Stereoselective Synthesis of the C(1)?–?C(28) Fragment of Amphidinol 3

Article abstract of DOI:10.1002/hlca.201500281

A stereoselective synthesis of the polyol side chain (C(1)?–?C(28)) of amphidinol 3 has been accomplished following Sharpless epoxidation, Crimmins aldol reaction, Jacobsen kinetic resolution, Sharpless asymmetric dihydroxylation, and our own reaction for

Full text of DOI:10.1002/hlca.201500281

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Helv. Chim. Acta 2016, 99, 436 – 446
FULL PAPER
Stereoselective Synthesis of the C(1) – C(28) Fragment of Amphidinol 3
by Jhillu S. Yadav*, Yerragorla Gopalarao, Dandekar Chandrakanth, and Basi V. Subba Reddy
Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India
(
phone: +91-40-27193737; fax: +91-40-27160512; e-mail: yadavpub@gmail.com)
A stereoselective synthesis of the polyol side chain (C(1) – C(28)) of amphidinol 3 has been accomplished following
Sharpless epoxidation, Crimmins aldol reaction, Jacobsen kinetic resolution, Sharpless asymmetric dihydroxylation, and our
own reaction for the synthesis of a chiral allylic alcohol from an epoxy alcohol. The olefin functionality was introduced by a
cross metathesis and Julia–Kocienski olefination.
Keywords: Amphidinol 3, Stereoselective synthesis, Sharpless epoxidation, Crimmins aldol, Kinetic resolution, Cross
metathesis, Julia-Kocienski olefination.
amphidinol 3 (1) has received special attention [5]. In
continuation of our efforts toward the synthesis of com-
Introduction
Marine dinoflagellate-derived polyketides, such as breve- plex natural products [6], we herein report a stereoselec-
toxins, ciguatoxin, maitotoxin, amphidinolides, okadaic tive approach for the synthesis of the C(1) – C(28) side
acid, and amphidinols, possess promising biological prop- chain of amphidinol 3 (1; Fig.).
erties [1]. In particular, amphidinol 3 (AM 3) was isolated
The present approach for the synthesis of the polyol
from the cultured cells (440 l) of the dinoflagellate fragment 2 involves Jacobsen hydrolytic kinetic resolution
Amphidinium klebsi, which is known to be hemolytic and
antifungal in nature [2]. It is the first molecule in
amphidinol’s family and its complete structure was estab-
[7], Sharpless asymmetric epoxidation [8], Sharpless asym-
metric dihydroxylation [9], Yadav’s approach [10], Crim-
mins aldol reaction [11], Grubbs cross metathesis [12],
lished by a newly developed configurational analysis [3]. and Julia–Kocienski olefination [13]. Our retrosynthetic
Amphidinol 3 contains a skipped polyene chain with two
analysis of the polyol side chain of AM3, 2, is shown in
highly oxygenated pyran rings and a polyol side chain Scheme 1. Retrosynthetically, the AM3 fragment 2 can be
with a total of 25 stereogenic centers on a contiguous 67
divided into two segments 3 and 4 by disconnecting the
C-skeleton. Recently, Oishi et al. [4], proposed the revised backbone at C(8)=C(9). The fragment 4 could be pre-
structure of amphidinol 3 and its absolute configuration
was found to be (R) at C(2). Owing to its complex struc-
ture and inherent biological activity, the synthesis of
pared by combining two fragments 7 (C(9) – C(21)) and
8 (C(20) – C(28)). Another fragment 3 was proposed to
be obtained from segments 5 and 6.
Figure. Structure of amphidinol 3 (1).
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2016 Verlag Helvetica Chimica Acta AG, Z u€ rich
DOI: 10.1002/hlca.201500281

Helv. Chim. Acta 2016, 99, 436 – 446
437
Scheme 1. Retrosynthesis of polyol side chain (C(1) – C(28)) of Amphidinol 3 (1).
Another key intermediate 6 was prepared from a com-
mercially available 3-butyn-1-ol (12). Protection of 12 with
Accordingly, the synthesis of intermediate 5 began from p-methoxybenzyl bromide in the presence of NaH in anhy-
Results and Discussion
(R)-benzylglycidyl ether 9. Ring opening of the epoxide 9
with vinyl magnesium bromide in the presence of a cat-
drous THF at 0 °C gave the PMB ether 13. Reaction of 13
with ethyl magnesium bromide followed by treatment with
alytic amount of CuCN gave the homoallylic alcohol 10. paraformaldehyde in anhydrous THF afforded the propar-
Debenzylation of 10 with Li in liquid NH [14] afforded the gyl alcohol 14. Reduction of 14 with LiAlH in anhydrous
3
4
diol 11, which was protected as its di(tert-butyldimethylsi-
lyl) ether 5 using tert-butyldimethylsilyl chloride (TBSCl)
THF at room temperature gave the desired trans-allylic
alcohol 15. Sharpless asymmetric epoxidation of 15 using
i
[15], imidazole, and a catalytic amount of 4-dimethylamino- Ti(O Pr) , diisopropyl tartrate ((ꢀ)-DIPT), and tert-butyl
4
pyridine (DMAP) in anhydrous CH Cl (Scheme 2).
2
hydroperoxide (TBHP) furnished the epoxy alcohol 16 [16]
2
Scheme 2
a) Vinyl magnesium bromide, CuCN, dry THF, ꢀ78 °C to 0 °C, 75%; b) Li, liq. NH
3
, THF, ꢀ30 °C, 20 min, 75%; c) TBSCl, imidazole, CH
2 2
Cl ,
0
°C – r.t., 92%.
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2016 Verlag Helvetica Chimica Acta AG, Z u€ rich
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438
Helv. Chim. Acta 2016, 99, 436 – 446
Scheme 3
a) PMBBr, NaH, dry THF, 0 °C, 88%; b) Mg, EtBr, dry THF, 0 °C – r.t., (CH
DIPT, TBHP, ꢀ20 °C, dry CH Cl , 85% yield, 90% d.e.; e) (C TiCl , Zn, ZnCl
2%; g) TBDPSCl, DMAP, imidazole, CH Cl , 0 °C – r.t., 90%; h) DDQ, CH
°C – r.t., 90%; j) Mo 24(NH O, H
ꢁ 4 H
2
O)
n
, 80%; c) LiAlH
, dry THF, r.t., 85%, > 95% ee; f) Grubbs’ II catalyst, CH
Cl , pH 7 buffer (9:1), 85%; i) p-TSH, TPP, DIAD, THF,
, EtOH, 0 °C – r.t., 88%.
4
, dry THF, 0 °C – r.t., 80%; d) Ti(OiPr)
4
, (–)-
2
2
5
H
5
)
2
2
2
Cl
2 2
,
7
2
2
2
2
0
7
O
4
)
6
2
2
O
2
with 9:1 ratio of diastereoisomers, which are separable by
column chromatography. Compound 16 was converted into and Et N in CH Cl afforded the mono-tosylate, which was
of 23 under Martinelli’s conditions [20] using TsCl, Bu SnO,
2
3
2
2
allylic alcohol 6 using our own protocol [10] (Scheme 3). In
used in the next step without further purification. Treat-
order to get the advanced intermediate 3, we adopted the ment of mono-tosylate with K CO in MeOH afforded the
2
3
cross metathesis strategy. Thus the cross-coupling of frag-
ments 5 and 6 using Grubbs’ II generation catalyst [12] Grignard reagent generated in situ from 6-bromo-1-hexene
10 mol-%) in CH Cl2 gave the trans-alkenol 17 exclu- and magnesium [21] at 0 °C in the presence of 10 mol-%
epoxide 24, which was then subjected to ring opening with
(
2
sively. Protection of 17 with TBDPSCl in the presence of
imidazole in CH Cl afforded the TBDPS ether and depro-
CuBr to afford the secondary alcohol, which was subse-
quently protected as its TBDPS ether using TBDPSCl, imi-
tection of 4-methoxybenzyl (PMB) ether using 2,3- dazole, and DMAP in CH Cl to give the silyl ether 7.
