An Enantioselective Synthesis of (5 S,6 R,11 S,14 R)-Acremodiol

Article abstract of DOI:10.1055/s-0036-1588557

An expeditious synthesis of the (5 S,6 R,11 S,14 R)-isomer of acremodiol was developed via a convergent route. One of the required building blocks was synthesized earlier via two sequential lipase-catalyzed secondary carbinol acetylations. The other unit

Full text of DOI:10.1055/s-0036-1588557

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–G
paper
A
en
P. Dey et al.
Paper
Synthesis
An Enantioselective Synthesis of (5S,6R,11S,14R)-Acremodiol
Papiya Dey§
Sucheta Chatterjee§
Sunita S. Gamre§
Mitsunobu esterification
O
O
Ga-mediated crotylation of
Lipase-catalyzed
acylation
Subrata Chattopadhyay
Anubha Sharma*
HO
(R)-2,3-cyclohexylidene
glyceraldehyde
O
O
OH
RCM
Bio-Organic Division, Bhabha Atomic Research Centre,
Mumbai 400 085, India
3.3% overall yield in 21 steps
anubhas@barc.gov.in
§ Equal contributions.
Received: 27.07.2017
Accepted after revision: 29.07.2017
Published online: 29.08.2017
report an efficient synthesis of (5S,6R,11S,14R)-1, a stereo-
mer of acremodiol that has not been synthesized so far. The
chemical structures of the acremodiol stereomers, synthe-
sized by Sharma et al. and in the present paper are shown
in Figure 1.
DOI: 10.1055/s-0036-1588557; Art ID: ss-2017-n0303-op
Abstract An expeditious synthesis of the (5S,6R,11S,14R)-isomer of
acremodiol was developed via a convergent route. One of the required
building blocks was synthesized earlier via two sequential lipase-cata-
lyzed secondary carbinol acetylations. The other unit was derived from
(R)-2,3-cyclohexylideneglyceraldehyde as a chiral template. The bis-
macrolide skeleton was constructed by an intermolecular esterification
O
O
O
1
O
O
O
14
5
16
HO
HO
HO
6
11
reaction under Mitsunobu conditions followed by
metathesis of the resultant α,ω-dialkenoic ester.
a ring-closing
O
O
O
O
O
O
OH
OH
OH
15
Keywords asymmetric synthesis, (R)-2,3-cyclohexylideneglyceralde-
hyde, macrodiolide, ring-closing metathesis, lipase-catalyzed trans-
esterification
(5R,6R,11R,14R)-1
Synthesized by Sharma et al.3c
(5R,6R,11S,14R)-1
(5S,6R,11S,14R)-1
Our synthesis
Figure 1 Various acremodiol stereomers that have been synthesized
Macrolides are prevalent in various natural sources1 and
often show impressive medicinal and other biological pro-
files, besides providing synthetic challenges.2 Amongst
these, acremodiol is a 14-membered bismacrolide isolated
from a soil sample of the Bermuda islands containing
acremonium-like anamorphic fungus.3a Based on NMR, ESI-
MS, and FAB-MS data, natural acremodiol was assigned the
structure (5R,6R,11R,14R)-1. It showed inhibitory property
against a series of Gram-positive bacteria and fungi,3a un-
like another closely related bis-lactone, colletodiol.3b It was
also active in cellular phagocytosis assay with dog PMNL
cells and reduced the oxidative burst at concentrations ≥4
μg/mL. Sharma et al. developed the first synthesis of
(5R,6R,11R,14R)-1, its 11-epimer, and acremonol.3c But the
spectroscopic and chirooptical data of the synthetic com-
pounds were not in agreement with the reported values for
the natural sample.3c Accordingly, a revision of structure
was suggested. Hence, there is a need to prepare isomers of
acremodiol for biological evaluation/structural confirma-
tion. Due to the presence of four stereogenic centers in it,
16 stereomers of acremodiol are possible. In this paper, we
Based on retrosynthesis, we envisioned that the synthe-
sis of (5S,6R,11S,14R)-1 (Scheme 1) could be achieved by a
ring-closing metathesis (RCM) of the immediate precursor
A-unit and global removal of the protecting group (Pg1 =
Bn). The A-unit, in turn, can be obtained by an esterification
reaction between the hept-6-ene-2,5-diol derivative B1 and
the 4,5-dihydroxyhexanoic acid derivative C under Mitsu-
nobu conditions4 followed by selective deprotection and ac-
rylation. Regarding the required building blocks, the B1-unit
was proposed to be derived easily from the B2-unit (Pg2 =
TBDPS) that was recently synthesized by us following a
chemoenzymatic route.5 The versatility of the B2-unit and
its stereomers has already been adequately demonstrated
via syntheses of several O-heterocycles by our group.5 We
planned to use (R)-2,3-cyclohexylideneglyceraldehyde (2)
as the chiral template to synthesize the C-unit. Compound 2
is an ideal starting material in asymmetric synthesis due to
the presence of diverse functionalities in it. Previously, we
have employed it extensively for the enantiomeric syn-
theses of a wide range of biologically active natural
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

B
P. Dey et al.
Paper
Synthesis
compounds, and as a chiral template for some asymmetric
transformations.6a–g,6j Moreover, its S-enantiomer can also
be easily obtained from inexpensive vitamin C.7
OH
O
O
i
iii
HO
O
O
CHO
OR
82%
97%
OBn
O
OR
2
ii
5
3 R = H
4 R = Bn
O
O
O
OPg1
95%
Pg1O
HO
OH
iv
82%
OBn
6 R = H
O
O
O
O
OTBDPS
OTBDPS
v
vi
vii
89%
R
(5S,6R,11S,14R)-1
A
91%
7 R = TBDPS
OH
88%
OPg2
OBn
OBn
OPg1
9 R = CHO
10 R = CO2H
viii
77%
8
O
Scheme 2 Reagents and conditions: (i) Ga, allyl bromide, [bmim][Br],
4 h; (ii) NaH, BnBr, Bu4NI, THF, reflux, 4 h; (iii) aq 2 N HCl, MeOH, 25 °C,
4 h; (iv) 1) p-TsCl, Bu2SnO, Et3N, CH2Cl2, 25 °C, 6 h, 2) LiAlH4, THF, reflux,
8 h; (v) TBDPSCl, imidazole, DMAP, CH2Cl2, 25 °C, 7 h; (vi) 1) BH3·SMe2,
THF, 0 °C, 3 h, 2) aq NaOH, H2O2, 0 °C, 3 h, then 25 °C, 12 h; (vii) PCC,
NaOAc, CH2Cl2, 0–25 °C, 3 h; (viii) NaClO2, NaHPO4·2H2O, H2O2, aq
MeCN, 0–15 °C, 6 h.
