An Efficient Stereoselective Synthesis of Key Fragments of Elaiophylin

Article abstract of DOI:10.1002/hlca.201600006

The stereoselective synthesis of key fragments 3 and 7 of elaiophylin has been accomplished from readily available epichlorohydrin as the starting material. The key reactions involved are Jacobsen's kinetic resolution, Prins cyclization, pyridinium chloro

Full text of DOI:10.1002/hlca.201600006

Helv. Chim. Acta 2016, 99, 1 – 7
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201600006
FULL PAPER
An Efficient Stereoselective Synthesis of Key Fragments of Elaiophylin
by Pannala Padmaja*a), Pedavenkatagari Narayana Reddyb), and Jhillu Singh Yadavc)
a) Department of Chemistry, JNTUH College of Engineering, Kukatpally, Hyderabad, Telangana-500 085, India
(e-mail: padduiict@gmail.com)
b) Department of Chemistry, Gitam School of Technology, Gitam University, Telangana-502 102, India
c) Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-5000 007, India
The stereoselective synthesis of key fragments 3 and 7 of elaiophylin has been accomplished from readily available
epichlorohydrin as the starting material. The key reactions involved are Jacobsen’s kinetic resolution, Prins cyclization,
pyridinium chlorochromate-mediated oxidative cleavage, Grignard reaction, and cross-metathesis reaction.
Keywords: Macrolide, Elaiophylin, Prins cyclization, Jacobsen’s kinetic resolution, Cross-metathesis reaction.
(6). The lactone 7 could easily accessed from 8 which in
turn could be prepared via Prins cyclization of dihydroxy
trans-olefin 9 and acetaldehyde 10.
Introduction
Elaiophylin (1), first isolated in 1959 from cultures of
Streptomyces melanosporus [1] and shortly thereafter
from a related microorganism (Fig.) [2]. Elaiophylin is a
16-membered macrolide which displays antimicrobial
activity against several strains of Gram-positive bacteria
Synthesis of Lactone Fragment (7)
The synthesis of lactone fragment 7 (Scheme 2) began
9 prepared from
epichlorohydrin [31].
[3][4]. Elaiophylin also has anthelmintic activity against with known dihydroxy trans-olefin
Trichonomonas vaginalis [5 – 10], as well as inhibitory
activity against K+-dependent adenosine triphosphatases
[11].
To carry out the crucial Prins cyclization reaction [32],
a mixture of 9 and acetaldehyde 10 in CH2Cl2 was treated
with trifluoroacetic acid (TFA) to afford trifluoroacetate
11. Hydrolysis of the trifluoroacetate 11 with K2CO3 in
MeOH, resulted in tetrasubstituted tetrahydropyran 8 in
As a result of its structural complexity and potent bio-
logical activity, elaiophylin has been a target of consider-
able synthetic interest. The first synthesis of elaiophylin
was accomplished by Kinoshita et al. [12][13]. Several 60% yield (over two steps). Then, selective protection of
other studies directed toward the synthesis of the elaio-
phylin framework have also been published [14 – 25]. As
part of our continuous interest in the total synthesis of
macrolides [26 – 31], we herein report an efficient stereos-
elective synthesis of key fragments of elaiophylin.
the primary OH group 8 as a benzyl ether in the presence
of NaH and BnBr in THF afforded 12 in 70% yield. The
alcohol 12 was protected as a methoxymethyl (MOM)
ether [33] 13 in 90% yield using methoxymethyl chloride
(MOMCl) in the presence of diisopropylethylamine
(DIPEA) and a catalytic amount of 4-dimethylaminopyri-
dine (DMAP). Cleavage of benzyl ether 13 with Li in liq-
uid NH3 resulted 14 in 90% yield [34]. Next objective was
Results and Discussion
We devised an strategy to synthesize elaiophylin (1) pyridinium chlorochromate (PCC)-mediated oxidative
(Scheme 1). We planned to prepare the OH ester 2, cleavage [35][36] of OH group in 14. Thus, upon treat-
dimerize it by conventional lactonization strategy. The
retrosynthetic analysis suggested that OH ester 2 could be
further simplified by disconnecting the C10–C11 bond,
leading to a fragment 3 and lactone fragment 7.
ment of 14 with PCC in refluxing benzene afford the
desired lactone 7 in 60% yield.
Synthesis of Fragment (3)
The fragment 3 could be prepared from functionalized
pyran 4 by a sequence of protection, functional group The synthesis of the other fragment 3 was initiated with
interconversions, and deprotection reactions. The pyran 4
dihydroxy trans-olefin 5 prepared from epichlorhydrin
could in turn be prepared by Prins cyclization of homoal- using known procedure [37]. Prins cyclization of homoal-
lylic alcohol 5 and (S)-3-(benzyloxy)-2-methylpropanal
lylic alcohol 5 with (S)-3-(benzyloxy)-2-methylpropanal
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Helv. Chim. Acta 2016, 99, 1 – 7
Figure. Structure of elaiophylin.
Scheme 1. Retrosynthetic Analysis of elaiophylin (1).
