Asymmetric total synthesis of (-)-mangiferaelactone by using an appropriately substituted thiophene as a masked synthon for C-alkyl glycoside

Article abstract of DOI:10.1016/j.tetasy.2015.06.001

Abstract Asymmetric total synthesis of naturally occurring nonenolide (-)-mangiferaelactone was attempted through RCAM (ring closing alkyne metathesis) reaction. As the attempted RCAM reaction failed, the synthesis was finally achieved by successful explo

Full text of DOI:10.1016/j.tetasy.2015.06.001

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric total synthesis of (À)-mangiferaelactone by using an
appropriately substituted thiophene as a masked synthon for C-alkyl
glycoside
⇑
Rajan Kumar, Rohan Kalyan Rej, Samik Nanda
Department of Chemistry, Indian Institute of Technology, Kharagpur, 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric total synthesis of naturally occurring nonenolide (À)-mangiferaelactone was attempted
through RCAM (ring closing alkyne metathesis) reaction. As the attempted RCAM reaction failed, the syn-
thesis was finally achieved by successful exploration of a ring closing metathesis (RCM) reaction. 2-
Propylthiophene was used as a masked synthon for n-heptyl glycoside, which served as main source
for one of the RCM precursors and accessed by reductive desulfurization (Mozingo type reduction) of
an appropriately substituted thiophene ribofuranoside. The other RCM precursor was accessed by apply-
ing an enzymatic kinetic resolution/Mitsunobu inversion sequence to an alkyne alcohol.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 9 May 2015
Accepted 2 June 2015
Available online xxxx
O
O
1. Introduction
HO2C
O
HO2C
O
6
6
Various polyhydroxylated nonenolides have been isolated
from several fungal sources, and have gained significant attrac-
tion in natural product research mainly due to their interesting bio-
logical profile, which include cholesterol biosynthesis inhibition
and microfilament formation.1 In addition they have also exhibited
profound phytotoxicity, and antibacterial activities.2 Mangifer-
aelactone 1 is such a polyhydroxylated small ring macrolide
recently isolated from small-scale culture of entophytic fungi
Pestalotiopsis mangiferae by Ortega et al.3 The parent lactone
showed a strong inhibition against bacteria Listeria monocytogenes
(MIC = 1.6863 mg/mL) and Bacillus cereus (0.5529 mg/mL). It also
exhibited mild antibacterial activity against Enterococcus cloacae,
Enterococcus faecalis, and Proteus mirabilis. The structural elucida-
tion of mangiferaelactone was judiciously done with the help of
extensive NMR (1H–1H COSY, HSQC, HMBC, and NOESY) and
HRMS analysis, whereas the absolute configuration was assigned
as (4R,7R,8R,9S) by VCD (vibrational circular dichorism) studies.
Mangiferaelactone is the enantiomer of xyolide ent-1 (Fig. 1) a
ten membered ring nonenolide isolated recently from an
Amazonian endophytes Xylaria feejeensis by Handelsman et al.4
The total synthesis of xyolide was reported by a few groups
including ours in recent times.5 We have been working on the
synthesis of medium sized ring macrolides by exploration of
OH
OH
5
5
OH
OH
3
4
1
3
4
1
7
8
7
8
O
2
O
2
9
9
1
O
nC7H15
O
nC7H15
1
ent-
xyolide
(4S,7S,8S,9R)
mangiferalactone
(4R,7R,8R,9S)
Figure 1. Naturally occurring nonenolide mangiferaelactone and its enantiomer
xyolide.
chemoenzymatic strategies and recently completed the synthesis
of structurally related nonenolides.6
Due to its unique structural features and biological importance
mangiferaelactone became an immediate target, and to date, two
asymmetric syntheses have been reported.7 Both of the syntheses
feature successful exploration of a late stage ‘E’-selective RCM (ring
closing metathesis) reaction. The metathesis precursor was assem-
bled by esterification reaction between properly functionalized
carboxylic acid and alcohol fragments, which were accessed from
D
-ribose in both the cases.
2. Result and discussion
The proposed retrosynthesis for the target molecules is pre-
sented in Scheme 1. We visualized that ring closing alkyne
⇑
Corresponding author. Tel.: +91 3222 283328; fax: +91 3222 282252.
E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).
http://dx.doi.org/10.1016/j.tetasy.2015.06.001
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kumar, R.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.06.001

2
R. Kumar et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
OP1
OP1
RCAM/RCM
OP1
O
O
O
O
O
O
1
+
HO
O
2
O
3
CO2H
4
5
R
O
R
O
R
P1 = TBS
RCAM = ring closing alkyne metathesis
RCM = ring closing metathesis
R = nC7H15
O
O
nPr
nC7H15
S
HO
Cl
D
-ribose
5
O
O
7
O
O
6
OP1
+
TMS
EKR/MI: Enzymatic kinetic resolution/Mitsunobu inversion
Scheme 1. Retrosynthetic analysis of mangiferaelactone 1 using C-alkylglycosides.
PMBO
CHO
CO2H
4
metathesis (RCAM) followed by E-selective reduction could be an
alternative approach to construct the C5–C6 unsaturation in
mangiferaelactone. RCAM followed by stereoselective reduction
of the alkyne functionality serves as an efficient strategy for the
construction of macrolide cores with well-defined olefinic unsatu-
ration embedded in it as demonstrated by Furstner et al. at least for
P12 membered rings.8 The RCAM precursor 3 was thought to be
assembled by union of two alkyne containing fragments 5 and 6.
The fragment 5 was proposed to be accessed from a C-alkyl gly-
coside 6 by employing an appropriately substituted thiophene as
a masked C4-synthon.9 We visualized that n-propylthiophene
could serve as a surrogate for the n-heptyl appendage present in
the target molecule after reductive desulfurization of the thio-
phene nucleus. The other alkyne fragment 4 was proposed to be
accessed by an enzymatic kinetic resolution/Mitsunobu inversion
sequence or Trost asymmetric alkynylation protocol10 as shown
in Scheme 1.
2.2. Synthesis of the fragment 25 and 26 having the (4R)
stereocentre of mangiferaelactone
The synthesis was began with known aldehyde 18, which was
treated with TMS acetylene in the presence of n-BuLi, to afford
the racemic alcohol 19 in 90% yield. The TMS group of alcohol 19
was removed by treating 18 with K2CO3 in MeOH to furnish alcohol
20 in 95% yield. Enzymatic kinetic resolution15 of racemic alcohol
20 was performed using vinyl acetate as the active acyl donor
and CAL-B (Candida antarctica lipase) as a biocatalyst in DIPE sol-
vent at 34 °C to afford alcohol (R)-20 (yield = 48%, ee = 96%) and
acetate (S)-21 (yield = 48%; ee = 96%). The unwanted acetate (S)-
21 was then hydrolyzed with 1% NaOH in MeOH and the resulting
alcohol was inverted by applying a Mitsunobu inversion to give
the desired alcohol (overall yield 83% after three steps). In an alter-
native approach aldehyde 18 was subjected to asymmetric alkyny-
lation reaction with TMS acetylene in the presence of Trost’s
(S,S)-Pro-Phenol ligand to furnish the alcohol 19 in 60% yield
(ee = 80%). As the obtained yield and enantioselectivity for com-
pound 19 by this method were not encouraging enough, we subse-
quently discarded this route. Free hydroxyl group of 20 was
protected as its TBS ether by treating it with imidazole and TBS-
Cl to afford compound 22 in 95% yield. Deprotection of the PMB
group was achieved by treating compound 22 with DDQ16 to pro-
vide primary alcohol 23 in 96% yield. Swern oxidation17 of the
compound 23 afforded aldehyde 24 in 90% yield. Aldehyde 24 on
further oxidation by Pinnick condition18 furnished the carboxylic
acid 4 in 80% yield (Scheme 3).
2.1. Synthesis of the alcohol fragment 10/11 containing
(7R,8R,9S) of the target molecule
The synthesis was initiated with 2,3-O-isoppropylidene-D-ri-
bose 8.11 The primary hydroxyl group in compound 8 was pro-
tected as the TBS ether using TBSCl and imidazole to furnish
compound 9 in 98% yield. Lactol 9 on reaction with 2-propylthio-
phene (n-BuLi, THF, 0 °C to rt) afforded the diol 10 as diastere-
omeric mixture (1:1) in 75% yield. Mitsunobu cyclization of
diol 10 with DIAD (diisopropyl azodicarboxylate) and Ph3P in
THF gave 2-propyl thiophene glycosides 11 (a-isomer 46% yield)
and 12 (b-isomer 45% yield). The ribofuranoside 11 and 12 were
finally subjected (separately) to Mozingo type reduction (reductive
desulfurization) with Raney-Ni in ethanol12 at reflux to afford
the C-heptylglycoside 13 and 14 (separately) in 75% yield. The
TBS group in compound 13/14 was deprotected by treating them
with TBAF (1 M) in THF to afford alcohols 7/15 in 88% yield. For
the synthesis of acetylenic alcohols 5 the key chloro derivatives 6
was prepared (in 88% yield) from compound 7 under Appel reac-
tion conditions.13 Subsequently base induced reductive elimina-
tion of compound 7 with LiNH2 in NH3 (l) afforded the alkyne
alcohol 5 in 85% yield.14 The unwanted C-heptylglycoside 14
was also converted to alkynol 5 through a diastereodivergent
route involving a Mitsunobu inversion reaction as shown in
Scheme 2.
