A facile chiral pool synthesis of 9-epi-decarestrictine-D, decarestrictine-D and O

Article abstract of DOI:10.1016/j.tetasy.2013.12.008

A facile chiral pool total synthesis of 9-epi-decarestrictine-D, decarestrictine-D and O has been achieved from l-(+)-diethyl tartrate. The strategy utilized is conventional and flexible. Wittig homologation and Grubbs ring closing metathesis are the key reactions employed for the synthesis of the title molecules.

Full text of DOI:10.1016/j.tetasy.2013.12.008

Tetrahedron: Asymmetry 25 (2014) 203–211
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A facile chiral pool synthesis of 9-epi-decarestrictine-D,
decarestrictine-D and O
⇑
Kuchena Vamshikrishna, Garlapati Srinu, Pabbaraja Srihari
Division of Natural Products Chemistry, GCL 1st Floor, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 October 2013
Accepted 12 December 2013
A facile chiral pool total synthesis of 9-epi-decarestrictine-D, decarestrictine-D and O has been achieved
from L-(+)-diethyl tartrate. The strategy utilized is conventional and flexible. Wittig homologation and
Grubbs ring closing metathesis are the key reactions employed for the synthesis of the title molecules.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
O
O
Natural products obtained from fungi have gained significant
interest in the synthetic community and the pharmaceutical indus-
try due to their structural diversity and intriguing biological activ-
ities.1 Decarestrictines, the 10-membered lactone secondary
metabolites2 isolated from various Penicillium strains, do not dis-
play antibacterial or antifungal activities, although a few of them
have been found to display significant inhibitory effects on choles-
terol biosynthesis and have thus attracted attention toward devel-
oping them as a new class of cholesterol-lowering drugs.3 These
metabolite decarestrictines A–O 1–9 exhibit similar structural ele-
ments that is (i) a 10-membered lactone ring; (ii) an exocyclic
methyl group; and (iii) compounds 1, 2 and 4–9 display E-config-
ured double bonds (Fig. 1). In addition, variations in the oxygena-
tion pattern ranging from C-3 to C-7 are observed. Decarestrictine
D 6 was isolated from the Canadian tuckahoe fungi Polyporous
tuberaster4 and named as tuckolide. The structures of these lac-
tones were established by spectroscopic techniques and by X-ray
diffraction analysis of 6 and a derivative of 3. The structural diver-
sity and potent activity as cholesterol lowering drugs is of signifi-
cant synthetic importance and has resulted in seminal publications
in the literature.5 In a continuation of our research on developing
concise approaches for asymmetric total synthesis of biologically
active natural products,6 we became interested in this class of mol-
ecules. Herein we report the total synthesis of decarestrictine-D
O
O
OH
O
OH
O
O
OH
O
1
decarestrictine A1
decarestrictine A2
2
3
decarestrictine B
O
O
O
O
O
O
OH
HO
OH
OH
OH
OH
OH
decarestrictine C1
4
5
decarestrictine D 6
decarestrictine C2
O
O
O
O
O
O
HO
OH
HO
OH
OH
O
O
OH
decarestrictine O 9
decarestrictine F 7
decarestrictine N 8
Figure 1. Structures of decarestrictines.
and O, from commercially available L-(+)-diethyl tartrate.
obtained by the coupling of acid 10 with alcohol 11 followed by
cyclization through Grubbs’ RCM protocol and deprotection of
the protecting groups. Acid 10 could be synthesized from 12 in four
steps through oxidation, Wittig homologation, deprotection of the
silylether, and oxidation of the resulting alcohol to give an acid
functionality. The secondary alcohol 11 can be obtained from 12
in five steps involving iodination, reductive elimination, deprotec-
tion of the silylether, oxidation, and finally a Grignard reaction.
2. Results and discussion
A retrosynthetic analysis of decarestrictine-D and O is depicted
in Scheme 1. The target molecule 6 (decarestrictine-D) could be
⇑
Corresponding author. Tel.: +91 4027191815; fax: +91 4027160512.
E-mail address: srihari@iict.res.in (P. Srihari).
Simultaneously, decarestrictine-O
9 can be synthesized by
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.12.008

204
K. Vamshikrishna et al. / Tetrahedron: Asymmetry 25 (2014) 203–211
O
O
O
OH
O
O
OH
O
11
16
OTBS
O
HO
O
O
OH
HO
OH
OH
O
O
HO
OH
OH
12
OH
O
O
O
decarestrictine-O 9
O
O
decarestrictine-D 6
10
15
OH
BnO
OH
BnO
O
O
O
O
L-(+)-diethyl tartrate
14
13
Scheme 1. Retrosynthesis for decarestrictine-D and O.
coupling of acid 16 with alcohol 15 followed by ring closing
metathesis and global deprotection of the protecting groups.
Compound 15 can be synthesized from 12 in five steps (oxidation,
1C-Wittig olefination, silyl deprotection, oxidation, and methyl
Grignard reaction), while compound 16 can be obtained from 12
in six steps (vide infra). Intermediate 12 can in turn be synthesized
from 13 in two steps that is protection of alcohol 13 as the corre-
sponding silyl ether and deprotection of the benzyl ether. Alcohol
13 can be accessed from compound 14 via a Wittig homologation
reaction and reductive opening of the resulting enol ether.
Compound 14 in turn can be easily synthesized from commercially
achieved with BnBr in the presence of NaH to yield the correspond-
ing benzyl ether 14 in 73% yield. Alcohol 14 was subjected to a
Swern oxidation8,6b followed by Wittig homologation using
methoxymethyl triphenylphosphonium chloride and lithium hex-
amethyldisilazide in dry THF to give the enol ether, which upon
hydrolysis using Hg(OAc)2 followed by an in situ reduction with
NaBH4 in THF/water (1:1.2) afforded homologated alcohol 13.9,6h
Protection of the resulting primary alcohol 13 as the corresponding
tert-butyldimethylsilyl ether 18 was achieved with tert-butyldi-
methylsilyl chloride (TBDMSCl) and imidazole in 92% yield. Deben-
zylation of 18 with Pd/C in dry THF gave the key intermediate 12 in
92% yield.
Compound 12 was used to access other fragments 10, 11, 15,
and 16 (vide infra). While compounds 10 and 11 can be utilized
for the construction of decarestrictine-D, compounds 15 and 16
were utilized for the preparation of decarestrictine-O. The synthe-
sis of fragment 10 began with the oxidation reaction of 12 under
Swern8 conditions to provide the aldehyde, which was subjected
to a one carbon Wittig homologation reaction with methyltriphen-
ylphosphonium iodide and potassium tert-butoxide to provide ole-
fin 19 (Scheme 3). Compound 19 upon desilylation with TBAF
afforded alcohol 20 which was oxidized to the aldehyde with IBX
and further oxidized to acid 10 under Pinnick–Lindgren condi-
tions10 in 70% yield.
available
The synthesis of decarestrictine-D 6 started from commercially
available (+)-diethyl -tartrate. -(+)-DET upon reaction with 2,2-
L-(+)-DET in three steps.
L
L
dimethoxy propane in dry benzene in the presence of a catalytic
amount of anhydrous p-toluenesulfonic acid under reflux condi-
tions furnished the acetonide protected diester, which upon reduc-
tion with lithium aluminum hydride in dry THF furnished 1,4-diol
17 (Scheme 2).7 Selective mono benzylation of diol 17 was
BnO
OH
HO
OH
b
a
(+)-DET
O
O
O
O
14, 73%
17, 83%
OTBS
OH
OTBS
OTBS
BnO
BnO
c
d
HO
a
b
O
O
O
O
O
O
O
O
13, 65%
19, 73%
12
18, 92%
OTBS
HO
e
OH
O
c
O
O
OH
O
O
O
O
12, 92%
20, 78%
10, 70%
Scheme 2. Synthesis of fragment 12. Reagents and conditions: (a) (i) 2,2-DMP,
benzene, cat. pTSA, 80 °C, 12 h, 92%, (ii) LiAlH4, THF, 45 °C, 5 h; (b) BnBr, NaH, THF,
0 °C to rt, 12 h; (c) (i) (COCl)2, DMSO, CH2Cl2, Et3N, ꢀ78 °C, 2.5 h, 85%, (ii)
PPh3CH2OCH3Cl, LiHMDS, THF, ꢀ10 °C to rt, 12 h, (iii) Hg(OAc)2, THF, then H2O (1.2
ratio w.r.t THF), NaBH4, 0 °C to rt, 1 h; (d) imidazole, TBDMSCl, CH2Cl2, 0 °C to rt,
2 h; (e) H2, Pd/C, THF, rt, 12 h.
