1H), 3.69 (br s,1H), 3.87
(ddd, J¼10.1, 10.1, 5.5 Hz, 1H), 5.63 (t, J¼3.5 Hz, 1H), 5.78 (d,
J¼12.8 Hz, 1H), 5.81 (d, J¼12.8 Hz, 1H), 7.18e7.32 (m, 5H); 13C NMR
4.2.53. 14-epi-1a,25-Dihydroxy-2a-(3-hydroxypropoxy)previtamin
D3 (14-epi-pre-1c). In the same procedure for 14-epi-pre-1a, 3c
(203 mg, 0.256 mmol), 2 (70 mg, 0.178 mmol), nBuLi (1.58 M hex-
ane solution, 0.18 mL, 0.284 mmol), and THF (3.4 mL) gave coupling
products (89 mg, 55%), and the compound obtained above (42 mg,
0.044 mmol), 10% solution of HF in MeCN (5 mL), MeCN (5 mL), and
(100 MHz, CDCl3)
d 17.6, 19.5, 20.7, 21.8, 22.9, 28.8, 29.1, 29.3, 29.8,
32.6, 34.0, 35.8, 38.9, 41.2, 44.3, 49.0, 51.2, 51.4, 67.3, 70.7, 71.2,
125.6, 125.8, 127.3, 128.4, 129.1, 130.4, 130.8, 132.9, 138.6, 140.6; EI-
LRMS m/z 506 (M)þ, 470, 452, 379, 195, 91; EI-HRMS calcd for
C34H50O3 506.3761, found 506.3760.
benzene (2 mL) afforded 14-epi-pre-1c (9.0 mg, 42%) as a colorless
22
oil: [
a
]
D
ꢁ2.46 (c 33.9, CHCl3); UV (EtOH) lmax 250.5 nm, lmin
227.0 nm; IR (neat) 3385, 2953, 1377, 1215, 1095 cmꢁ1
(400 MHz, CDCl3)
;
1H NMR
d
0.91 (s, 3H), 0.95 (d, J¼6.4 Hz, 3H), 1.02e2.05
4.2.57. 14-epi-1
pre-1g ). In the same procedure for 14-epi-pre-1a, 3g
0.351 mmol), 2 (92 mg, 0.234 mmol), nBuLi (1.57 M hexane solu-
tion, 246 L, 0.386 mmol), and THF (6 mL) gave coupling products
a,25-Dihydroxy-2b-methylprevitamin D3 (14-epi-
(m, 32H), 2.65 (dd, J¼17.0, 5.7 Hz, 1H), 2.72 (br s, 1H), 3.23 (dd,
J¼10.0, 4.2 Hz, 1H), 3.74 (m, 1H), 3.85 (t, J¼5.6 Hz, 2H), 3.89e3.96
(m, 2H), 4.22 (d, J¼4.2 Hz, 1H), 5.65 (t, J¼3.3 Hz, 1H), 5.79 (d,
J¼13.2 Hz, 1H), 5.81 (d, J¼13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
a
a
(210 mg,
m
(66 mg, 37%), and the compound obtained above (36 mg,
0.046 mmol), TBAF (0.92 mL, 1.0 M THF solution, 0.92 mmol), and
d
18.0, 19.5, 20.6, 21.7, 23.0, 28.5, 28.9, 29.2, 29.8, 31.9, 33.9, 34.0,
35.8, 36.3, 41.3, 44.3, 51.0, 60.8, 65.7, 68.0, 69.0, 71.1, 83.1, 100.5,
125.9, 127.0, 128.7, 131.1, 133.1, 138.5; EI-LRMS m/z 490 (M)þ, 472,
454, 378, 145, 59; EI-HRMS calcd for C30H50O5 490.3658, found
490.3662.
THF (4 mL) afforded 14-epi-pre-1g
a
(20 mg, 100%) as a colorless
23
oil: [
227.0 nm; IR (neat) 3370, 2961, 1456, 1379 cmꢁ1
(600 MHz, C6D6)
a]
D
ꢁ18.4 (c 0.038, CHCl3); UV (EtOH) lmax 252.5 nm, lmin
;
1H NMR
d
1.01 (s, 3H), 1.02 (d, J¼6.3 Hz, 3H), 1.03 (d,
J¼6.9 Hz, 3H), 1.15 (s, 3H), 1.15 (s, 3H), 1.32e1.62 (m, 10H), 1.86 (s,
3H), 1.87e2.04 (m, 3H), 2.07 (m, 2H), 2.15e2.21 (m 2H), 2.48e2.51
(m, 1H), 3.77 (d, J¼4.4 Hz, 1H), 4.06 (m, 1H), 5.83, (m, 1H), 5.91 (d,
J¼12.1 Hz, 1H), 5.94 (d, J¼12.1 Hz, 1H); 13C NMR (150 MHz, C6D6)
4.2.54. 14-epi-1
1d). In the same procedure for 14-epi-pre-1a, 3d (280 mg,
0.437 mmol),
(115 mg, 0.299 mmol), nBuLi (1.57 M hexane
a,25-Dihydroxy-2a-butylprevitamin D3 (14-epi-pre-
2

5422
D. Sawada et al. / Tetrahedron 66 (2010) 5407e5423
d
11.8, 14.2, 17.3, 19.9, 21.2, 22.0, 23.2, 28.9, 29.3, 29.8, 29.9, 34.3,
dissolved in 50
m
L of absolute ethanol in 12ꢂ75-mm polypropylene
34.5, 35.2, 36.3, 41.5, 42.0, 44.6, 51.4, 52.2, 67.4, 70.4, 75.8, 125.9,
128.4, 128.6, 129.9, 132.7, 139.3; FABMS m/z 453 (MþNa)þ,
HRFABMS calcd for C28H46NaO3 453.3345, found 453.3363.