2.3. Fragment coupling by RCAM/RCM
After construction of both the fragments (acid 4 and alcohol 5),
our next job was to couple them by esterification followed by
RCAM. The alcohol fragment 5 was coupled with the acid 4 using
2,4,6-trichlorobenzoyl chloride in Et3N and DMAP (Yamaguchi
esterification protocol)19 to afford the ester 25 in 96% yield
(Scheme 4). We attempted cyclization of 25 by the RCAM reaction
using tris(triphenylsilyloxy)molybdenum nitride pyridine complex
as catalyst,20 but the reaction did not proceed to yield the desired
ring closing product. We thought that the presence of bulky TBS
and acetonide group adjacent to the two alkyne termini might be
blocking the RCAM catalyst. Hence the TBS and the acetonide
group were subsequently deprotected from compound 25 to afford
Please cite this article in press as: Kumar, R.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.06.001

R. Kumar et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
O
nPr
c
O
OH
O
OH
S
OH
+
HO
S
OH
HO
b
Ref 8
a
nPr
PgO
PgO
OH
O
O
OH
HO
O
d
O
O
O
8
9
10
nPr
nPr
O
O
C7H15
C7H15
S
S
e
O
PgO
HO
O
+
PgO
PgO
O
O
O
O
O
O
O
O
13
7
12
11
f
Pg = TBS
C7H15
O
C7H15
O
O
g
Cl
HO
O
O
d
5
6
C7H15
C7H15
O
O
O
C7H15
C7H15
C7H15
O
O
O
O
HO
HO
h
Cl
g
f
PgO
e
HO
O
O
O
O
O
O
17
5
14
15
16
Scheme 2. Reagents and conditions: (a) TBDMSCl, imidazole, DCM, rt, 98%; (b) n-BuLi, THF 0 °C–rt, 2 h, 75%; (c) DIAD, Ph3P, THF 0 °C–rt, 3 h, 91%; (d) Raney-Ni, EtOH, 80 °C,
4 h, 75%; (e) 1 M TBAF, THF, 88%; (f) Ph3P, CCl4, 5 h, reflux 88%; (g) LiNH2, NH3 (l), À30 °C, THF, 5 h, 85%; (h) DIAD, Ph3P, PhCO2H, 1% NaOH, 86% (for two steps).
TMS
a
b
+
PMBO
CHO
PMBO
TMS
PMBO
OH
OH
18
19
20
c
PMBO
e
f
+
d
PMBO
PMBO
OTBS
22
OH
OAc
g
(S)-21
(R)-20
h
HOOC
OHC
HO
4
OTBS
OH
OTBS
OTBS
24
23
R
i
PMBO
PMBO
CHO
TMS
+
19
R = TMS;
R = H; 20
j
18
Ph
OH
Ph
OH N
N
Ph
Ph OH
(S,S)-ProPhenol ligand
i
Scheme 3. Reagents and conditions: (a) n-BuLi, TMS acetylene, THF, À78 °C–rt, 90%; (b) K2CO3, MeOH, 0 °C, 95%; (c) CAL-B, vinyl acetate, Pr2O, 4 Å-MS, 1 h; (d) (i) K2CO3,
MeOH; (ii) PPh3, DIAD, PhCOOH; (iii) 1% NaOH in MeOH; (e) imidazole, TBS-Cl, DCM, rt 95%; (f) DDQ, DCM/H2O (19:1), rt, 1 h, 96%; (g) (COCl)2, DMSO, Et3N, DCM, À78 °C, 90%;
(h) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O (1:1), rt, 2 h 80%; (i) (S,S)-Pro-Phenol, Ph3PO, Me2Zn, toluene, 60%; (j) same as b, 95%.
compound 26 and 27 as depicted in Scheme 4. Compound 26 and
27 were separately subjected to the RCAM reaction under similar
conditions, however the RCAM reaction did not proceed at all in
either case (starting material was recovered). As the attempted
RCAM reaction was failed to yield the desired lactone core, we
switched over to an RCM strategy to complete the synthesis.
Please cite this article in press as: Kumar, R.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.06.001

4
R. Kumar et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
O
nC7H15
nC7H15
O
O
O
HO
CO2H
b
a
O
TBSO
no reaction
O
RCAM
+
25
OTBS
5
c
4
O
nC7H15
O
O
N
b
RCAM
no reaction
O
Ph3SiO
OSiPh3
N
HO
Mo
Ph3SiO
26
d
tris(triphenylsilyloxy)molybdenum
nitride pyridine complex (RCAM catalyst)
O
nC7H15
OH
b
O
no reaction
RCAM
HO
OH
27
O
O
C7H15
O
C7H15
O
C7H15
OH
O
O
O
O
g
O
O
f
e
O
O
26
OH
CO2H
OH
29
OH
28
(-)-Mangiferaelectone (1)
No of steps
17
Overall yield
7.78%
i) This work
Grubbs catalyst 2nd generation
ii) Ramana's work7a
iii) Das's work7b
2.5%
18
17
15.2%
Scheme 4. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, toluene 0 °C to rt, 6 h, 96%; (b) tris(triphenylsilyloxy)molybdenum nitride pyridine
complex, toluene, 80 °C; (c) HF-pyridine, THF, 4 h, 88%; (d) 2 N HCl, THF, rt, 6 h, 90%; (e) Lindlar’s catalyst, H2, Pd–C, EtOAc, 80%; (f) G-II (10 mol %), DCM, 10 h, 85%; (g)
succinic anhydride, EDCIÁHCl, DMAP, and then same as d.
Compound 26, upon partial reduction with Lindlar catalyst and H2
atmosphere afforded the di-olefinic precursor 28 in 80% yield. Ring
closing metathesis (RCM) of the resulting diene ester 28 was suc-
cessfully achieved by using the Grubbs second generation catalyst
(G-II) to afford the 10-membered lactone 29 as a single E-
stereoisomer in good yield (85%).21 Resulting hydroxylactone 29
was then subjected to esterification with succinic anhydride in
the presence of DMAP followed by treatment with 2 N HCl that fur-
nished the target molecule mangiferaelactone 1 in 90% yield (over-
all yield = 8.6% from compound 9; Scheme 4). The specific rotation
and spectroscopic data (1H, 13C NMR, 1H–1H COSY, HSQC, NOESY,
and MS) of the compound were found to be identical to those
reported in the literature.4
4. Experimental
4.1. General
All oxygen and/or moisture-sensitive reactions were carried out
under an N2 atmosphere in glassware that had been flame-dried
under a vacuum (w0.5 mmHg) and purged with N2 prior to use.
Unless otherwise stated, materials were obtained from commercial
suppliers and used without further purification. CAL-B (immobi-
lized on acrylic resin) was purchased from Sigma Aldrich Co,
USA. THF, diethyl ether, toluene were distilled from sodium ben-
zophenone ketyl. Dichloromethane (DCM) was distilled from cal-
cium hydride. Reactions were monitored by thin-layer
chromatography (TLC) carried out on 0.25 mm silica gel plates
with UV light, ethanolic anisaldehyde, and phosphomolybdic
acid/heat as developing agents. Silica gel 100–200 mesh was used
for column chromatography. Yields refer to chromatographically
and spectroscopically homogeneous materials unless otherwise
stated. NMR spectra were recorded on 600, 400, and 200 MHz
spectrometers at 25 °C in CDCl3 using TMS as the internal standard.
Chemical shifts are shown in d, 13C NMR spectra were recorded
with a complete proton decoupling environment. The chemical
shift value is listed as dH and dC for 1H and 13C, respectively.
Mass spectrometric analysis was performed in the CRF, IIT-
3. Conclusion
In conclusion an efficient stereoselective synthesis of
(À)-mangiferaelactone was achieved by using a C-alkylribofuranoside
as a chiral precursor. The C-alkylribofuranoside was accessed
from a C-thiopheneribofuranoside by reductive desulfurization.