(6) [38] in the presence of TFA in CH2Cl2 resulted triflu- yield 4. The primary OH group in 4 was selectively tosy-
lated to compound 16 using tosyl chloride, TEA in
CH2Cl2 at 0 °C in 85% yield. The alcohol in compound
oroacetate 15 which without purification but after workup
was subjected to hydrolysis using K2CO3 in MeOH to
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Scheme 2. Synthesis of fragment (7).
a) Acetaldehyde 10, TFA, CH2Cl2, r.t., 3 h. b) K2CO3, MeOH, r.t., 0.5 h; 60% (over two steps). c) NaH, BnBr, TBAI, THF, 0 °C to r.t., 8 h;
70%. d) MOMCl, DIPEA, DMAP, CH2Cl2, 0 °C to r.t., 3 h; 90%. e) Li, liq. NH3, THF, ꢀ33 °C, 5 min; 90%. f) Pyridinium chlorochromate
(PCC), benzene, reflux, 6 h; 60%.
16 was protected as a TIPS ether 17 using triisopropylsilyl secondary alcohol of 19 was protected as its MOM ether
triflouoromethanesulphonate and 2,6-lutidine in CH2Cl2 20 in the presence of MOMCl, DMAP, and DIPEA as
at 0 °C for 1 h in 90% yield. Treatment of 17 with NaI in base in CH2Cl2. Treatment of 20 with Li in liquid NH3
refluxing acetone furnished iodomethyl pyran 18. Treat-
resulted in benzyl ether cleavage to furnish primary alco-
ment of iodomethyl pyran 18 with Zn dust in refluxing hol 21 in 90% yield. Alcohol 21 was subjected to oxida-
EtOH resulted alcohol 19 in 80% yield [39 – 45]. The tion with Dess–Martin periodinane [46][47] in dry CH2Cl2
Scheme 3. Synthesis of fragment (3).
a) (S)-3-(Benzyloxy)-2-methylpropanal (6), TFA, CH2Cl2, r.t., 3 h. b) K2CO3, MeOH, r.t., 0.5 h; 60% (over two steps). c) TsCl, TEA, CH2Cl2,
r.t., 0 °C to r.t., 5 h; 85%. d) TIPS-OTf, 2,6-lutidine, dry CH2Cl2, 0 °C to r.t., 1 h; 90%. e) NaI, acetone, reflux, 24 h; 95%. f) Zinc powder,
EtOH, reflux, 1 h; 80%. g) Methoxymethyl chloride (MOMCl), DIPEA, DMAP, CH2Cl2, 0 °C to r.t., 3 h; 90%. h) Li, liq. NH3, THF, ꢀ33 °C,
5 min; 90%. i) Dess–Martin periodinane (DMP), NaHCO3, CH2Cl2, 0 °C to r.t., 1 h; 80%. j) Ethylmagnesium bromide, dry THF, 0 °C, 2 h;
90%. k) DMP, NaHCO3, CH2Cl2, 0 °C to r.t., 1 h; 85%. l) Ethyl acrylate, Grubbs’ second-generation catalyst, CH2Cl2, r.t., 1 h; 90%.
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Helv. Chim. Acta 2016, 99, 1 – 7
at 0 °C to room temperature for 1 h to furnish aldehyde mixture was stirred for 3 h, then sat. aq. NaHCO3 soln.
22 in 80% yield. The alcohol 23 could be easily obtained (20 ml) was added, and pH was adjusted to > 7 by addi-
by Grignard reaction of aldehyde 22 with EtMgBr in tion of Et3N. The layers were separated and the aq. layer
THF at room temperature in 90% yield. The resultant
alcohol 23 was oxidized to ketone 24 in 90% yield using
Dess–Martin periodinane. Treatment of keto compound
24 with ethyl acrylate in the presence of 10 mol-%
Grubbs’ second-generation catalyst under nitrogen atmo-
was extracted with CH2Cl2 (3 9 40 ml) and the org. lay-
ers were combined and the solvent was removed under
reduced pressure. The residue was dissolved in MeOH
(30 ml) and stirred with K2CO3 (1.95 g) for 0.5 h. The
MeOH was then removed under reduced pressure and
sphere in CH2Cl2 at room temperature afforded 3 in 90% H2O (15 ml) was added. The mixture was extracted with
yield (Scheme 3).
CH2Cl2 (3 9 20 ml) and the combined org. layers were
dried (Na2SO4) and the solvent was removed under
reduced pressure. CC of the crude afforded 8 (2 g, 60%)
Conclusions
25
as a colorless oil. ½aꢁD = ꢀ4.5 (c = 0.02, CHCl3). IR
1
(neat): 3399, 2933, 2876, 1727, 1376, 1113, 1062, 1013. H-
In conclusion, we have developed an efficient stereoselec-
tive synthetic pathway for the synthesis of key fragments NMR (300 MHz, CDCl3): 0.91 (t, J = 7.5, 3 H); 1.23 (d,
7 and 3 of elaiophylin. To date, over 100 mg quantities of J = 6.2, 3 H); 1.39 – 1.93 (m, 5 H); 1.95 – 2.47 (br. s, 1
key fragments 7 and 3 has been synthesized using this
H); 3.23 – 3.37 (m, 1 H); 3.38 – 3.72 (m, 4 H). 13C-NMR
route and efforts towards the coupling of both fragments (75 MHz, CDCl3): 9.8; 19.3; 19.4; 37.0; 50.8; 65.9; 69.6;
and total synthesis of elaiophylin is presently under inves-
tigation in our laboratory.
74.7; 75.6. ESI-MS: 174 (M+).
(6R)-2,6-Anhydro-1-O-benzyl-3,5-dideoxy-5-ethyl-6-methyl-
D-xylo-hexitol (12). To a suspension of NaH (60%, 0.10 g,
The authors P. Padmaja and P. N. Reddy are thankful to 4.48 mmol) in dry THF (20 ml) was added dropwise a
Dr. J. S. Yadav, former director CSIR-IICT.
soln. of alcohol 8 (0.65 g, 3.73 mmol) in THF (10 ml) at
0 °C. To this mixture, TBAI (0.02 g) and benzyl bromide
(0.44 ml, 3.73 mmol) were added subsequently and stir-
ring was continued for 2 h at same temp. and 6 h at r.t.