O
CO2H
CHO
C
2
+
Pg1O
Pg1O
OPg2
OH
B1
B2
Synthesis of B1-Unit
Pg1,2 = orthogonal protecting groups
Earlier we have synthesized all the stereomers of the
B1-unit starting from (±)-sulcatol (11) using two highly en-
antioselective Novozym 435®-catalyzed acylation reac-
tions5 as the key steps. The acetate 12, obtained during that
course of the synthesis was ideally disposed to provide the
B1-unit. Hence, it was converted into the corresponding al-
lylic alcohol 13, by treatment with K2CO3 in MeOH (Scheme
3). Its benzylation to 14 and subsequent desilylation gave
the alcohol 15 (B1-unit equivalent).
Scheme 1 Retrosynthesis of (5S,6R,11S,14R)-1
To realize the synthetic plan, the initial task was the
preparation of the C unit from the aldehyde 2 and transfor-
mation of the B2-unit to the required B1-unit. These are se-
quentially described below.
Synthesis of C-Unit
It commenced from the homoallylic alcohol 3,6h,i,k which
was conveniently prepared by a Ga-mediated allylation6e of
2 in the room temperature ionic liquid, 1-butyl-3-methyl-
imidazolium bromide ([bmim][Br]). The reaction proceed-
ed with 94:6 diastereoselectivity to yield the anti-isomer 3
as the major product, which was isolated by column chro-
matography as a pure enantiomer. It is worth mentioning
that the designated allylation reaction can be carried out
with near-stoichiometric amounts of the substrates and
only 0.5 equivalent of Ga-metal, unlike most of the reported
Barbier-type protocols. Benzylation of the alcohol 3 fur-
nished 4,6c,8a which on treatment with aqueous methanolic
HCl8b afforded the diol 59a (Scheme 2). This was converted
into the alcohol 69b by Martinelli monotosylation (Bu2SnO,
p-TsCl, Et3N),9c followed by LiAlH4 reduction. Its silylation
with tert-butyldiphenylsilyl chloride (TBDPSCl), imidazole
and 4-dimethylaminopyridine (DMAP) gave 7, which was
regioselectively hydroborated with BH3·SMe2, and the inter-
mediate trialkylborane oxidized with H2O2/NaOH to afford
the alcohol 8. Its PCC oxidation to the aldehyde 9, followed
by Pinnick oxidation furnished the acid 10 (C-unit equiva-
lent).
OTBDPS
OTBDPS
OH
iii
i
95%
OBn
14
OR
11
12 R = Ac
13 R = H
ii
92%
OH
iv
89%
OBn
15
Scheme 3 Reagents and conditions: i) Ref. 5; ii) K2CO3, MeOH, 25 °C,
4 h; iii) NaH, BnBr, Bu4NI, THF, reflux, 4 h; iv) Bu4NF, THF, 0 °C, 7 h.
Synthesis of (5S,6R,11S,14R)-1
For the synthesis, the acid 10 was esterified with alco-
hol 15 under Mitsunobu conditions (Ph3P, DIAD) to obtain
the ester 16 (Scheme 4). Its desilylation turned out to be
quite problematic. When attempted with Bu4NF in THF, de-
composition of the ester could not be avoided even at 0 °C,
and the recovery of the generated 15 was also unsatisfacto-
ry (55% yield). Use of HF in MeCN also led to degradation
of 16 to some unidentified products. Although use of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

C
P. Dey et al.
Paper
Synthesis
HF·pyridine in THF is seldom recommended for deprotec-
tion of secondary TBDPS ethers,10a we obtained the desired
alcohol 17 in a modest (42%) yield under these conditions.
Carrying out the reaction in THF and pyridine10b (1:1 v/v) as
the solvent led to 17 in a markedly improved yield (87%)
without any ester hydrolysis or decomposition. Its conver-
sion into the acrylate 18 with acryloyl chloride/Hünig’s
base in CH2Cl2 proceeded uneventfully. An RCM11 reaction
between the terminal olefin moieties in 18 with Grubbs I
catalyst in CH2Cl2 at 40 °C gave the macrodiolide 19 along
with unreacted 18 (16% yield) under high dilution condi-
tions (2 mM of 18 in CH2Cl2). The E-geometry of the incipi-
did not furnish the natural acremodiol, our synthetic plan
relies on use of inexpensive reagents/materials and opera-
tionally simple and selective reactions, making it more effi-
cient and potentially scalable.
The chemicals were procured from Fluka or Sigma Aldrich and were
used as received. Other reagents were of AR grade. Novozym 435® li-
pase was purchased from Sigma Aldrich. All anhydrous reactions
were carried out under an argon atmosphere, using freshly dried sol-
vents. All organic extracts were dried over anhyd Na2SO4. IR spectra
were recorded as films with a JASCO model A-202 spectrophotome-
ter. 1H and 13C NMR spectra were recorded in CDCl3 (unless otherwise
mentioned) with a Bruker AC-200 instrument or 500 MHz Varian
NMR spectrometer. Optical rotations were recorded on a Jasco DIP-
360 digital polarimeter. Elemental analyses were recorded on Ele-
mentar Vario micro cube. Melting points were recorded on Büchi M
560 instrument.
1
ent olefin was confirmed from the H NMR olefinic reso-
nances, namely at δ = 5.86 (d, J = 16.0 Hz, 1 H) and δ = 6.64
(dd, J = 16.0, 9.5 Hz, 1 H). Attempted debenzylation of 19
with DDQ in CH2Cl2/H2O (4:1)12 furnished an intractable
mixture of products. Finally, the required debenzylation
was accomplished with TiCl4 in CH2Cl213 to afford the target
compound in 85% yield. However, the spectral data, and
(2R,3S)-1,2-Cyclohexylidenedioxyhex-5-en-3-ol (3)
A mixture of Ga metal (0.820 g, 11.77 mmol) and allyl bromide (2.44
mL, 28.23 mmol) in [bmim][Br] (50 mL) was stirred at r.t. for 0.5 h,
followed by addition of 2 (4.0 g, 23.53 mmol). After stirring at r.t. for 4
h, the mixture was extracted with Et2O (2 × 30 mL), the combined or-
ganic extracts were evaporated in vacuo, and the residue purified by
column chromatography (silica gel, 0–15% EtOAc/hexane) to obtain 3
26
the optical rotation {[α]D –13.0 (c 0.89, MeOH)} of
(5S,6R,11S,14R)-1 were not in correspondence with the re-
25
ported value {[α]D +98 (c 0.3, MeOH)} of natural acremo-
diol.3a The 1H and 13C spectral data of all three isomers
(shown in Figure 1) along with those reported for natural
acremodiol have been provided in the Supporting Informa-
tion to allow comparison of the changes.