Attempts to construct the macrolactone core in the target molecule
through exploration of RCAM reaction remain elusive. Finally
stereoselective RCM reaction was employed at the penultimate
stage to complete the synthesis of the target molecule.
Please cite this article in press as: Kumar, R.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.06.001

R. Kumar et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
Kharagpur (TOF analyzer). Optical rotations were measured on a
JASCO digital polarimeter. HPLC analysis was performed with
CHIRALPAK AD-H and OJ-H (Daicel) column by using Shimadzu
Prominence LC-20AT system (UV–Vis detector).
6.6 Hz), 4.64–4.58 (m, 1H), 4.13–4.11 (m, 1H), 3.78–3.75 (m, 2H),
2.73 (t, 2H, J = 7.5 Hz), 1.71–1.60 (m, 2H), 1.58 (s, 3H), 1.35
(s, 3H), 1.03–0.99 (m, 3H), 0.95 (s, 9H), 0.07 (s, 6H).
13C NMR (100 MHz, CDCl3), dC: 145.7, 140.0, 124.4, 123.5, 114.3,
86.7, 84.6, 82.6, 81.9, 63.3, 32.2, 27.5, 25.9, 25.5, 24.8, 18.3, 13.6,
À5.2, À5.4. HRMS (ESI) for C21H36O4SiSNa [M+Na]+, calculated:
435.2001; found: 435.2002.
4.1.1. (3aR,6R,6aR)-6-((tert-Butyldimethylsilyloxy)methyl)-2,2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol 9
To a stirred solution of 8 (2.25 g, 11.8 mmol) in dry DCM
(31 mL) were added imidazole (2.0 g, 29.5 mmol) and tert-
butyldimethylsilylchloride (2.07 g, 13.75 mmol) at room tempera-
ture and the mixture was stirred for 3 h. The solvent was removed
in vacuo and the residue partitioned between ethyl acetate and
water. The organic layer was washed with brine, dried over anhy-
drous Na2SO4, and evaporated. The residue was purified by silica
gel column chromatography (EtOAc/hexane, 1:5) to afford
compound 9 (3.52 g) in 98% yield as a colorless oil (9:1, anomeric
mixture). Rf = 0.4 (EtOAc/hexane, 1:5). 1H NMR (200 MHz, CDCl3)
for major isomer, dH: 5.27 (d, 1H, J = 11.2 Hz), 4.78 (d, 1H,
J = 11.4 Hz), 4.69 (d, 1H, J = 6.0 Hz), 4.50 (d, 1H, J = 6.0 Hz), 4.34
(br s, 1H), 3.75 (d, 2H, J = 2.2 Hz), 1.47 (s, 3H), 1.31 (s, 3H), 0.92
(s, 9H), 0.13 (s, 6H). 13C NMR (50 MHz, CDCl3), dC: 112.1, 103.5,
87.6, 87.0, 81.9, 64.9, 26.5, 25.8, 25.0, 18.3, À5.5. HRMS (ESI) for
4.1.4. tert-Butyl(((3aR,4R,6S,6aS)-6-heptyl-2,2-dimethyltetrahy-
drofuro[3,4-d][1,3]dioxol-4-yl)methoxy)dimethylsilane 13
Compound 12 (1.46 g, 3.54 mmol) and Raney nickel (12 mL) in
ethanol (100 mL) were stirred at reflux for 4 h. After completion
of the reaction (TLC analysis) the mixture was filtered over a bed
of Celite and washed with ethanol (3 Â 100 mL). Evaporation of
the solvent and purification of the residue by silica gel column
chromatography (EtOAc/hexane, 1:25) furnished compound 13
(1.03 g) in 75% yield as a liquid. Rf = 0.4 ((EtOAc/hexane, 1:25).
[a
]
D
28 = À25.7 (c 0.8, CHCl3). 1H NMR (200 MHz, CDCl3), dH: 4.61
(dd, 1H, J = 3.6, 6.6 Hz), 4.29–4.26 (m, 1H), 4.23–4.00 (m, 1H),
3.96 (t, 1H, J = 3.8 Hz), 3.85–3.69 (m, 2H), 1.60–1.53 (m, 2H), 1.52
(s, 3H), 1.34 (s, 3H), 1.32–1.27 (m, 10H), 0.97–0.89 (m, 12H), 0.06
(s, 6H). 13C NMR (50 MHz, CDCl3), dC: 113.7, 85.0, 84.5, 84.2, 81.9,
63.6, 33.8, 31.7, 29.5, 29.1, 27.4, 25.9, 25.5, 22.6, 18.3, 14.0, À5.2,
C
14H28O5SiNa [M+Na]+, calculated: 327.1603; found: 327.1605.
À5.4. HRMS (ESI) for
C
21H42O4SiNa [M+Na]+, calculated:
4.1.2. (R)-2-(tert-Butyldimethylsilyloxy)-1-((4R,5S)-5-(hydroxy-
(5-propylthiophen-2-yl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)
ethanol 10
409.2750; found: 409.2752.
4.1.5. (3aR,4R,6S,6aS)-6-Heptyl-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)methanol 7
To a solution of 2-propyl thiophene (5.3 g, 42.0 mmol) in anhy-
drous THF (40 mL) was added n-BuLi (26.4 mL, 42.18 mmol, 1.6 M
in hexane) dropwise over 20 min at 0 °C after which the solution
was stirred at room temperature for 0.5 h. To the resultant solution
was added dropwise a solution of 9 (3 g, 9.85 mmol) in dry THF
(30 mL) over 15 min at 0 °C. The reaction mixture was then stirred
at room temperature for 2 h and treated with aq NH4Cl solution
(60 mL). The aqueous layer was separated, extracted with CHCl3
(3 Â 150 mL), and dried (Na2SO4). Evaporation of the solvent under
reduced pressure and purification of the residue by silica gel col-
umn chromatography (EtOAc/hexane, 1:10) afforded compound
10 as a diastereomeric mixture (3.4 g) in 75% yield as a syrup.
Rf = 0.2 (EtOAc/hexane, 1:10).
To an ice-cooled solution of 13 (1.03 g, 2.66 mmol) in dry THF
(10 mL) was added a 1 M solution of TBAF (3.99 mL, 3.99 mmol)
and stirred for 2 h at room temperature. After completion of the
reaction, water was added to the reaction mixture and THF was
removed under vacuum. The aqueous layer was then extracted
with ethyl acetate and washed with saturated aqueous NaHCO3
and brine. The organic extract was dried over anhydrous Na2SO4
and concentrated under vacuum. The residue was then purified
by silica gel column chromatography (EtOAc/hexane, 1:3) to afford
compound 7 (0.637 g) in 88% yield as a colorless oil. Rf = 0.4
(EtOAc/hexane, 1:3).
[
a]
30 = À3.4 (c 1.6, CHCl3). 1H NMR
D
(600 MHz, CDCl3), dH: 4.61 (dd, 1H, J = 4.8, 6.6 Hz), 4.30 (dd, 1H,
J = 5.4, 6.6 Hz), 3.98 (dd, 1H, J = 4.2, 7.8 Hz), 3.89– 3.83 (m, 2H),
3.68 (dd, 1H, J = 4.5, 11.7 Hz), 2.19 (br s, 1H), 1.67–1.59 (m, 4H),
1.55 (s, 3H), 1.44–1.33 (m, 2H), 1.32 (s, 3H), 1.31–1.28 (m, 6H),
0.86 (t, 3H, J = 6.3 Hz). 13C NMR (100 MHz, CDCl3), dC: 114.7, 85.2,
84.7, 84.1, 81.5, 62.9, 33.8, 31.9, 29.8, 29.3, 27.5, 25.6, 25.6, 22.7,
14.2.
4.1.3. tert-Butyl(((3aR,4R,6R,6aR)-2,2-dimethyl-6-(5-propylthio-
phen-2-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)
dimethylsilane 12 and tert-butyl(((3aR,4R,6S,6aR)-2,2-dimethyl-
6-(5-propylthiophen-2-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)
methoxy)dimethylsilane 11
A
mixture of 10 (3.4 g, 7.90 mmol) and Ph3P (5.18 g,
HRMS (ESI) for C15H28O4Na [M+Na]+, calculated: 295.1885;
found: 295.1880.
19.75 mmol) in THF (30 mL) was stirred for 15 min and then trea-
ted with a solution of DIAD (3.98 g, 19.75 mmol) in THF (32 mL)
dropwise at 0 °C. After stirring for 2.5 h at room temperature, the
reaction mixture was evaporated under reduced pressure and the
residue was purified by silica gel column chromatography
(EtOAc/hexane, 1:20) to afford compound 11 and 12 in 91% yield.