The reaction was quenched by crushed ice flakes until a
clear soln. (biphasic) formed. The mixture was extracted
with AcOEt (2 9 30 ml). The org. extracts were washed
with H2O (1 9 20 ml), brine (1 9 20 ml), and dried
(Na2SO4). Evaporation of the solvents followed by CC
afforded the pure product 12 (0.7 g, 70% yield) as a col-
Experimental Part
General
All reagents were reagent grade and used without further
purification unless specified otherwise. Solvents were dis-
tilled before use: THF, toluene, and Et2O were distilled
from Na, benzophenone ketyl; MeOH from Mg and I2;
and CH2Cl2 from CaH2. All air- or moisture-sensitive
reactions were conducted under N2 or Ar in flame-dried
or oven-dried glassware with magnetic stirring. Column
chromatography (CC): silica gel (SiO2, 60 – 120 mesh or
100 – 200 mesh) packed in glass columns. Technical grade
AcOEt and petroleum ether used for CC were distilled
before use. Optical rotations: JASCO DIP 300 digital
polarimeter using a 1 ml cell with a 1 dm path length. IR
Spectra: PerkinElmer IR-683 spectrophotometer (Perkin-
Elmer, Waltham, MA, USA); KBr pellets and CHCl3;
25
orless liquid. ½aꢁD = +5.6 (c = 0.65, CHCl3). IR (neat):
3437, 2964, 2930, 2875, 1108, 1025. 1H-NMR (300 MHz,
CDCl3): 0.90 (t, J = 7.5. 3 H); 1.26 (d, J = 6.0, 3 H);
1.36 – 1.83 (m, 4 H); 1.91 – 2.04 (m, 1 H); 3.23 – 3.46 (m,
2 H); 3.46 – 3.71 (m, 3 H); 4.57 (d, J = 6.0, 2 H);
7.22 – 7.43 (m, 5 H). 13C-NMR (75 MHz, CDCl3): 9.7;
19.2; 19.4; 37.9; 50.7; 69.7; 73.0; 73.3; 74.4; 74.8; 127.5;
127.7; 128.3; 130.2. ESI-MS: 287 ([M + Na]+).
(6R)-2,6-Anhydro-1-O-benzyl-3,5-dideoxy-5-ethyl-4-O-
(methoxymethyl)-6-methyl-D-xylo-hexitol (13). To alcohol
12 (0.61 g, 2.3 mmol) in anh. CH2Cl2 (20 ml) at 0 °C
were added diisopropylethyl amine (3.15 ml, 18.4 mmol),
cat. DMAP, and MOMCl (0.69 g, 9.2 mmol) successively,
and the mixture was stirred for 3 h at r.t. Then, the reac-
tions was quenched by adding H2O (6 ml) and extracted
with CH2Cl2. The org. extracts were washed with brine
(5 ml), dried (Na2SO4), and concentrated under vacuum
to remove the solvent and the crude was purified by CC
to afford the pure product 13 (0.65 g, 90%) as an oil.
1
neat (as mentioned); ṽ in cmꢀ1. H- and 13C-NMR spec-
tra: Varian Gemini FT-200, Bruker Avance 300, and Bru-
ker Avance 500 spectrometers (Bruker, Beijing, P. R.
China) at 200, 300, or 500 MHz, resp., in CDCl3 or C6D6;
d in ppm rel. to Me4Si as internal standard, J in Hz. ESI-
MS: CEC-21-11013 or Finnigan Mat 1210 double-focusing
mass spectrometers operating at a direct inlet system or
LC/MSD Trap SL (Agilent Technologies, Santa Clara,
CA, USA); in m/z.
25
½aꢁD = ꢀ25.7 (c = 1.95, CHCl3). IR (neat): 3449, 2933,
1
2884, 1100, 1037, 738. H-NMR (300 MHz, CDCl3): 0.87
(6R)-2,6-Anhydro-3,5-dideoxy-5-ethyl-6-methyl-D-xylo-
hexitol (8). Trifluoroacetic acid (30.5 ml) was added
slowly to a soln. of the homoallylic alcohol 9 (2.48 g,
19.0 mmol) and acetaldehyde 10 (3.2 g, 57.2 mmol) in
CH2Cl2 (15 ml) at r.t. under a N2 atmosphere. The
(t, J = 7.5, 3 H); 1.24 (d, J = 6.2, 3 H); 1.31 – 1.73 (m, 4
H); 1.99 – 2.14 (m, 1 H); 3.20 – 3.62 (m, 8 H); 4.41 – 4.64
(m, 3 H); 4.68 – 4.79 (d, J = 6.9, 1 H); 7.15 – 7.37 (m, 5
H). 13C-NMR (75 MHz, CDCl3): 9.2; 19.0; 19.4; 34.8; 48.5;
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Helv. Chim. Acta 2016, 99, 1 – 7
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55.4; 73.0; 73.2; 74.3; 74.8; 75.2; 94.8; 127.4; 127.6; 128.2;