25
(4.1 g, 82%) as a colorless oil; [α]D24 +10.5 (c 1.24, CHCl3) {Lit.6k [α]D
+10.2 (c 1.41, CHCl3)}; Rf = 0.52 (20% EtOAc/hexane).
IR (thin film): 3453, 1642, 1101, 1044 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 5.93–5.72 (m, 1 H, H-5), 5.17–5.09 (m,
2 H, H-6), 4.02–3.89 (m, 3 H, H-2, H-3, HB-1), 3.81–3.73 (m, 1 H, HA-1),
2.38–2.10 (m, 2 H, H-4), 1.82 (br s, 1 H, OH), 1.64–1.49 (m, 8 H, 4 ×
ring CH2), 1.47–1.24 (m, 2 H, ring CH2).
O
O
1
O
O
2
2' 3'
3
4
i
iii
1'
4'
5'
10
BnO
BnO
89%
78%
5
7'
O
O
OR
6'
OBn
OBn
6
(4S,5R)-4-Benzyloxy-5,6-cyclohexylidenedioxyhex-1-ene (4)
ii
16 R = TBDPS
17 R = H
18
To a stirred suspension of hexane-washed NaH (1.81 g, 50% suspen-
sion in oil, 37.68 mmol) in THF (10 mL) was added 3 (4.00 g, 18.84
mmol) in THF (50 mL). After refluxing the mixture for 1 h, it was
brought to r.t., BnBr (2.69 mL, 22.61 mmol) and Bu4NI (10 mol %)
were added, and the mixture refluxed until completion of the reac-
tion (TLC, 4 h). The mixture was brought to r.t., extracted with Et2O (3
× 25 mL), the combined organic extracts were washed with H2O (2 ×
10 mL) and brine (1 × 5 mL), and dried. Removal of solvent in vacuo,
followed by column chromatography (silica gel, 0–10% EtOAc/hexane)
87%
O
1
O
3
14
iv
55%
5
16
RO
O7
O
11
OR
15
9
v
19 R = Bn
(5S,6R,11S,14R)-1 R = H
85%
25
of the residue afforded pure 4 (5.4 g, 95%) as a colorless oil [α]D
Scheme 4 Reagents and conditions: i) 15, Ph3P, DIAD, THF, 0 to 25 °C,
18 h; ii) HF·Pyr, THF–pyridine (1:1 v/v), 25 °C, 6 h; iii) acryloyl chloride,
DIPEA, CH2Cl2, 25 °C, 3 h; iv) Grubbs I catalyst, CH2Cl2, 40 °C, 48 h; v)
TiCl4, CH2Cl2, 0 to 25 °C, 0.5 h.
+27.5 (c 1.47, CHCl3) {Lit.8a [α]D25 +16.7 (c 1.15, CHCl3)}; Rf = 0.91 (10%
EtOAc/hexane).
IR (thin film): 3067, 3031, 1641, 998, 926 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 7.33–7.29 (m, 5 H, C6H5), 5.99–5.78 (m,
1 H, H-2), 5.18–5.05 (m, 2 H, H-1), 4.68–4.54 (m, 2 H, OCH2Ph), 4.12–
3.98 (m, 2 H, H-5, H-4), 3.92–3.83 (m, 1 H, HB-6), 3.60–3.52 (m, 1 H,
HA-6), 2.44–2.34 (m, 2 H, H-3), 1.62–1.55 (m, 8 H, 4 × ring CH2), 1.44–
1.26 (m, 2 H, ring CH2).
In summary, we have developed a convergent synthesis
of (5S,6R,11S,14R)-1, which features our own chemoenzy-
matic route and a Ga-mediated carbonyl allylation, as the
key steps. Synthesis of the target was achieved in 21 steps
in an overall yield of 3.3% as compared to the only report of
the synthesis of (5R,6R,11R,14R)-1 (22 steps, 0.7% yield) and
its C-11 epimer (26 steps, 0.6% yield), using a Sharpless ep-
oxidation, a Sharpless dihydroxylation, and a Jacobsen reso-
lution for installing the stereocenters. Though our synthesis
(2R,3S)-3-Benzyloxyhex-5-ene-l,2-diol (5)
A mixture of 4 (5.35 g, 17.69 mmol) and aq 2 N HCl (4–5 drops) in
MeOH (10 mL) was stirred at 25 °C until completion of the reaction
(TLC, 4 h). Cyclohexanone dimethyl ketal formed in the reaction was
removed by washing with hexane (3 × 20 mL). The MeOH layer was
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

D
P. Dey et al.
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Synthesis
concentrated in vacuo, the residue diluted with H2O (30 mL), and ex-
tracted with EtOAc (3 × 20 mL). The combined organic extracts were
washed successively with H2O (3 × 20 mL), aq 10% NaHCO3 (2 × 10
mL), H2O (2 × 20 mL), and brine (1 × 10 mL), and dried. Solvent remov-
al followed by column chromatography (silica gel, 0–5% MeOH/CHCl3)
of the residue gave pure 5 (3.8 g, 97%) as a colorless oil; [α]D26 +35.2 (c
lowed by purification of the residue by column chromatography (sili-
ca gel, 0–5% EtOAc/hexane) afforded pure 7 (4.3 g, 91%) as a colorless
oil; [α]D26 –6.0 (c 1.24, CHCl3); Rf = 0.70 (5% EtOAc/hexane).
IR (thin film): 3071, 1641, 998, 914 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 7.71–7.66 (m, 4 H, C6H5), 7.39–7.31 (m,
11 H, C6H5), 5.79–5.61 (m, 1 H, H-2), 5.04–4.95 (m, 2 H, H-1), 4.73 (d,
J = 11.6 Hz, 1 H, OCHBPh), 4.55 (d, J = 11.6 Hz, 1 H, OCHAPh), 3.94–3.89
(m, 1 H, H-4), 3.43–3.39 (m, 1 H, H-5), 2.33–2.18 (m, 2 H, H-3), 1.07
[merged s (at δ = 1.07) and d, J = 6.2 Hz, 12 H, H-6, t-C4H9].
25
1.05, CHCl3) {Lit.9a [α]D +33.9 (c 1.0, CHCl3)}; Rf = 0.48 (5% MeOH/
CHCl3).