4.1.6. (3aS,4S,6S,6aS)-4-(Chloromethyl)-6-heptyl-2,2-dimethyl-
tetrahydrofuro[3,4-d][1,3]dioxole 6
To a stirred solution of compound 7 (0.637 g, 2.33 mmol) in CCl4
(11 mL) was added TPP (0.916 g, 3.49 mmol) followed by a cat-
alytic amount of imidazole and the resulting reaction mixture
was refluxed for 4 h. The reaction mixture was then cooled to
0 °C, diluted with hexane, and filtered through a bed of Celite.
After evaporation of the solvent under reduced pressure, the crude
product was purified by silica gel column chromatography
(EtOAc/hexane, 1:15) to afford compound 6 (0.596 g) in 88% yield
Compound 11: Rf = 0.2 (EtOAc/hexane, 1:20). [
a
]
28 = À38.8 (c 3.0,
D
CHCl3). 1H NMR (400 MHz, CDCl3), dH: 6.85 (d, 1H, J = 3.2 Hz),
6.63 (d, 1H, J = 3.2 Hz), 5.41 (d, 1H, J = 4 Hz), 4.95 (d, 1H, 6 Hz),
4.73 (dd, 1H, J = 4.0, 6.0 Hz), 4.16 (m, 1H), 3.84 (dd, 1H, J = 3.6,
10.8 Hz), 3.77 (dd, 1H, J = 2.8, 10.8 Hz), 2.75 (t, 2H, J = 7.6 Hz),
1.69–1.67 (m, 2H), 1.59 (s, 3H), 1.35 (s, 3H), 0.98–0.96 (m, 3H),
0.94 (s, 9H), 0.08 (s, 6H); 13C NMR (100 MHz, CDCl3), dC: 147.4,
136.1, 126.5, 122.9, 112.8, 84.0, 83.5, 82.8, 81.4, 65.5, 32.5, 26.5,
26.0, 25.0, 24.9, 18.3, 13.9, À5.3, À5.4. HRMS (ESI) for
as a colorless oil. Rf = 0.5 (EtOAc/hexane, 1:15). [
a
]
30 = À13.8
D
(c 2.2, CHCl3). 1H NMR (600 MHz, CDCl3), dH: 4.60 (dd, 1H, J = 3.9,
6.9 Hz), 4.36 (dd, 1H, J = 4.8, 6.6 Hz), 4.14 (q, 1H, J = 4.6 Hz), 3.91
(dd, 1H, J = 6.6, 11.4 Hz), 3.66 (dd, 1H, J = 4.8, 11.4 Hz), 3.62 (dd,
1H, J = 5.7, 11.7 Hz), 1.64–1.60 (m, 2H), 1.59 (s, 3H), 1.58–1.40
(m, 2H), 1.39 (s, 3H), 1.39–1.28 (m, 8H), 0.89 (t, 3H, J = 6.6 Hz).
13C NMR (50 MHz, CDCl3), dC: 1 14.4, 84.8, 84.7, 82.9, 82.8, 44.5,
C
21H36O4SiSNa [M+Na]+, calculated: 435.2001; found: 435.2002.
Compound 12: Rf = 0.3 (EtOAc/hexane, 1:20). [
a
]
D
28 = À66.9 (c 0.4,
CHCl3). 1H NMR (200 MHz, CDCl3), dH: 6.84 (d, 1H, J = 3.4 Hz),
6.61 (d, 1H, J = 3.4 Hz), 5.01 (d, 1H, J = 5 Hz), 4.75 (dd, 1H, J = 3.4,
Please cite this article in press as: Kumar, R.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.06.001

6
R. Kumar et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
33.6, 31.7, 29.4, 29.0, 27.2, 25.3 (2C), 22.5, 14.0. HRMS (ESI) for
15H28O3Cl [M+H]+, calculated: 291.1727; found: 291.1732.
as a colorless oil. Its analytical data match well with those of
reported compounds.14c
C
4.1.11. (R)-1-(4S,5R)-5-Ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl)
octan-1-ol 17
4.1.7. (S)-1-((4S,5R)-5-Ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl)
octan-1-ol 5
Compound 17 was prepared according to the procedure
described for compound 5 starting from compound 16 (0.601 g,
2.06 mmol). Purification by silica gel chromatography (EtOAc/
hexane, 1:5) afforded compound 17 (0.45 g) in 85% yield as a col-
To freshly distilled ammonia (5 mL) in a 100 mL two-necked
round-bottomed flask fitted with a cold finger condenser were
added freshly cut pieces of lithium metal (0.14 g, 20.44 mmol) at
À33 °C and the resulting gray suspension was stirred for 30 min.
To this reaction mixture was added chloro compound 6 (0.596 g,
2.04 mmol) in anhydrous THF (4 mL) over a period of 5 min.
After being stirred at À33 °C for 5 h, the reaction was quenched
by the portion wise addition of solid NH4Cl after which the ammo-
nia was allowed to evaporate. The reaction mixture was then
diluted with water (8 mL) and extracted with Et2O (3 Â 10 mL).
The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure.
The crude product was purified by silica gel column chromatogra-
phy (EtOAc/hexane, 1:5) to afford compound 5 (0.44 g) in 85% yield
orless oil. Rf = 0.2 (EtOAc/hexane, 1:5). [a]
30 = +46 (c 1.4, CHCl3).
D
1H NMR (200 MHz, CDCl3), dH: 4.74 (dd, J = 5.7, 2.4 Hz, 1H), 4.01–
3.85 (m, 2H), 2.56 (d, 1H, J = 2.4 Hz,), 2.28 (br s, 1H), 1.57 (s, 3H),
1.55–1.40 (m, 3H), 1.37 (s, 3H), 1.36–1.18 (m, 9H), 0.88 (t, 3H,
J = 6.6 Hz). 13C NMR (50 MHz, CDCl3), dC: 110.4, 81.0, 79.5, 75.9,
71.2, 66.9, 32.7, 31.7, 29.3, 29.1, 27.4, 25.9, 25.2, 22.6, 14.0.
HRMS (ESI) for C15H26O3Na [M+Na]+, calculated: 277.1779; found:
277.1786.
4.1.12. ( )-6-(4-Methoxybenzyloxy)-1-(trimethylsilyl)hex-1-yn-
3-ol 19
as a colorless oil. Rf = 0.3 (EtOAc/hexane, 1:5). [a]
32 = +7.8 (c 2.2,
D
To a solution of trimethylsilylacetylene (1.95 mL, 14.10 mmol)
in anhydrous THF (10 mL) was added dropwise n-BuLi (2.0 M in
hexane, 6.5 mL, 12.95 mmol) at 0 °C for 30 min. To a stirred solu-
tion of aldehyde 18 (2.45 g, 11.75 mmol) in anhydrous THF
(10 mL) at À78 °C was added the pre-formed solution of lithium
trimethylsilylacetylide via a cannula. After the mixture had been
stirred at À78 °C for 40 min, the reaction was gradually warmed
to rt. After stirring at rt for 30 min, the reaction was quenched by
the addition of a saturated aqueous NH4Cl solution. The mixture
was extracted with ethyl acetate. The organic layer was washed
with brine, dried over anhydrous MgSO4, and concentrated in
vacuo. Purification by silica gel chromatography (EtOAc/hexane,
1:4) afforded racemic 19 (3.42 g) in 95% yield as a pale yellow
oil. Rf = 0.3 (EtOAc/hexane, 1:4). 1H NMR (200 MHz, CDCl3), dH:
7.2 9 (d, 2H, J = 8.6 Hz), 6.90 (d, 2H, J = 8.6 Hz), 4.52–4.45 (m,
3H), 3.82 (s, 3H), 3.53 (m, 2H), 2.89 (br s, 1H), 1.90–1.80 (m, 4H),
0.19 (s, 9H). 13C NMR (50 MHz, CDCl3), dC: 159.3, 130.2, 129.5,
113.9, 107.0, 89.2, 72.6, 69.9, 62.5, 55.4, 35.2, 25.5, 0.1. HRMS
(ESI) for C17H26O3SiNa [M+Na]+, calculated: 329.1548; found:
329.1551.
CHCl3). 1H NMR (600 MHz, CDCl3), dH: 4.90 (dd, 1H, J = 2.1,
5.1 Hz), 3.94–3.93 (m, 2H), 2.64 (d, 1H, J = 2.4 Hz), 2.07 (br s, 1H),
1.80–1.78 (m, 1H), 1.58–1.55 (m, 1H), 1.54 (s, 3H), 1.50–1.34 (m,
2H), 1.33 (s, 3H), 1.32–1.30 (m, 8H), 0.90 (t, 3H, J = 6.9 Hz). 13C
NMR (50 MHz, CDCl3), dC: 110.6, 80.6, 80.3, 76.1, 71.3, 68.0, 33.9,
31.8, 29.5, 29.2, 27.5, 25.8, 25.1, 22.6, 14.0. HRMS (ESI) for
C
15H26O3Na [M+Na]+, calculated: 277.1779; found: 277.1780.