Scheme 3. Synthesis of fragment 10. Reagents and conditions: (a) (i) (COCl)2,
DMSO, CH2Cl2, Et3N, ꢀ78 °C, 2.5 h, (ii) PPh3CH3I, tBuOK, THF, 0 °C to rt, 12 h; (b)
1.0 M TBAF, THF, 0 °C to rt, 2 h; (c) (i) IBX, CH2Cl2, DMSO, 0 °C to rt, 6 h, 87%;
(ii) 2-methyl-2-butene, NaH2PO4, NaClO2, tBuOH:H2O (1:1), acetone, 0 °C to rt, 12 h.

K. Vamshikrishna et al. / Tetrahedron: Asymmetry 25 (2014) 203–211
205
Alcohol 12 was converted into the corresponding iodide 2111
upon treatment with I2, TPP, and imidazole in dry THF at room
temperature and subjected to a ring opening reaction with nBuLi
to afford chiral allyl alcohol 22 in 98% yield (Scheme 4). Protection
of the secondary alcohol 22 as the corresponding methoxymethyl
ether was achieved with chloromethylmethyl ether and N,N-
diisopropylethylamine in CH2Cl2 to afford 23. Desilylation of 23
with 1 M tetra-n-butylammonium flouride (TBAF) afforded the
primary alcohol 24, which was oxidized to the aldehyde and then
subjected to a Grignard reaction with methyl magnesium bromide
to provide 11 as an inseparable mixture of diastereomers in a 6:4
ratio.12
With the key intermediates 10 and 11 in hand, the stage was set
for the construction of the target molecule 6 (Scheme 5). Coupling
of acid 10 with alcohol 11 using DCC, DMAP in CH2Cl2 yielded es-
ters 25 (40.2%) and 25a (26.8%) respectively in 6:4 ratio which
were easily separable through column chromatography at this
stage. Independent ring closing metathesis reaction of 25 and
25a with Grubbs’ 2nd generation13,14 catalyst in CH2Cl2 provided
the corresponding lactones 26 and 26a respectively. Finally global
deprotection of compound 26 and also its C9-epimer 26a was
achieved using BF3ꢁOEt2, in DMS15 to get the decarestrictine-D 6
and 9-epi-decarestrictine respectively.
OTBS
OTBS
HO
I
a
b
O
O
O
O
12
21, 94%
OH
OMOM
c
d
OTBS
2.1. Synthesis of decarestrictine-O
OTBS
23, 83%
22, 98%
The synthesis of fragment 15 and 16 is shown in Scheme 6.
Accordingly, alcohol 20 was oxidized to aldehyde using IBX and
then subjected to a Grignard reaction with 3 M methylmagnesium
iodide in diethyl ether to furnish the easily separable secondary
alcohols 155k,5l (47% yield) and its diastereomer 15a (20% yield)
in 7:3 ratio respectively. The other fragment 16 was prepared from
alcohol 24 in two steps that is IBX mediated oxidation followed by
Pinnick oxidation10 to provide the acid fragment 16.
O
OMOM
O
OH
e
OH
24, 91%
11, 67%
Scheme 4. Synthesis of fragment 11. Reagents and conditions: (a) I2, TPP,
imidazole, THF, 0 °C to rt, 2 h; (b) nBuLi, THF, ꢀ78 °C, 2 h; (c) MOMCl, DIPEA,
CH2Cl2, 0 °C to rt, 12 h; (d) 1.0 M TBAF, THF, 0 °C to rt, 2 h; (e) (i) IBX, CH2Cl2, DMSO,
0 °C to rt, 6 h, (ii) MeMgI, diethylether, ꢀ40 °C, 3 h, (diastereomers in a 6:4 ratio).
The coupling of key fragments 15 and 16 was achieved under
standard conditions with DCC and DMAP in CH2Cl2 to provide ester
OH
OH
OH
O
O
a
O
O
O
O
O
O
OMOM
O
O
15a, 20%
20
15, 47%
O
OH
O
O
OH
25, 40.2%
a
+
OMOM
OMOM
b
O
O
O
COOH
OH
10
11
O
24
16, 71%
OMOM
, 26.8%
O
Scheme 6. Synthesis of fragments 15 and 16. Reagents and conditions: (a) (i) IBX,
CH2Cl2, DMSO, 0 °C to rt, 6 h, (ii) MeMgI, diethylether, ꢀ40 °C, 5 h, (15:15a, 7:3); (b)
(i) IBX, CH2Cl2, DMSO, 0 °C to rt, 6 h, 81%, (ii) 2-methyl-2-butene, NaH2PO4, NaClO2,
tBuOH/H2O (1:1), acetone, 0–5 °C, 12 h.
O
25a
25:25a, 6:4
O
O
O
O
O
O
OH
c
b
O
25
OMOM
O
O
O
HO
OH
a
O
OH
OMOM
O
OH
O
O
O
decarestrictine-D 6, 62%
26, 80%
27, 66%
16, 71%
15, 47%
O
O
O
O
O
O
c
b
O
O
25a
OMOM
O
HO
OH
OH
c
b
O
OMOM
O
HO
OH
O
OH
9-epi-decarestrictine-D 6a, 61%
26a, 78%
28, 70%
decarestrictine-O 9, 55%
Scheme 5. Synthesis of decarestrictine-D, 9-epi-decarestrictine-D. Reagents and
conditions: (a) DCC, DMAP, CH2Cl2, 0 °C to rt, 12 h, (25:25a, 6:4); (b) Grubb’s 2nd
generation catalyst, CH2Cl2, reflux, 24 h, for 26, 26a; (c) BF3ꢁOEt2, DMS, 0 °C, 20 min,
6, and 6a.
Scheme 7. Synthesis of decarestrictine-O. Reagents and conditions: (a) DCC, DMAP,
CH2Cl2, 0 °C to rt, 12 h; (b) Grubb’s 2nd generation catalyst, CH2Cl2, reflux, 12 h;
(c) (i) BF3ꢁOEt2, DMS, 0 °C, 20 min, (ii) 1 M HCl, THF, 2 h.

206
K. Vamshikrishna et al. / Tetrahedron: Asymmetry 25 (2014) 203–211
27 (Scheme 7) in 65% yield. The di-olefin 27 was subjected to a ring
closing metathesis reaction with Grubbs’ 2nd generation catalyst
to provide the precursor 28 exclusively in the E-form (the geome-
try was confirmed by the coupling constant value J = 15.8 Hz for
one of the olefinic proton). Compound 28 upon exposure to 1 M
HCl at room temperature underwent a one-pot isopropylidene
and MOM deprotection to yield the target molecule decarestric-
tine-O in 55% yield.
2-methyl-2-butene (9.34 mL, 3.7 equiv) was added via syringe, fol-
lowed by NaH2PO4 (3.54 g, 22.7 mmol, 4.5 equiv) and NaClO2 (80%
technical grade, 2.06 g, 22.7 mmol, 4.5 equiv) as solids. The bipha-
sic reaction was stirred vigorously for 12 h, after which saturated
aqueous NH4Cl (10 mL) was added. The reaction mixture was ex-
tracted with CH2Cl2 (3 ꢂ 15 mL) and the combined organic layer
was dried over Na2SO4, filtered, and concentrated in vacuo to give
a crude liquid, which was purified by column chromatography to
give acid 10 (0.66 g, 70%) as a light yellow liquid; Rf = 0.20 (hex-
ane/EtOAc, 80:20); ½a D25
ꢃ
¼ ꢀ29:2 (c 1.8, CHCl3); IR mmax (Neat):
3. Conclusion
3424, 2989, 1767, 1164, 931 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d
5.88–5.76 (m, 1H), 5.39 (d, J = 17.0 Hz, 1H), 5.29 (d, J = 10.4 Hz,
1H), 4.13–4.06 (m, 2H), 2.66–2.58 (m, 2H), 1.44 (s, 3H), 1.43 (s,
3H); 13C NMR (75 MHz, CDCl3); d 176.0, 134.3, 119.8, 109.5, 82.1,
76.4, 36.7, 27.0, 26.9; ESIMS: m/z 209 [M+Na]+; HRESIMS for C9H14-
O4Na [M+Na]+ found 209.07854 calcd 209.07843.
In conclusion, we have accomplished the total synthesis of
decarestrictine-D and O from a common intermediate involving
conventional reactions. Both the coupling partners were prepared
from a single raw material; the commercially available (+)-diethyl
L-tartrate. The strategy utilized is flexible and can be further
exploited toward the synthesis of other decanolide natural prod-
ucts and their analogues in order to screen their biological
activities.