tubes. The chick intestinal VDR (0.2 mg) and 1 mg of gelatin in 1 mL
of phosphate buffer solution (25 nM KH2PO4, 0.1 M KCl, and 1 mM
dithiothreitol, pH 7.4) were added to each tube in an ice bath. The
assay tubes were incubated in a shaking water bath for 1 h at 25 ꢀC
and then chilled in an ice bath. One milliliter of 40% polypropylene
glycol 6000 in distilled water was added to each tube, which was
mixed vigorously and centrifuged at 2,260ꢂg for 60 min at 4 ꢀC.
After the supernatant was decanted, the bottom of the tube con-
taining the pellet was cut off into a scintillation vial containing
10 mL of dioxane-based scintillation fluid and the radioactivity was
measured with a Beckman liquid scintillation counter (Model
LS6500). The relative potency of the analog was calculated from the
4.2.58. 14-epi-1
pre-1g ). In the same procedure for 14-epi-pre-1a, 3g
0.331 mmol), 2 (87 mg, 0.221 mmol), nBuLi (1.57 M hexane solu-
tion, 232 L, 0.364 mmol), and THF (7 mL) gave coupling products
(84 mg, 49%), and the compound obtained above (29 mg,
0.0375 mmol), TBAF (0.75 mL, 1.0 M THF solution, 0.75 mmol), and
b,25-Dihydroxy-2
b
-methylprevitamin D3 (14-epi-
b
b
(198 mg,
m
THF (3 mL) afforded 14-epi-pre-1g
b
(16 mg,100%) as a colorless oil:
ꢁ35.4 (c 0.54, CHCl3); UV (EtOH) lmax 252.5 nm, lmin
227.0 nm; IR (neat) 3370, 2961, 1456, 1379 cmꢁ1 1H NMR
(600 MHz, C6D6)
23
[a]
D
;
concentration needed to displace 50% of [26,27-methyl-3H]-1
dihydroxyvitamin D3 from the receptor compared with the activity
of 1
,25-dihydroxyvitamin D3 (assigned a 100% value).30
a,25-
d
1.03 (d, J¼6.2 Hz, 3H), 1.05 (s, 3H), 1.12 (s, 3H),
1.12 (s, 3H), 1.22 (d, J¼7.2 Hz, 3H), 1.33e1.55 (m, 13H), 1.87e1.90 (m,
1H),1.99 (s, 3H), 2.03e2.12 (m, 3H), 2.23e2.28 (m, 2H), 2.33 (m,1H),
3.64 (m,1H), 3.69 (m,1H), 5.84, (m,1H), 5.95 (s,1H), 5.95 (s,1H); 13C
a
4.4. General procedure for transactivation assay of human
osteocalcin promoter
NMR (150 MHz, C6D6)
d 14.5, 18.7, 20.1, 21.4, 21.9, 23.3, 29.0, 29.3,
29.8, 30.2, 34.2, 34.7, 36.4, 37.2, 38.9, 41.4, 44.6, 51.0, 52.9, 70.3, 70.8,
73.3, 126.1, 127.3, 128.5, 132.1, 132.5, 139.4; FABMS m/z 453
(MþNa)þ, HRFABMS calcd for C28H46NaO3 453.3345, found
453.3332.
The human osteocalcin gene promoter fragment e838/þ10 was
cloned into the reporter plasmid pGL3 (Promega) as reported.31
Human VDR and RXR gene were cloned into expression vector
pcDNA3 (Invitrogen). Hos cells maintained in phenol red free
DMEM (Invitrogen) containing 10% FCS (Invitrogen). Prior to
transfections, the cells were plated in a 96 well plate at the density
of 400,000 cells per well in the Opti-MEM (Invitrogen). The cells
were transfected with human osteocalcin reporter vector (pGL3-
hOc: 100 ng/well), human VDR and RXR expression vector (pcDNA-
hVDR, pcDNA-hRXR: 10 ng/well) and phRL-TK (Promega: 25 ng/
4.2.59. 14-epi-1
(14-epi-pre-1h
b,25-Dihydroxy-2
b-(3-hydroxypropyl)previtamin D3
b
). >In the same procedure for 14-epi-pre-1a, 3h
b
(45 mg, 0.051 mmol), 2 (13 mg, 0.034 mmol), nBuLi (1.57 M hexane
solution, 0.036 mL, 0.056 mmol), and THF (1.5 mL) gave coupling
products (13 mg, 36%), and the compound obtained above (12 mg,
0.0113 mmol), TBAF (0.23 mL, 1.0 M THF solution, 0.23 mmol), and
THF (1 mL) afforded 14-epi-pre-1h
b
(5.4 mg, 100%) as a colorless
well) using 0.45 mL of Lipofectamine 2000 reagent (Invitrogen).