4.1.8. tert-Butyl(((3aR,4R,6R,6aS)-6-heptyl-2,2-dimethyltetrahy-
drofuro[3,4-d][1,3]dioxol-4-yl)methoxy)dimethylsilane 14
Compound 14 was synthesized by desulfurization of compound
11 (1.49 g, 3.61 mmol) as described earlier. Purification by silica
gel column chromatography (EtOAc/hexane, 1:25) gave compound
14 (1.05 g) in 75% yield as a liquid. Rf = 0.3 (EtOAc/hexane, 1:25).
[a
]
D
28 = À14.6 (c 1.0, CHCl3). 1H NMR (600 MHz, CDCl3), dH: 4.81
(dd, 1H, J = 0.6, 6.0 Hz), 4.62 (dd, 1H, J = 3.6, 6.0 Hz), 4.06–4.03
(m, 2H), 3.70 (dd, 2H, J = 2.7, 3.9 Hz), 1.67–1.66 (m, 2H), 1.60–
1.51 (m, 1H), 1.43 (s, 3H), 1.34 (s, 3H), 1.32–1.27 (m, 9H), 0.93 (s,
9H), 0.92–0.84 (m, 3H), 0.07 (s, 6H). 13C NMR (150 MHz, CDCl3),
dC: 111.9, 83.9, 83.1, 82.5, 82.2, 64.7, 31.8, 29.7, 29.4, 29.2, 26.3,
26.3, 25.8, 25.1, 22.6, 14.1, À5.5, À5.5. HRMS (ESI) for
4.1.13. ( )-6-(4-Methoxybenzyloxy)hex-1-yn-3-ol 20
C
21H42O4SiNa [M+Na]+, calculated: 409.2749; found: 409.2749.
To a solution of racemic compound 19 (3.42 g, 11.15 mmol) in
methanol (80 mL) was added K2CO3 (1.5 g, 11.15 mmol) and the
mixture was stirred at 0 °C for 5 h. The mixture was then poured
into 120 mL of saturated aqueous ammonium chloride solution
and concentrated in vacuo. The mixture was extracted with ethyl
acetate and organic layer was washed with brine and dried over
anhydrous MgSO4. The organic layer was concentrated in vacuo
to afford the crude residue, which upon purification by silica gel
chromatography (EtOAc/hexane, 1:3) afforded racemic compound
20 (2.59 g) in 99% yield as a pale yellow oil. Rf = 0.3 (EtOAc/
4.1.9. (3aR,4R,6R,6aS)-6-Heptyl-2,2-dimethyltetrahydrofuro[3,4-d]
[1,3]dioxol-4-yl)methanol 15
Compound 15 was prepared according to the procedure
described for compound 7 starting from compound 14 (1.04 g,
2.68 mmol). Purification by silica gel chromatography
(EtOAc/hexane, 1:3) afforded compound 15 (0.642 g) in 88% yield
as a colorless oil. Rf = 0.3 (EtOAc/hexane, 1:3). [
a
]
30 = À2.3 (c 2.2,
D
CHCl3). 1H NMR (400 MHz, CDCl3), dH: 4.62–4.56 (m, 2H), 4.09
(t, 1H, J = 6.2 Hz), 3.84 (td, 1H, J = 3.7, 6.6 Hz), 3.56 (d, 2H,
J = 6.4 Hz), 2.02 (br s, 1H), 1.68 (q, 2H, J = 7.33 Hz) 1.48 (s, 3H),
1.43–1.36 (m, 2H), 1.32 (s, 3H), 1.29–1.22 (m, 8H), 0.86 (t, 3H,
J = 6.6 Hz). 13C NMR (100 MHz, CDCl3), dC: 112.6, 84.1, 82.5, 81.8,
81.1, 61.7, 31.9, 29.8, 29.3, 29.2, 26.5, 26.4, 25.3, 22.8, 14.2.
HRMS (ESI) for C15H28O4Na [M+Na]+, calculated: 295.1885; found:
295.1880.
hexane, 1:3). 1H NMR (400 MHz, CDCl3), dH: 7.2
5 (d, 2H,
J = 8.4 Hz), 6.8 7 (d, 2H, J = 8.4 Hz), 4.45 (ABq, 2H, J = 11.2 Hz),
4.41–4.39 (m, 1H), 3.80 (s, 3H), 3.53–3.51 (m, 2H), 2.44 (d, 1H,
J = 2.0 Hz), 2.25 (br s, 1H), 1.90–1.74 (m, 4H). 13C NMR (50 MHz,
CDCl3), dC: 159.3, 130.1, 129.5, 113.9, 85.1, 72.8, 69.8, 61.9, 55.4,
33.2, 25.5. HRMS (ESI) for
257.1153; found: 257.1159.
C
14H18O3Na [M+Na]+, calculated:
4.1.10. (3aS,4S,6R,6aS)-4-(Chloromethyl)-6-heptyl-2,2-dimethyl-
tetrahydrofuro[3,4-d][1,3]dioxole 16
Compound 16 was prepared according to the procedure
described for compound 6 starting from compound 15 (0.642 g,
2.35 mmol). Purification by silica gel chromatography
(EtOAc/hexane, 1:10) afforded compound 16 (0.601 g) in 88% yield
4.1.14. (S)-6-(4-Methoxybenzyloxy)hex-1-yn-3-yl acetate 21
In a typical resolution experiment, a solution of racemic alcohol
20 (2.5 g, 11.05 mmol) in anhydrous diisopropyl ether (49 ml) was
stirred with vinyl acetate (1 equiv, 1.11 mL) and powdered molec-
ular sieves (16 mg, 4 Å) followed by the addition of CAL-B (0.8 g).
The reaction mixture was stirred in an orbit shaker (250 rpm) at
Please cite this article in press as: Kumar, R.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.06.001

R. Kumar et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
7
34 °C temperature for 1 h. After 50% conversion (by TLC analysis),
the reaction mixture was filtered through a pad of Celite and evap-
orated to dryness. The alcohol and the acetate were separated by
silica gel column chromatography (EtOAc/hexane, 1:10). Rf = 0.5
1H NMR (600 MHz, CDCl3), dH: 7.2 8 (d, 2H, J = 8.4 Hz), 6.8 9 (d,
2H, J = 8.4 Hz), 4.45 (s, 2H), 4.40–4.38 (m, 1H), 3.82 (s, 3H), 3.49
(m, 2H), 2.39 (d, 1H, J = 2.4 Hz), 1.78–1.77 (m, 4H), 0.91 (s, 9H),
0.14 (s, 3H), 0.11 (s, 3H). 13C NMR (50 MHz, CDCl3), dC: 159.0,
130.6, 129.1, 113.7, 85.4, 72.4, 72.1, 69.6, 62.5, 55.2, 35.2, 25.7,
25.3, 18.1, À4.6, À5.1. HRMS (ESI) for C20H32O3SiNa [M+Na]+, cal-
culated: 371.2018; found: 371.2024.
((EtOAc/hexane, 1:10).
[
a]
28 = À37.5 (c 1.0, CHCl3). 1H NMR
D
(200 MHz, CDCl3), dH: 7.28 (d, 2H, J = 8.6 Hz), 6.90 (d, 2H,
J = 8.6 Hz), 5.39 (dt, 1H, J = 2.0, 6.0 Hz), 4.46 (s, 2H), 3.80 (s, 3H),
3.50 (t, 2H, J = 5.9 Hz), 2.49 (d, 1H, J = 2.0 Hz), 2.10 (s, 3H), 1.97–
1.77 (m, 4H). 13C NMR (50 MHz, CDCl3), dC: 169.9, 159.1, 130.4,
129.2, 113.8, 81.0, 73.6, 72.5, 69.1, 63.5, 55.2, 31.4, 25.2, 20.9.
HRMS (ESI) for C16H20O4Na [M+Na]+, calculated: 299.1259; found:
299.1263.
4.3.2. (R)-4-(tert-Butyldimethylsilyloxy)hex-5-yn-1-ol 23
Compound 22 (3.22 g, 9.23 mmol) was dissolved in 40 mL of
DCM/phosphate buffer (19:1; pH = 7) and the solution was cooled
to 0 °C. DDQ (2.51 g, 11.07 mmol) was added portion wise to the
solution and the mixture was stirred at this temperature for 1 h.
Then, the reaction mixture was filtered through a pad of Celite.