IR (thin film): 3386, 3068, 3010, 1641, 917 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 7.33–7.25 (m, 5 H, C6H5), 5.92–5.79 (m,
1 H, H-5), 5.20–5.12 (m, 2 H, H-6), 4.69–4.47 (m, 2 H, OCH2Ph), 3.73–
3.63 (m, 4 H, H-2, H-3, H-1), 2.54–2.25 (m, 2 H, H-4), 1.75 (br s, 2 H,
OH).
13C NMR (50 MHz, CDCl3): δ = 139.1, 136.0, 135.5, 134.5, 133.9, 129.6,
129.5, 128.2, 127.6, 127.5, 127.4, 127.3, 116.5, 83.5, 72.7, 71.4, 35.8,
27.0, 19.2, 18.3.
Anal. Calcd for C29H36O2Si: C, 78.33; H, 8.16. Found: C, 78.62; H, 7.93.
(2R,3S)-3-Benzyloxyhex-5-en-2-ol (6)
(4S,5R)-4-Benzyloxy-5-tert-butyldiphenylsilyloxyhexan-1-ol (8)
To a cooled (0 °C) and stirred solution of 5 (3.83 g, 17.23 mmol) and
Et3N (2.88 mL, 20.68 mmol) in CH2Cl2 (50 mL) was added p-TsCl (3.61
g, 18.95 mmol) followed by Bu2SnO (129 mg, 0.52 mmol). After stir-
ring for 6 h at r.t., H2O (15 mL) was added to the mixture, the organic
layer separated, and the aqueous layer extracted with CHCl3 (2 × 10
mL). The combined organic extracts were washed with H2O (1 × 10
mL) and brine (1 × 5 mL), and dried. Solvent removal followed by col-
umn chromatography (silica gel, 0–15% EtOAc/hexane) of the residue
gave the corresponding primary monotosylate (5.5 g, 85%) as a color-
less oil; [α]D25 +33.9 (c 1.06, CHCl3); Rf = 0.33 (20% EtOAc/hexane).
To a stirred and cooled (0 °C) solution of 7 (4.30 g, 9.67 mmol) in THF
(20 mL) was added BH3·SMe2 (644 μL, 95% purity, 6.45 mmol), and the
mixture stirred for 3 h at the same temperature. Aq 3 N NaOH (3.87
mL) was added to the mixture at 0 °C, followed by aq 30% H2O2 (3.87
mL). After stirring for 3 h at 0 °C and 12 h at 25 °C, the mixture was
extracted with EtOAc (3 × 15 mL). The combined organic extracts
were washed with H2O (2 × 10 mL), aq 10% HCl (1 × 10 mL), H2O (2 ×
10 mL), and brine (1 × 5 mL), and dried. Solvent removal followed by
column chromatography (silica gel, 0–15% EtOAc/hexane) of the resi-
due furnished pure 8 (3.9 g, 88%) as a colorless oil; [α]D25 –4.0 (c 1.01,
CHCl3); Rf = 0.52 (15% EtOAc/hexane).
IR (thin film): 3528, 3030, 1640, 1360, 1176, 974, 915 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 7.79–7.75 (d, J = 8.4 Hz, 2 H, C6H5),
7.33–7.24 (m, 7 H, C6H5), 5.92–5.71 (m, 1 H, H-5), 5.16–5.06 (m, 2 H,
H-6), 4.59 (d, J = 11.2 Hz, 1 H, OCHBPh), 4.41 (d, J = 11.2 Hz, 1 H,
OCHAPh), 4.24–4.06 (m, 2 H, H-1), 3.88–3.81 (m, 1 H, H-2), 3.56–3.48
(m, 1 H, H-3), 2.42–2.36 [merged s (at δ = 2.42) and m, 5 H, CH3, H-4],
1.85 (br s, 1 H, OH).
IR (thin film): 3405, 3070, 3010, 1642, 998 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 7.71–7.64 (m, 4 H, C6H5), 7.38–7.29 (m,
11 H, C6H5), 4.81 (d, J = 11.6 Hz, 1 H, OCHBPh), 4.47 (d, J = 11.6 Hz, 1 H,
OCHAPh), 3.93–3.89 (m, 1 H, H-4), 3.54–3.48 (m, 2 H, H-1), 3.38–3.34
(m, 1 H, H-5), 1.55–1.49 (m, 5 H, H-3, H-2, OH), 1.06 [merged s (at δ =
1.06) and d, J = 6.2 Hz, 12 H, H-6, t-C4H9].
13C NMR (50 MHz, CDCl3): δ = 138.8, 136.0, 134.5, 133.9, 129.6, 128.3,
127.8, 127.6, 127.5, 83.7, 72.8, 71.9, 62.8, 29.2, 27.4, 27.0, 19.2, 18.4.
13C NMR (50 MHz, CDCl3): δ = 144.8, 137.7, 133.6, 132.3, 129.7, 128.2,
127.8, 127.6, 117.8, 78.1, 71.9, 71.3, 70.3, 34.2, 21.4.
Anal. Calcd for C20H24O5S: C, 63.81; H, 6.43. Found: C, 64.03; H, 6.82.
Anal. Calcd for C29H38O3Si: C, 75.28; H, 8.28. Found: C, 75.57; H, 8.11.
To a suspension of LiAlH4 (424 mg, 11.16 mmol) in THF (30 mL) was
added dropwise the above tosylate (4.20 g, 11.16 mmol) in THF (20
mL). The mixture was refluxed for 8 h, brought to r.t., and the excess
hydride decomposed with sat. aq Na2SO4. The mixture was filtered,
the filtrate concentrated in vacuo, and the residue purified by column
chromatography (silica gel, 0–15% EtOAc/hexane) to obtain pure 6
(4S,5R)-4-Benzyloxy-5-tert-butyldiphenylsilyloxyhexanal (9)
To a cooled (0 °C) and stirred suspension of PCC (2.54 g, 11.77 mmol)
and NaOAc (10 mol%) in CH2Cl2 (30 mL) was added the alcohol 8 (3.63
g, 7.85 mmol) in one lot. After stirring for 3 h at 25 °C, the reaction
mixture was diluted with Et2O (30 mL) and the supernatant passed
through a column of silica gel. Removal of solvent in vacuo followed
by column chromatography of the residue (silica gel, 0–10%
26
30
(2.2 g, 96%) as a colorless oil; [α]D +5.8 (c 1.01, CHCl3) {Lit.9b [α]D
+3.8 (c 0.3, CHCl3)}; Rf = 0.53 (10% EtOAc/hexane).
IR (thin film): 3440, 3068, 3009, 1641, 995, 916 cm–1
.
26
EtOAc/hexane) furnished pure 9 (3.2 g, 89%) as a colorless oil; [α]D
–8.4 (c 1.30, CHCl3); Rf = 0.59 (15% EtOAc/hexane).
