Total synthesis of (+)-anamarine

Article abstract of DOI:10.1016/j.tet.2014.04.068

An enantiospecific total synthesis of polyhydroxy δ-pyrone natural product (+)-anamarine is accomplished. The main features of the synthesis include the stereoselective reduction of the ketone obtained by the desymmetrization of the bis-dimethyl amide of

Full text of DOI:10.1016/j.tet.2014.04.068

Accepted Manuscript
Total Synthesis of (+)-Anamarine
Kavirayani R. Prasad , S. Mothish Kumar
PII:
S0040-4020(14)00602-4
10.1016/j.tet.2014.04.068
TET 25518
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 February 2014
Revised Date: 23 April 2014
Accepted Date: 24 April 2014
Please cite this article as: Prasad KR, Mothish Kumar S, Total Synthesis of (+)-Anamarine, Tetrahedron
(2014), doi: 10.1016/j.tet.2014.04.068.
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Graphical Abstract
Total Synthesis of (+)-Anamarine
Leave this area blank for abstract info.
Kavirayani R. Prasad* and S. Mothish Kumar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, INDIA

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Total Synthesis of (+)-Anamarine
Kavirayani R. Prasad* and S. Mothish Kumar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, INDIA
FAX: +0091-80-23600529; E-mail: prasad@orgchem.iisc.ernet.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An enantiospecific total synthesis of polyhydroxy δ-pyrone natural product (+)-anamarine is
accomplished. The main features of the synthesis include the steroselective reduction of the
ketone obtained by the desymmetrization of the bis-dimethyl amide of tartaric acid and further
elaboration involving asymmetric Brown’s allylation and ring closing metathesis.
Available online
2
014 Elsevier Ltd. All rights reserved.
Keywords:
Anamarine
polyhydroxy lactone
δ-pyrone
1
. Introduction
2
. Results and Discussion
Polyhydroxy lactone containing natural products such as
anamarine 1, spicigerolide 2, syntrolide 3 and synargentolides 4-
(Fig 1) are a class of δ-pyranone compounds isolated from
Synthesis of (+)-1 can be anticipated by elaboration of the olefin
in the masked tetrol 8. Formation of the masked tetrol unit 8 with
contiguous chiral hydroxy groups was envisaged from the γ-
hydroxy amide 9 synthesized from the bis-dimethylamide 10
derived from L-(+)-tartaric acid (scheme 1).
7
various plant species possessing contiguous chiral hydroxy
1
units. Owing to the therapeutic significance of most of the plant
products in folk medicine, synthesis of these natural products and
their analogues has attracted the attention of synthetic chemists.
We have been involved in the synthesis of structurally similar
natural products based on the expansion of tartaric acid as a four
carbon-four hydroxy synthon. Pivotal reaction in our synthesis is
elaboration of the γ-hydroxy amide obtained by
desymmetrization of the bis-dimethyl amide of tartaric acid by
controlled addition of Grignard reagent followed by
OAc
O
OTBS
AcO
AcO
O
O
Me
O
Me
OAc
OMOM
(+)-anamarine 1
8
2
stereoselective reduction. In continuation of our efforts, herein,
NMe2
OH
we report the synthesis of (+)-anamarine from L-(+)-tartaric
3
O
O
O
acid.
Me
O
O
O
O
NMe2
NMe2
1
0
9
Scheme 1. Retrosynthesis for (+)-anamarine 1.
Accordingly, synthesis of the γ-hydroxy amide
9
was
commenced with the addition of MeMgCl to the bis-
dimethylamide 10 leading to the mono-keto amide 11 in 69%
yield. However, our efforts to reduce the ketone in 11
stereoselectively to the required γ-hydroxy amide 9 were futile
4
(scheme 2).
Fig 1: Polyhydroxy lactone containing natural products.

2
Tetrahedron
the corresponding aldehyde which on reaction with commercially
ACCEPTED MANUSCRIPT
available Wittig ylide 17 furnished the α, β-unsaturated aldehyde
8 in 71% yield for two steps. Allylation of the aldehyde with
1
8
Brown’s Ipc B-allyl afforded the required homoallylic alcohol
2
1
9 in 74% yield along with the minor isomer 19a in 10% yield.