4.1.2. ((4S,5S)-5-(2-(tert-Butyldimethylsilyloxy)ethyl)-2,2-dime-
thyl-1,3-dioxolan-4-yl)methanol 12
To a solution of compound 18 (8.0 g, 21.1 mmol, 1.0 equiv) in
anhydrous THF (20 mL) was treated with 10% Pd/C (300 mg). The
flask was filled with H2 and stirred for 12 h after the reaction mix-
ture was filtered on a pad of Celite using EtOAc (100 mL). The fil-
trate was concentrated under reduced pressure to give a crude
material, which was purified by column chromatography
Rf = 0.10 (hexane/EtOAc, 90:10) to give 12 (5.62 g, 92% yield) as a
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were recorded in CDCl3 or ace-
tone-d6, CD3OD as solvent on 300 MHz, 500 MHz, and 600 MHz
spectrometer at ambient temperature. Coupling constants J are gi-
ven in Hz. Chemical shifts are reported in ppm on a scale downfield
from TMS as the internal standard and signal patterns are indicated
as follows: s = singlet, d = doublet, t = triplet, q = quartet,
sext = sextet, m = multiplet, br = broad. FTIR spectra were recorded
on KBr pellets (Neat) or in CHCl3 and reported in wave numbers
(cmꢀ1). Optical rotations were measured on a digital polarimeter
using a 1 mL cell with a 1 dm path length. For low (MS) and high
(HRMS) resolution, m/z ratios are reported as values in atomic
mass units. Mass analysis was carried out in the ESI mode. All re-
agents were of reagent grade and used without further purification
unless specified otherwise. Solvents for reactions were distilled
prior to use: THF, and diethyl ether were distilled from Na and ben-
zophenone ketyl; MeOH from Mg and I2; CH2Cl2 from CaH2. All air
or moisturesensitive reactions were conducted under a nitrogen or
argon atmosphere in flame-dried or oven-dried glassware with
magnetic stirring. Column chromatography was carried out using
silica gel (100–200 mesh) packed in glass columns. Technical grade
ethyl acetate and petroleum ether used for column chromatogra-
phy were distilled prior to use.
yellow oil; ½a 2D5
ꢃ
¼ ꢀ19:5 (c 2.3, CHCl3); IR mmax (Neat): 3458,
2931, 1375, 1253, 1094, 838 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d
4.03–3.99 (m, 1H), 3.84–3.71 (m, 4H), 3.66–3.64 (m, 1H), 2.05 (br
s, 1H), 1.87–1.76 (m, 2H), 1.41 (s, 3H), 1.39 (s, 3H), 0.89 (s, 9H),
0.06 (s, 6H); 13C NMR (75 MHz, CDCl3): d 108.5, 81.3, 74.5, 62.1,
59.9, 36.1, 27.3, 26.9, 25.8, 18.2, ꢀ5.4; ESIMS: m/z 291 [M+H]+;
HRESIMS for C14H31O4Si [M+H]+ found 291.19882 calcd 291.19861.
4.1.3. 2-((4S,5S)-5-(Benzyloxymethyl)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)ethanol 13
To the solution of dry DMSO (11.3 mL, 158.7 mmol, 4.0 equiv) in
dry CH2Cl2 (50 mL) was added dropwise oxalyl chloride (6.9 mL,
79.4 mmol, 2.0 equiv) at ꢀ78 °C over 15 min and stirred for
20 min at the same temperature. To this reaction mixture, com-
pound 14 (10.0 g, 39.7 mmol, 1.0 equiv) in dry CH2Cl2 (60 mL)
was added drop wise over 15 min at ꢀ78 °C and the reaction mix-
ture was stirred at the same temperature for 2 h. The reaction was
quenched with Et3N (33.0 mL, 238.1 mmol, 6.0 equiv) at ꢀ78 °C,
and then allowed to warm to room temperature, after which water
(100 mL) was added, the organic layer was separated, the aqueous
layer was extracted with CH2Cl2 (2 ꢂ 100 mL), the combined or-
ganic layer washed with brine (80 mL), dried over anhydrous Na2-
SO4, and the solvent was removed under reduced pressure to give a
crude aldehyde, which was utilized for the next reaction without
further purification (8.5 g, 85%). To a cooled (ꢀ10 °C), stirred sus-
pension of (methoxymethyl)triphenylphosphonium chloride
(29.1 g, 85.0 mmol, 2.5 equiv) in 200 mL of dry THF under an N2
atmosphere was added (79.9 mL, 2.35 equiv) 1.0 M lithium bis(tri-
methylsilyl) amide in THF. The reaction mixture was stirred at the
same temperature for 30 min. This solution was transferred via
cannula to a solution of the above aldehyde in THF (100 mL). The
resulting solution was then stirred at ꢀ10 °C for 2 h and then al-
lowed to warm to room temperature, and stirred for 10 h. The reac-
tion mixture was diluted with saturated aq NaHCO3 (200 mL) and
extracted with Et2O (3 ꢂ 100). The combined organic layer was
washed with brine (100 mL), dried over anhydrous Na2SO4, fil-
tered, and concentrated under reduced pressure to give a crude
enol ether, which was purified by flash column chromatography
to give a yellowish liquid (6.2 g, 65%). This enol ether was dissolved
in 70 mL of THF, to which was added Hg(OAc)2 (10.7 g, 33.5 mmol,
4.1.1. 2-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)acetic
acid 10
To a clear solution of IBX (3.25 g, 11.6 mmol, 2.0 equiv), in a 1:1
ratio of dry DMSO and CH2Cl2 (20 mL), was added compound 20
(1.0 g, 5.8 mmol, 1.0 equiv) in dry CH2Cl2 (10 mL) at 0 °C over 5
min. The reaction mixture was allowed to warm to room temper-
ature, and stirred at the same temperature for 6 h. After complete
consumption of the starting material, the reaction mixture was
quenched with the addition of water (15 mL), and the white solid
formed was filtered over a small pad of Celite, and the filtrate then
extracted with diethyl ether (2 ꢂ 10 mL). The combined organic
layer was washed with brine (10 mL), and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure to give
a crude product, which was purified by flash column chromatogra-
phy to give the aldehyde (0.86 g, 87%) as a yellow liquid. Rf = 0.80
(hexane/EtOAc, 80:20). The aldehyde (0.86 g, 5.1 mmol, 1.0 equiv)
t
obtained above was dissolved in BuOH (22.5 mL), H2O (22.5 mL)
and acetone (12.6 mL) in a 100-mL round-bottom flask. Next, 2 M

K. Vamshikrishna et al. / Tetrahedron: Asymmetry 25 (2014) 203–211
207
1.5 equiv) at 0 °C and then allowed to warm to room temperature.
The reaction mixture was stirred at same temperature for 30 min.
To this mixture was added H2O (84 mL) (1.2 times w.r.t to THF),
and the reaction mixture was cooled to 0 °C, after which NaBH4
(5.08 g, 133.1 mmol, 6.0 equiv) was added to the reaction mixture
portionwise over 30 min. Next the reaction mixture was allowed to
warm to room temperature over 30 min. and then stirred for an-
other 30 min. The organic layer was separated and the aqueous
layer was extracted with EtOAc (2 ꢂ 80 mL). The combined organic
layer was washed with brine, dried over anhydrous Na2SO4, con-
centrated under reduced pressure, and purified with column chro-
matography to give 13 (5.4 g, 91%) as a colorless liquid. Rf = 0.5
tracted with diethyl ether (2 ꢂ 8 mL). The combined organic layer
was washed with brine (5 mL) and dried over anhydrous Na2SO4.
Evaporation of the solvent under reduced pressure afforded a crude
product, which was purified by column chromatography
Rf = 0.40 (hexane/EtOAc, 80:20) to give 15 (0.101 g, 47%) and 15a,
(0.04 g, 20%) as a light yellowish oil; ½a D25
ꢃ
¼ ꢀ5:9 (c 1.7, CHCl3);
IR mmax (Neat): 3432, 2985, 1375, 1239, 1047, 989 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 5.85–5.73 (m, 1H), 5.39–5.24 (m, 2H), 4.12–
3.99 (m, 2H), 3.98–3.89 (m, 1H), 2.43 (br s, 1H), 1.79–1.58 (m,
2H), 1.42 (s, 3H), 1.41 (s, 3H), 1.22 (d, J = 6.4 Hz, 3H); 13C NMR
(75 MHz, CDCl3); d 134.7, 119.3, 108.9, 82.3, 77.9, 65.1, 39.2,
27.2, 26.9, 23.6; ESIMS: m/z 209 [M+Na]+; HRESIMS for C10H18O3Na
[M+Na]+ found 209.11549 calcd: 209.11482.