2
2
2
2
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in CH Cl /
2
Another key intermediate 8 was prepared from a chi-
ral epoxide 9 [22]. Ring opening of epoxide 9 with alkynyl
2
H O (9:1) at pH 7 afforded the primary alcohol 18. Mit-
2
sunobu reaction [17] of 18 with 1-phenyl-1H-tetrazole-5- ether under Yamaguchi conditions [23] afforded the sec-
thiol using diisopropyl azodicarboxylate (DIAD) and tri- ondary alcohol 25, which was then protected as its benzyl
phenylphosphine (TPP) in THF gave the sulfide 19. Oxida- ether 26 using benzyl bromide in the presence of NaH
tion of sulfide 19 using a catalytic amount of ammonium and a catalytic amount of TBAI in anhydrous THF
molybdate [18] in the presence of H O in EtOH furnished (Scheme 5). Treatment of 26 with a catalytic amount of
2
2
the sulfone 3 in good yield. p-TSA in MeOH gave the propargyl alcohol 27, which
We next attempted the synthesis of intermediate 7. was then converted into trans-allylic alcohol 28 using
Accordingly, the exposure of a racemic epoxide to Jacobsen LiAlH under reflux conditions. Asymmetric epoxidation
4
hydrolytic kinetic resolution (HKR) conditions gave the p- of allylic alcohol 28 under Sharpless conditions [(+)-diiso-
methoxy benzyl glycidyl ether 21 [19] (Scheme 4). Regiose- propyl tartrate, titanium(IV)isopropoxide, and tert-butyl
lective ring opening of 21 with homoallyl MgBr , formed
2
hydroperoxide] in CH Cl at ꢀ23 °C afforded the epoxy
2
2
in situ from 4-bromo-1-butene and Mg in THF in the pres-
alcohol 29 in 9:1 diastereoisomeric ratio [8]. The epoxy
ence of CuBr gave the alkenol 22. Protection of 22 as its alcohol 29 was further converted into allylic alcohol 30
silyl ether followed by Sharpless asymmetric dihydroxyla- using our own methodology [10], involving the reaction of
t
tion using AD-mix-a in BuOH and H O (1:1) at 0 °C epoxy alcohol with (Et) TiCl and granulated Zn contain-
2
2
afforded the diol 23 as a mixture of diastereoisomers in the ing ZnCl in THF under inert atmosphere. Protection of
2
ratio of 8:2. Selective tosylation of the primary OH group
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allylic alcohol 30 as its silyl ether 31 with TBDMSCl in
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Helv. Chim. Acta 2016, 99, 436 – 446
439
Scheme 4
t
a) 4-Bromo-1-butene, Mg, CuBr, THF, ꢀ40 °C – r.t., 90%; b) TBDPSCl, DMAP, imidazole, CH
2 2
Cl , 0 °C – r.t., 92%; c) AD-mix-a, BuOH/
2 3 2 2 2 2 3
H O, 90%; d) TsCl, Et N, Bu SnO, CH Cl , 0 °C – r.t., 95%; e) K CO , MeOH, 80%; f) 6-bromo-1-hexene, Mg, CuBr, THF, 0 °C, 85%;
2 2
g) TBDPSCl, DMAP, imidazole, CH Cl , reflux, 95%.
the presence of imidazole and DMAP in CH Cl at 0 °C
followed by ozonolysis of the olefin gave the aldehyde.
Having success in achieving key intermediates with
required stereochemistry, we attempted the coupling of seg-
2
2
Crimmins syn aldol reaction [11] of the above aldehyde ments 7 and 8 by cross metathesis. Thus the cross-coupling of
with (S)-1-(5-benzyl-2-thioxothiazolidin-3-yl)-propan-1- olefins 7 and 8 in 1:3 ratio in the presence of Grubbs’ II gen-
one using titanium tetrachloride and (ꢀ)-sparteine in eration catalyst (10 mol-%) in CH Cl afforded the com-
2
2
CH Cl under anhydrous conditions at 0 °C furnished the pound 36 (Scheme 6). Asymmetric dihydroxylation [9] of 36
2
2
syn-aldol product 32 as a single diastereoisomer. The OH under Sharpless conditions gave the diol 37 as a mixture of
group of 32 was then protected with TBS-triflate and 2,6- diastereoisomers in the ratio of 9:1. Protection of the diol
lutidine in CH Cl2 at 0 °C to afford the TBS ether 33. using TBSOTf and 2,6-lutidine in CH Cl gave the bis-silyl
2
2
2
Removal of the chiral auxiliary from 33 with LiBH4 in ether 38 in good yield. Treatment of 38 with DDQ in
THF/MeOH (9:1) at 0 °C gave the primary alcohol 34. CH Cl /H O (9:1) at pH 7 buffer gave the primary alcohol
2
2
2
Protection of the OH group of 35 with TsCl in the pres-
39. Oxidation of the primary alcohol 39 with Dess–Martin
ence of Et N and DMAP in CH Cl followed by treat- periodinane [25] afforded the aldehyde 4. Finally, the cou-
3
2
2
ment with vinyl magnesium bromide in the presence of
0 mol-% Li CuCl in Et O at ꢀ78 °C provided the Julia–Kocienski olefination [13] using KHMDS at ꢀ78 °C
pling of aldehyde 4 with C(1) – C(8) fragment 3 through a
afforded the fully protected C(1) – C(28) polyol fragment 2
1
desired product 8 in good yield [24].
2
4
2
Scheme 5
a) BuLi, BF
3
ꢁOEt
, TBHP, CH
P, 90%; i) (S)-1-(5-benzyl-2-thioxothiazolidin-3-yl-propan-1-one, TiCl
°C, 95%; k) LiBH , THF/MeOH, 91%; l) TsCl, DMAP, Et N, CH Cl , 92%; m) Li
5%.
2
, THF, ꢀ78 °C, 80%; b) NaH, BnBr, TBAI, THF, 95%; c) p-TSA, MeOH, 95%; d) LiAlH
Cl TiCl , Zn, ZnCl , Dry THF, r.t., 85%; g) TBSCl, imidazole, CH
, ꢀ20 °C, 90%; f) (Et)
, (–)-sparteine, CH Cl , 0 °C, 85%; j) 2,6,-lutidine, TBSOTf, CH
CuCl , vinyl magnesium bromide, dry Et
O, ꢀ78 to 0 °C,
4
, THF, reflux, 80%; e) L-(+)-DIPT,
Cl , 0 °C – r.t., 92%; h) O
Cl
i
Ti(O Pr)
Ph
4
2
2
2
2
2
2
2
3
,
3
4
2
2
2
2
,
0
4
3
2
2
2
4
2
7
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2016 Verlag Helvetica Chimica Acta AG, Z u€ rich
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440
Helv. Chim. Acta 2016, 99, 436 – 446
Scheme 6
a) Grubbs’ II, CH
2
Cl
2
, 70% (9:1 E/Z); b) AD-mix-a, MeSO
2
NH
2
2 2 2 2 2
, t-BuOH/H O, 80%; c) 2,6-lutidine, TBSOTf, CH Cl , 95 %; d) DDQ, CH Cl /
H
2
O (pH 7 buffer) (9:1), 87%; e) DMP, NaHCO
3
, CH
2
Cl
2
; f) KHMDS, THF, 18-crown-6 ether, ꢀ78 °C – r.t., 80%.
of amphidinol 3 (1) in 9:1 ratio of (E/Z)-isomers (C(9)=C distilled prior to use: THF, toluene, and Et O were dis-
2
(
10)).
tilled from Na and benzophenone ketyl, MeOH from Mg
and I , CH Cl from CaH . All air- or moisture-sensitive
reactions were conducted under N or Ar atmosphere in
2
2
2
2
2
Conclusions
flame-dried or oven-dried glassware. Column chromatog-
In conclusion, we have accomplished a highly stereoselective raphy (CC) was carried out using silica gel (SiO ; 60 – 120
2
synthesis of the C(1) – C(28) fragment of amphidinol 3. This mesh or 100 – 200 mesh) packed in glass columns. Techni-
approach establishes ten stereogenic centers of amphidinol cal grade AcOEt and petroleum ether (PE) used for CC
3
. Our approach successfully utilizes the Jacobsen hydrolytic were distilled prior to use. Optical rotations were mea-
kinetic resolution, Sharpless asymmetric epoxidation, Sharp- sured on digital polarimeter using a 1 ml cell with a 1 dm
less asymmetric dihydroxylation, Yadav’s protocol, Crim- path length, Horiba (Japan) high-sensitive polarimeter
mins aldol reaction, cross metathesis, and Julia–Kocienski SEPA-300 at 25 °C. IR Spectra: PerkinElmer IR-683 spec-
1
olefination protocols. It is a modular approach to produce trophotometer (Shelton, USA) with NaCl optics. H-NMR
1
3
other diastereoisomers of amphidinol 3; therefore, it would (200 and 300 MHz) and C-NMR (50 and 75 MHz) spec-
serve as a better option for new analogues.
tra: Varian Gemini FT-200 (Paloalto, USA) and Bruker
Avance 300 (Switzerland) instruments with TMS as inter-
nal standard in CDCl ; the coupling constant J is given in
YGR and DCK thank CSIR for the award of fellowships.
3
Hz. The chemical shifts are reported in ppm downfield
from TMS (Me Si) as internal standard and signal patterns
4
Experimental Part
are indicated as follows: s, singlet; d, doublet; t, triplet; q,
quartet; sext., sextet; m, multiplet; br., broad. MS: Agilent
Technologies 1100 Series (Agilent ChemStation software;
Waldbronn, Germany). Mass analysis was done in the ESI
General
All reagents were reagent grade and used without further
purification unless specified otherwise. Solvents were mode.
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Helv. Chim. Acta 2016, 99, 436 – 446
441
(
5R)-2,2,3,3,8,8,9,9-Octamethyl-5-(prop-2-en-1-yl)-4,7-dioxa- H); 2.18 – 2.06 (m, 1 H); 1.83 – 1.71 (m, 1 H); 1.58 (br. s, 1
3
,8-disiladecane (5). To a soln. of alcohol 11 [14] (1.5 g, H); 0.88 (s, 9 H); 0.86 (s, 9 H); 0.04 (s, 6 H); 0.03 (s, 6 H).
1
3
1
4.70 mmol) in CH Cl (30 ml) at 0 °C were added imida-
C-NMR (75 MHz, CDCl ): 159.1; 134.7; 134.6; 130.0;
3
2
2
zole (4.23 g, 58.8 mmol); tert-butyl(chloro)dimethylsilane 129.2; 127.5; 113.7; 72.8; 71.6; 68.0; 66.7; 55.2; 37.2; 36.6;
6.61 g, 44.1 mmol) and a cat. amount of DMAP. The mix- 25.9; 25.8; 18.2; 18.0; ꢀ4.4; ꢀ4.6; ꢀ5.3; ꢀ5.4. ESI-MS: 547
(
+
þ
2
ture was stirred at 0 °C for 1 h followed by warming it to ([M + Na] ). HR-ESI-MS: 547.3247 (C28H NaO Si ,
r.t., and then poured into H O followed by separation of [M + Na] ; calc. 547.3251).