Cinnamoylation of the alcohol in 19 produced the ester 20 which
on reaction with Grubbs’ second generation catalyst afforded the
lactone 21 in 72% yield. Global deprotection of the protecting
groups in 21 gave the corresponding tetrol lactone, which on
acylation with acetic anhydride gave (+)-anamarine 1 in 44%
yield for two steps (scheme 4). The spectral and physical
properties of 1 were in complete agreement with that reported in
3d
the literature.
Scheme 2. Synthesis of the γ-hydroxy amide 9.
We reasoned that the 1,3-dithiane moiety would be an
appropriate surrogate for the required methyl group. It was
contemplated that the desulfurization of 1,3-dithiane moiety in 12
should lead to the required γ-hydroxy amide 9. Thus, following a
procedure described by us earlier, addition of 2-lithio-1,3-
dithiane to the bis-dimethylamide 10 furnished the monoketo
5
amide 13 which on reduction with Zn(BH ) afforded the
4
2
2c
erythro alcohol 12 as the major product in 80% isolated yield
along with the minor threo isomer 12a in 8% yield.
Desulfurization of the 1,3-dithiane moiety in the hydroxy amide
1
2 with Raney Nickel under hydrogen atmosphere cleanly
produced 9 in 90% yield. Protection of the hydroxy group in 9 as
the TBS ether 14 followed by addition of vinylmagnesium
bromide afforded the α, β-unsaturated ketone 15 in 85% yield.
6
Reduction of the ketone 15 under Luche conditions furnished an
inseparable mixture of isomers of the corresponding alcohol 16
in 96% yield (dr 85:15). Protection of the hydroxy group in 16 as7
the MOM ether furnished a separable mixture of diastereomers 8
and 8a, with the required isomer 8 in 74% yield (scheme 3).
Scheme 4. Synthesis of (+)-anamarine 1.
3
. Conclusions
In conclusion, a facile synthesis of (+)-anamarine 1 is
accomplished from the bis-dimethyl amide of L-(+)-tartaric acid
in 4.8% overall yield in 14 linear steps. The synthesis showcased
the use of 1,3-dithiane as directing group in stereoselective
reduction as well a surrogate for the methyl group while Brown’s
allylation and RCM were used to install the required
functionalities.
4
. Experimental section
General Procedures: Column chromatography was performed
on silica gel, Acme grade 100-200 mesh. TLC plates were
visualized either with UV, in an iodine chamber, or with
phosphomolybdic acid spray, unless noted otherwise. Unless
stated otherwise, all reagents were purchased from commercial
sources and used without additional purification. THF and Et O
2
were freshly distilled over Na-benzophenone ketyl. Melting
1
points were uncorrected. Unless stated otherwise, H NMR and
C NMR spectra were recorded on 400 MHz machine in CDCl3
13
Scheme 3. Synthesis of the masked tetrol unit 8.
as solvent with TMS as reference unless otherwise indicated.
Unless stated otherwise, all the reactions were performed under
inert atmosphere. All the specific rotations were determined at 24
°C.