The residue was then washed with 25 mL of DCM. The combined
organic solution was washed successively with 5% NaHCO3 solu-
tion, water, and brine solution. The organic layer was then dried
over anhydrous MgSO4 and evaporated in vacuo. Purification by
silica gel chromatography (EtOAc/hexane, 1:3) afforded compound
(R)-23 (2.02 g) in 96% yield as colorless oil. Rf = 0.3 (EtOAc/hexane,
4.1.15. (R)-6-(4-Methoxybenzyloxy)hex-1-yn-3-ol 20
To a stirred solution of (S)-acetate 21 (1.46 g, 5.3 mmol) in
12 mL of MeOH was added K2CO3 (219 mg, 1.6 mmol) and stirred
for 4 h. Methanol was evaporated in vacuo and 75 mL of diethyl
ether was added to it. The organic part was washed with water
(12 mL), saturated NH4Cl solution (12 mL), and then with brine
solution (12 mL). The organic part was dried over anhydrous
MgSO4 and solvent was removed in vacuo to afford the crude alco-
hol, which was used for the next step without further purification.
1:3). [a]
28 = 41.6 (c 1.0, CHCl3).
D
1H NMR (600 MHz, CDCl3), dH: 4.46–4.44 (m, 1H), 3.70–3.67 (m,
2H), 2.42 (d, 1H, J = 2.4 Hz), 1.81–1.76 (m, 4H), 0.92 (s, 9H), 0.16 (s,
3H), 0.14 (s, 3H). 13C NMR (150 MHz, CDCl3), dC: 84.9, 72.53, 62.5,
34.9, 28.2, 25.7, 18.1, À4.6, À5.1. HRMS (ESI) for C12H24O2SiNa
[M+Na]+, calculated: 251.1443; found: 251.1450.
4.2. Mitsunobu inversion
To a stirred solution of the alcohol (1.24 g, 5.3 mmol) in 22 mL
of anhydrous THF were added TPP (2 g, 7.8 mmol), DIAD (1.5 mL,
7.8 mmol), and benzoic acid (0.95 g, 7.8 mmol) at 0 °C. The reaction
was stirred overnight at room temperature, after which THF was
removed in vacuo and the residue was taken in ethyl acetate
(50 mL). The organic part was washed with saturated NaHCO3
(2 Â 7.5 mL) and brine (12 mL) solution, and then dried over anhy-
drous MgSO4. The organic solvent was evaporated in vacuo and
purification was accomplished by silica gel chromatography
(EtOAc/hexane, 1:8) to afford the (R)-benzoate (1.5 g) as a colorless
liquid in 85% yield.
4.3.3. (R)-4-(tert-Butyldimethylsilyloxy)hex-5-ynoic acid 4
Aldehyde 24 (1.8 g, 7.95 mmol) was dissolved in tBuOH (40 mL)
and a 2.0 M solution of 2-methyl-2-butene (23.87 mL, 47.74 mmol)
in THF was added to it. To this mixture was added a solution of
NaClO2 (4.32 g, 47.74 mmol) and NaH2PO4 (2.86 g, 23.85 mmol)
in H2O (40 mL). After one hour, the yellow biphasic reaction mix-
ture was poured onto H2O (50 mL) and EtOAc (60 mL). The organic
layer was separated and the aqueous part was washed with EtOAc
(2 Â 50 mL). The combined organic part was washed with brine
solution (140 mL) and dried over anhydrous MgSO4 and concen-
trated under reduced pressure to afford the crude acid. The crude
material was purified by silica gel chromatography (EtOAc/
hexane, 1:1) to afford acid 25 (1.54 g) in 80% yield as a colorless
4.3. Benzoate hydrolysis
To a stirred solution of the benzoate (1.5 g, 4.43 mmol) in 50 mL
of MeOH was added NaOH (0.53 g, 13.10 mmol) at room tempera-
ture and stirred for 12 h at room temperature. After completion of
the reaction MeOH was evaporated in vacuo and the crude residue
was diluted with 62 mL of diethyl ether. The organic part was
washed with (2 Â 15 mL) water, brine solution (15 mL), and then
dried over anhydrous MgSO4. The organic solvent was evaporated
in vacuo and purification by silica gel chromatography
(EtOAc/hexane, 1:3) afforded the (R)-alcohol 20 (1.03 g) as a color-
oil. Rf = 0.3 (EtOAc/hexane, 1:1) [a]
28 = 28.9 (c 1.0, CHCl3).
D
1H NMR (600 MHz, CDCl3), dH: 4.5 0 (dt, 1H, J = 1.8, 6.0 Hz), 2.5 8
(dd, 2H, J = 8.1, 15.3 Hz), 2.42 (d, 1H, J = 2.4 Hz), 2.05–2.00 (m, 2H),
0.92 (s, 9H), 0.16 (s, 3H), 0.13 (s, 3H). 13C NMR (50 MHz, CDCl3), dC:
179.9, 84.4, 72.8, 61.4, 33.3, 29.4, 25.8, 18.1, À4.7, À5.5. HRMS (ESI)
for C12H23O3Si [M+H]+, calculated: 243.1418; found: 243.1416.
4.3.4. (R)-4-(tert-Butyldimethylsilyloxy)hex-5-ynal 24
less liquid in 100% yield. Rf = 0.3 (EtOAc/hexane, 1:3). [
a
]
28 = 3.5
Oxalyl chloride (1.16 ml, 13.26 mmol) was taken in DCM
(32 mL) and the reaction vessel was kept at À78 °C. Dimethyl sul-
foxide (DMSO, 1.88 ml, 26.52 mmol) was then added and the reac-
tion mixture was kept at the same temperature for 25 min. Alcohol
23 (2.02 g, 8.84 mmol) in DCM was then added to it and the mix-
ture was kept for a further 45 min at the same temperature, after
which triethyl amine (7.37 ml, 53 mmol) was added and the reac-
tion mixture was gradually warmed to the room temperature over
1 h. The reaction was quenched by adding water and extracted
with DCM. The organic layer was washed successively with water,
NaHCO3 solution, and brine. The organic layer was dried (MgSO4)
and evaporated. Purification through silica gel chromatography
(EtOAc/hexane, 1:10) afforded aldehyde 24 (1.8 g) in 90% yield.
Rf = 0.4 (EtOAc/hexane, 1:10).
D
(c 1.6, EtOH).
4.3.1. (R)-tert-Butyl(6-(4-methoxybenzyloxy)hex-1-yn-3-yloxy)
dimethylsilane 22
To a stirred solution of alcohol (R)-20 (2.28 g, 9.73 mmol) and
imidazole (1.32 g, 19.46 mmol) in dry CH2Cl2 (30 mL), TBSCl
(1.76 g, 11.67 mmol) was added portion wise at 0 °C. The reaction
mixture was stirred at the same temperature for 2 h and then
quenched with water (15 mL). The dichloromethane (CH2Cl2) layer
was separated, and the aqueous layer was extracted with addi-
tional CH2Cl2 (2 Â 20 mL). The combined organic layers were
washed with water, saturated Na2CO3 solution, and brine solution.
The organic layer was then dried over anhydrous MgSO4. The
organic solvent was removed in vacuo, and purification was
accomplished by silica gel chromatography (EtOAc/hexane, 1:10)
to afford the compound (R)-22 (3.22 g) in 95% yield as a colorless
4.3.5. Asymmetric catalytic alkynylation of aldehyde 18
A microwave vial equipped with a stirrer bar was charged with
trimethylsilylacetylene (2 mmol, 196 mg), (S,S)-Pro-Phenol ligand
liquid. Rf = 0.3 ((EtOAc/hexane, 1:10). [a]
30 = 27.9 (c 1.8, EtOH).
D
Please cite this article in press as: Kumar, R.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.06.001

8
R. Kumar et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
(0.4 mmol, 251 mg), and P(O)Ph3 (0.8 mmol, 219 mg). Dry toluene
(30 mL) was then added and the mixture was cooled to 0 °C under
N2. A solution of Me2Zn (5 mL; 1.2 M in toluene) was then slowly
added over 25 min and the mixture was stirred at 0 °C for
30 min. The mixture was then placed at À20 °C, after which alde-
hyde 18 (8 mmol, 1.66 g) was slowly added to the solution over
30 min. The resulting mixture was then stirred at the same tem-
perature for 2 h before being quenched by the slow addition of
30 mL of aqueous NH4Cl. After stirring for 15 min, this solution
was extracted four times each with 30 mL of diethyl ether. The
organic extracts were dried over MgSO4, filtered, and the solvent
was evaporated in vacuum. Purification of the crude residue by sil-
ica gel chromatography (EtOAc/hexane, 1:4) afforded alcohol 25
(1.46 g) in 60% yield with ee = 80% as a pale yellow oil. Rf = 0.3
(EtOAc/hexane, 1:4).