5
2
5
+
2
the org. layer. The aq. layer was extracted with CH Cl
(3R,4E,7R)-7,8-Bis{[tert-butyl(dimethyl)silyl]oxy}-3-{[tert-butyl
and the combined org. extracts were dried (MgSO ) and (diphenyl)silyl]oxy}oct-4-en-1-ol (18). To a stirred biphasic
2
2
4
concentrated. The crude product was purified by flash CC soln. of ether 17 (300 mg, 0.4 mmol) in CH Cl (10 ml)
2
2
(
SiO ; 5% AcOEt in hexanes) to yield 5 (4.46 g, 92% and pH 7 buffer (1 ml) at 0 °C was added DDQ (133 mg,
2
20
yield) as a colorless liquid. ½aꢂ = ꢀ1.72 (c = 1.0, CHCl ). 0.59 mmol). The mixture was stirred at 0 °C for 2 h and
D
3
1
IR (neat): 3070, 2958, 1452, 1125, 906. H-NMR
300 MHz, CDCl ): 5.86 – 5.71 (m, 1 H); 5.10 – 4.96 (m, 2
the reaction quenched with sat. NaHCO soln. The sepa-
3
(
rated aq. phase was extracted with CH Cl (3 9 10 ml).
2
3
2
H); 3.70 – 3.63 (m, 1 H); 3.50 – 3.36 (m, 2 H); 2.36 – 2.25 The combined org. layers were washed with sat. NaHCO3
(
m, 1 H); 2.18 – 2.07 (m, 1 H); 0.88 (s, 9 H); 0.86 (s, 9 H); soln. and brine, dried (Na SO ), and evaporated under
2 4
13
0
7
.03 (s, 12 H). C-NMR (75 MHz, CDCl ): 135.2; 116.7; vacuum. The residue was purified by CC (AcOEt/hexane)
3
2
0
2.8; 66.8; 39.0; 25.9; 25.8; 18.3; 18.1; ꢀ2.9; ꢀ4.3; ꢀ4.6; to deliver 213 mg (85%) of 18 as colorless oil. ½aꢂ = +9.0
D
+
ꢀ
5.3. ESI-MS: 353 ([M + Na] ). HR-ESI-MS: 353.2300 (c = 1.0, CHCl ). IR (neat): 3452, 3030, 1612, 1241, 1152.
3
þ
+
1
(
C17H38NaO2Si , [M + Na] ; calc. 353.2308).
H-NMR (300 MHz, CDCl ): 7.92 – 7.80 (m, 4 H);
3
2
(3R)-5-[(4-Methoxybenzyl)oxy]pent-1-en-3-ol (6). To a
red soln. of titanocene (7.85 g, 31.5 mmol) in dry THF
7.65 – 7.48 (m, 6 H); 5.72 – 5.44 (m, 2 H); 4.60 – 4.49 (m,
1 H); 3.92 (br. s, 1 H); 3.80 – 3.70 (m, 2 H); 3.63 – 3.46
(
80 ml) containing freshly fused ZnCl2 (1.39 g, (m, 2 H); 2.37 – 2.07 (m, 3 H); 2.03 – 1.73 (m, 2 H); 1.24
13
1
and the mixture stirred for 1 h. The resulting green soln. NMR (75 MHz, CDCl ): 135.9; 135.8; 135.0; 133.8; 133.6;
0.5 mmol) was added Zn powder (1.39 g, 10.5 mmol)
(s, 9 H); 1.06 (s, 9 H); 1.03 (s, 9 H); 0.20 (s, 12 H). C-
3
was added to 16 (2.5 g, 10.5 mmol) in dry THF (20 ml) 129.7; 129.5; 127.5; 127.3; 126.2; 74.9; 73.2; 72.8; 68.7; 59.5;
through a cannula. After 5 min, the mixture was treated
with 5% HCl (20 ml) and extracted thoroughly with
Et O. The Et O layer was washed with H O, 10% aq.
39.8; 36.3; 27.0; 25.9; 25.8; 19.2; 18.2; 18.0; ꢀ4.4; ꢀ4.7;
+
ꢀ5.3. ESI-MS: 661 ([M + NH ] ). HR-ESI-MS: 665.3866
4
þ
+
(C36H62NaO4Si , [M + Na] ; calc. 665.3853).
2
2
2
3
NaHCO , H O, and brine, and dried (Na SO ). Evapora-
3
5-{[(3R,4E,7R)-7,8-Bis{[tert-butyl(dimethyl)silyl]oxy}-3-{[tert-
butyl(diphenyl)silyl]oxy}oct-4-en-1-yl]sulfanyl}-1-phenyl-1H-
tetrazole (19). DIAD (94.3 mg, 0.466 mmol) was added to
a soln. of alcohol 18 (0.2 g, 0.311 mmol), 1-phenyl-1H-tet-
2
2
4
tion of the solvent and purification by CC afforded pure
alcohol 6 (1.98 g, 85% yield) as a colorless liquid.
2
D
0
½
aꢂ = ꢀ9.8 (c = 1, CHCl ). IR (neat): 3443, 2934, 2861,
3
1
1
612, 1512, 1246, 1092, 819. H-NMR (500 MHz, CDCl ): razole-5-thiol (72 mg, 0.404 mmol), and TPP (106 mg,
3
7
.20 (d, J = 8.4, 2 H); 6.82 (d, J = 8.4, 2 H); 5.89 – 5.76 0.404 mmol) in THF (10 ml) at 0 °C. The mixture was
(m, 1 H); 5.24 (d, J = 17.1, 1 H); 5.07 (d, J = 10.5, 1 H); stirred at r.t. for 3 h and quenched with sat. NaCl (10 ml)
4
.42 (s, 2 H); 4.28 (br. s, 1 H); 3.79 (s, 3 H); 3.70 – 3.52 soln. The org. layer was separated and the aq. layer was
1
3
(m, 2 H); 2.80 – 2.68 (m, 1 H); 1.88 – 1.67 (m, 2 H). C-
extracted with AcOEt. The combined org. layers were
NMR (75 MHz, CDCl ): 159.1; 140.4; 129.9; 129.2; 114.2; dried (MgSO ) and concentrated. The purification of the
3
4
1
13.7; 72.8; 71.7; 67.9; 55.1; 36.1. ESI-MS: 245
+
crude product by flash CC (AcOEt in hexane) provided
20
([M + Na] ).
3R,4E,7R)-7,8-bis{[tert-butyl(dimethyl)silyl]oxy}-1-[(4-meth- CHCl ). IR (neat):1662, 1590, 1563, 1512. H-NMR
19 (225 mg, 90%) as an oil. ½aꢂ = ꢀ2.20 (c = 1.05,
D
1
(
3
oxybenzyl)oxy]oct-4-en-3-ol (17). Grubbs’ II generation cat-
alyst (0.85 g, 0.1 mmol, 10 mol-%) was dissolved in 2 ml of
degassed CH Cl and it was added drop wise to a soln. of 6
(300 MHz, CDCl ): 7.70 – 7.49 (m, 9 H); 7.42 – 7.26 (m,
3
6 H); 5.51 – 5.41 (m, 2 H); 4.35 – 4.21 (m, 1 H);
3.66 – 3.56 (m, 1 H); 3.46 – 3.26 (m, 4 H); 2.27 – 1.87 (m,
4 H); 1.08 (s, 9 H); 0.90 (s, 9 H); 0.86 (s, 9 H); 0.03 (s, 12
2
2
(
0.22 g, 1 mmol) and 5 (0.490 g, 1.5 mmol) in 3 ml of
1
3
CH Cl degassed by Ar. After completion of addition, the H). C-NMR (75 MHz, CDCl ): 154.2; 135.9; 135.8;133.9;
2
2
3
mixture was allowed to stir for 12 h under reflux condi-
tions. The solvent was removed under reduced pressure
and the crude product was purified by SiO CC (AcOEt/
133.7; 133.5; 129.9; 129.6; 129.4; 128.3; 127.5; 127.3; 123.6;
72.7; 72.5; 66.5; 37.0; 36.7; 28.9; 27.0; 25.9; 25.8; 19.2; 18.2;
+
18.0; ꢀ4.4; ꢀ4.7; ꢀ5.32; ꢀ5.39. ESI-MS: 825 ([M + Na] ).
2
þ
HR-ESI-MS: 825.4044 (C43H66N4NaO3SSi , [M + Na] ;
3
+
hexane) to afford the pure product 17 (0.374 g, 72% yield
20
based on 6) as a colorless liquid. ½aꢂ = ꢀ2.83 (c = 1.0, calc. 825.4061).