(hexane/EtOAc, 50:50). ½a D25
ꢃ
¼ ꢀ7:9 (c 1.7, CHCl3); IR mmax (Neat):
3442, 2872, 1453, 1374, 1216, 1083 cmꢀ1
;
1H NMR (300 MHz,
CDCl3): d 7.38–7.28 (m, 5H), 4.62–4.54 (m, 2H), 4.02–3.89 (m,
2H), 3.78 (t, J = 6.0 Hz, 2H), 3.65–3.53 (m, 2H), 2.48 (br s, 1H),
1.94–1.75 (m, 2H), 1.42 (s, 3H), 1.40 (s, 3H); 13C NMR (75 MHz,
CDCl3); d 137.6, 128.3, 127.6, 127.5, 108.9, 79.6, 77.4, 73.5, 70.2,
60.2, 35.2, 27.1, 26.8; ESIMS: m/z 289 [M+Na]+; HRESIMS for C15-
H22O4Na [M+Na]+ found 289.14163 calcd 289.14103.
4.1.6. (S)-3-(Methoxymethoxy)pent-4-enoic acid 16
To a clear solution of IBX (5.75 g, 20.5 mmol, 2.0 equiv), in a 1:1
ratio of dry DMSO and CH2Cl2 (60 mL), was added compound 24
(1.50 g, 10.3 mmol, 1.0 equiv) in dry CH2Cl2 (15 mL) at 0 °C over
5 min. The reaction mixture was allowed to warm to room temper-
ature, and stirred at same temperature for 6 h. After the complete
consumption of the starting material, the reaction mixture was
quenched with water (30 mL), and the white solid formed was fil-
tered off over a pad of Celite. The filtrate was then extracted with
diethyl ether (3 ꢂ 20 mL), and washed with brine (20 mL), and
dried over anhydrous Na2SO4. The solvent was removed under re-
duced pressure to give a crude aldehyde (1.2 g, 81%). To a solution
of the aldehyde (1.2 g, 8.3 mmol, 1.0 equiv) in tBuOH (30 mL), H2O
(30 mL) and acetone (17.5 mL) in a 250-mL round-bottom flask,
2 M 2-methyl-2-butene (15.4 mL, 30.8 mmol, 3.7 equiv) was added
via syringe, followed by NaH2PO4 (5.85 g, 37.5 mmol, 4.5 equiv)
and NaClO2 (80% technical grade, 3.39 g, 37.5 mmol, 4.5 equiv) as
solids. The biphasic reaction was stirred vigorously 12 h, after
which saturated aqueous NH4Cl (30 mL) was added. The reaction
mixture was extracted with CH2Cl2 (3 ꢂ 30 mL) and the combined
organic layers were dried over Na2SO4, filtered, and concentrated
in vacuo to give a crude liquid, which was purified by column chro-
matography Rf = 0.20 (hexane/EtOAc, 80:20) to afford 10 (0.95 g,
4.1.4. ((4S,5S)-5-(Benzyloxymethyl)-2,2-dimethyl-1,3-dioxolan-
4-yl)methanol 14
A solution of diol 17 (30.0 g, 185.2 mmol, 1.0 equiv) in dry THF
(200 mL) was slowly added to a suspension of 60% NaH (7.8 g,
194.5 mmol, 1.05 equiv) in dry THF (100 mL) at 0 °C over a period
of 30 min and the resulting mixture was stirred at ambient tem-
perature for 1 h until the evolution of gas had ceased. To this mix-
ture was added dropwise a solution of benzyl bromide (21.9 mL,
185.2 mmol, 1.0 equiv) over 30 min and the resulting mixture
was stirred for 12 h. The reaction mixture was then quenched with
ice flakes at 0 °C and extracted with EtOAc (2 ꢂ 200 mL). The
organic layer was washed with brine (200 mL), dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure,
purified with silica gel column chromatography to give 14 (34.0 g,
73%) as
¼ þ8:3 (c 1.0, CHCl3); IR
1453, 1375, 1250, 1216, 1167, 1085, 847, 741, 699 cmꢀ1
a
yellowish liquid; Rf = 0.6 (hexane/EtOAc, 80:20);
max (Neat): 3466, 2988, 2932, 2872,
1H NMR
½
a 2D5
ꢃ
m
;
71%) as a light transparent liquid; ½a D25
ꢃ
¼ ꢀ77:3 (c 0.75, CHCl3);
(300 MHz, CDCl3): d 7.38–7.28 (m, 5H), 4.56 (m, 2H), 4.02–3.96
(m, 1H), 3.92–3.86 (m, 1H), 3.74–3.63 (m, 3H), 3.54–3.48 (m, 1 H),
2.18 (br s, 1H), 1.39 (s, 3 H), 1.38 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 137.4, 128.3, 127.6, 127.5, 109.2, 79.4, 76.3, 73.4, 70.2, 62.2, 26.8,
26.7; ESIMS: m/z 275 [M+Na]+.
IR mmax (Neat): 3400, 2949, 1716, 1151, 1032, 924 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d 5.79–5.67 (m, 1H), 5.32 (d, J = 17.4 Hz, 1H),
5.25 (d, J = 10.6 Hz, 1H), 4.70 (d, J = 6.8 Hz, 1H), 4.56 (d, J = 6.8 Hz,
1H), 4.53–4.46 (m, 1H), 3.35 (s, 3H), 2.74–2.52 (m, 2H); 13C NMR
(125 MHz, CDCl3); d 175.6, 136.2, 118.3, 93.7, 73.5, 55.3, 40.5.
4.1.5. (R)-1-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-
propan-2-ol 15
4.1.7. ((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)dimethanol
17
To a clear solution of IBX (0.65 g, 2.3 mmol, 2.0 equiv), in anhy-
drous DMSO and anhydrous CH2Cl2 (1:1 ratio, 10 mL), was added
compound 20 (0.20 g, 1.2 mmol, 1.0 equiv) dissolved in dry CH2Cl2
(5 mL) at 0 °C over 5 min. The reaction mixture was allowed to
warm to room temperature, and stirred at the same temperature
for 6 h. After complete consumption of the starting material, the
reaction mixture was quenched with water (5 mL), and the white
solid formed was filtered off over a small pad of Celite. The filtrate
was then extracted with diethyl ether (2 ꢂ 10 mL), washed with
brine (5 mL), and dried over anhydrous Na2SO4. The solvent was
evaporated under reduced pressure to give a crude aldehyde,
which was utilized for the next step without further purification.
To a solution of the above prepared aldehyde in diethyl ether
(8 mL), was added dropwise a 3 M solution of methyl magnesium
iodide in diethyl ether (1.57 mL, 4.0 equiv), at ꢀ40 °C over
15 min. The reaction mixture was stirred at same temperature
for 3 h and after complete consumption of the starting material,
the reaction mixture was quenched with saturated aq NH4Cl
(5 mL), at ꢀ40 °C and then allowed to warm to room temperature.
The organic layer was separated and the aqueous layer was ex-
A
solution of (+)-diethyl
L-tartrate (50.0 g, 242.7 mmol,
1.0 equiv) and p-toluenesulfonic acid (375 mg, 2.2 mmol,
0.01 equiv) in benzene (500 mL) and 2,2-dimethoxypropane
(44.5 mL, 364.1 mmol, 2.5 equiv) was heated at reflux for 12 h.
The mixture was allowed to cool to ambient temperature, washed
with an aq saturated sodium bicarbonate solution (150 mL) and
then dried over anhydrous Na2SO4. The solvent was evaporated
and the residue was purified by column chromatography (hex-
ane/EtOAc 8:2) to give the acetonide protected DET (55.0 g, 92%),
as a colorless liquid. The above prepared solution of acetonide pro-
tected compound (55.0 g, 223.6 mmol, 1 equiv) in dry THF
(300 mL) was slowly added to a suspension of LiAlH4 (12.1 g,
317.7 mmol, 1.8 equiv) in dry THF (200 mL) at 0 °C over a period
of 30 min. The resulting mixture was heated at 45 °C for 5 h to
complete the reaction. The reaction was quenched carefully with
a saturated aq Na2SO4 solution (300 mL) at 0 °C and the resulting
suspension was stirred for 3 h before it was filtered through a
pad of silica gel. The filtrate was dried over anhydrous Na2SO4,
the solvent was evaporated and the residue was purified by col-
umn chromatography to give diol 17 (27.8 g, 83%), as a colorless

208
K. Vamshikrishna et al. / Tetrahedron: Asymmetry 25 (2014) 203–211
liquid; Rf = 0.30 (hexane/EtOAc, 60:40);
½
a 2D5
ꢃ
¼ þ10:8 (c 0.5,
(75 MHz, CDCl3); d 135.2, 118.4, 108.4, 82.5, 77.3, 59.7, 34.9,
27.2, 26.8, 25.8, 18.2, ꢀ5.4, ꢀ5.5; ESIMS: m/z 309 [M+Na]+; HRE-
SIMS for C15H30O3NaSi [M+Na]+ found 309.18628 calcd 309.18564.