After accomplishing the synthesis of the masked tetrol unit 8,
extension of the olefin in 8 to the lactone in anamarine was
undertaken. Accordingly, ozonolysis of the olefin in 8 produced

3
Preparation of (4R,5R)-5-acetyl-N,N,2,2
A
-te
C
tr
C
am
E
e
P
th
T
yl
E
-1
D
,3- MApe
N
tro
U
le
S
um
C
e
R
th
I
e
P
r/E
T
tOAc (2:3) as eluent to yield 9 (0.73 g, 90%)
2
4
dioxolane-4-carboxamide (11): In a two necked, 50 mL, round
bottomed flask equipped with a magnetic stirbar, rubber septum,
and argon inlet was placed 10 (0.5 g, 2.04 mmol). It was
dissolved in dry THF (7 mL) and the solution was cooled to −10
as colorless oil. R 0.4 (60% EtOAc/ Petroleum ether); [α]
–
f
D
-
1
1
22.6 (c 1.0, CHCl ); IR (neat) 3433, 2937, 1645, 1382 cm ; H
NMR (400 MHz, CDCl ) δ 4.52–4.48 (m, 2H), 3.94–3.93 (m,
1H), 3.14 (s, 3H), 2.90 (s, 3H), 2.02 (s, 1H), 1.42 (s, 3H), 1.35 (s,
3
3
H
13
°
C. A solution of methylmagnesium bromide (0.82 mL of 3.0 M
3H), 1.16 (d, J = 6.4 Hz, 3H); C NMR (100 MHz, CDCl
) δ
3 C
solution in THF, 2.45 mmol) was added at such a rate that the
internal temperature does not rise above −10 °C. Progress of the
reaction was monitored by TLC and after the reaction was
complete (~0.5 h), it was cautiously quenched by the addition of
169.6, 110.0, 81.2, 74.2, 67.2, 37.2, 35.9, 26.7, 25.8, 19.2;
HRMS: [M+Na] found 240.1213. C10
240.1212.
H19NO +Na requires
4
saturated NH Cl solution (10 mL) and extracted with EtOAc
Preparation
of
(4R,5R)-5-((S)-1-((tert-
4
(3×15 mL). The combined organic extracts were washed with
butyldimethylsilyl)oxy)ethyl)-N,N,2,2-tetramethyl-1,3-
dioxolane-4-carboxamide (14): To a pre-cooled (0 °C) solution
brine (10 mL) and dried over anhydrous Na SO . Evaporation of
2
4
the solvent followed by silica gel column chromatography of the
of the alcohol 9 (0.82 g, 3.77 mmol) in CH Cl (8 mL) were
2 2
residue with petroleum ether/EtOAc (1:1) as eluent yielded 11
added DMAP (92 mg, 0.75 mmol), imidazole (0.51 g, 7.55
mmol) followed by TBSCl (0.87 g, 5.66 mmol) under argon
atmosphere. The reaction mixture was refluxed for 12 h. After
completion of the reaction (TLC), it was poured into cold water
(15 mL) and extracted with diethyl ether (2 × 15 mL). The
ethereal layer was washed with brine (10 mL) and dried over
(
0.3 g, 69%) as colorless oil. R 0.5 (50% EtOAc/ Petroleum
f
24
ether); [α] +16.2 (c 1.2, CHCl ); IR (neat) 2991, 2939, 1720,
1
D
3
-
1 1
655, 1379 cm ; H NMR (400 MHz, CDCl ) δ 5.12 (d, J = 6.0
3 H
Hz, 1H), 4.76 (d, J = 6.0 Hz, 1H), 3.11 (s, 3H), 2.96 (s, 3H), 2.27
13
(
s, 3H), 1.40 (s, 6H); C NMR (100 MHz, CDCl ) δ 207.4,
3 C
1
67.9, 112.0, 82.3, 74.8, 36.9, 35.9, 26.9, 26.2, 25.9; HRMS:
anhydrous Na SO . Evaporation of the solvent followed by
2 4
[
M+Na] found 238.1054. C H NO +Na requires 238.1055.