1H NMR (200 MHz, CDCl3): δ = 7.35–7.31 (m, 5 H, C6H5), 5.95–5.77 (m,
1 H, H-5), 5.17–5.04 (m, 2 H, H-6), 4.69–4.52 (m, 2 H, OCH2Ph), 3.97–
3.87 (m, 1 H, H-3), 3.46–3.38 (m, 1 H, H-2), 2.46–2.23 (m, 2 H, H-4),
2.00 (br s, 1 H, OH), 1.18 (d, J = 6.4 Hz, 3 H, H-1).
IR (thin film): 3071, 3014, 2725, 1722 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 9.64 (t, J = 1.6 Hz, 1 H, H-1), 7.70–7.68
(m, 4 H, C6H5), 7.39–7.27 (m, 11 H, C6H5), 4.78–4.61 (m, 1 H, OCHBPh ),
4.49–4.32 (m, 1 H, OCHAPh), 3.96–3.89 (m, 1 H, H-4), 3.37–3.31 (m, 1
H, H-5), 2.38 (dt, J = 7.2, 1.6 Hz, 2 H, H-2), 1.84–1.76 (m, 2 H, H-3),
1.08–1.06 (m, 12 H, H-6, t-C4H9).
13C NMR (50 MHz, CDCl3): δ = 18.7, 19.2, 23.1, 27.0, 40.3, 71.1, 72.4,
82.6, 127.5, 127.6, 127.7, 127.8, 128.2, 129.6, 129.7, 133.6, 134.3,
135.9, 138.5, 202.5.
(4S,5R)-4-Benzyloxy-5-tert-butyldiphenylsilyloxyhex-1-ene (7)
To a stirred solution of 6 (2.20 g, 10.67 mmol), imidazole (1.09 g,
16.00 mmol), and DMAP (catalytic) in CH2Cl2 (20 mL) was added
dropwise TBDPSCl (3.32 mL, 12.80 mmol). After stirring the mixture
for 7 h at r.t., it was poured into ice-cold H2O (20 mL), the organic lay-
er separated, and the aqueous portion extracted with CHCl3 (3 × 10
mL). The combined organic extracts were washed with H2O (2 × 10
mL) and brine (1 × 5 mL), and dried. Removal of solvent in vacuo fol-
Anal. Calcd for C29H36O3Si: C, 75.61; H, 7.88. Found: C, 75.97; H, 7.50.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

E
P. Dey et al.
Paper
Synthesis
(4S,5R)-4-Benzyloxy-5-tert-butyldiphenylsilyloxyhexanoic Acid
(10)
tracts were washed with H2O (2 × 20 mL) and brine (1 × 5 mL), and
dried. Removal of solvent followed by column chromatography of the
residue (silica gel, 0–10% EtOAc/hexane) furnished 15 (1.26 g, 89%) as
To a stirred solution of 9 (3.00 g, 6.51 mmol) in MeCN (10 mL) was
added NaH2PO4·2H2O (203 mg, 1.30 mmol) in H2O (1 mL) and aq 30%
H2O2 (810 μL, 7.16 mmol). The mixture was cooled to 0 °C, NaClO2
(1.18 g, 13.02 mmol) in H2O (1 mL) added dropwise over 0.5 h and
stirred at 15 °C until completion of the reaction (6 h, monitored by
gas evolution). After the addition of NaHSO3 (250 mg), the mixture
was extracted with EtOAc (3 × 30 mL). The combined organic layers
were washed with H2O (2 × 15 mL) and brine (1 × 10 mL), and concen-
trated in vacuo to get a residue, which on column chromatography
(silica gel, 0–10% EtOAc/hexane) furnished pure 10 (2.4 g, 77%) as a
viscous colorless oil; [α]D26 –8.3 (c 1.10, CHCl3); Rf = 0.47 (25% EtOAc/
hexane).
a colorless oil; [α]D –19.8 (c 1.03, CHCl3) {Lit.5 [α]D –20.6 (c 1.06,
CHCl3)}; Rf = 0.49 (20% EtOAc/hexane).
32
25
IR (thin film): 3405, 3065, 3030, 1643 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H, C6H5), 5.80–5.73 (m,
1 H, H-6), 5.26–5.21 (m, 2 H, H-7), 4.60 (d, J = 11.5 Hz, 1 H, OCHBPh),
4.36 (d, J = 11.5 Hz, 1 H, OCHAPh), 3.80–3.78 (m, 2 H, H-5, H-2), 1.72–
1.50 (m, 5 H, H-4, H-3, OH), 1.18 (d, J = 6.5 Hz, 3 H, H-1).
(4S,5R)-[(2R,5S)-5-Benzyloxyhept-6-en-2-yl]-4-benzyloxy-5-tert-
butyldiphenylsilyloxy hexanoate (16)
A solution of 10 (2.22 g, 4.66 mmol), 15 (1.03 g, 4.66 mmol), and PPh3
(1.83 g, 6.99 mmol), in THF (20 mL) was stirred, cooled to 0 °C and
treated with DIAD (1.38 mL, 6.99 mmol). The mixture was stirred for
18 h at r.t., diluted with H2O, and extracted with EtOAc (2 × 15 mL).
The combined organic extracts were washed with H2O (2 × 10 mL)
and brine (1 × 5 mL), and dried. After concentrating in vacuo, the resi-
due was subjected to column chromatography (silica gel, 0–20%
IR (thin film): 3500–2500, 3070, 1709 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 7.72–7.65 (m, 4 H, C6H5), 7.41–7.29 (m,
11 H, C6H5), 4.75 (d, J = 11.6 Hz, 1 H, OCHBPh), 4.43 (d, J = 11.6 Hz, 1 H,
OCHAPh), 3.98–3.87 (m, 1 H, H-4), 3.43–3.35 (m, 1 H, H-5), 2.42–2.33
(m, 2 H, H-2), 1.91–1.70 (m, 2 H, H-3), 1.06 [merged s (at δ = 1.07) and
d, J = 5.0 Hz, 12 H, H-6, t-C4H9].
13C NMR (50 MHz, CDCl3): δ = 179.8, 138.7, 135.9, 134.4, 133.7, 129.7,
129.6, 128.3, 127.7, 127.6, 127.5, 82.6, 72.6, 71.2, 30.4, 27.0, 25.5,
19.2, 18.6.
26
EtOAc/hexane) to give pure 16 (2.5 g, 78%) as a colorless oil; [α]D
–17.1 (c 1.01, CHCl3); Rf = 0.69 (10% EtOAc/hexane).