MeOH); IR (Neat): 3401, 2988, 2935, 2881, 1376, 1251, 1218,
1165, 1108, 1053, 844 cmꢀ1 1H NMR (300 MHz, CDCl3): d 3.97–
;
3.89 (m, 2H), 3.76–3.65 (m, 4H), 1.39 (s, 6H); 13C NMR (75 MHz,
CDCl3): d 109.2, 78.3, 62.0, 26.8; ESIMS: m/z 185 [M+Na]+.
4.1.10. 2-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-
ethanol 20
4.1.8. (2-((4S,5S)-5-((Benzyloxymethyl)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)ethoxy)(tert-butyl)dimethylsilane 18
To a solution of compound 19 (1.80 g, 6.3 mmol, 1.0 equiv) in
dry THF (20 mL) was added dropwise a 1.0 M TBAF solution in
THF (9.44 mL, 1.5 equiv) over 10 min at 0 °C. The reaction mixture
was then allowed to warm to room temperature while stirring for
2 h. After complete consumption of the starting material (moni-
tored by TLC), the reaction mixture was quenched with saturated
aq NH4Cl (15 mL), and diluted with EtOAc (10 mL) and water
(10 mL). The organic layer was separated and the aqueous layer
was extracted with EtOAc (2 ꢂ 15 mL). The combined organic layer
was washed with brine (15 mL), and dried over anhydrous Na2SO4.
Evaporation of the solvent under reduced pressure followed by sil-
ica gel column chromatography afforded alcohol 20 (0.85 g, 78%) as
To compound 13 (0.9 g, 3.4 mmol, 1.0 equiv) in anhydrous CH2-
Cl2 (15.0 mL) was added imidazole (0.3 g, 4.4 mmol, 1.3 equiv) at
room temperature. The mixture was then stirred at room temper-
ature for 20 min after which the reaction mixture was cooled to
0 °C, and to this was added tert-butyldimethylsilylchloride
(TBDMSCl) (0.6 g, 4.1 mmol, 1.2 equiv) portionwise. The reaction
mixture was allowed to warm to room temperature and stirred
for 2 h. Water (15 mL) was then added to the reaction mixture
and the organic layer was separated and the aqueous layer ex-
tracted with CH2Cl2 (2 ꢂ 15 mL). The combined organic layer was
washed with brine (15 mL), dried over anhydrous Na2SO4 and then
the solvent was removed under reduced pressure to give the crude
material, which was purified by column chromatography to give
18 (1.184 g, 92%) as a yellow oil; Rf = 0.90 (hexane/EtOAc, 90:10);
a light yellowish oil; Rf = 0.20 (hexane/EtOAc, 80:20); ½a D25
¼ ꢀ7:2
ꢃ
(c 0.8, CHCl3); IR mmax (Neat): 3425, 2986, 2880, 1375, 1241,
1058, 873 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.84–5.73 (m, 1H),
;
5.35 (d, J = 16.8 Hz, 1H), 5.25 (d, J = 10.2 Hz, 1H), 4.04 (t,
J = 7.7 Hz, 1H), 3.85–3.76 (m, 3H), 2.45 (br s, 1H), 1.89-1.69 (m,
2H), 1.40 (s, 6H); 13C NMR (75 MHz, CDCl3); d 134.7, 119.0,
108.9, 82.5, 79.0, 60.1, 33.8, 27.1, 26.8; ESIMS: m/z 195 [M+Na]+;
HRESIMS for C9H16O3Na [M+Na]+ found 195.09971 calcd
195.09917.
½
a 2D5
ꢃ
¼ ꢀ16:50 (c 1.0, CHCl3); IR mmax (Neat): 2931, 1252, 1094,
838 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.35–7.27 (m, 5H), 4.63–
;
4.54 (m, 2H), 3.98–3.86 (m, 2H), 3.80–3.67 (m, 2H), 3.58 (d,
J = 4.5 Hz, 2H), 1.88–1.69 (m, 2H), 1.41 (s, 3H), 1.39 (s, 3H), 0.88
(s, 9H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3): d 137.9, 128.3,
127.5, 108.7, 79.9, 74.9, 73.9, 70.3, 59.7, 36.2, 27.2, 26.9, 25.9,
18.2, ꢀ5.5; ESIMS: m/z 381 [M+H]+; HRESIMS for C21H37O4-
Si[M+H]+ found 381.24625 calcd 381.24556.
4.1.11. tert-Butyl-2-((4S,5R)-5-(iodomethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)ethoxy)dimethylsilane 21
To a solution of compound 12 (3.7 g, 12.6 mmol, 1.0 equiv) in
dry THF (40 mL) were added imidazole (2.6 g, 38.3 mmol,
3.0 equiv), and TPP (6.68 g, 25.5 mmol, 2.0 equiv) at room temper-
ature. The reaction mixture was cooled to 0 °C and to this, molec-
ular I2 (7.13 g, 28.1 mmol, 2.2 equiv) in dry THF (70 mL) was added
dropwise over 15 min. The reaction mixture was then allowed to
warm to room temperature and stirred at the same temperature
for 2 h. After complete consumption of the starting material, the
reaction mixture was quenched with a saturated aq Na2S2O3ꢁ5H2O
(100 mL) solution and then diluted with EtOAc (50 mL). The organ-
ic layer was separated and the aqueous layer was extracted with
EtOAc (2 ꢂ 50 mL). The combined organic layer was washed with
brine, dried over anhydrous Na2SO4, and evaporated under reduced
pressure to give a crude material, which was purified by flash col-
umn chromatography to give 21 (4.8 g, 94%) as a light yellowish li-
4.1.9. tert-Butyl-(2-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-
4-yl)ethoxy)dimethylsilane 19
To a solution of dry DMSO (2.50 mL, 34.5 mmol, 4.0 equiv) in
dry CH2Cl2 (10 mL) was added dropwise oxalyl chloride (1.51 mL,
17.3 mmol, 2.0 equiv) at ꢀ78 °C over 15 min and stirred for
20 min at the same temperature. To this mixture, compound 12
(2.50 g, 8.6 mmol, 1.0 equiv) in dry CH2Cl2 (25 mL) was added
dropwise over 15 min at ꢀ78 °C and the reaction mixture was stir-
red at the same temperature for 2 h. The reaction was quenched
with Et3N (7.18 mL, 51.7 mmol, 6.0 equiv) at ꢀ78 °C, and the reac-
tion mixture was then allowed to warm to room temperature, after
which water (30 mL) was added, the organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (2 ꢂ 20 mL).
The combined organic layers were washed with brine (20 mL),
and dried over anhydrous Na2SO4, the solvent was evaporated un-
der reduced pressure to give a crude aldehyde, which was utilized
for the next reaction without further purification. The aldehyde ob-
tained was taken in dry THF (20 mL) and added to a mixture of
quid. Rf = 0.90 (hexane/EtOAc, 90:10); ½a D25
ꢃ
¼ ꢀ28:3 (c 0.6, CHCl3);
IR mmax (Neat): 2931, 1375, 1252, 1093, 836 cmꢀ1
;
1H NMR
(500 MHz, CDCl3): d 3.92–3.88 (m, 1H), 3.82–3.68 (m, 3H), 3.36–
3.25 (m, 2H), 1.91–1.84 (m, 1H), 1.82–1.76 (m, 1H), 1.44 (s, 3H),
1.41 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H); 13C NMR (125 MHz, CDCl3):
d 108.8, 79.6, 78.5, 59.5, 36.4, 27.5, 27.3, 25.9, 18.2, 5.8, ꢀ5.3, ꢀ5.4;
ESIMS: m/z 401 [M+H]+; HRESIMS for C14H30O3ISi [M+H]+ found
401.10071 calcd 401.10034.