purification of the resulting residue by silica gel column
chromatography using petroleum ether/EtOAc (7:3) as eluent
10
17
4
furnished 14 (1.22 g, 98%) as colorless oil. R 0.5 (30% EtOAc/
Preparation
of
(4R,5S)-5-((R)-(1,3-dithian-2-
f
24
Petroleum ether); [α]
–16.1 (c 1.1, CHCl ); IR (neat) 2953,
yl)(hydroxy)methyl)-N,N,2,2-tetramethyl-1,3-dioxolane-4-
carboxamide (12): To a solution of 13 (1.5 g, 4.7 mmol) in THF
D
3
-
1
1
2858, 1654, 1257 cm ; H NMR (400 MHz, CDCl
.54 (m, 2H), 4.03–4.00 (m, 1H), 3.15 (s, 3H), 2.96 (s, 3H), 1.43
s, 3H), 1.37 (s, 3H), 1.12 (d, J = 6.4 Hz, 3H), 0.87 (s, 9H), 0.07
) δ 4.60–
3 H
o
4
(10 mL) was added Zn(BH ) (15 mL) at −78 C and was allowed
4
2
(
to stir at the same temperature for 1 h. After completion of the
reaction (monitored by TLC) it was quenched with saturated
13
(s, 6H); C NMR (100 MHz, CDCl ) δ 169.3, 109.9, 81.6, 72.9,
3 C
6
7.9, 36.9, 35.6, 26.7, 25.8, 25.6 (3C), 20.6, 17.8, –4.5, –4.7;
NH Cl (20 mL), extracted with EtOAc (3 x 20 mL). The
4
HRMS: [M+Na] found 354.2076. C H NO Si+Na requires
combined organic layers were washed with brine (30 mL) and
dried over anhydrous Na SO . Evaporation of the solvent gave
16 33
4
3
54.2077.
2
4
the crude residue as a mixture of diastereomers (9:1, 91%) which
was purified through silica gel column chromatography using
petroleum ether/EtOAc (2:3) as eluent to furnish the major
diastereomer 12 (1.2 g, 80 %) as a pale yellow crystalline solid.
Preparation
of
1-((4R,5R)-5-((S)-1-((tert-
butyldimethylsilyl)oxy)ethyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)prop-2-en-1-one (15): In a two necked, 50 mL, round
bottomed flask equipped with a magnetic stirbar, rubber septum,
and argon inlet was placed 14 (0.65 g, 1.95 mmol). It was
dissolved in dry THF (7 mL) and the solution was cooled to −10
°C. A freshly prepared THF solution of vinylmagnesium bromide
(4 mL of 0.7 M solution in THF, 2.93 mmol) was added at such a
rate that the internal temperature does not rise above −10 °C.
Progress of the reaction was monitored by TLC and after the
reaction was complete (~0.5 h), it was cautiously quenched by
the addition of cold 1N HCl solution (10 mL) and extracted with
EtOAc (3×15 mL). The combined organic extracts were washed
o
24
R 0.5 (60% EtOAc/ Petroleum ether); mp. 116-119 C; [α]
–
f
D
-
1
5.3 (c 1.8, CHCl ); IR (KBr) 3425, 2994, 2889, 1639, 1404 cm
3
1
1
;
H NMR (400 MHz, CDCl ) δ 4.69 (t, J = 7.2 Hz, 1H), 4.56
3
H
(
3
(
1
7
d, J = 7.2 Hz, 1H), 4.18 (d, J = 2.6 Hz, 1H), 3.98 – 3.95 (m, 1H),
.87 (d, J = 5.2 Hz, 1H), 3.13 (s, 3H), 3.02 – 2.96 (m, 2H), 2.94
s, 3H), 2.87–2.72 (m, 2H) , 2.05–1.93 (m, 2H), 1.40 (s, 3H),
13
.37 (s, 3H); C NMR (100 MHz, CDCl ) δ 169.7, 110.4, 77.4,
3 C
6.7, 76.5, 48.9, 37.3, 36.1, 29.3, 28.6, 26.8, 26.1, 25.7; HRMS:
[
M+Na] found 344.0967. C H NO S +Na requires 344.0966.
13 23 4 2
Minor diastereomer (12a) as a pale yellow solid, (0.12 g, 8%)
with brine (10 mL) and dried over anhydrous Na SO .