4.3.8. (R)-((S)-1-((4S,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-
yl)octyl)4-hydroxyhex-5-enoate 28
Compound 26 (0.2 g, 0.54 mmol) was taken in anhydrous EtOAc
(5 ml) in a round bottom flask. Lindlar catalyst (30 mg) and cat-
alytic amount of quinoline were added and the reaction mixture
was stirred for 4 h at room temperature under H2 (500 psi) atmo-
sphere. After the completion of reaction it was filtered with a
Celite pad and the organic solvent was dried over anhydrous
MgSO4 and then concentrated in vacuo. The crude material
was then purified by silica gel column chromatography (EtOAc/
hexane, 1:10) to afford compound 28 (0.16 g) in 80% yield as a col-
orless oil. Rf = 0.2 (EtOAc/hexane, 1:10). [a]
30 = +3.4 (c 1.4, CHCl3).
D
1H NMR (200 MHz, CDCl3), dH: 5.94–5.72 (m, 2H), 5.38–5.11 (m,
4H), 4.96–4.87 (m, 1H), 4.61 (t, 1H, J = 6.9 Hz), 4.22–4.11 (m, 2H),
2.47–2.39 (m, 4H), 1.89–1.74 (m, 2H), 1.58 (s, 3H), 1.48 (s, 3H),
1.37–1.26 (m, 10H), 0.88 (t, 3H, J = 6.2 Hz). 13C NMR (50 MHz,
CDCl3), dC: 173.1, 140.5, 133.3, 118.6, 115.2, 108.9, 78.9, 78.4,
72.2, 72.1, 31.9, 31.6, 31.2, 30.4, 29.6, 29.2, 27.6, 25.3, 24.7, 22.7,
14.2. HRMS (ESI) for C21H36O5Na [M+Na]+, calculated: 391.2461;
found: 391.2465.
4.3.6. (R)-((S)-1-((4S,5R)-5-Ethynyl-2,2-dimethyl-1,3-dioxolan-
4-yl)octyl)4-(tert-butyldimethylsilyloxy)hex-5-ynoate 25
Distilled Et3N (1.3 mL, 9.54 mmol) was added to a solution of
acid 4 (1.16 g, 4.77 mmol) in anhydrous toluene (172 mL) at room
temperature. Distilled 2,4,6-trichlorobenzoyl chloride (0.97 mL,
6.36 mmol) was added dropwise and the resulting clear, colorless
solution was stirred at room temperature. After 1 h, TLC showed
4.3.9. (3aS,4S,9R,11aR,E)-4-Heptyl-9-hydroxy-2,2-dimethyl-7,8,9,
11a-tetrahydro-3aH-[1,3]dioxolo[4,5-c]oxecin-6(4H)-one 29
The starting compound 28 (80 mg, 0.21 mmol) was taken in
anhydrous degassed DCM (30 mL). Grubbs second generation
metathesis catalyst (G-II, 7 mg, 0.008 mmol) was then added and
the solution was stirred at room temperature for 12 h. The solution
was then evaporated and the contents of the flask were directly
loaded onto a silica gel column. The crude material was then puri-
fied by silica gel column chromatography (EtOAc/hexane, 1:4) to
afford the product 29 (52 mg) in 85% yield as a liquid. Rf = 0.3
the complete consumption of the acid. Alcohol
5 (0.81 g,
3.18 mmol) in anhydrous toluene (180 mL) was then added, fol-
lowed by DMAP (1.4 g, 11.13 mmol) to give a white suspension.
After completion of the reaction (5 h), as indicated by TLC analysis,
toluene was evaporated under reduced pressure to afford a crude
product. The crude residue was directly loaded on a silica gel col-
umn and purified by column chromatography (EtOAc/hexane,
1:15) to afford the compound 25 (1.46 g) in 96% as a liquid.
(EtOAc/hexane, 1:4). [
a
]
30 = À73.4 (c 1.4, CHCl3).
D
Rf = 0.3 (EtOAc/hexane 1:15). [
a]
28 = 25.4 (c 1.0, CHCl3). HRMS
D
1H NMR (400 MHz, CDCl3), dH: 5.7 8 (dd, 1H, J = 3.0, 15.8 Hz),
5.62 (dd, 1H, J = 8.6, 15.8 Hz), 4.89 (td, 1H, J = 2.4, 10.8 Hz), 4.66
(br s, 1H), 4.14–4.09 (m, 1H), 3.94 (dd, 1H, J = 4.8, 10 Hz), 2.32–
2.31 (m, 2H), 2.03–2.01 (m, 3H), 1.80–1.74 (m, 1H), 1.52 (s, 3H),
1.35 (s, 3H), 1.26–1.23 (m, 10H), 0.84 (t, 3H, J = 6.6 Hz); 13C NMR
(50 MHz, CDCl3), dC: 175.2, 128.4, 126.6, 109.5, 78.7, 75.8, 75.8,
71.2, 33.8, 32.1, 31.9, 31.4, 29.5, 29.3, 28.6, 26.3, 24.6, 22.8, 14.2.
HRMS (ESI) for C19H32O5Na [M+Na]+, calculated: 363.2148.; found:
363.2150.
(ESI) for
C
27H46O5Si [M+H]+, calculated: 479.3193; found:
479.3183. 1H NMR (600 MHz, CDCl3), dH: 5.1 8 (dt, 1H, J = 3.9,
11.4 Hz), 4.84 (dd, 1H, J = 2.1, 6.3 Hz), 4.46 (td, 1H, J = 2.0, 6.0 Hz),
4.19 (dd, 1H, J = 6.3, 7.5 Hz), 2.52 (d, 1H, J = 2.4 Hz), 2.50–2.46 (m,
2H), 2.41 (d, 1H, J = 2.4 Hz), 2.00–1.99 (m, 2H), 1.87–1.85
(m, 1H), 1.70–1.67 (m, 1H), 1.57 (s, 3H), 1.55 (s, 3H), 1.37–1.28
(m, 10H), 0.92 (s, 9H), 0.90 (t, 3H, J = 3.3 Hz), 0.16 (s, 3H), 0.13 (s,
3H). 13C NMR (150 MHz, CDCl3), dC: 172.3, 110.9, 84.7, 79.5, 78.5,
77.9, 73.6, 72.9, 68.2, 61.7, 33.6, 31.9, 31.6, 29.9, 29.8, 29.4, 27.4,
25.9, 24.8, 22.8, 18.3, 14.3, À4.4, À4.9.
4.3.10. 4-((5R,8R,9R,10S,E)-10-Heptyl-8,9-dihydroxy-2-oxo-3,4,5,
8,9,10-hexahydro-2H-oxecin-5-yloxy)-4-oxobutanoic acid 1
Succinic anhydride (22 mg, 0.22 mmol) was taken in dry DCM
(2 ml). Next, DCC (61 mg, 0.3 mmol), DMAP (5 mg), and alcohol
19 (50 mg, 0.15 mmol) were sequentially added to the reaction
mixture. The reaction mixture was kept at room temperature for
24 h, after which DCM was evaporated and the crude ester was
used for the next step.
To a solution of the obtained crude ester (59.47 mg, 0.13 mmol)
in THF (10 ml), HCl (2 ml, 2 M) was added at room temperature
and stirred for 6 h. Water was then added to the reaction mixture
and it was extracted with ethyl acetate. The organic layer was
washed with NaHCO3 and brine. It was then dried over MgSO4,
concentrated in a rotary evaporator, and purified by silica gel col-
umn chromatography (EtOAc/hexane, 1:1) to afford the target
molecule mangiferaelactone 1 (47.95 mg) in 80% overall yield for
4.3.7. (R)-((S)-1-((4S,5R)-5-Ethynyl-2,2-dimethyl-1,3-dioxolan-
4-yl)octyl)4-hydroxyhex-5-ynoate 26
Compound 25 (1.46 g, 3.04 mmol) was dissolved in 12 ml of
anhydrous THF in a polyethylene vessel and 3 ml of HF-Py was
added to it at 0 °C. The mixture was then stirred for 7 h at room
temperature followed by the addition of 75 mL of EtOAc and
25 mL of brine solution. The organic layer was then separated
and the aqueous layer was washed with (2 Â 75 mL) EtOAc. The
combined organic part was washed with brine (30 mL) and the
solution was dried over anhydrous MgSO4 and then concentrated
in vacuo. The crude material was then purified by silica gel column
chromatography (EtOAc/hexane, 1:5) to afford compound 26
(0.97 g) in 88% yield as a liquid. Rf = 0.3 (EtOAc/hexane, 1:5).