methyltriphenylphosphoniumiodide
(10.50 g,
25.7 mmol,
3.0 equiv) and potassium tert-butoxide (2.70 g, 24.1 mmol,
2.8 equiv) in dry THF (50 mL), at 0 °C. The reaction mixture was al-
lowed to warm to room temperature and stirred for 12 h. The reac-
tion mixture was quenched with water (20 mL) and diluted with
diethyl ether and hexane (1:1) (60 mL). The white precipitate
formed was filtered off through a small pad of Celite and the fil-
trate was dried over anhydrous Na2SO4. Evaporation of the solvent
under reduced pressure gave a crude material, which was purified
by column chromatography to give 19 (1.80 g, 73%) as a light yel-
4.1.12. (S)-5-(tert-Butyldimethylsilyloxy)pent-1-en-3-ol 22
To a solution of compound 21 (4.8 g, 12.0 mmol, 1.0 equiv) in
dry THF (50 mL) was added dropwise 1.6 M nBuLi (15.0 mL,
2.0 equiv) at ꢀ78 °C over 15 min. The reaction mixture was then
stirred at the same temperature for 2 h. After complete consump-
tion of the starting material, the reaction mixture was quenched
with water (50 mL), at ꢀ78 °C and allowed to warm to room tem-
perature. The reaction mixture was diluted with EtOAc (50 mL), the
organic layer was separated, the aqueous layer was extracted with
EtOAc (2 ꢂ 50 mL), the combined organic layer was washed with
brine (50 mL) dried over anhydrous Na2SO4, the solvent was
lowish oil; Rf = 0.90 (hexane/EtOAc, 90:10); ½a D25
¼ ꢀ10:0 (c 1.05,
ꢃ
CHCl3); IR mmax (Neat): 2932, 2859, 1374, 1253, 1090, 837 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d 5.83–5.77 (m, 1H), 5.36 (td, J = 1.1,
17.3 Hz, 1H), 5.24 (d, J = 10.2 Hz, 1H), 4.03 (t, J = 8.3 Hz, 1H),
3.82–3.69 (m, 3H), 1.83–1.77 (m, 1H), 1.75–1.69 (m, 1H), 1.41 (s,
3H), 1.40 (s, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR

K. Vamshikrishna et al. / Tetrahedron: Asymmetry 25 (2014) 203–211
209
removed under reduced pressure to give a crude material, which
was purified by column chromatography to give 22 (2.54 g, 98%)
as light yellowish liquid. Rf = 0.50 (hexane/EtOAc, 90:10);
plete consumption of the starting material, the reaction mixture
was quenched with water (30 mL) and the resulting white solid
formed was filtered over a pad of Celite. The filtrate was then ex-
tracted with diethyl ether (3 ꢂ 20 mL), washed with brine
(20 mL), and dried over anhydrous Na2SO4. The solvent was re-
moved under reduced pressure to give the crude product, which
was utilized for the next reaction without further purification. To
a solution of the above prepared aldehyde in diethyl ether
(20 mL), was added dropwise a 3 M solution of methyl magnesium
iodide (13.7 mL, 4.0 equiv), at ꢀ40 °C over 15 min. The reaction
mixture was then stirred at the same temperature for 3 h. After
complete consumption of the starting material, the reaction mix-
ture was quenched with saturated aq NH4Cl (15 mL), at ꢀ40 °C
and then allowed to warm to room temperature. The organic layer
was separated and the aqueous layer was extracted with diethyl
ether (2 ꢂ 10 mL). The combined organic layer was washed with
brine (10 mL), and dried over anhydrous Na2SO4. Evaporation of
the solvent followed by purification with column chromatography
gave an inseparable mixture of diastereomers 11 (1.10 g, 67.0%) as
a light yellowish oil Rf = 0.40 (hexane/EtOAc, 80:20).
½
a 2D5
ꢃ
¼ þ11:76 (c 0.34, CHCl3); IR mmax (Neat): 3424, 2954, 1468,
1254, 1099, 836 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.93–5.82
;
(m, 1H), 5.27 (d, J = 17.2 Hz, 1H), 5.10 (d, J = 10.4 Hz, 1H), 4.42–
4.32 (m, 1H), 3.94–3.75 (m, 2H), 1.83–1.65 (m, 2H), 0.89 (s, 9H),
0.07 (s, 6H); 13C NMR (75 MHz, CDCl3): d 140.5, 114.0, 73.3, 61.8,
38.1, 25.8, 18.0, ꢀ5.6; ESIMS: m/z 217 [M+H]+; HRESIMS for C11H25-
O2Si [M+H]+ found 217.16208, calcd 217.16183.
4.1.13. (S)-9,9,10,10-Tetramethyl-5-vinyl-2,4,8-trioxa-9-silaun-
decane 23
To a solution of compound 22 (1.0 g, 4.6 mmol, 1.0 equiv) in dry
CH2Cl2 (10 mL) was added DIPEA (3.23 mL, 18.5 mmol, 4.0 equiv)
at room temperature, and stirred for 15 min. The reaction mixture
was cooled to 0 °C and to this was added dropwise methoxymethyl
chloride (0.75 mL, 9.3 mmol, 2.0 equiv), over 5 min. Next, the reac-
tion mixture was allowed to warm to room temperature and stir-
red at the same temperature for 12 h. After complete
consumption of the starting material, the reaction mixture was
washed with aqueous saturated CuSO4 (3 ꢂ 10 mL). The organic
layer was washed with brine (10 mL), dried over anhydrous Na2-
SO4, and evaporated under reduced pressure to give a crude mate-
rial, which was purified by column chromatography to give 23
(1.0 g, 83%) as a light yellowish liquid. Rf = 0.70 (hexane/EtOAc,
To a solution of acid 10 (0.4 g, 2.2 mmol, 1.0 equiv), in dry CH2-
Cl2 was added mixture of diastereomers 11 (0.28 g, 1.7 mmol,
0.8 equiv), DCC (0.89 g, 4.3 mmol, 2.0 equiv), DMAP (0.53 g,
4.3 mmol, 2.0 equiv) at room temperature. The reaction mixture
was stirred at the same temperature for 12 h, then concentrated
under reduced pressure and purified by column chromatography
to give 25 (0.23 g, 40.2%) and it’s diastereomer 25a (0.15 g,
26.8%) (6:4 ratio) as colorless oils; Rf = 0.30 (hexane/EtOAc,
90:10); ½a 2D5
ꢃ
¼ ꢀ51:6 (c 0.53, CHCl3); IR mmax (Neat): 2927, 1254,
1096, 1035, 836 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 5.75–5.64
90:10); 25: ½a 2D5
ꢃ
¼ ꢀ55:9 (c 1.1, CHCl3); IR mmax (Neat): 2985,
(m, 1H), 5.24–5.16 (m, 2H), 4.69 (d, J = 6.6 Hz, 1H), 4.54 (d,
J = 6.8 Hz, 1H), 4.17 (q, J = 7.2, 13.4 Hz, 1H), 3.77–3.63 (m, 2H),
3.36 (s, 3H), 1.89–1.78 (m, 1H), 1.75–1.66 (m, 1H), 0.89 (s, 9H),
0.04 (s, 6H); 13C NMR (125 MHz, CDCl3): d 138.3, 117.0, 93.9,
74.3, 59.3, 55.3, 38.6, 25.9, 25.8, 18.2, ꢀ5.4; ESIMS: m/z 261
[M+H]+.
1736, 1178, 1033, 924 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d 5.86–
5.79 (m, 1H), 5.71–5.64 (m, 1H), 5.38 (dd, J = 0.9, 17.2 Hz, 1H),
5.27 (dd, J = 1.2, 10.2 Hz, 1H), 5.24–5.20 (m, 1H), 5.19–5.17 (m,
1H), 5.14–5.10 (m, 1H), 4.67 (d, J = 6.7 Hz, 1H), 4.49 (d, J = 6.7 Hz,
1H), 4.14–4.04 (m, 3H), 3.32 (s, 3H), 2.59–2.50 (m, 2H), 1.83–1.71
(m, 2H), 1.41 (s, 6H), 1.25 (d, J = 6.3 Hz, 3H); 13C NMR (125 MHz,
CDCl3); d 170.0, 138.0, 134.6, 119.5, 117.3, 109.2, 93.9, 82.2, 76.8,
73.8, 68.4, 55.7, 42.0, 37.2, 27.1, 26.9, 20.5; ESIMS: m/z 351
[M+Na]+; HRESIMS for C17H28O6Na [M+Na]+ found 351.17734,
calcd 351.17781.