138.1. ESI-MS: 331 ([M + Na]+).
(6R)-2,6-Anhydro-3,5-dideoxy-5-ethyl-4-O-(methoxymethyl)-
6-methyl-D-xylo-hexitol (14). To a soln. of Li (0.05 g,
3407, 2926, 2863, 1095, 744. H-NMR (300 MHz, CDCl3):
0.85 (d, J = 6.9, 3 H); 0.95 (d, J = 6.2, 3 H), 1.30 – 1.60
(m, 2 H); 1.74 – 1.91 (m, 1 H); 1.93 – 2.24 (m, 1 H);
3.16 – 3.85 (m, 7 H); 4.45 (d, J = 4.1, 2 H); 7.16 – 7.36
8.0 mmol) in liquid NH3 (20 ml) was added compound 13 (m, 5 H). 13C-NMR (75 MHz, CDCl3): 9.5; 12.0; 34.1;
(0.62 g, 2.01 mmol) in dry THF (2 ml). The mixture was
stirred for 5 min, and then the reaction was quenched
with solid NH4Cl (350 mg). NH3 was allowed to evapo- 2,6-Anhydro-6-[(2S)-1-(benzyloxy)propan-2-yl]-3,5-dideoxy-
36.6; 40.3; 67.4; 70.4; 71.4; 73.0; 75.4; 79.4; 127.3; 127.4;
128.2; 138.5. ESI-MS: 317 ([M + Na]+).
rate and the residual mixture was taken in Et2O (10 ml)
and washed with H2O (10 ml), brine (3 ml), and dried
(Na2SO4). Removal of the solvent and purification by CC
of the crude product afforded alcohol 14 (0.4 g, 90%) as
5-methyl-1-O-[(4-methylphenyl)sulfonyl]-D-xylo-hexitol
(16). To a soln. of diol 4 (3.28 g, 11.1 mmol) in dry
CH2Cl2 (5 ml), Et3N (6.2 ml, 44.6 mmol) was added at
78 °C followed by addition of tosyl chloride (2.53 g,
13.3 mmol) over 2 h. The mixture was allowed to warm
to r.t. and to stir for 5 h. The reaction was treated with
aq. 1N HCl (2 ml) and extracted with CH2Cl2
25
a colorless liquid. ½aꢁD = ꢀ43.2 (c = 1.15, CHCl3). IR
1
(neat): 3447, 2935, 2885, 1379, 1096, 1040, 915. H-NMR
(300 MHz, CDCl3): 0.88 (t, J = 7.5, 3 H); 1.25 (d, J = 6.0,
3
H); 1.40 – 1.76 (m, 4 H); 1.94 – 2.06 (m, 1 H); (3 9 10 ml). The org. layer was washed with sat. aq.
3.30 – 3.68 (m, 8 H); 4.62 (d, J = 6.7, 1 H); 4.78 (d, NaHCO3 (6 ml) and H2O (6 ml). The combined org. phases
J = 6.7, 1 H). 13C-NMR (75 MHz, CDCl3): 9.4; 19.1; 19.4; were dried (Na2SO4) and concentrated under reduced pres-
34.0; 48.7; 55.5; 65.9; 74.9; 75.0; 75.5; 95.1. ESI-MS: 241
([M + Na]+).
(4R,5R,6R)-5-ethyltetrahydro-4-(methoxymethoxy)-6-methyl-
2H-pyran-2-one (7). To the activated molecular sieves
ꢀ
(3A; 3 g) were added PCC (2.84 g, 13.2 mmol) and dry
sure. Flash chromatography of the crude afforded tosylate
25
16 (4.25 g, 85%) as a gummy liquid. ½aꢁD = +10.3 (c = 0.7,
CHCl3). IR (neat): 3449, 2924, 2854, 1730, 1177, 769. 1H-
NMR (300 MHz, CDCl3): 0.74 (d, J = 7.3, 3 H); 0.90 (d,
J = 6.5, 3 H); 1.07 – 1.52 (m, 2 H); 1.66 (br. s, 1 H);
benzene (22 ml). To this mixture was added a soln. of 14 1.79 – 2.19 (m, 2 H); 2.43 (s, 3 H); 3.03 – 3.43 (m, 4 H);
(0.36 g, 1.65 mmol) in benzene (20 ml) and stirred under
reflux for 6 h. Et2O (50 ml) was added and the mixture
3.43 – 3.63 (m, 1 H); 3.75 – 4.18 (m, 2 H); 4.43 (d, J = 4.1,
2 H); 7.15 – 7.44 (m, 7 H); 7.72 (d, J = 8.2, 2 H). 13C-NMR
was filtered through a short pad of Celite and SiO2. The (75 MHz, CDCl3): 9.3; 11.9; 21.6; 34.0; 36.8; 40.1; 71.9; 72.4;
filter cake was washed thoroughly with Et2O (2 9 30 ml) 72.8; 73.0; 73.1; 79.4; 127.4; 127.5; 127.8; 128.3; 129.7; 132.8;
and the filtrate was concentrated. The residue after flash
138.6; 144.7. ESI-MS: 471 ([M + Na]+).