D
1
CHCl ). IR (neat): 3390, 2940, 1428, 1642, 1034. H-NMR
5-{[(3R,4E,7R)-7,8-Bis{[tert-butyl(dimethyl)silyl]oxy}-3-{[tert-
butyl(diphenyl)silyl]oxy}oct-4-en-1-yl]sulfonyl}-1-phenyl-1H-
3
(
300 MHz, CDCl ): 7.25 – 7.16 (m, 2 H); 6.88 – 6.78 (m, 2
3
H); 5.72 – 5.61 (m, 1 H); 5.54 – 5.44 (m, 1 H); 4.43 (s, 2 H); tetrazole (3). To a soln. of 19 (200 mg, 0.25 mmol) in 3 ml
4
3
.29 – 4.21 (m, 1 H); 3.79 (s, 3 H); 3.71 – 3.53 (m, 2 H); of EtOH at 0 °C was added 0.1 ml of a soln. of the oxidant
.50 – 3.35 (m, 2 H); 2.66 – 2.54 (m, 2 H); 2.35 – 2.22 (m, 1
(made from 62 mg of Mo O (NH ) ꢁ 4 H O in 0.1 ml of
7
24
4 6
2
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2016 Verlag Helvetica Chimica Acta AG, Z u€ rich
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442
Helv. Chim. Acta 2016, 99, 436 – 446
3
quenched with H O, filtered through a Celite pad, and the 30 min. The mixture was extracted with AcOEt
0% w/v aq. H O ). The mixture was stirred at r.t. for 48 h,
of sodium sulfite, then warmed to r.t., and stirred for
2
2
2
filtrate extracted with AcOEt. The combined org. layers
were dried and concentrated to leave a residue that was
purified by CC over SiO2 (hexane/AcOEt) to provide
(3 9 10 ml). The org. layer was washed with 2N KOH
soln. and then dried (anh. Na SO ). Removal of solvent
2
4
and purification by SiO CC afforded the diol 23 (0.77 g,
2
2
0
20
1
83 mg (88%) of 3 as a colorless viscous oil. ½aꢂ = +3.0 90 %) as a gummy liquid. ½aꢂD = +9.45 (c = 1.85, CHCl ).
D
3
1
(c = 1.8, CHCl ). IR (neat): 2928, 1597, 1497, 1466, 1107. IR (neat): 3400, 2858, 1612, 1302, 1109, 1037. H-NMR
3
1
H-NMR (300 MHz, CDCl ): 7.70 – 7.54 (m, 9 H); (300 MHz, CDCl ): 7.63 (d, J = 6.7, 4 H); 7.42 – 7.27 (m,
3
3
7
.42 – 7.29 (m, 6 H); 5.65 – 5.54 (m, 1 H); 5.47 – 5.39 (m, 1
6 H); 7.05 (d, J = 8.4, 2 H); 6.76 (d, J = 8.4, 2 H); 4.24 (s,
H); 4.40 – 4.33 (m, 1 H); 3.72 – 3.58 (m, 3 H); 3.45 – 3.32 2 H); 3.85 – 3.76 (m, 1 H); 3.78 (s, 3 H); 3.55 – 3.44 (m, 2
(
9
m, 2 H); 2.25 – 2.07 (m, 2 H); 2.06 – 1.95 (m, 2 H); 1.08 (s, H); 3.37 – 3.23 (m, 3 H); 1.57 – 1.12 (m, 8 H); 1.03 (s, 9
1
3
H); 0.88 (s, 9 H); 0.85 (s, 9 H); 0.02 (s, 12 H). C-NMR H).
13
C-NMR (75 MHz, CDCl ): 159.0; 135.9; 135.8;
3
(
75 MHz, CDCl ): 153.3; 135.8; 135.7; 135.7; 133.4; 133.2; 134.3; 134.1; 130.4; 129.5; 129.4; 129.2; 127.4; 127.3; 113.6;
3
1
1
1
32.5; 131.3; 129.8; 129.6; 129.6; 129.0; 128.9; 127.7; 127.5; 73.4; 72.7; 72.0; 71.9; 66.6; 55.2; 34.1; 33.0; 27.0; 20.6; 19.3.
+
25.0; 72.5; 71.2; 66.3; 52.1; 36.8; 29.6; 27.0; 25.9; 25.8; 19.2; ESI-MS: 545 ([M + Na] ). HR-ESI-MS: 545.2683
+
+
8.2; 18.0; ꢀ4.45; ꢀ4.80; ꢀ5.35; ꢀ5.41. ESI-MS: 858 (C H NaO Si , [M + Na] ; calc. 545.2699).
3
1
42
5
+
þ
3
(
[M + Na] ). HR-ESI-MS: 857.3959 (C43H66N4NaO5SSi ,
tert-Butyl({(2R)-1-[(4-methoxybenzyl)oxy]-5-[(2S)-oxiran-2-
yl]pentan-2-yl}oxy)diphenylsilane (24). To a stirred soln. of
diol 23 (0.7 g, 1.34 mmol) in dry CH Cl (10 ml), Bu SnO
+
[
M + Na] ; calc. 857.3959).
2R)-1-[(4-Methoxybenzyl)oxy]hept-6-en-2-ol (22).
(
A
2
2
2
5
1
1
0 ml three-necked flask containing Mg turnings (310 mg, (6.6 mg, 0.026 mmol), TsCl (0.254 g, 1.34 mmol), and
2.88 mmol) and a stirring bar were dried in an oven at
Et N (0.28 ml, 2.0 mmol) were added at 0 °C and allowed
3
00 °C for 2 h and cooled to r.t. under a stream of dry
to stirred at r.t. for 6 h. Later, the reaction was quenched
with sat. NaHCO3 (5 ml), then extracted with CH Cl2
N . A portion of 4-bromo 1-butene (1.04 g, 7.73 mmol) in
2
2
anh. THF (20 ml) was introduced and the reaction was
initiated with a small crystal of I and the remaining soln. under vacuum to afford the mono-tosylate. This was used
(2 9 10 ml), dried with anh. Na SO , and concentrated
2
4
2
was added over 10 min at r.t. under a cool H O circula-
2
for the next step without purification. To a stirred soln. of
the above monotosylate in dry MeOH (10 ml) was added
tion. The stirring was continued for another 2 h at r.t.
and the mixture was cooled to ꢀ40 °C. Then CuI (49 mg, solid K CO (0.346 g, 2.54 mmol) at 0 °C and stirred at
2
3
0
stir for 30 min and then a soln. of epoxide 21 (0.5 g, K CO was filtered through a Celite pad. MeOH was
.258 mmol) was added and the mixture was allowed to
the same temp. for 1 h. After completion of the reaction,
2
3
2
1
1
.58 mmol) in dry THF was added drop wise over evaporated and extracted with CHCl3 (2 9 10 ml). The
0 min. The resulting mixture was stirred at ꢀ40 °C for combined org. layers were dried (anh. Na SO ) and con-
2
4
h and then allowed to stir at r.t. over 2 h. After comple-
centrated under vacuum. The residue was purified by
tion, the reaction was quenched by sat. aq. NH Cl and SiO2 CC (60 – 120 mesh, AcOEt/hexane) to afford the
4
extracted by Et O, washed with H O, and brine and dried
2
compound 24 (0.54 g, 80%, over two steps) as a liquid.
2
2
0
(
tion on SiO gave the pure product 22 (0.58 g, 90%) as a
Na SO ). Removal of the solvent followed by purifica- ½aꢂ = +10.74 (c = 1.35, CHCl ). IR (neat): 3010, 1622,
2
4
D
3
1
1250, 910. H-NMR (300 MHz, CDCl ): 7.66 – 7.60 (m, 4
3
2
20
colorless liquid. ½aꢂ = ꢀ2.6 (c = 2.5, CHCl ). IR (neat): H); 7.41 – 7.26 (m, 6 H); 7.03 (d, J = 8.3, 2 H); 6.75 (d,
D
3
1
454, 2999, 1640, 1612, 1460, 1248, 1035. H-NMR
3
J = 9.0, 2 H); 4.22 (s, 2 H); 3.86 – 3.79 (m, 1 H); 3.78 (s,
3 H); 3.35 – 3.25 (m, 2 H); 2.75 – 2.68 (m, 1 H);
2.64 – 2.60 (m, 1 H); 2.33 – 2.28 (m, 1 H); 1.58 – 1.23 (m,
(
300 MHz, CDCl ): 7.20 (d, J = 8.4, 2 H); 6.83 (d, J = 8.6,
3
2
H); 5.83 – 5.67 (m, 1 H); 5.02 – 4.88 (m, 2 H); 4.45 (s, 2
1
3
H); 3.79 (s, 3 H); 3.77 – 3.68 (m, 1 H); 3.41 (dd, J = 3.0, 6 H); 1.03 (s, 9 H). C-NMR (75 MHz, CDCl ): 158.9;
3
9
1
.2, 1 H); 3.26 – 3.18 (m, 1 H); 2.10 – 2.01 (m, 2 H); 135.9; 135.8; 134.4; 134.0; 130.4; 129.5; 129.4; 129.1; 127.4;
1
3
.60 – 1.32 (m, 4 H); 1.25 (br. s, 1 H).
C-NMR 127.3; 113.5; 73.4; 72.6; 71.8; 52.2; 52.1; 47.0; 33.9; 32.4;
+
(
75 MHz, CDCl ): 159.2; 138.5; 129.9; 129.3; 127.0; 114.5; 27.0; 21.0; 19.3. ESI-MS: 527 ([M + Na] ).
3
1
13.7; 74.2; 72.9; 70.1; 55.1; 33.6; 32.4; 24.6. ESI-MS: 273
+
(5R,9R)-5-(Hept-6-en-1-yl)-9-{[(4-methoxybenzyl)oxy]
methyl}-2,2,12,12-tetramethyl-3,3,11,11-tetraphenyl-4,10-
dioxa-3,11-disilatridecane (7). To a stirred soln. of 24
(0.4 g, 0.68 mmol) in CH Cl (10 ml), imidazole (47.6 mg,
þ
(
[M + Na] ). HR-ESI-MS: 273.1476 (C H22NaO ,
15
3
+
[
M + Na] ; calc. 273.1467).