4.1.14. (S)-3-(Methoxymethoxy)pent-4-en-1-ol 24
To a solution of compound 23 (1.0 g, 3.9 mmol, 1.0 equiv) in dry
THF (10 mL), was added dropwise a 1.0 M TBAF solution in THF
(5.8 mL, 5.8 mmol, 1.5 equiv) over 10 min at 0 °C. The reaction
mixture was then allowed to warm to room temperature while
stirring for 2 h. After complete consumption of the starting mate-
rial, the reaction mixture was quenched with a saturated aq NH4Cl
(5 mL) solution, diluted with EtOAc (5 mL), and water (5 mL). The
organic layer was separated and the aqueous layer was extracted
with EtOAc (2 ꢂ 10 mL). The combined organic layer was washed
with brine (10 mL), dried over anhydrous Na2SO4, and evaporated
under reduced pressure to give a crude material, which was puri-
fied by column chromatography to give alcohol 24 (0.51 g, 91%)
25a: ½a 2D5
ꢃ
¼ ꢀ28:1 (c 1.6, CHCl3); 1H NMR (300 MHz, CDCl3): d
5.88–5.76 (m, 1H), 5.70–5.58 (m, 1H), 5.38 (d, J = 16.8 Hz, 1H),
5.32–5.17 (m, 3H), 5.07–4.97 (m, 1H), 4.67 (d, J = 6.8 Hz, 1H),
4.51 (d, J = 6.6 Hz, 1H), 4.14–4.04 (m, 3H), 3.36 (s, 3H), 2.54 (d,
J = 5.7 Hz, 2H), 2.10–1.97 (m, 1H), 1.68–1.59 (m, 1H), 1.42 (s, 3H),
1.41 (s, 3H), 1.27 (d, J = 6.2 Hz, 3H); 13C NMR (125 MHz, CDCl3); d
169.6, 137.4, 134.6, 119.5, 118.2, 109.2, 93.6, 82.2, 76.7, 74.4,
68.7, 55.5, 41.4, 37.3, 27.1, 26.9, 20.1.
4.1.16. (3aS,7R,9S,11aS,E)-9-(Methoxymethoxy)-2,2,7-trimethyl-
3a,4,8,9-tetrahydro-7H-[1,3]dioxolo[4,5-d]oxecin-5(11aH)-one
26
as a colorless oil. Rf = 0.50 (hexane/EtOAc, 60:40); ½a D25
¼ ꢀ92:0 (c
ꢃ
0.40, CHCl3); IR mmax (Neat): 3421, 2947, 1152, 1097, 1031,
923 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.77–5.65 (m, 1H), 5.26–
;
To a degassed solution of compound 25 (0.03 g, 0.1 mmol,
1.0 equiv), in dry CH2Cl2 (100 mL) was added Grubbs’ II generation
catalyst (0.008 g, 0.01 mmol, 0.1 equiv) and the reaction mixture
was refluxed for 24 h. The reaction mixture was concentrated un-
der reduced pressure and purified by column chromatography to
give 26 (0.022 g, 80%) as a colorless oil; Rf = 0.50 (hexane/EtOAc,
5.18 (m, 2H), 4.69 (d, J = 6.8 Hz, 1H), 4.54 (d, J = 6.8 Hz, 1H), 4.24
(d, J = 7.6, 13.6 Hz, 1H), 3.83–3.69 (m, 2H), 3.38 (s, 3H), 2.40 (br s,
1H), 1.85–1.79 (m, 2H); 13C NMR (125 MHz, CDCl3): d 137.5,
117.2, 93.7, 75.6, 59.3, 55.3, 37.6.
80:20); ½a 2D5
ꢃ
¼ ꢀ8:3 (c 0.6, CHCl3); IR mmax (Neat): 2932, 1727,
4.1.15. (2R,4S)-4-(Methoxymethoxy)hex-5-en-2-yl 2-((4S,5S)-2,
2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)acetate 25 and (2S,4S)-4-
(methoxymethoxy)hex-5-en-2-yl 2-((4S,5S)-2,2-dimethyl-5-vinyl-
1,3-dioxolan-4-yl)acetate 25a
To a clear solution of IBX (5.75 g, 20.5 mmol, 2.0 equiv), in a 1:1
ratio of dry DMSO and CH2Cl2 (60 mL), was added compound 24
(1.50 g, 10.3 mmol, 1.0 equiv) in dry CH2Cl2 (15 mL) at 0 °C over
5 min. The reaction mixture was then allowed to warm to room
temperature, and stirred at same temperature for 6 h. After com-
1236, 1074 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d 5.92–5.78 (m,
2H), 5.07–5.03 (m, 1H), 4.68 (d, J = 6.7 Hz, 1H), 4.50 (d, J = 6.7 Hz,
1H), 4.27–4.23 (m, 1H), 4.20 (t, J = 8.5 Hz, 1H), 3.97–3.92 (m, 1H),
3.35 (s, 3H), 2.42 (dd, J = 10.8, 14.8 Hz, 1H), 2.10–2.06 (m,1H),
1.91–1.82 (m, 1H), 1.79–1.72 (m, 1H), 1.44 (s, 3H), 1.41 (s, 3H),
1.25 (d, J = 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3); d 168.9,
132.2, 131.6, 109.3, 93.9, 82.2, 75.2, 69.9, 68.4, 55.5, 42.8, 38.3,
26.9, 21.8; ESIMS: m/z 323 [M+Na]+.

210
K. Vamshikrishna et al. / Tetrahedron: Asymmetry 25 (2014) 203–211
4.1.17. (3aS,7S,9S,11aS,E)-9-(Methoxymethoxy)-2,2,7-trimethyl-
3a,4,8,9-tetrahydro-7H-[1,3]dioxolo[4,5-d]oxecin-5(11aH)-one
26a
4.1.21. (3aS,5R,9S,11aS,E)-9-(Methoxymethoxy)-2,2,5-trimethyl-
4,5,8,9-tetrahydro-3aH-[1,3]dioxolo[4,5-d]oxecin-7(11aH)-one
28
Similar procedure was followed as used earlier for the synthesis
To a degassed solution of compound 27 (0.075 g, 0.23 mmol,
1.0 equiv), in dry CH2Cl2 (200 mL) was added Grubbs’ II generation
catalyst (0.019 g, 0.023 mmol, 0.1 equiv) and the reaction mixture
was refluxed for 24 h. The reaction mixture was concentrated un-
der reduced pressure and then purified by column chromatogra-
phy to give 28 (0.048 g, 70%) as a colorless oil. Rf = 0.30 (hexane/
of 26 to give 26a in 78% yield as a colorless liquid; ½a D25
¼ þ24:4 (c
ꢃ
0.9, CHCl3); 1H NMR (500 MHz, CDCl3): d 5.91 (dd, J = 1.8, 15.6 Hz,
1H), 5.56 (ddd, J = 1.8, 9.5, 15.6 Hz, 1H), 5.24–5.18 (m, 1H), 4.65 (s,
2H), 4.45 (br s, 1H), 4.06 (t, J = 9.0 Hz, 1H), 3.77–3.72 (m, 1H), 3.36
(s, 3H), 2.78 (dd, J = 2.4, 11.3 Hz, 1H), 2.36 (t, J = 11.3 Hz, 1H), 1.85–
1.83 (m, 2H), 1.43 (s, 3H), 1.42 (s, 3H), 1.21 (d, J = 6.4 Hz, 3H); 13C
NMR (125 MHz, CDCl3); d 170.3, 138.8, 119.9, 108.8, 95.0, 84.6,
77.5, 71.7, 67.8, 55.5, 39.5, 37.3, 26.9, 26.8, 21.3.
EtOAc, 80:20); ½a D25
ꢃ
¼ ꢀ58:5 (c 0.85, CHCl3); IR mmax (Neat): 2983,
1733, 1374, 1236, 1158, 1040, 998 cmꢀ1
;
1H NMR (600 MHz,
CDCl3): d 5.86 (dd, J = 2.3, 15.8 Hz, 1H), 5.67 (dd, J = 9.4, 15.8 Hz,
1H), 5.10–5.06 (m, 1H), 4.70 (s, 2H), 4.63 (br s, 1H), 4.07 (t,
J = 9.0 Hz, 1H), 3.64 (t, J = 8.7 Hz, 1H), 3.40 (s, 3H), 2.67 (dd,
J = 3.0, 12.4 Hz, 1H), 2.48 (dd, J = 4.1, 12.4 Hz, 1H), 2.04–1.92 (m,
2H), 1.40 (s, 3H), 1.39 (s, 3H), 1.22 (d, J = 6.4 Hz, 3H); 13C NMR
(75 MHz, CDCl3); d 168.8, 134.9, 123.9, 108.1, 94.7, 84.0, 81.5,
70.6, 69.2, 55.6, 42.6, 38.5, 27.0, 26.9, 21.9; ESIMS: m/z 323
[M+Na]+; HRESIMS for C15H24O6Na [M+Na]+ found 323.14630
calcd. 323.14651.