IR (thin film): 3070, 3031, 1730, 998, 928 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 7.70–7.64 (m, 4 H, C6H5), 7.39–7.28 (m,
16 H, C6H5), 5.77–5.60 (m, 1 H, H-6′), 5.23–5.14 (m, 2 H, H-7′), 4.89–
4.80 (m, 1 H, H-2′), 4.72 (d, J = 11.4 Hz, 1 H, OCHBPh), 4.56 (d, J = 11.8
Hz, 1 H, OCHAPh), 4.42 (d, J = 11.4 Hz, 1 H, OCHBPh), 4.31 (d, J = 12.0
Hz, 1 H, OCHAPh), 3.92–3.87 (m, 1 H, H-5′), 3.74–3.64 (m, 1 H, H-4),
3.40–3.32 (m, 1 H, H-5), 2.37–2.18 (m, 2 H, H-2), 1.62–1.52 (m, 6 H,
H-3, H-3′, H-4′), 1.14 (d, J = 6.4 Hz, 3 H, H-1′), 1.03 [merged s (at δ =
1.05) and d, J = 7.0 Hz, 12 H, H-6, t-C4H9].
Anal. Calcd for C29H36O4Si: C, 73.07; H, 7.61. Found: C, 72.93; H, 7.26.
(3S,6S)-6-tert-Butyldiphenylsilyloxyhept-1-en-3-ol (13)
A mixture of 12 (3.43 g, 8.35 mmol) and K2CO3 (1.38 g, 10.02 mmol)
in MeOH (20 mL) was stirred at 25 °for 4 h. After filtration, the residue
was concentrated in vacuo, dissolved in Et2O (150 mL), and washed
with H2O (2 × 30 mL) and brine (1 × 10 mL), and dried. Removal of
solvent in vacuo followed by column chromatography (silica gel, 0–5%
EtOAc/hexane) of the residue afforded pure 13 (2.84 g, 92%) as a col-
13C NMR (50 MHz, CDCl3): δ = 173.3, 138.9, 138.7, 136.0, 135.9, 134.5,
133.7, 129.6, 129.5, 128.3, 128.2, 127.7, 127.6, 127.4, 117.4, 82.9, 80.0,
72.7, 71.4, 70.5, 70.0, 31.5, 31.2, 30.9, 27.0, 26.0, 19.9, 19.2, 18.6.
24
24
orless liquid; [α]D –9.6 (c 1.06, CHCl3) {Lit.5 [α]D –10.1 (c 1.06,
CHCl3)}; Rf = 0.53 (10% EtOAc/hexane).
IR (thin film): 3420, 3050, 997 cm–1
.
Anal. Calcd for C43H54O5Si: C, 76.07; H, 8.02. Found: C, 76.21; H, 8.10.
1H NMR (200 MHz, CDCl3): δ = 7.70–7.65 (m, 4 H, C6H5), 7.42–7.31 (m,
6 H, C6H5), 5.87–5.70 (m, 1 H, H-2), 5.20–5.02 (m, 2 H, H-1), 4.00–3.87
(m, 2 H, H-3, H-6), 1.71 (br s, 1 H, OH), 1.55–1.52 (m, 4 H, H-4, H-5),
1.06 [merged s (at δ = 1.06) and d, J = 5.6 Hz, 12 H, H-7, t-C4H9].
(4S,5R)-[(2R,5S)-5-Benzyloxyhept-6-en-2-yl]-4-benzyloxy-5-hy-
droxyhexanoate (17)
To a mixture of 16 (1.40 g, 2.06 mmol) and pyridine/THF (1:1, 20 mL)
in a Teflon vessel was added HF·pyridine (70:30, 2 mL). After stirring
at r.t. for 6 h, the mixture was extracted with EtOAc (3 × 20 mL). The
combined organic layers were washed with H2O (2 × 10 mL) and brine
(1 × 10 mL) and concentrated in vacuo. The residue was column chro-
matographed (silica gel, 0–25% EtOAc/hexane) to afford pure 17 (790
mg, 87%) as a colorless oil; [α]D27 –11.3 (c 1.03, CHCl3); Rf = 0.43 (15%
EtOAc/hexane).
(3S,6S)-3-Benzyloxy-6-tert-butyldiphenylsilyloxyhept-1-ene (14)
Benzylation of 13 (2.61 g, 7.09 mmol) with hexane-washed NaH
(0.680 g, 14.16 mmol, 50% suspension in oil), BnBr (1.01 mL, 8.51
mmol), and Bu4NI (10 mol%) in THF (40 mL), followed by workup and
column chromatography (silica gel, 0–5% EtOAc/hexane) afforded
31
pure 14 (3.09 g, 95%) as a colorless oil; [α]D –24.2 (c 1.24, CHCl3)
{Lit.5 [α]D23 –25.0 (c 1.20, CHCl3)}; Rf = 0.56 (5% EtOAc/hexane).
IR (thin film): 3406, 3067, 1720, 1642, 994, 927 cm–1
.
IR (thin film): 3070, 1642 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.36–7.27 (m, 10 H, 2 × C6H5), 5.72–
5.67 (m, 1 H, H-6′), 5.25–5.20 (m, 2 H, H-7′), 4.91–4.87 (m, 1 H, H-2′),
4.59 (d, J = 12.5 Hz, 1 H, OCHBPh), 4.57 (d, J = 11.5 Hz, 1 H, OCHAPh),
4.54 (d, J = 11.0 Hz, 1 H, OCHBPh), 4.33 (d, J = 11.5 Hz, 1 H, OCHAPh),
3.98–3.93 (m, 1 H, H-5′), 3.74–3.70 (m, 1 H, H-4), 3.36–3.35 (m, 1 H,
H-5), 2.51–2.44 (m, 1 H, HB-2), 2.39–2.32 (m, 1 H, HA-2), 1.95–1.81
(m, 3 H, H-3, OH), 1.73–1.64 (m, 2 H, H-3′), 1.53–1.48 (m, 2 H, H-4′),
1.19 (two overlapping d, J = 7.0, 6.0 Hz, 6 H, H-1′, H-6).
1H NMR (500 MHz, CDCl3): δ = 7.68–7.62 (m, 4 H, C6H5), 7.43–7.27 (m,
11 H, C6H5), 5.72-5.65 (m, 1 H, H-2), 5.21–5.09 (m, 2 H, H-1), 4.55 (d,
J = 12.0 Hz, 1 H, OCHBPh), 4.29 (d, J = 12.0 Hz, 1 H, OCHAPh), 3.88–3.83
(m, 1 H, H-3), 3.67–3.60 (m, 1 H, H-6), 1.69–1.43 (m, 4 H, H-4, H-5),
1.05 [merged s (at δ = 1.06) and d, J = 5.5 Hz, 12 H, H-7, t-C4H9].