(2S,6R)-6-{[tert-Butyl(diphenyl)silyl]oxy}-7-[(4-methox-
ybenzyl)oxy]heptane-1,2-diol (23). The mixture of 10 ml
2
2
1.36 mmol) was added. After 5 min, TBSCl (0.28 g,
t
of BuOH, 10 ml of H O, and 2.29 g of AD-mix-a was 1.02 mmol) and cat. DMAP were added and stirred at r.t.
2
stirred at r.t. until both phases are clear and then the soln.
for 2 h. The reaction was quenched by adding H O
2
was cooled to 0 °C. The olefin 22 (0.8 g, 1.63 mmol) dis- (5 ml) and extracted with CH Cl (3 9 10 ml). The org.
2
2
t
solved in 2 ml of BuOH was added at once and the extracts were washed with brine (5 ml), dried (anh.
heterogeneous slurry is stirred vigorously at 0 °C for Na SO ) and concentrated under vacuum to remove the
2
4
about 8 h, until TLC revealed the absence of the starting
material. The reaction was quenched at 0 °C by addition
solvent and the crude was purified by CC to afford the
pure product 7 (0.53 g, 95%) as a colorless liquid.
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Helv. Chim. Acta 2016, 99, 436 – 446
443
2
D
0
20
colorless oil (5.40 g, 85.0% yield). ½aꢂ = ꢀ10.3 (c = 1.65,
½
aꢂ = ꢀ7.6 (c = 1.35, CHCl ). IR (neat): 2930, 1641,
3
D
1
1
248, 1039, 702. H-NMR (300 MHz, CDCl ):7.64 – 7.54 CHCl ). IR (neat): 3408, 2916, 2866, 1718, 1494, 1454,
3 3
m, 8 H); 7.39 – 7.23 (m, 12 H); 7.03 – 6.96 (m, 2 H); 1271, 1093, 904. H-NMR (300 MHz, CDCl ): 7.36 – 7.21
1
(
3
6
2
3
2
.77 – 6.70 (m, 2 H); 5.81 – 5.63 (m, 1 H); 4.97 – 4.85 (m, (m, 10 H); 4.70 – 4.50 (m, 4 H); 3.83 – 3.66 (m, 2 H);
H); 4.17 (s, 2 H); 3.78 (s, 3 H); 3.74 – 3.69 (m, 1 H); 3.65 – 3.44 (m, 3 H); 3.05 – 2.96 (m, 1 H); 2.85 – 2.79 (m,
.63 – 3.55 (m, 1 H); 3.25 – 3.15 (m, 2 H); 2.00 – 1.88 (m, 1 H); 1.87 – 1.78 (m, 2 H); 1.43 (br. s, 1 H). C-NMR
1
3
H); 1.33 – 1.17 (m, 14 H); 1.01 (s, 9 H); 1.00 (s, 9 H). (75 MHz, CDCl ): 138.3; 138.2; 128.3; 127.7; 127.6; 127.5;
3
1
3
C-NMR (75 MHz, CDCl ): 159.4; 139.1; 135.9; 135.8; 75.5; 73.3; 71.9; 71.6; 61.5; 58.1; 53.0; 34.0. ESI-MS: 351
3
+
þ
1
1
3
34.6; 134.5; 129.4; 129.3; 129.1; 127.3; 127.3; 127.2; 114.0; ([M + Na] ). HR-ESI-MS: 351.1586
13.5; 73.6; 72.9; 72.5; 72.1; 55.2; 36.4; 36.3; 35.9; 34.3;
3.6; 29.1; 28.8; 27.0; 26.9; 24.5; 20.1; 19.3. ESI-MS: 844
(C20H24NaO ,
4
+
[M + Na] ; calc. 351.1572).
{[(3S,5R)-5,6-Bis(benzyloxy)hex-1-en-3-yl]oxy}(tert-butyl)
dimethylsilane (31). To a stirred soln. of alcohol 30
(4.0 g, 12.8 mmol) in dry CH Cl 30 ml) at 0 °C, imida-
+
þ
(
[M + NH ] ). HR-ESI-MS: 827.4925 (C H70O4Si ,
4
53
2
+
[
M + H] ; calc. 827.4890).
2
2
(
2R)-1-(Benzyloxy)-6-(tetrahydro-2H-pyran-2-yloxy)hex-4-
zole (1.85 g, 25.64 mmol), TBSCl (2.30 g, 15.38 mmol),
and cat. amount of DMAP were added under N atmo-
yn-2-ol (25). A soln. of BuLi in hexane (28.5 ml,
5.7 mmol, 1.6M soln.) was added to a soln. of 2-(prop-2-
yn-1-yloxy)tetrahydro-2H-pyran (6.40 g, 45.7 mmol) in
2
4
sphere and stirred for 6 h. The mixture was warmed to
r.t., diluted with H O (10 ml), and extracted with CH Cl
2
2
2
THF (40 ml) at ꢀ78 °C under N atmosphere, and the (2 9 15 ml). The combined org. layers were washed with
2
mixture was stirred for 15 min. Then BF ꢁ OEt (6.0 ml, brine (1 9 10 ml), dried (anh. Na SO ), filtered, and con-
3
2
2
4
4
8.8 mmol) was added to the soln. and stirring was con-
centrated under vacuum to afford the crude product. CC
tinued for 15 min at ꢀ78 °C. Finally, a soln. of epoxide 9 of the crude product afforded 31 as a colorless liquid
2
D
0
(
5.0 g, 30.5 mmol) in dry THF (20 ml) was added, and
(5.02 g, 92%). ½aꢂ = +6.4 (c = 0.85, CHCl ). IR (neat):
3
after stirring the mixture for 3 h at ꢀ78 °C, the reaction
3065, 2949, 1643, 1496, 1361, 1253, 1207, 1093, 923, 837,
1
was quenched by adding sat. aq. NH Cl soln. (20 ml). 777. H-NMR (300 MHz, CDCl ): 7.56 – 7.38 (m, 10 H);
4
3
The mixture was extracted with AcOEt and dried (anh.
Na SO ). Evaporation of the solvent resulted in crude
6.0 – 5.84 (m, 1 H); 5.24 – 5.13 (m, 2 H); 4.89 – 4.68 (m,
4 H); 4.45 – 4.36 (m, 1 H); 3.88 – 3.78 (m, 1 H); 3.71 (d,
2
4
alcohol which was purified by CC to afford pure 25 J = 3.1, 2 H); 2.08 – 1.95 (m, 1 H); 1.91 – 1.78 (m, 1 H);
2
D
0
13
(
(
1
7
4
8.34 g, 90% yield) as a viscous liquid. ½aꢂ = ꢀ5.6 1.06 (s, 9 H); 0.20 (s, 6 H). C-NMR (75 MHz, CDCl3):
c = 1.5, CHCl ). IR (neat): 3431, 2943, 2868, 2233, 1728, 141.1; 138.8; 138.3; 128.2; 128.1; 127.7; 127.5; 127.4; 127.3;
446, 1367, 1248, 1109. H-NMR (300 MHz, CDCl3): 114.2; 74.9; 73.2; 72.9; 71.6; 71.1; 40.4; 25.8; 25.8; 18.1;
3
1
+
.36 – 7.22 (m, 5 H); 4.77 – 4.73 (m, 1 H); 4.55 (s, 2 H); ꢀ4.3; ꢀ4.9. ESI-MS: 449 ([M + Na] ). HR-ESI-MS
+
+
.24 – 4.12 (m, 2 H); 3.94 – 3.87 (m, 1 H); 3.79 (ddd, 449.2486 (C H NaO Si , [M + Na] ; calc. 449.2488).
2
6
38
3
J = 2.6, 8.9, 11.5, 1 H); 3.59 – 3.54 (m, 1 H); 3.53 – 3.42 (2S,3S,4S,6R)-6,7-Bis(benzyloxy)-1-[(4S)-4-benzyl-2-thioxo-
(
m, 2 H); 2.53 – 2.33 (m, 2 H); 1.88 – 1.77 (m, 1 H); 1,3-thiazolidin-3-yl]-4-{[tert-butyl(dimethyl)silyl]oxy}-3-
.74 – 1.38 (m, 6 H). C-NMR (75 MHz, CDCl ): 137.7; hydroxy-2-methylheptan-1-one (32). A soln. of 31 (4.0,
3
1
3
1
1
5
28.3; 127.6; 96.7; 84.2; 82.0; 78.1; 73.3; 72.8; 68.8; 61.9;
+
9.45 mmol) in CH Cl (40 ml) was cooled to ꢀ78 °C and
2
2
4.4; 30.1; 25.2; 23.4; 18.9. ESI-MS: 322 ([M + Na] ), 305
ozone was bubbled though it until the soln. turned to light
blue. To this cold soln., TPP (3.7 g, 14.17 mmol) was
added and stirring was maintained at r.t. for 5 h. The sol-
+
(
{
[M + H] ).