4.1.18. (4S,5S,8S,10R,E)-4,5,8-Trihydroxy-10-methyl-4,5,9,10-tet-
rahydro-3H-oxecin-2(8H)-one 6 (decarestrictine-D)
To a solution of compound 26 (0.022 g, 0.073 mmol, 1.0 equiv)
in DMS (3 mL), were added 3 drops of BF3ꢁOEt2 at 0 °C, and the
reaction mixture was stirred at same temperature for 30 min.
The reaction mixture was quenched with solid NaHCO3 (0.5 g)
and filtered through small pad of Celite. The filtrate was concen-
trated under reduced pressure to give the crude product, which
was purified by flash column chromatography to give 6 (0.010 g,
4.1.22. (4S,7S,8S,10R,E)-4,7,8-Trihydroxy-10-methyl-3,4,7,8,9,10-
hexahydrooxecin-2-one 9 (decarestrictine-O)
62%) as
¼ ꢀ47:85 (c 0.7, CHCl3); IR mmax (KBr): 3408, 2924, 1710,
1272, 1043 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.95–5.80 (m,
a
white solid Rf = 0.10 (hexane/EtOAc, 40:60);
To a solution of compound 28 (20 mg, 0.0067 mmol, 1.0 equiv)
in DMS (3 mL), were added 3 drops of BF3ꢁOEt2 at 0 °C, and the
reaction mixture was stirred at the same temperature for 20 min.
The reaction mixture was quenched with solid NaHCO3 (0.5 g)
and filtered through a pad of Celite. The filtrate was concentrated
under reduced pressure to give a crude product, which was puri-
fied by flash column chromatography to give a MOM deprotected
alcohol as a transparent liquid. To the above-synthesized alcohol
in THF (3 mL) was added 1 M HCl (3 mL), at room temperature
and the reaction mixture was stirred at same temperature for
2 h. After complete consumption of the starting material, the reac-
tion mixture was quenched by the addition of solid NaHCO3 (1.0 g),
and then diluted with EtOAc (2 mL) and water (2 mL). The organic
layer was separated and the aqueous layer was extracted with
EtOAc (2 ꢂ 5 mL). The combined organic layer was washed with
brine (5 mL), and dried over anhydrous Na2SO4. The solvent was
evaporated under reduced pressure to give a crude product, which
was purified by column chromatography to give 9 (8 mg, 55%) as a
½ ꢃ
a 2D5
;
2H), 5.30–5.18 (m, 1H), 4.41 (br s, 1H), 4.22–4.15 (m, 1H), 4.06–
4.03 (m, 1H), 2.61 (dd, J = 1.7, 14.5 Hz, 1H), 2.39 (dd, J = 6.4,
14.4 Hz, 1H), 1.96–1.76 (m, 2H), 1.25 (d, J = 6.4 Hz, 3H); 13C NMR
(75 MHz, CDCl3); d 174.6, 133.7, 129.8, 74.0, 72.5, 72.2, 68.2,
43.0, 33.2, 21.2; ESIMS: m/z 217 [M+H]+; HRESIMS for C10H17O5
[M+H]+ found 217.10701 calcd 217.10705.
4.1.19. (4S,5S,8S,10S,E)-4,5,8-Trihydroxy-10-methyl-4,5,9,10-tet-
rahydro-3H-oxecin-2(8H)-one 6a (9-epi-decarestrictine-D)
A similar procedure was followed as used earlier for the synthe-
sis of 6 to give 6a in 61% yield as a colorless liquid from 26a;
½
a 2D5
ꢃ
¼ ꢀ4:2 (c 0.7, MeOH); 1H NMR (300 MHz, CDCl3 + acetone-
d6): d 5.82 (dd, J = 1.9, 15.7 Hz, 1H), 5.51–5.42 (m, 1H), 5.38–5.27
(m, 1H), 4.48 (br s, 1H), 3.88–3.77 (m, 2H), 2.47 (dd, J = 2.8,
13.2 Hz, 1H), 2.21 (dd, J = 10.9, 13.0 Hz, 1H), 1.80–1.76 (m, 2H),
1.16 (d, J = 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3 + acetone-d6);
d 172.5, 137.9, 124.9, 80.9, 74.9, 68.2, 66.3, 42.4, 41.8, 22.2.
white gummy solid. Rf = 0.10 (hexane/EtOAc, 40:60); ½a D25
¼ ꢀ22:5
ꢃ
(c 0.2, MeOH); lit.5l
½
a 2D5
ꢃ
¼ ꢀ18:0 (c 0.2, MeOH); IR mmax (KBr):
3415, 2904, 1702, 1276, 1088 cmꢀ1
;
1H NMR (500 MHz, CDCl3 + -
CD3OD): 5.94 (dd, J = 3.2, 15.7 Hz, 1H), 5.59 (dd, J = 10.8,
d
15.7 Hz, 1H), 4.80 (qt, J = 6.7, 13.6 Hz, 1H), 4.68 (q, J = 4.6, 7.2 Hz,
1H), 3.80 (t, J = 9.0 Hz, 1H), 3.43 (t, J = 9.0 Hz, 1H), 2.58 (dd,
J = 3.7, 11.9 Hz, 1H), 2.49 (dd, J = 3.5, 11.9 Hz, 1H), 2.00–1.94 (m,
1H), 1.80 (d, J = 15.9 Hz, 1H), 1.25 (d, J = 6.6 Hz, 3H); 13C NMR
(125 MHz, CDCl3 + CD3OD); d 171.8, 137.5, 126.9, 79.9, 77.1, 70.8,
67.9, 44.4, 44.1, 23.2; ESIMS: m/z 239 [M+Na]+; HRESIMS for C10-
H16O5Na [M+Na]+ found 239.08890 calcd for 239.08899.
4.1.20. (S)-((R)-1-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-
yl)propan-2-yl) 3-(methoxymethoxy)pent-4-enoate 27
To a solution of compound 15 (0.065 g, 0.35 mmol, 1.0 equiv),
and compound 16 (0.061 g, 0.38 mmol, 1.1 equiv), in dry CH2Cl2
(5 mL) was added DCC (0.144 g, 0.69 mmol, 2.0 equiv), and DMAP
(0.085 g, 0.69 mmol, 2.0 equiv), at 0 °C. The reaction mixture was
allowed to warm to room temperature and stirred at same temper-
ature for 12 h. After the reaction mixture was concentrated, the
crude product was purified by column chromatography to give
27 (0.075 g, 66%) as a transparent liquid. Rf = 0.60 (hexane/EtOAc,
Acknowledgments
80:20); ½a 2D5
ꢃ
¼ ꢀ45:8 (c 0.90, CHCl3); IR mmax (Neat): 2985, 1736,
V.K. thanks CSIR, New Delhi, G.S. thanks UGC, New Delhi for
financial assistance. The authors thank CSIR, New Delhi for a re-
search grant under XII Five year plan programme ORIGIN (budget
head CSC-0108) and partial funding from CSIR Young Scientist
Award Scheme (P-81-113).
1375, 1178, 1034, 927 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d 5.81–
5.70 (m, 2H), 5.37–5.21 (m, 4H), 5.07 (qt, J = 5.9, 12.5, 19.1 Hz,
1H), 4.68 (d, J = 6.6 Hz, 1H), 4.54 (d, J = 6.6 Hz, 1H), 4.47 (q,
J = 7.3, 13.2 Hz, 1H), 3.95 (t, J = 8.1 Hz, 1H), 3.71 (dt, J = 2.9,
8.8 Hz, 1H), 3.34 (s, 3H), 2.62–2.59 (m, 1H), 2.49–2.45 (m, 1H),
1.85–1.82 (m, 1H), 1.69–1.65 (m, 1H), 1.38 (s, 3H), 1.36 (s, 3H),
1.26 (d, J = 5.9 Hz, 3H); 13C NMR (75 MHz, CDCl3); d 170.0, 136.6,
134.8, 119.2, 118.1, 108.8, 93.9, 82.7, 76.9, 73.7, 68.9, 55.5, 41.1,
38.2, 27.2, 26.8, 20.6; ESIMS: m/z 351 [M+Na]+; HRESIMS for C17-
H28O6Na [M+Na]+ found 351.17868 calcd 351.17781.
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