(2S,5S)-5-Benzyloxyhept-6-en-2-ol (15)
13C NMR (125 MHz, CDCl3): δ = 173.5, 138.7, 138.6, 138.2, 128.5,
128.3, 127.9, 127.8, 127.7, 127.5, 117.5, 81.9, 80.0, 72.1, 70.8, 70.1,
67.4, 31.6, 31.3, 30.3, 23.6, 20.0, 18.0.
To a cooled (0 °C) and stirred solution of 14 (2.95 g, 6.44 mmol) in THF
(20 mL) was added Bu4NF (9.66 mL, 9.66 mmol, 1 M in THF). After
stirring for 7 h, the reaction mixture was poured into ice-cold H2O (15
mL) and extracted with EtOAc (3 × 20 mL). The combined organic ex-
Anal. Calcd for C27H36O5: C, 73.61; H, 8.24. Found: C, 73.95; H, 8.62.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

F
P. Dey et al.
Paper
Synthesis
(4S,5R)-[(2R,5S)-5-Benzyloxyhept-6-en-2-yl]-5-acryloyloxy-4-ben-
zyloxyhexanoate (18)
85%) as a white solid; mp 133–135 °C (Lit.3a mp 110–112 °C for natu-
ral 1); [α]D26 –13.0 (c 0.89, MeOH) {Lit.3a [α]D25 +98 (c 0.3, MeOH) for
natural 1)}; Rf = 0.43 (5% MeOH/CHCl3).
To a cooled (0 °C) solution of 17 (790 mg, 1.79 mmol) in CH2Cl2 (15
mL) were added DIPEA (0.60 mL, 3.59 mmol) and acryloyl chloride
(0.29 mL, 3.59 mmol). After stirring at r.t. for 3 h, the mixture was
poured into ice-cold H2O (20 mL), the organic layer separated, and the
aqueous portion extracted with CHCl3 (3 × 10 mL). The combined or-
ganic extracts were washed with H2O (2 × 10 mL) and brine (1 × 5
mL), and dried. Removal of solvent in vacuo followed by purification
of the residue by column chromatography (silica gel, 0–20%
EtOAc/hexane) afforded pure 18 (790 mg, 89%) as a colorless oil;
[α]D26 –26.1 (c 1.22, CHCl3); Rf = 0.51 (10% EtOAc/hexane).
IR (thin film deposited from a CHCl3 solution): 3405, 1723, 1653,
1648, 985 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 6.56 (dd, 16.5, 8.5 Hz, 1 H, H-10), 5.92
(d, J = 16.0 Hz, 1 H, H-9), 5.27–5.22 (m, 1 H, H-6), 4.90–4.87 (m, 1 H,
H-14), 4.39 (br s, 1 H, OH-5), 4.17–4.11 (m, 1 H, H-11), 3.72–3.76 (m,
1 H, H-5), 2.92–2.86 (m, 1 H, HB-3), 2.61–2.56 (m, 1 H, HA-3), 2.17–
2.11 (m, 1 H, HB-4), 2.00–1.94 (m, 1 H, HA-4), 1.89–1.84 (m, 1 H, HB-
13), 1.79–1.74 (m, 3 H, HA-13, HB-12, OH-11), 1.69–1.60 (m, 1 H, HA-
12), 1.27 (d, J = 7.0 Hz, 3 H, H-15), 1.20 (d, J = 6.5 Hz, 3 H, H-16).
IR (thin film): 3066, 3029, 1725, 1639, 1620, 987, 928 cm–1
.
13C NMR (125 MHz, CDCl3): δ = 175.1, 164.9, 147.8, 123.2, 74.1, 72.6,
1H NMR (500 MHz, CDCl3): δ = 7.34–7.26 (m, 10 H, 2 × C6H5), 6.41 (d,
J = 17.5, Hz, 1 H, olefinic), 6.13 (dd, J = 17.5, 10.5 Hz, 1 H, olefinic),
5.83 (d, J = 10.5 Hz, 1 H, olefinic), 5.76–5.68 (m, 1 H, H-6′), 5.25–5.16
(m, 3 H, H-7′, H-5), 4.91–4.87 (m, 1 H, H-2′), 4.71 (d, J = 11.5 Hz, 1 H,
OCHBPh), 4.59 (d, J = 12.0 Hz, 1 H, OCHAPh), 4.48 (d, J = 11.0 Hz, 1 H,
OCHBPh), 4.34 (d, J = 11.5 Hz, 1 H, OCHAPh), 3.75–3.70 (m, 1 H, H-5′),
3.55–3.51 (m, 1 H, H-4), 2.48–2.43 (m, 1 H, HB-2), 2.39–2.33 (m, 1 H,
HA-2), 1.89–1.82 (m, 2 H, H-3), 1.71–1.64 (m, 2 H, H-3′), 1.55–1.49 (m,
2 H, H-4′), 1.31 (d, J = 6.0 Hz, 3 H, H-6), 1.18 (d, J = 6.5 Hz, 3 H, H-1′).
71.5, 70.4, 31.9, 29.7, 28.8, 26.2, 19.2, 16.6.
Anal. Calcd for C14H22O6: C, 58.73; H, 7.74. Found: C, 59.07; H, 7.68.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588557.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
13C NMR (125 MHz, CDCl3): δ = 173.0, 165.5, 138.7, 138.6, 138.2,
128.7, 128.4, 128.3, 127.9, 127.7, 127.4, 117.4, 80.0, 79.8, 72.6, 71.7,
70.7, 70.1, 31.6, 31.2, 30.7, 25.8, 19.9, 15.0.
References
(1) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2005, 22, 15.
Anal. Calcd for C30H38O6: C, 72.85; H, 7.74. Found: C, 72.46; H, 7.62.
(2) (a) Õmura, S. In Macrolide Antibiotics. Chemistry, Biology and
Practice; Õmura, S., Ed.; Academic Press: Orlando, 1984, 509.
(b) Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41, 3569.
(c) Tadashi, N. In Macrolide Antibiotics: Chemistry, Biology and
Practice, 2nd ed.; Õmura, S., Ed.; Academic Press: San Diego,
2002, 181.
(3) (a) Berg, A.; Notni, J.; Dorfelt, H.; Grafe, U. J. Antibiot. 2002, 55,
660; and references cited therein. (b) Grove, J. F.; Speake, R. N.;
Ward, G. J. Chem. Soc. 1966, 230. (c) Sharma, G. V. M.;
Mallesham, S.; Chandra Mouli, C. Tetrahedron: Asymmetry 2009,
20, 2513.