chromatography afforded the lactone 7 (0.2 g, 60%) as a (6R)-2,6-Anhydro-6-[(2S)-1-(benzyloxy)propan-2-yl]-3,5-
25
colorless liquid. ½aꢁD = +24.5 (c = 0.65, CHCl3). IR (neat): dideoxy-5-methyl-1-O-[(4-methylphenyl)sulfonyl]-4-O-
1
3449, 2927, 1747, 1036, 764. H-NMR (300 MHz, CDCl3):
[tri(propan-2-yl)silyl]-D-xylo-hexitol (17). To a stirred
1.00 (t, J = 7.3. 3 H); 1.22 – 1.31 (m, 2 H); 1.42 (d, soln. of compound 16 (4.11 g, 9.17 mmol) in dry CH2Cl2
J = 6.2, 3 H); 1.50 – 1.67 (m, 1 H); 2.55 – 2.73 (m, 2 H); (25 ml) was added 2,6-lutidine (3.2 ml, 27.5 mmol) at
3.36 (s, 3 H); 3.90 (q, J = 4.5, 1 H); 3.95 – 4.06 (m, 1 H); 0 °C, then added triisopropylsilyl triflouoromethane-
4.62 (q, J = 7.1, 2 H). 13C-NMR (75 MHz, CDCl3): 10.4; sulphonate (2.9 ml, 11.0 mmol). The mixture was stirred
19.8; 22.2; 35.5; 48.0; 55.6; 72.8; 76.6; 95.0; 174.9. HR-EI-
MS: 203.1282 ([M + H]+, C10H19O4þ; calc. 203.1278).
(6R)-2,6-Anhydro-6-[(2S)-1-(benzyloxy)propan-2-yl]-3,5-
dideoxy-5-methyl-D-xylo-hexitol (4). Trifluoroacetic acid
(50.9 ml) was added slowly to a soln. of the homoallylic
for 1 h at 0 °C, the reaction was quenched with a sat. aq.
NH4Cl soln. (10 ml) and extracted with CH2Cl2. The org.
layer was separated and aq. layer was extracted with
CH2Cl2. Combined org. layer was washed with H2O,
brine, and dried (Na2SO4). Solvent was removed in vacuo
alcohol 5 (3.68 g, 31.7 mmol) and (S)-3-(benzyloxy)-2- and purified the residue by SiO2 CC to afford 17 (5.0 g,
25
methylpropanal (6; 16.9 g, 95.1 mmol) in CH2Cl2 (50 ml) 90% yield). ½aꢁD = ꢀ6.8 (c = 0.8, CHCl3). IR (neat): 3448,
at r.t. under a N2 atmosphere. The mixture was stirred for
2927, 2862, 1364, 1178, 1092, 979, 670. 1H-NMR
3 h and then sat. aq. NaHCO3 soln. (40 ml) was added (300 MHz, CDCl3): 0.74 (d, J = 6.9, 3 H); 0.90 (d, J = 6.6,
and pH was adjusted to > 7 by addition of Et3N. The lay- 3 H); 1.05 (s, 18 H); 1.18 – 1.60 (m, 5 H); 1.75 – 1.88 (dd,
ers were separated and the aq. layer was extracted with
CH2Cl2 (3 9 40 ml) and the org. layers were combined
and the solvent was removed under reduced pressure.
The residue was dissolved in MeOH (30 ml) and stirred
J = 2.8, 12.2, 1 H); 1.92 – 2.09 (m, 1 H); 2.43 (s, 3 H);
3.08 – 3.28 (m, H); 3.31 – 3.41 (t, J = 8.6, H);
2
1
3.43 – 3.59 (m, 2 H); 3.81 – 3.99 (m, 2 H); 4.45 (q,
J = 12.2, 2 H); 7.13 – 7.40 (m, 7 H); 7.65 – 7.85 (m, 2 H).
with K2CO3 (1.95 g) for 0.5 h. The MeOH was then 13C-NMR (75 MHz, CDCl3): 9.3; 12.4; 12.7; 18.1; 21.6;
removed under reduced pressure and H2O (15 ml) was
added. The mixture was extracted with CH2Cl2 127.5; 127.8; 128.3; 129.7; 132.9; 138.7; 144.6. ESI-MS: 627
(3 9 20 ml) and the combined org. layers were dried
([M + Na]+).
34.2; 37.6; 40.7; 72.1; 72.2; 73.0; 73.1; 74.1; 79.5; 127.4;
(MgSO4) and the solvent was removed under reduced (1R,5R)-1,5-Anhydro-1-[(2S)-1-(benzyloxy)propan-2-yl]-
pressure. CC of the crude afforded 4 (5.6 g, 60%) as a 2,4-dideoxy-5-(iodomethyl)-2-methyl-3-O-[tri(propan-2-yl)
25
colorless oil. ½aꢁD = +8.7 (c = 1.8, CHCl3). IR (neat):
silyl]-D-threo-pentitol (18). NaI (17.7 g, 118 mmol) was
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Helv. Chim. Acta 2016, 99, 1 – 7
added to a soln. of 17 (4.82 g, 7.9 mmol) in 10 ml of ace-
tone and heated to reflux for 24 h. Acetone was removed
H); 0.80 (d, J = 6.7, 3 H), 1.08 (s, 18 H); 1.22 – 1.31 (m, 3
H); 1.62 – 1.80 (m, 1 H); 1.81 – 2.00 (m, 1 H); 2.27 – 2.51
under reduced pressure. To the residue was added H2O (m, 2 H); 3.43 (s, 3 H); 3.46 (d, J = 8.1, 2 H); 3.75 – 3.86
(8 ml) and AcOEt (10 ml) and the org. layer was sepa-
rated, dried (Na2SO4), concentrated, and chro-
matographed to afford 18 (4.25 g, 95%) as a liquid.