(2S,3S)-3-[(2R)-2,3-Bis(benzyloxy)propyl]oxiran-2-yl}metha-
nol (29). To a freshly flame-dried double-necked round- vent was evaporated and the residue was purified by CC
bottom flask equipped with activated molecular sieves on SiO2 (hexane/AcOEt) afford aldehyde (3.38 g; 85%)
4 A, ca. 5 g) and dry CH Cl (60 ml) at ꢀ20 °C were as a colorless oil; this was used for the next step. Tita-
ꢀ
(
2
2
i
added Ti(O Pr) (0.83 ml, 2.76 mmol), L-(+)-diisopropyl nium tetrachloride (0.88 ml, 7.97 mmol) was added slowly
4
tartrate (0.5 ml, 2.41 mmol), and the mixture was stirred
for 20 min. To this mixture, allyl alcohol 28 (6.0 g, propan-1-one (2.10 g, 7.97 mmol) in CH Cl (50 ml) at
to a soln. of 1-[(5S)-5-benzyl-2-thioxo-1,3-thiazolidin-3-yl]
2
2
1
(
9.5 mmol), followed by an interval of 20 min, TBHP
7.8 ml, 42.8 mmol, 5.5M soln. in decane) were added and
stirring was continued till completion of the reaction
0 °C and stirred for 5 min. To this yellow suspension, (–)-
sparteine (4.5 ml, 19.92 mmol) was added. After stirring
for 20 min, to the dark red enolate, freshly prepared
1
with H O (17 ml) and stirred vigorously for 30 min. The
4 h). The mixture was warmed to 0 °C and quenched above aldehyde (3.38 g, 7.97 mmol, 1.0 equiv.) dissolved
in CH Cl (8 ml) was added slowly to the above mixture
2 2
2
mixture was filtered through a sintered funnel and the fil-
at 0 °C. After 4 h, the reaction was quenched with the
trate was again stirred along with 20% aq. NaOH soln. addition of half-sat. NH Cl. The org. layer was separated
4
(
rated and aq. layer was extracted with CH Cl2 The combined org. layers were dried (Na SO ), filtered,
5 ml) sat. with solid NaCl. The biphasic soln. was sepa-
and the aq. layer was extracted (2 9 40 ml) with CH Cl .
2 2
2
2
4
(
Na SO ) and concentrated under vacuum. The crude resi-
due was purified by CC to afford the pure epoxide 29 as ½aꢂ = ꢀ36.5 (c = 2.0, CHCl ). IR (neat): 3492, 2930,
2 9 30 ml). The combined org. extracts were dried (anh.
concentrated, and the crude product was purified by CC
to provide the title compound 32 (4.68 g, 85%) as an oil:
2
4
2
0
D
3
©
2016 Verlag Helvetica Chimica Acta AG, Z u€ rich
www.helv.wiley.com

444
Helv. Chim. Acta 2016, 99, 436 – 446
1
858, 1707, 1454, 1342, 1257, 1099, 837. H-NMR
2
NH Cl soln. (20 ml) at 0 °C, Et O was evaporated, and the
4 2
(
300 MHz, CDCl ): 7.34 – 7.10 (m, 15 H); 5.08 – 4.97 (m, mixture was extracted with AcOEt (2 9 20 ml). The com-
3
1
H); 4.78 – 4.54 (m, 3 H); 4.50 (s, 2 H); 3.99 – 3.89 (m, 2
H); 3.87 – 3.78 (m, 1 H); 3.49 (d, J = 4.9, 2 H); 3.23 (dd, trated under vacuum. The residue was purified by CC SiO2
J = 3.2, 13.0, 1 H); 3.02 – 2.91 (m, 2 H); 2.76 (dd, J = 6.9, (60 – 120 mesh, AcOEt/hexane) to afford compound 8
bined org. layers were dried (anh. Na SO ), and concen-
2 4
2
0
1
1
0
2
1
4
1.3, 1 H); 2.59 (d, J = 11.3, 1 H); 2.01 – 1.93 (m, 1 H); (0.73 mg, 75%) as a liquid. ½aꢂ = ꢀ19.6 (c = 1.45, CHCl ).
D
3
1
.76 – 1.65 (m, 1 H); 1.22 (d, J = 6.7, 3 H); 0.89 (s, 9 H); IR (neat): 2930, 2856, 1639, 1462, 1379, 1253, 1097, 835. H-
1
3
.08 (s, 3 H); 0.04 (s, 3 H). C-NMR (75 MHz, CDCl3): NMR (300 MHz, CDCl3): 7.57 – 7.37 (m, 10 H);
00.1; 177.5; 138.4; 138.0; 136.5; 129.3; 128.7; 128.2; 127.5; 5.94 – 5.77 (m, 1 H); 5.08 – 4.97 (m, 2 H); 4.86 – 4.68 (m, 4
27.3; 127.0; 126.8; 74.3; 73.3; 73.2; 72.4; 71.4; 69.8; 69.3;
H); 4.00 – 3.86 (m, 2 H); 3.77 – 3.66 (m, 3 H); 2.39 – 2.25
0.7; 36.4; 35.8; 31.5; 29.6; 25.8; 17.8; 10.0; ꢀ4.2; ꢀ4.6. (m, 1 H); 2.13 – 1.71 (m, 4 H); 1.11 – 1.00 (m, 21 H);
+
13
ESI-MS: 716 ([M + Na] ). HR-ESI-MS: 694.3046 0.30 – 0.12 (m, 12 H). C-NMR (75 MHz, CDCl ): 138.9;
3
+
+
(
C H NO S Si , [M + H] ; calc. 694.3051).
138.3; 137.6; 128.2; 128.1; 127.6; 127.5; 127.4; 127.2; 115.8;
80.0; 75.9; 73.3; 72.7; 72.6; 71.2; 38.9; 36.5; 35.1; 29.6; 26.1;
26.0; 18.4; 18.0; 15.1; ꢀ3.3; ꢀ3.6; ꢀ4.5; ꢀ4.7. ESI-MS: 631
38
52
5 2
(
2S,3R,4S,6R)-6,7-Bis(benzyloxy)-3,4-bis{[tert-butyl(dimethyl)
silyl]oxy}-2-methylheptan-1-ol (34). To a soln. of compound
3 (2.2 g, 2.27 mmol) in a solvent mixture of (THF/
+
+
3
([M + NH ] ). HR-ESI-MS: 635.3942 (C H NaO Si ,
4 36 60 4 2
+
MeOH 9:1) 20 ml at 0 °C was LiBH (79 mg, 3.40 mmol). [M + Na] ; calc. 635.3928).
4
The mixture was stirred for 1 h at 0 °C followed by an
additional 1 h at r.t., then it was cooled to 0 °C, quenched {[tert-butyl(dimethyl)silyl]oxy}-16-{[tert-butyl(diphenyl)silyl]
with sat. aq. sodium potassium tartrate soln. (5 ml), oxy}-20-{[(4-methoxybenzyl)oxy]methyl}-2,2,3,3,7,23,23-hep-
diluted with AcOEt (15 ml), and sat. aq. sodium potas- tamethyl-22,22-diphenyl-4,21-dioxa-3,22-disilatetracos-9-ene
(5S,6R,7S,9E,16R,20R)-5-[(2R)-2,3-Bis(benzyloxy)propyl]-6-
sium tartrate soln. (10 ml). The mixture was stirred for
0 min at r.t. followed by separation of layers. The aq.
layer was extracted with AcOEt, the combined org. layers
(36). Grubbs’ II catalyst (13.83 mg, 0.01632 mmol) was
dissolved in CH Cl (1.0 ml) and added drop wise to a
soln. of the compound 8 (100 mg, 0.1631 mmol) and com-
3
2
2
were dried (MgSO ), and concentrated. The crude pro- pound 7 (404 mg, 0.4893 mmol) in CH Cl (3 ml) at r.t.
4
2
2
duct was purified by flash CC (AcOEt/hexanes) to pro-
vide the title compound 34 (1.5 g, 91%) as an oil.
After completion of addition, the mixture was allowed to
reflux for 0.25 h. The solvent was removed under reduced
pressure and the crude product was purified by SiO CC
20
½
aꢂ = ꢀ5.0 (c = 1.2, CHCl ). IR (neat): 3468, 3032, 2930,
D
3
2
1
591, 1469, 1361, 1253, 1209, 1049, 835. H-NMR
1
(PE/AcOEt) to afford the pure product 36 (161 mg, 70%)
2
0
D
(
300 MHz, CDCl ): 7.40 – 7.20 (m, 10 H); 4.71 – 4.53 (m, as an oil. ½aꢂ = ꢀ3.39 (c = 1.0, CHCl ). IR (neat): 2976,
3
3
1
4
3
3
6
1
7
H); 3.97 – 3.88 (m, 1 H); 3.83 – 3.70 (m, 2 H); 2854, 1647, 1458, 1361, 1251, 1109, 1030, 910, 767. H-
.64 – 3.49 (m, 2 H); 3.48 – 3.39 (m, 2 H); 1.94 – 1.66 (m, NMR (300 MHz, CDCl3): 7.71 – 7.60 (m, H);
H); 1.35 – 1.25 (m, 1 H); 0.98 – 0.87 (m, 21 H); 0.06 (s, 7.47 – 7.20 (m, 22 H); 7.09 – 7.01 (m, 2 H); 6.82 – 6.75
8
1
3
H); 0.02 (s, 6 H). C-NMR (75 MHz, CDCl ): 138.8; (m, 2 H); 5.43 – 5.18 (m, 2 H); 4.71 – 4.54 (m, 4 H); 4.22
3
28.2; 128.2; 127.7; 127.5; 127.5; 127.3; 77.5; 75.7; 73.3;
(s, 2 H); 3.86 – 3.72 (m, 4 H); 3.70 – 3.43 (m, 3 H);
3.1; 72.5; 71.3; 65.4; 39.3; 35.8; 26.0; 25.9; 18.2; 18.0; 12.9; 3.33 – 3.20 (m, 2 H); 2.18 – 1.50 (m, 5 H); 1.46 – 1.12 (m,
+
ꢀ
3.5; ꢀ3.8; ꢀ4.7; ꢀ5.0. ESI-MS: 625 ([M + Na] ). HR- 19 H); 1.10 – 1.03 (m, 21 H); 0.96 (s, 9 H); 0.90 (s, 9 H);
þ
+
13
0.15 – 0.02 (m, 12 H). C-NMR (75 MHz, CDCl ): 158.9;
ESI-MS: 625.3697 (C34H58NaO5Si , [M + Na] ; calc.