[a]
28 = +21.3 (c 1.0, CHCl3). 1H NMR (600 MHz, CDCl3), dH: 5.1 6
D
two steps. Rf = 0.3 (EtOAc/hexane 2:1). [
a
]
30 = À2.3 (c 1.0, MeOH).
(q, 1H, J = 3.8 Hz), 4.83 (dd, 1H, J = 2.4, 6.0 Hz), 4.49– 4.47 (m,
1H), 4.18 (dd, 1H, J = 6.0, 7.8 Hz), 2.60–2.48 (m, 4H), 2.05–2.01
(m, 2H), 1.85 (m, 1H), 1.67–1.66 (m, 1H), 1.53 (s, 3H), 1.35 (s,
3H), 1.34–1.24 (m, 10H), 0.89–0.87 (m, 3H). 13C NMR (150 MHz,
CDCl3), dC: 172.5, 110.8, 84.0, 79.2, 78.2, 76.2, 73.7, 73.4, 67.9,
61.1, 32.2, 31.7, 31.4, 30.0, 29.5, 29.1, 27.2, 25.7, 24.5, 22.6, 14.0.
HRMS (ESI) for C21H32O5Na [M+Na]+, calculated: 387.2148; found:
387.2149.
D
1H NMR (600 MHz, CDCl3), dH: 5.87 (dd, 1H, J = 1.8, 15.6 Hz), 5.52
(ddd, 1H, J = 1.4, 9.6, 15.4 Hz), 5.16 (d, 1H, J = 4.8 Hz), 5.03–5.00
(m, 1H), 4.52–4.49 (m, 1H), 3.59 (dd, 1H, J = 2.7, 9.9 Hz), 2.66 (t,
2H, J = 4.8 Hz), 2.61 (t, 2H, J = 5.4 Hz), 2.39–2.36 (m, 1H), 2.19–
2.08 (m, 2H), 2.08–2.00 (m, 1H), 1.99–1.88 (m, 1H), 1.56–1.54
(m, 1H), 1.37–1.26 (m, 10H), 0.88 (t, 3H, J = 7.2 Hz). 13C NMR
(150 MHz, CDCl3), dC: 176.1, 174.6, 171.7, 132.9, 123.4, 73.4, 72.4,
Please cite this article in press as: Kumar, R.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.06.001

R. Kumar et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
9
Karhale, D. S.; Yadav, J. S. Synlett 2013, 2679–2682; (c) Rej, R. K.; Jana, A.;
Nanda, S. Tetrahedron 2014, 70, 2634–2642.
70.9, 31.8, 31.55, 31.2, 29.6, 29.5, 29.4, 29.2, 28.9, 24.6, 22.6, 14.1.
1H NMR (600 MHz, CD3OD), dH: 5.91 (dd, 1H, J = 2.1, 15.6 Hz), 5.49
(ddd, 1H, J = 2.2, 9.5, 15.5 Hz), 5.18 (dt, 1H, J = 4.7, 10.2 Hz), 5.13
(dt, 1H, J = 2.6, 9.4 Hz), 4.40 (br d, 1H, J = 2.2 Hz), 3.52 (dd, 1H,
J = 2.4, 9.7 Hz), 2.56 (s, 4H), 2.34 (ddd, 1H, J = 2.2, 6.1, 13.9 Hz),
2.10 (dt, 1H, J = 1.9, 13.9 Hz), 2.00–1.95 (m, 1H), 1.91 (dt, 1H,
J = 2.2, 13.2 Hz), 1.87–1.82 (m, 1H), 1.49–1.47 (m, 1H), 1.36–1.25
(m, 10H), 0.88 (t, 3H, J = 6.8 Hz). 13C NMR (150 MHz, CD3OD), dC:
175.9 (2C), 173.5, 136.0, 123.8, 78.2, 74.5, 73.5, 72.2, 33.1, 32.8,
32.3, 30.9, 30.8 (2C), 30.5, 25.7, 23.8, 14.6. HRMS (ESI) for
6. (a) Jana, N.; Mahaptra, T.; Nanda, S. Tetrahedron: Asymmetry 2009, 20, 2622–
2628; (b) Das, T.; Jana, N.; Nanda, S. Tetrahedron Lett. 2010, 51, 2644–2647; (c)
Das, T.; Bhuniya, R.; Nanda, S. Tetrahedron: Asymmetry 2010, 21, 2206–2211;
(d) Mahapatra, T.; Das, T.; Nanda, S. Bull. Chem. Soc. Jpn. 2011, 84, 511–519; (e)
Das, T.; Nanda, S. Tetrahedron Lett. 2012, 53, 256–258; (f) Das, T.; Mahaptra, T.;
Nanda, S. Tetrahedron Lett. 2012, 53, 1186–1189; (g) Rej, R. K.; Nanda, S. Eur. J.
Org. Chem. 2014, 4, 860–871; (h) Rej, R. K.; Nanda, S. Tetrahedron 2014, 70,
4457–4470.
7. (a) Vadhadiya, P. M.; Ramana, C. V. Tetrahedron Lett. 2014, 55, 6263–6265; (b)
Maram, L.; Das, B. Synlett 2014, 2327–2330.
8. Lacombe, F.; Radkowski, K.; Seidel, G.; Furstner, A. Tetrahedron 2004, 60, 7315–
7324.
C
20H32O8Na [M+Na]+, calculated: 423.1995.; found: 423.2016.
9. Krishna, P. R.; Lavany, B.; Ilangovan, A.; Sharma, G. V. M. Tetrahedron:
Asymmetry 2000, 11, 4463–4472.
10. Trost, B. M.; Quintard, A. Angew. Chem., Int. Ed. 2012, 51, 6704–6708.
11. Moon, H. R.; Choi, W. J.; Kim, H. O.; Jeong, L. S. Tetrahedron: Asymmetry 2002,
13, 1189–1193.
12. Mozingo, R.; Wolf, D. E.; Harris, S. A.; Folkers, K. J. J. Am. Chem. Soc. 1946, 65,
1013.
Acknowledgements
Financial support from CSIR-India is gratefully acknowledged
(Grant: 02(0020)/11/EMR-II). We are also thankful to DST-India
(IRPHA) for NMR instrument. Two of the authors RKR and RK are
thankful to CSIR-India and UGC for providing research fellowship.
13. Appel, R. Angew. Chem., Int. Ed. 1975, 14, 801–811.
14. (a) Yadav, J. S.; Chander, M. C.; Joshi, B. V. Tetrahedron Lett. 1988, 29, 2737–
2740; (b) Yadav, J. S.; Chander, M. C.; Rao, C. S. Tetrahedron Lett. 1989, 30, 5455–
5458; (c) Yadav, J. S.; Bayapelly, K.; Alugubelli, S. R.; Pabbaraja, S.; Vangale, J. R.;
Kalivendi, S. V. J. Org. Chem. 2011, 76, 2568–2576.
15. Bornscheuer, U. T.; Kazlauskas, R. J. In Hydrolases in Organic Synthesis; Wiley-
VCH: Weinheim, 1999. ISBN: 3-527-30104-6.
16. Horita, K.; Yoshioka, T.; Tanaka, Y.; Oikawa, Y.; Yonemitsu, O. Tetrahedron 1986,
42, 3021–3028.
17. Mancuso, A. J.; Brownfain, D. S.; Swern, D. J. Org. Chem. 1979, 44, 4148–4150.
18. Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091–2096.
19. Inanga, J.; Hirata, K.; Sacki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989–1993.
References
1. Ishida, T.; Wada, K. J. Chem. Soc., Chem. Commun. 1975, 6, 209–210.
2. Hiep, N. T.; Choi, Y.; Kim, N.; Hong, S. S.; Hong, S. B.; Hwang, B. Y.; Lee, H. J.; Lee,
S. J.; Jang, D. S.; Lee, D. J. Nat. Prod. 2012, 75, 784–788.
3. Ortega, H. E.; Shem, Y. Y.; TenDyke, K.; Rios, N.; Cubilla-Rios, L. Tetrahedron Lett.
2014, 55, 2642–2645.
4. Baraban, E. G.; Morin, J. B.; Phillips, G. M.; Phillips, A. J.; Strobel, S. A.;
Handelsman, J. Tetrahedron Lett. 2013, 54, 4058–4060.
5. (a) Reddy, B. V. S.; Reddy, P. S.; Reddy, B. P.; Yadav, J. S.; Ghamdi, A. A. K. A.
Tetrahedron Lett 2013, 54, 5758–5760; (b) Mohapatra, D. K.; Reddy, D. P.;
20. Heppekausen, J.; Stad, R.; Goddard, R.; Furstner, A. J. Am. Chem. Soc. 2010, 132,
11045–11057.
21. Scholl, M.; Deng, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956.
Please cite this article in press as: Kumar, R.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.06.001