(dd, J = 1.7, 9.8, 1 H); 4.04 – 4.17 (m, 1 H); 4.64 (d,
J = 6.4, 1 H); 4.83 (d, J = 6.6, 1 H); 4.96 – 5.14 (m, 2 H);
5.54 – 5.77 (m, 1 H). 13C-NMR (75 MHz, CDCl3): 8.8;
25
½aꢁD = ꢀ16.0 (c = 1.05, CHCl3). IR (neat): 3449, 2937, 9.1; 13.3; 18.4; 36.6; 38.9; 40.0; 56.1; 64.9; 71.3; 80.4; 99.0;
1
2863, 1460, 1093, 677. H-NMR (300 MHz, CDCl3): 0.85 117.1; 134.5. ESI-MS: 411 ([M + Na]+).
(d, J = 6.7, 3 H); 0.93 (d, J = 6.4, 3 H); 1.07 (s, 18 H); (2R,3S,4R,5R)-3-(Methoxymethoxy)-2,4-dimethyl-5-{[tri
1.16 – 1.70 (m, 5 H); 1.94 – 2.23 (m, 2 H); 3.00 – 3.17 (m, (propan-2-yl)silyl]oxy}oct-7-enal (22). To a soln. of
2 H); 3.18 – 3.26 (dd, J = 1.8, 10.1, 1 H); 3.26 – 3.40 (m, 2
H); 3.41 – 3.64 (m, 2 H); 4.51 (s, 2 H); 7.27 – 7.38 (m, 5
alcohol 21 (1.13 g, 2.9 mmol) in dry CH2Cl2 (20 ml),
Dess–Martin periodinane (2.47 g, 5.8 mmol) and
H). 13C-NMR (75 MHz, CDCl3): 9.6; 11.9; 12.3; 12.7; 18.1; NaHCO3 (0.48 g, 5.8 mmol) were added at 0 °C under
34.4; 40.6; 41.5; 73.1; 73.2; 74.3; 74.5; 79.5; 127.4; 127.7;
128.2; 138.8. ESI-MS: 560 (M+).
(2S,3R,4R,5R)-1-(Benzyloxy)-2,4-dimethyl-5-{[tri(propan-
N2 atmosphere. The turbid soln. was allowed to warm to
r.t. and stirred for 1 h. The reaction was diluted with
CH2Cl2 (15 ml), quenched with sat. aq. NaHCO3 (10 ml),
2-yl)silyl]oxy}oct-7-en-3-ol (19). To the iodide 18 (4.18 g, and sat. aq. Na2S2O3 (10 ml). The mixture was vigorously
7.46 mmol) in EtOH (25 ml), Zn dust (9.7 g, 149 mmol) stirred until a clear soln. was formed. The org. layer was
was added. The mixture was refluxed for 1 h and then separated and the aq. layer was extracted with CH2Cl2
was cooled to 25 °C. Addition of solid NH4Cl (0.5 g) and (2 9 20 ml). The combined org. extracts were washed
Et2O (10 ml) followed by stirring for 5 min gave a gray with brine (1 9 50 ml), dried (Na2SO4), filtered and con-
suspension. The suspension was filtered through Celite centrated. CC separation over SiO2 afforded aldehyde 22
and filtrate was concentrated under reduced pressure. (0.90 g, 80%) as a colorless oil. IR (neat): 3449, 2927,
1
Purification by flash chromatography gave 19 (2.6 g, 80%) 2860, 1637, 1035, 761, 672. H-NMR (300 MHz, CDCl3):
25
as a colorless liquid. ½aꢁD = +4.7 (c = 1.25, CHCl3). IR 0.84 (m, 6 H); 1.08 (s, 18 H); 1.22 – 1.30 (m, 3 H);
(neat): 3488, 2938, 2864, 1459, 1090, 882, 675. 1H-NMR
1.69 – 1.84 (m, 1 H); 2.29 – 2.53 (m, 3 H); 3.20 (s, 3 H);
(300 MHz, CDCl3): 0.76 (d, J = 6.7, 3 H), 0.89 (d, J = 6.7, 4.04 – 4.35 (m, 2 H); 4.57 (d, J = 6.7, 1 H); 4.72 (d,
3 H); 1.08 (s, 18 H); 1.34 – 1.46 (m, 3 H); 1.72 – 1.96 (m, J = 6.9, 1 H); 4.93 – 5.20 (m, 2 H); 5.53 – 5.84 (m, 1 H);
2
H); 2.32 – 2.47 (m, 2 H); 3.37 – 3.58 (m, 2 H); 9.70 (s, 1 H). 13C-NMR (75 MHz, CDCl3): 6.2; 8.8; 13.2;
3.77 – 3.90 (m, 1 H); 4.10 – 4.22 (m, 1 H); 4.50 (q, 18.4; 38.9; 40.2; 49.0; 55.5; 70.9; 80.2; 98.3; 117.2; 134.3;
J = 7.5, 2 H); 4.94 – 5.16 (m, 2 H); 5.66 – 5.90 (m, 1 H); 203.9. ESI-MS: 409 ([M + Na]+).
7.14 – 7.46 (m, 5 H). 13C-NMR (75 MHz, CDCl3): 9.1; (4S,5R,6R,7R)-5-(Methoxymethoxy)-4,6-dimethyl-7-{[tri
12.1; 12.6; 18.1; 35.6; 38.0; 39.8; 73.2; 73.4; 74.6; 76.1;
116.9; 127.4; 127.5; 128.3; 135.6; 138.6. ESI-MS: 435 (M+).