(4) (a) Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.;
Pavan Kumar, K. V. P. Chem. Rev. 2009, 109, 2551. (b) Dembinski,
R. Eur. J. Org. Chem. 2004, 2763.
(5) Chatterjee, S.; Ghadigaonkar, S.; Sur, P.; Sharma, A.;
Chattopadhyay, S. J. Org. Chem. 2014, 79, 8067.
(6) (a) Salaskar, A.; Sharma, A.; Chattopadhyay, S. Tetrahedron:
Asymmetry 2005, 17, 325. (b) Sharma, A.; Gamre, S.;
Chattopadhyay, S. Tetrahedron Lett. 2007, 48, 633. (c) Sharma,
A.; Gamre, S.; Chattopadhyay, S. Tetrahedron Lett. 2007, 48,
3705. (d) Roy, S.; Sharma, A.; Mula, S.; Chattopadhyay, S. Chem.
Eur. J. 2009, 15, 1713. (e) Goswami, D.; Chattopadhyay, A.;
Chattopadhyay, S. Tetrahedron: Asymmetry 2009, 20, 1957.
(f) Biswas, S.; Chattopadhyay, S.; Sharma, A. Tetrahedron: Asym-
metry 2010, 21, 27. (g) Goswami, D.; Sur, P.; Chattopadhyay, A.;
Sharma, A.; Chattopadhyay, S. Synthesis 2011, 1626. (h) Reddy,
V. V.; Reddy, B. V. S. Helv. Chim. Acta 2016, 99, 636.
(i) Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104. (j) Chatterjee,
S.; Kanojia, S. V.; Chattopadhyay, S.; Sharma, A. Tetrahedron:
Asymmetry 2011, 22, 367. (k) Chattopadhyay, A.; Mamdapur, V.
R. J. Org. Chem. 1995, 60, 585.
(9E,5S,6R,11S,14R)-5,11-Dibenzyloxy-6,14-dimethyl-1,7-dioxa-
cyclotetradec-9-ene-2,8-dione (19)
A mixture of 18 (300 mg, 0.61 mmol) and Grubbs I catalyst (150 mg,
0.18 mmol) in degassed CH2Cl2 (300 mL) was stirred at 40 °C for 48 h.
After concentrating the mixture in vacuo, the residue was subjected
to purification by preparative TLC (silica gel, 10% EtOAc/hexane) to
furnish pure 19 (130 mg, 55% based on conversion) and recovered 18
28
(50 mg) as a white solid; mp 91–93 °C; [α]D –45.3 (c 1.11, CHCl3);
Rf = 0.42 (10% EtOAc/hexane).
IR (thin film deposited from CHCl3 solution): 3019, 1720, 1648, 1029,
985 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.37–7.27 (m, 10 H, 2 × C6H5), 6.64 (dd,
J = 16.0, 9.5 Hz, 1 H, H-10), 5.86 (d, J = 16.0 Hz, 1 H, H-9), 5.21–5.15
(m, 1 H, H-6), 4.76–4.73 (m, 1 H, H-14), 4.57 (d, J = 11.5 Hz, 1 H,
OCHBPh), 4.53 (d, J = 10.5 Hz, 1 H, OCHAPh), 4.49 (d, J = 10.5 Hz, 1 H,
OCHBPh), 4.37 (d, J = 12.0 Hz, 1 H, OCHAPh), 3.78–3.73 (m, 1 H, H-11),
3.34–3.30 (m, 1 H, H-5), 2.41–2.32 (m, 2 H, H-3), 2.10–1.99 (m, 2 H,
H-4), 1.89–1.82 (m, 2 H, H-13), 1.70–1.66 (m, 1 H, H-12), 1.58–1.51
(m, 1 H, H-12), 1.34 (d, J = 6.0 Hz, 3 H, H-15), 1.13 (d, J = 6.5 Hz, 3 H, H-
16).
13C NMR (125 MHz, CDCl3): δ = 172.3, 164.8, 147.9, 137.9, 137.8,
128.5, 128.2, 127.7, 125.0, 81.7, 78.4, 72.0, 71.3, 70.5, 69.1, 31.7, 28.6,
28.1, 24.4, 18.8, 17.6.
Anal. Calcd for C28H34O6: C, 72.08; H, 7.35. Found: C, 72.38; H, 7.25.
(5S,6R,11S,14R)-1
To a stirred and cooled (0 °C) solution of 19 (25 mg, 0.05 mmol) in
CH2Cl2 (2 mL) was added TiCl4 (11.8 μL, 0.11 mmol) and the mixture
stirred at r.t. until the completion of the reaction (TLC, 0.5 h). After
concentration in vacuo, the residue was purified by preparative TLC
(silica gel, 5% MeOH/CHCl3) to get pure (5S,6R,11S,14R)-1 (13 mg,
(7) Benaglia, M.; Caporale, M.; Puglisi, A. Enantiomer 2002, 7, 383.
(8) (a) Mohapatra, D. K.; Reddy, D. S.; Mallampudi, N. A.; Gaddam,
J.; Polepalli, S.; Jain, N.; Yadav, J. S. Org. Biomol. Chem. 2014, 12,
9683. (b) Evans, D. A.; Burch, J. D. Org. Lett. 2001, 3, 503.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

G
P. Dey et al.
Paper
Synthesis
(9) (a) Srilatha, M.; Das, B. Helv. Chim. Acta 2015, 98, 267.
(b) Bujaranipalli, S.; Eppa, G. C.; Das, S. Synlett 2013, 24, 1117.
(c) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.;
Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447.
(10) (a) Crouch, R. D. Tetrahedron 2013, 69, 2383. (b) Bhatt, U.;
Christmann, M.; Quitschalle, M.; Claus, E.; Kalesse, M. J. Org.
Chem. 2001, 66, 1885.
(11) (a) Gradillas, A.; Perez-Castells, J. Angew. Chem. Int. Ed. 2006, 45,
6086. (b) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R.
H. J. Am. Chem. Soc. 2003, 125, 11360.
(12) Zhu, B.; Panek, J. S. Org. Lett. 2000, 2, 2575.
(13) (a) Hori, H.; Nishida, Y.; Ohrui, H.; Meguro, H. J. Org. Chem.
1989, 54, 1346. (b) Radha Krishna, P.; Reddy, P. V. N. Tetrahedron
Lett. 2006, 47, 7473. (c) Gurjar, M. K.; Nagaprasad, R.; Ramana,
C. V. Tetrahedron Lett. 2003, 44, 2873.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G