22
oil; [
227.0 nm; IR (neat) 3350, 2930, 1458, 1377, 1210 cmꢁ1
(400 MHz, CDCl3)
a]
þ60.9 (c 0.023, CHCl3); UV (EtOH) lmax 250.0 nm, lmin
After incubation at 37 ꢀC for 3 h, the culture media were replaced to
phenol red free DMEM containing 10% FCS. The cells were treated
with ethanol vehicle or various concentrations of compounds (from
0.1 pM to 100 nM). After incubation at 37 ꢀC for 24 h, the luciferase
activity of the cells was quantitated by luminometor (Berthold)
using Dual-Glo luciferase assay system (Promega).
D
;
1H NMR
d
0.91 (s, 3H), 0.93 (d, J¼6.3 Hz, 3H), 1.10 (m, 1H),
1.21 (s, 3H), 1.28 (s, 3H), 1.33e2.06 (m, 21H), 1.82 (s, 3H), 2.28 (m,
1H), 2.49 (m,1H), 3.67e3.75 (m, 2H), 3.86 (m, 1H), 4.10 (m,1H), 5.79
(d, J¼12.2 Hz, 1H), 5.92 (d, J¼12.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
d 18.4, 19.7, 21.0, 21.8, 22.9, 25.0, 28.7, 29.1, 29.7, 29.8, 33.8,
34.3, 35.9, 38.5, 41.1, 41.9, 44.4, 50.9, 52.4, 63.1, 69.5, 71.1, 71.4, 77.2,
125.5, 127.3, 127.8, 131.2, 132.3, 138.8; FABMS m/z 497 (MþNa)þ,
HRFABMS calcd for C30H50NaO4 497.3607, found 497.3616.
Acknowledgements
We are grateful to Ms. Junko Shimode and Ms. Ayako Kawaji
(Teikyo University) for the spectroscopic measurements. This work
was supported in part by Grants-in-Aid from the Ministry of Edu-
cation, Culture, Sports, Science and Technology, Japan (to D.S and N.
S.) and by a Grant-in-Aid from the Japan Society for the Promotion
of Science (to A.K.).
4.2.60. 14-epi-1
b
,25-Dihydroxy-2
b-(3-hydroxypropoxy)previtamin
D3 (14-epi-pre-1i
b
). In the same procedure for 14-epi-pre-1a, 3i
b
(50 mg, 0.056 mmol), 2 (15 mg, 0.038 mmol), nBuLi (1.57 M hexane
solution, 0.39 mL, 0.061 mmol), and THF (2 mL) gave coupling
products (22 mg, 57%), and the compound obtained above (18 mg,
0.0175 mmol), TBAF (0.35 mL, 1.0 M THF solution, 0.35 mmol), and
Supplementary data
THF (1.5 mL) afforded 14-epi-pre-1i
b
(7.4 mg, 86%) as a colorless
23
oil: [
227.5 nm; IR (neat) 3385, 2950, 1377, 1212, 1096 cmꢁ1
(400 MHz, CDCl3)
a]
ꢁ10.7 (c 0.15, CHCl3); UV (EtOH) lmax 251.5 nm, lmin
D
1H NMR and 13C NMR spectra for ten new previtamin D3 analogs
14-epi-pre-1aeib. Supplementary data associated with this article
can be found in online version at doi:10.1016/j.tet.2010.05.028.
;
1H NMR
d
0.91 (s, 3H), 0.94 (d, J¼6.6 Hz, 3H), 1.10 (m, 1H),
1.21 (s, 3H), 1.21 (s, 3H), 1.22e1.60 (m, 15H), 1.74e1.78 (m, 1H), 1.78
(s, 3H),1.87 (m, 3H), 2.02e2.06 (m, 3H), 2.41 (m, 2H), 3.00 (br s, 2H),
3.48 (m, 1H), 3.81e3.91 (m, 4H), 4.13 (m, 2H), 5.62 (m, 1H), 5.80 (d,
J¼12.9 Hz, 1H), 5.84 (d, J¼12.9 Hz, 1H); 13C NMR (150 MHz, C6D6)
References and notes
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1
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b
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references cited therein.
Workshop on Vitamin D, Brugge, October 4-8, 2009 and will appear as a special
issue selected article from the Workshop as follows: Sawada, D.; Tsukuda, Y.;