(5R,6R,7R)-5-[(2S)-1-(Benzyloxy)propan-2-yl]-6,10-dimethyl-
9,9-di(propan-2-yl)-7-(prop-2-en-1-yl)-2,4,8-trioxa-9-silaun-
(propan-2-yl)silyl]oxy}dec-9-en-3-ol (23). Freshly pre-
pared EtMgBr (prepared in situ from 0.15 g (6.37 mmol)
of Mg and 0.69 g (6.37 mmol) of EtBr in 10 ml of dry
THF) was added drop wise to a stirred soln. of aldehyde
decane (20). The compound 20 (2.5 g, 90%) was prepared 22 (0.82 g, 2.12 mmol) in dry THF (10 ml) at 0 °C. After
from 19 (2.5 g, 5.7 mmol) as a yellow liquid following the addition was completed, the mixture was allowed to stir
same procedure as described for the synthesis of 13. at r.t. for 2 h and then quenched with sat. aq. NH4Cl soln.
25
½aꢁD = +1.0 (c = 1.15, CHCl3). IR (neat): 3448, 2929, 2864, The org. layer was separated and the compound from aq.
1636, 1037, 763, 673. 1H-NMR (300 MHz, CDCl3): 0.81 layer was extracted with AcOEt (2 9 10 ml). The com-
(d, J = 6.4, 6 H); 1.06 (s, 18 H); 1.19 – 1.40 (m, 3 H); bined org. layers were washed with H2O and brine, and
1.58 – 1.83 (m, 1 H); 1.90 – 2.16 (m, 1 H); 2.23 – 2.48 (m, dried (Na2SO4). Concentration under reduced pressure
2
H); 3.23 – 3.48 (m, 5 H); 3.67 – 3.84 (m, 1 H); and purification by SiO2 CC afforded 23 (0.80 g, 90%) as
25
4.05 – 4.28 (m, 1 H); 4.47 (s, 2 H); 4.63 (d, J = 2.6, 2 H); a viscous liquid. ½aꢁD = +8.0 (c = 1.85, CHCl3). IR (neat):
4.92 – 5.14 (m, 2 H); 5.53 – 5.82 (m, 1 H); 7.16 – 7.39 (m, 3449, 2927, 2863, 1460, 1035, 674. 1H-NMR (300 MHz,
5 H). 13C-NMR (75 MHz, CDCl3): 9.1; 9.8; 13.1; 18.4; CDCl3): 0.81 (d, J = 6.7, 3 H); 0.88 (d, J = 6.7, 3 H); 0.94
34.9; 39.0; 40.3; 55.6; 71.4; 72.8; 73.5; 80.9; 98.6; 116.8;
127.3; 127.6; 128.2; 134.8; 138.6. ESI-MS: 501 ([M + Na]+).
(2S,3R,4R,5R)-3-(Methoxymethoxy)-2,4-dimethyl-5-{[tri
(propan-2-yl)silyl]oxy}oct-7-en-1-ol (21). The compound
21 (1.5 g, 90%) was prepared from 20 (2.0 g, 4.18 mmol)
(t, J = 7.5, 3 H); 1.09 (s, 18 H); 1.22 – 1.33 (m, 2 H);
1.35 – 1.58 (m, 3 H); 1.59 – 1.81 (m, 2 H); 2.29 – 2.46
(m, 2 H); 2.88 – 3.11 (br. s, 1 H); 3.39 (s, 3 H);
3.51 – 3.70 (m, 2 H); 4.01 – 4.17 (td, J = 2.2, 3.7, 1 H);
4.69 (d, J = 6.0, 1 H); 4.74 (d, J = 6.0, 1 H); 4.98 – 5.13
(m, 2 H); 5.57 – 5.79 (m, 1 H). 13C-NMR (75 MHz,
as a yellow liquid following the same procedure as
25
described for the synthesis of 14. ½aꢁD = +25.4 (c = 0.45, CDCl3): 6.4; 9.3; 10.5; 13.2; 18.4; 28.0; 38.7; 39.6; 40.1;
CHCl3). IR (neat): 3426, 2939, 2865, 1462, 1158, 1036,
1
55.8; 71.5; 77.5; 86.9; 99.0; 117.1; 134.4. ESI-MS: 439
([M + Na]+).
915, 676. H-NMR (300 MHz, CDCl3): 0.73 (d, J = 6.9, 3
€
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Helv. Chim. Acta 2016, 99, 1 – 7
7
[13] K. Toshima, K. Tatsuta, M. Kinoshita, Bull. Chem. Soc. Jpn.
1988, 61, 2369.
(4R,5S,6R,7R)-5-(Methoxymethoxy)-4,6-dimethyl-7-{[tri
(propan-2-yl)silyl]oxy}dec-9-en-3-one (24). The com-
pound 24 (0.65 g, 85%) was prepared from 23 (0.76 g,
1.82 mmol) as a yellow liquid following the same proce-
[14] D. Seebach, H.-F. Chow, R. F. W. Jackson, M. A. Sutter, S.
Thaisrivongs, J. Zimmerman, Liebigs Ann. Chem. 1986, 1281.
[15] D. Seebach, H.-F. Chow, R. F. W. Jackson, K. Lawson, M. A.
Sutter, S. Thaisrivongs, J. Zimmerman, J. Am. Chem. Soc. 1985,
107, 5292.