2
3
6
25.3720).
5S,6R)-5-[(2R)-2,3-Bis(benzyloxy)propyl]-2,2,3,3,8,8,9,9-
139.0; 138.4; 135.9; 135.9; 135.8; 134.7; 134.2; 130.5; 129.4;
129.3; 129.1; 128.2; 128.2; 127.6; 127.5; 127.5; 127.48;
(
octamethyl-6-[(2S)-pent-4-en-2-yl]-4,7-dioxa-3,8-disilade- 127.42; 127.37; 127.31; 127.2; 113.5; 76.0; 73.6; 73.4; 72.8;
cane (8). To a stirred soln. of alcohol 34 (1.0 g, 72.6; 72.2; 71.2; 55.2; 37.7; 37.1; 36.5; 36.4; 35.1; 34.5; 32.7;
1
1
0
.65 mmol) in dry CH Cl (10 ml), TsCl (347 mg, 29.7; 29.6; 27.1; 27.0; 26.18; 26.11; 26.0; 19.4; 19.3; 18.5;
2 2
.82 mmol), and Et N (0.35 ml, 2.47 mmol) were added at
3
18.0; 15.2; 14.1; ꢀ3.2; ꢀ3.6; ꢀ4.5; ꢀ4.7. ESI-MS: 1430
+
þ
°C and allowed to stirred at r.t. for 5 h. Later, the mixture
([M + NH ] ). HR-ESI-MS: 1433.8413 (C87H126NaO8Si ,
4
4
+
was extracted with CH Cl (2 9 25 ml), dried (anh.
[M + Na] ; calc. 1433.8427).
(5S,6R,7S,9S,10S,16R,20R)-5-[(2R)-2,3-Bis(benzyloxy)propyl]-
purified by CC (60 – 120 mesh, AcOEt/hexane) to afford 6-{[tert-butyl(dimethyl)silyl]oxy}-16-{[tert-butyl(diphenyl)
2
2
Na SO ), and concentrated under vacuum. The residue was
2
4
monotosylated product 35 (1.2 g, 95%) as a liquid. This
was used for the next step. To the stirred soln. of the mono-
silyl]oxy}-20-{[(4-methoxybenzyl)oxy]methyl}-2,2,3,3,7,23,23-
heptamethyl-22,22-diphenyl-4,21-dioxa-3,22-disilatetracosane-
tosylated compound 35 (1.2 g, 1.58 mmol) in dry Et O 9,10-diol (37). AD-mix-a (148 mg, 1.4 g/mmol) and
2
(
20 ml) was added Li CuCl (0.16 ml, 0.16 mmol, 1.0 molar
2
methane sulfonamide (10 mg, 0.1062 mmol) were added
4
t
to a 1:1 soln. of BuOH/H O (2 ml total). The soln. was
stirred for 20 min at r.t., and then cooled in an ice bath
soln. in Et O) at ꢀ78 °C and stirred at the same temp. for
2
2
1
h. Vinyl magnesium bromide (6.32 ml, 6.32 mmol, 1.0M
soln. in Et O) was added slowly at ꢀ40 °C under N atmo- until a bright orange precipitate was formed. The reaction
2
2
sphere and then the mixture was stirred for 3 h at the same
temp. After 2 h, the reaction was quenched with sat. aq. (150 mg, 0.1062 mmol) in 0.5 ml of BuOH was added
was stirred vigorously and a soln. of the compound 36
t
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© 2016 Verlag Helvetica Chimica Acta AG, Z u€ rich

Helv. Chim. Acta 2016, 99, 436 – 446
445
drop wise to the oxidant soln. and stirred for 32 h in an
ice bath. The reaction was quenched with sodium sulfite
18.4; 18.0; 17.9; 17.9; 14.1; ꢀ3.3; ꢀ3.5; ꢀ3.9; ꢀ4.4; ꢀ4.5;
+
ꢀ4.0; ꢀ5.2. ESI-MS: 1348 ([M + Na-t-butyl groups] ).
þ
+
(
150 mg), and the mixture was stirred for 30 min. The
HR-ESI-MS: 1696.0221 (C99H156NaO10Si , [M + Na] ;
calc. 1696.0211).
6
mixture was diluted with AcOEt and washed with 4 ml of
NaHCO3. The aq. layer was washed with AcOEt
(2R,6R,12S,13S,15S,16R,17S,19R)-19,20-Bis(benzyloxy)-
12,13,16,17-tetrakis{[tert-butyl(dimethyl)silyl]oxy}-2,6-bis
{[tert-butyl(diphenyl)silyl]oxy}-15-methylicosan-1-ol (39). To
(
(
2 9 10 ml). The combined org. layers were dried
Na SO ) and concentrated. The crude oil was purified by
2
4
CC (hexanes/AcOEt) to yield 37 (122 mg; 80%) of a 14:1 a 0 °C soln. of PMB ether 38 (100 mg, 0.06 mmol) in
mixture of diastereoisomers which were inseparable by CH Cl (5 ml) was added pH 7 buffer (0.5 ml) and DDQ
2
2
2
D
0
HPLC. ½aꢂ = ꢀ6.38 (c = 1.0, CHCl ). IR (neat): 3437,
(20.4 mg, 0.09 mmol) in three portions over 30 min. Upon
addition of DDQ the mixture became orange and as
3
1
070, 2932, 1587, 1464, 1249, 1109, 704. H-NMR
3
(
300 MHz, CDCl ): 7.70 – 7.57 (m, 9 H); 7.43 – 7.19 (m, DDQ was consumed the reaction soln. became dark
3
2
4
1
3
1
1 H); 7.08 – 7.01 (m, 2 H); 6.81 – 6.74 (m, 2 H); green. The reaction was monitored by TLC analysis (ca.
.68 – 4.52 (m, 4 H); 4.28 – 4.19 (m, 2 H); 3.90 – 3.84 (m, 1.5 h) and then diluted with CH Cl (5 ml) and sat.
2
2
H); 3.83 – 3.73 (m, 4 H); 3.68 – 3.49 (m, 3 H); NaHCO (5 ml). The mixture was then stirred vigorously
3
.34 – 3.09 (m, 3 H); 2.38 – 2.26 (m, 1 H); 2.10 – 1.96 (m, for 10 min. The phases were separated and the aq. layer
H); 1.86 (br. s, 2 H); 1.68 – 1.57 (m, 1 H); 1.47 – 1.10 was washed with CH Cl (3 9 5 ml). The org. phases
m, 21 H); 1.05 (s, 21 H); 0.96 (s, 9 H); 0.92 (s, 9 H); were combined, dried (Na SO ), and concentrated. The
2
2
(
2 4
1
3
0
1
1
7
3
2
.14 – 0.01 (m, 12 H). C-NMR (75 MHz, CDCl ): 158.9; crude residue was purified by CC (hexane/AcOEt) to give
3
2
D
0
38.9; 138.3; 135.9; 134.7; 134.1; 130.5; 129.4; 129.3; 129.1; 39 (81 mg, 87%) as oil: ½aꢂ = +8.3 (c = 0.3, CHCl ). IR
3
1
(neat): 3412, 2926, 2854, 1464, 1255, 1109, 775. H-NMR
28.1; 128.3; 128.2; 127.7; 127.6; 127.45; 127.41; 113.6; 81.2;
6.0; 75.2; 73.6; 73.4; 73.0; 72.6; 72.29; 71.24; 55.2; 38.7;
(300 MHz, CDCl ): 7.66 – 7.50 (m, 9 H); 7.43 – 7.17 (m,
3
6.4; 36.1; 35.3; 34.3; 33.6; 31.9; 29.7; 29.3; 27.1; 27.0; 26.1; 21 H); 4.66 – 4.50 (m, 4 H); 3.84 – 3.70 (m, 1 H);
6.0; 22.7; 20.2; 19.4; 18.4; 14.1; ꢀ3.3; ꢀ3.6; ꢀ4.4; ꢀ4.6. 3.68 – 3.47 (m, 4 H); 3.43 – 3.26 (m, 1 H); 2.12 – 1.95 (m,
+
ESI-MS: 1462 ([M + NH ] ). HR-ESI-MS: 1467.8510 2 H); 1.93 – 1.76 (m, 1 H); 1.73 – 1.48 (m, 2 H);
4
þ
+
(
C87H128NaO10Si , [M + Na] ; calc. 1467.8482).