25
dure as described for the synthesis of 22. ½aꢁD = ꢀ14.0
(c = 0.95, CHCl3). IR (neat): 3447, 2924, 2859, 1713, 1461,
1035, 770, 675. 1H-NMR (300 MHz, CDCl3): 0.83 (d,
J = 6.7, 3 H); 0.98 – 1.19 (m, 24 H); 1.20 – 1.50 (m, 3 H);
1.58 – 1.82 (m, 1 H); 2.24 – 2.47 (m, 3 H); 2.47 – 2.71 (m,
2 H); 3.20 (s, 3 H); 3.99 – 4.27 (m, 2 H); 4.44 (d, J = 6.6,
1 H); 4.56 (d, J = 6.6, 1 H); 4.95 – 5.17 (m, 2 H);
5.52 – 5.80 (m, 1 H). 13C-NMR (75 MHz, CDCl3): 7.9;
8.4; 9.1; 13.2; 18.4; 33.6; 39.5; 40.2; 48.5; 55.8; 71.0; 81.2;
98.1; 117.1; 134.4; 212.5. ESI-MS: 437 ([M + Na]+).
[16] T. Wakamatsu, H. Nakamura, E. Nara, Tetrahedron Lett. 1986,
27, 3895.
[17] T. Wakamatsu, S. Yamada, H. Nakamura, Y. Ban, Heterocycles
1987, 25, 43.
[18] H. Nakamura, K. Arata, T. Wakamatsu, Y. Ban, M. Shibasaki,
Chem. Pharm. Bull. 1990, 38, 2435.
[19] F. E. Ziegler, J. S. Tung, J. Org. Chem. 1991, 56, 6530.
[20] J. S. Yadav, Y. G. Rao, V. Rajender, RSC Adv. 2013, 3, 55.
[21] R. Barth, J. Mulzer, Tetrahedron 2008, 64, 4718.
[22] I. Paterson, H.-G. Lombart, C. Allerton, Org. Lett. 1999, 1, 19.
[23] D. A. Evans, D. M. Fitch, J. Org. Chem. 1997, 62, 454.
[24] I. Paterson, J. Man, Tetrahedron Lett. 1997, 38, 695.
[25] K. U. Bindseil, A. Zeeck, J. Org. Chem. 1993, 58, 5487.
[26] J. S. Yadav, K. B. Reddy, G. Sabitha, Tetrahedron 2008, 64, 1971.
[27] J. S. Yadav, C. S. Reddy, Org. Lett. 2009, 11, 1705.
[28] J. S. Yadav, M. R. Pattanayak, P. P. Das, D. K. Mohapatra,
Org. Lett. 2011, 13, 1710.
Ethyl (2E,5R,6R,7S,8R)-7-(Methoxymethoxy)-6,8-dimethyl-
9-oxo-5-{[tri(propan-2-yl)silyl]oxy}undec-2-enoate (3). To a
stirred soln. of compound 24 (0.61 g, 1.47 mmol) in anh.
CH2Cl2 (0.5 ml) under N2 atmosphere were added ethyl
acrylate and Grubbs’ second-generation catalyst (0.12 g,
10 mol-%). The mixture was stirred at r.t. until consump-
tion of all the starting material (1 h). The mixture was
concentrated to dryness and applied to CC (SiO2) to
[29] J. S. Yadav, C. N. Reddy, G. Sabitha, Tetrahedron Lett. 2012,
53, 2504.
25
afford 3 in 90% yield (0.65 g). ½aꢁD = +1.1 (c = 1.65,
[30] J. S. Yadav, S. K. Das, G. Sabitha, J. Org. Chem. 2012, 77,
11109.
CHCl3). IR (neat): 3431, 2941, 2867, 1720, 1166, 1035,
1
[31] J. S. Yadav, M. S. Reddy, A. R. Prasad, Tetrahedron Lett. 2005,
46, 2133.
676. H-NMR (300 MHz, CDCl3): 0.84 (d, J = 6.7, 3 H);
0.95 – 1.17 (m, 21 H); 1.19 – 1.36 (m, 6 H); 1.36 – 1.46
(m, 3 H); 1.49 – 1.66 (m, 1 H); 2.26 – 2.70 (m, 5 H); 3.22
(s, 3 H); 4.07 (dd, J = 1.5, 9.0, 1 H), 4.18 (q, J = 6.7, 2 H);
4.23 – 4.32 (m, 1 H); 4.47 (d, J = 6.0, 1 H); 4.55 (d,
J = 6.0, 1 H); 5.83 (d, J = 15.8, 1 H); 6.70 – 6.88 (m, 1 H).
13C-NMR (75 MHz, CDCl3): 7.8; 8.7; 9.3; 13.0; 14.2; 18.3;
33.6; 38.7; 40.3; 48.3; 55.8; 60.2; 70.4; 80.9; 98.0; 123.4;
144.3; 166.2; 212.4. HR-EI-MS: 487.3448 ([M + H]+,
C26H51O6Si+; calc. 487.3449).
[32] J. S. Yadav, B. V. S. Reddy, M. S. Reddy, N. Niranjan, A. R.
Prasad, Eur. J. Org. Chem. 2003, 1779.
[33] L.-S. Li, Y.-L. Wu, Tetrahedron 2002, 58, 9049.
ꢁ
ꢁ
[34] K. D. Philips, J. Zemlicka, J. P. Horwitz, Carbohydr. Res. 1973,
30, 281.
[35] S. Baskaran, S. Chandrasekaran, Tetrahedron Lett. 1990, 31,
2775.
[36] S. M. Ali, K. Ramesh, R. T. Borchardt, Tetrahedron Lett. 1990,
31, 1509.
[37] M. S. Reddy, M. Narender, K. R. Rao, Tetrahedron 2007, 63,
11011.
[38] B. M. Trost, Y. Kondo, Tetrahedron Lett. 1991, 32, 1613.
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Received January 9, 2016
Accepted March 23, 2016
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€
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www.helv.wiley.com