5S,6R,7S,9S,10S,16R,20R)-5-[(2R)-2,3-Bis(benzyloxy)pro-
1.44 – 1.14 (m, 21 H); 1.09 – 1.01 (m, 22 H); 0.96 – 0.82
4
1
3
( (m, 36 H); 0.12 – 0.02 (m, 24 H). C-NMR (75 MHz,
pyl]-6,9,10-tris{[tert-butyl(dimethyl)silyl]oxy}-16-{[tert-butyl CDCl ): 139.0; 138.4; 135.9; 135.8; 134.0; 129.9; 129.7;
3
(
3
diphenyl)silyl]oxy}-20-{[(4-methoxybenzyl)oxy]methyl}-2,2,
,3,7,23,23-heptamethyl-22,22-diphenyl-4,21-dioxa-3,22-disi- 77.4; 76.1; 75.0; 73.9; 73.5; 73.3; 72.2; 71.2; 68.0; 38.8; 36.4;
latetracosane (38). To a soln. of diol 37 (100 mg, 35.7; 33.7; 32.5; 31.9; 30.1; 29.9; 29.7; 29.3; 27.2; 27.0; 27.0;
129.5; 129.3; 128.28; 128.20; 127.7; 127.5; 127.4; 127.3; 81.4;
0
.0690 mmol) in CH Cl (4 ml) was added 2,6-lutidine
2
26.4; 26.1; 26.0; 25.9; 25.8; 25.1; 22.7; 19.7; 19.39; 19.33;
18.5; 18.4; 18.2; 17.98; 17.94; 14.1; ꢀ3.2; ꢀ3.4; ꢀ3.5; ꢀ3.9;
ꢀ4.0; ꢀ4.3; ꢀ4.4; ꢀ4.5; ꢀ4.7; ꢀ4.8. HR-ESI-MS:
2
(
0.05 ml, 0.414 mmol), and the mixture was cooled to
°C. To this mixture was added drop wise TBSOTf
0.04 ml, 0.01656 mmol) and the mixture was main-
0
+
+
(
1575.9575 (C H NaO Si , [M + Na] ; calc. 1575.9636).
91 148 9 6
tained for 1 h. The reaction was quenched with sat. aq. (6R,8E,10R,12E,14R,18R,24S,25S,27S,28R,29S)-29-[(2R)-2,3-
NaHCO . The mixture was diluted with H O and the Bis(benzyloxy)propyl]-6,24,25,28-tetrakis{[tert-butyl(dimethyl)
3
2
layers were separated. The aq. layer was extracted with
CH Cl (2 9 10 ml), the combined org. phases were
silyl]oxy}-10,14,18-tris{[tert-butyl(diphenyl)silyl]oxy}-2,2,3,3,
27,31,31,32,32-nonamethyl-4,30-dioxa-3,31-disilatritriaconta-
8,12-diene (2). To a 0 °C soln. of alcohol 39 (10 mg,
2
2
washed with H O and with brine, dried (MgSO ), fil-
2
4
tered and concentrated in vacuo. Purification by CC 0.01 mmol) and NaHCO (2.5 mg, 0.03 mmol) in CH Cl
2
3
2
(
Et O/hexane) furnished (110 mg, 95%) 38 as oil.
2
(2 ml) was added Dess–Martin periodinane (6 mg,
20
½aꢂ = ꢀ9.1 (c = 1.2, CHCl ). IR (neat): 2926, 2854, 0.0135 mmol). The mixture was stirred for 3 h in an ice
D
3
1
732, 1462, 1255, 1082, 968, 771. H-NMR (300 MHz,
1
bath and then poured into Et O (5 ml). The Et O mixture
2 2
CDCl ): 7.68 – 7.50 (m, 9 H); 7.41 – 7.15 (m, 21 H); was stirred vigorously for 20 min and the mixture was fil-
3
7
.09 – 7.01 (m, 2 H); 6.83 – 6.76 (m, 2 H); 4.63 (s, 2
H); 4.57 – 4.51 (m, H); 4.26 – 4.16 (m, H); and dried (Na SO ), and filtered. The solvent was removed
.82 – 3.71 (m, 4 H); 3.69 – 3.59 (m, 1 H); 3.59 – 3.47 in vacuo and the crude oil was purified by CC afford the
m, 3 H); 3.32 – 3.19 (m, 2 H); 1.98 – 1.87 (m, 1 H); aldehyde 4 (9 mg, 90%) and it was subjected to Julia olefi-
.81 – 1.64 (m, 1 H); 1.64 – 1.49 (m, 3 H); 1.40 – 1.12 nation reaction directly. To a stirred soln. of sulfone 3
m, 20 H); 1.07 – 1.00 (m, 21 H); 0.95 – 0.81 (m, 36 (10 mg, 0.01 mmol) in dry THF (2 ml) was added a soln. of
tered over Celite pad and washed with Et O (2 9 5 ml)
2
2
2
2
4
3
(
1
(
1
3
H); 0.17 – 0.03 (m, 24 H). C-NMR (75 MHz, CDCl3): aldehyde 4 (9 mg) in THF (2 ml) and the mixture was
1
1
1
3
2
58.9; 139.1; 138.5; 135.9; 135.8; 134.7; 134.1; 129.4;
29.3; 129.1; 128.3; 128.2; 127.6; 127.5; 127.4; 127.3; (0.03 ml, 0.01 mmol) was added drop wise to the sulfone/
cooled to ꢀ78 °C. A 0.5M soln. of KHMDS in toluene
27.2; 113.5; 81.3; 77.2; 76.2; 73.7; 73.3; 72.6; 71.2; 55.2;
8.7; 36.4; 35.8; 35.3; 34.5; 32.5; 31.9; 30.2; 29.7; 29.6;
9.3; 27.1; 27.2; 27.0; 26.1; 25.9; 25.8; 19.4; 19.3; 18.5;
aldehyde mixture over a period of 5 min. The mixture was
maintained for 4 h and then allowed to warm to r.t. over a
2 h period. The reaction was quenched with sat. aq. NH Cl,
4
©
2016 Verlag Helvetica Chimica Acta AG, Z u€ rich
www.helv.wiley.com

446
Helv. Chim. Acta 2016, 99, 436 – 446
and the mixture was diluted with Et O and H O. The lay-
2
Biomol. Chem. 2013, 11, 6829; T. Tsuruda, M. Ebine, A.
Umeda, T. Oishi, J. Org. Chem. 2015, 80, 859; A. Grisin, P. A.
Evans, Chem. Sci. 2015, 6, 6407.
2
ers were separated; the combined org. phases were washed
with brine and dried (MgSO ), filtered, and concentrated
4
[
6] J. S. Yadav, L. Chetia, Org. Lett. 2007, 9, 4587; J. S. Yadav, M.
R. Pattanayak, P. P. Das, D. K. Mohapatra, Org. Lett. 2011, 13,
1710; J. S. Yadav, V. Rajender, Y. G. Rao, Org. Lett. 2010, 12,
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in vacuo. Purification by CC (AcOEt/hexane) furnished
1
20
0 mg (80%) of alkene 2 as colorless oil: ½aꢂ = ꢀ41.6
D
(
c = 0.3, CHCl ). IR (neat): 2926, 2856, 1464, 1366, 1252,
3
1
1
7
2
106. H-NMR (300 MHz, CDCl ): 7.80 – 7.57 (m, 12 H);
3
2
544.
7] M. E. Furrow, S. E. Schaus, E. N. Jacobsen, J. Org. Chem.
998, 63, 6776.
.51 – 7.27 (m, 28 H); 5.50 – 5.35 (m, 2 H); 5.33 – 5.10 (m,
H); 4.74 – 4.56 (m, 4 H); 4.11 – 3.91 (m, 1 H); 3.89 – 3.76
[
[
1
(m, 1 H); 3.75 – 3.52 (m, 7 H); 3.52 – 3.39 (m, 2 H);
8] A. Pfenninger, Synthesis 1986, 89; Y. Gao, J. M. Klunder, R. M.
Hanson, H. Masamune, S. Y. Ko, K. B. Sharpless, J. Am. Chem.
Soc. 1987, 109, 5765.
2
3
0
1
1
7
3
2
.16 – 1.91 (m, 2 H); 1.85 – 1.55 (m, 4 H); 1.49 – 1.26 (m,
0 H); 1.15 – 1.03 (m, 21 H); 1.02 – 0.86 (m, 54 H);
1
3
[
9] H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev.
.23 – 0.02 (m, 36 H). C-NMR (75 MHz, CDCl ): 138.5;
3
1
994, 94, 2483.
10] J. S. Yadav, T. Shekharam, V. R. Gadgil, Chem. Commun.
990, 843.
38.3; 135.8; 134.8; 134.5; 134.5; 134.2; 133.5; 129.3; 128.27;
28.20; 127.5; 127.3; 127.2; 126.5; 126.0; 82.9; 81.9; 78.9;
4.5; 73.7; 73.3; 71.2; 66.7; 41.3; 38.1; 37.7; 37.2; 32.7; 31.9;
1.4; 30.1; 29.7; 29.3; 27.0; 26.1; 26.04; 26.0; 25.9; 25.8; 24.4;
2.7; 19.4; 19.2; 18.3; 18.2; 18.1; 17.9; 14.1; ꢀ3.2; ꢀ3.4; ꢀ3.6;
[
[
1
11] M. T. Crimmins, B. W. King, E. A. Tabet, K. Chaudhary, J.
Org. Chem. 2001, 66, 894.
[12] R. H. Grubbs, Tetrahedron 2004, 60, 7117; R. H. Grubbs, S.
Chang, Tetrahedron 1998, 54, 4413; T. M. Trnka, R. H. Grubbs,
Acc. Chem. Res. 2001, 34, 18; M. Schuster, S. Blechert, Angew.
Chem., Int. Ed. 1997, 36, 2036.
ꢀ
4.0; ꢀ4.3; ꢀ4.5; ꢀ4.8; ꢀ5.3.
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Received November 3, 2015
Accepted April 18, 2016
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