Evaporation of the solvent followed by silica gel column
chromatography of the residue with petroleum ether/EtOAc (9:1)
2 4
o
24
R 0.4 (60% EtOAc/ Petroleum ether); mp. 133-135 C; [α]
f
–
D
5
1
.8 (c 1.1, CHCl ); IR (KBr) 3426, 2994, 2932, 2889, 1638,
3
-1 1
403, 1254, 1066, 847 cm ; H NMR (400 MHz, CDCl ) δ 5.03
as eluent yielded 15 (0.52 g, 85%) as colorless oil. R
f
0.7 (10%
+20.6 (c 1.6, CHCl ); IR (neat)
D 3
3
H
24
(d, J = 7.6 Hz, 1H), 4.66 (d, J = 7.6 Hz, 1H), 3.96-3.93 (m, 2H),
EtOAc/ Petroleum ether); [α]
2981, 2956, 2934, 2859, 1703, 1381, 1255, 1090, 835, 777 cm ;
-
1
3
2
1
.12 (s, 3H), 3.00-2.88 (m, 6H), 2.68-2.61 (m, 2H), 2.02-1.97 (m,
13
1
H), 1.42 (s, 3H), 1.36 (s, 3H); C NMR (100 MHz, CDCl ) δ
H NMR (400 MHz, CDCl ) δ 6.85 (dd, J = 17.2, 10.4 Hz, 1H),
3 H
3
C
68.6, 110.3, 76.9, 74.6, 68.7, 47.6, 37.0, 35.6, 26.9, 26.5, 26.3
6.45 (dd, J = 17.2, 1.4 Hz, 1H), 5.84 (dd, J = 10.5, 1.4 Hz, 1H).
4.55 (d, J = 6.0 Hz, 1H), 4.17 (dd, J = 6.0, 4.4 Hz, 1H), 4.02-3.96
(m, 1H), 1.48 (s, 3H), 1.32 (s, 3H), 1.18 (d, J = 6.4 Hz, 3H), 0.89
(
2C), 25.3; HRMS: [M+Na] found 344.0965. C H NO S +Na
13 23 4 2
requires 344.0966.
13
(
s, 9H), 0.09 (s, 6H); C NMR (100 MHz, CDCl ) δ 198.9,
3 C
1
1
32.0, 129.9, 110.6, 81.9, 80.3, 68.4, 26.9, 25.9, 25.7 (3C), 20.3,
8.0, –4.4, –4.6; HRMS: [M+Na] found 337.1815.
Preparation
tetramethyl-1,3-dioxolane-4-carboxamide (9): To a solution of
2 (1.2 g, 3.7 mmol) in ethanol (25 mL) was added Raney nickel
15 mL suspension in ethanol) and the resulting suspension was
allowed to reflux under hydrogen atmosphere for 15 h. After
completion of the reaction (monitored by TLC), it was filtered
of
(4R,5S)-5-((S)-1-hydroxyethyl)-N,N,2,2-
C H O Si+Na requires 337.1811.
1
(
16 30
4
Preparation
butyldimethylsilyl)oxy)ethyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)prop-2-en-1-ol (16): A solution of CeCl ·7H O (0.87 g, 2.33
mmol) in MeOH (11 mL) was cooled to 0 °C. NaBH (0.14 g,
3
of
1-((4S,5R)-5-((S)-1-((tert-
through a celite pad and the celite pad was washed with CH Cl2
3
2
2
(40 mL). Evaporation of the solvent afforded the crude product
4
.65 mmol) was added portion wise to the above CeCl solution
which was purified by silica gel column chromatography using
3

4
Tetrahedron
and was allowed to stir for 10 min. The resultant suspension
solution of 8 (0.3 g, 0.83 mmol) containing solid NaHCO (0.010
ACCEPTED MANUSCRIPT
3
was transferred to a flask containing 15 (0.46 g, 1.46 mmol) in
MeOH (20 mL) at −78 °C through a dropper and stirred at the
same temperature for 0.5 h. After completion of the reaction
g), until the pale blue color persisted. Excess ozone was flushed
off with oxygen and Me S (1.0 mL) was added. The reaction
2
mixture was warmed to 0 °C and stirred at the same temperature
for 3 h. The reaction mixture was concentrated under reduced
pressure and filtered through a short pad of celite. The celite pad
was washed with ether (20 mL). Evaporation of the solvent
yielded the crude aldehyde which was subjected to the next
reaction without further purification.
(
TLC) it was cautiously quenched by the addition of water (3
mL). Excess methanol was evaporated off and the resulted
residue was diluted with water (15 mL) and extracted with
EtOAc (3×15 mL). The combined organic layers were washed
with brine (10 mL), dried over anhydrous Na SO4 and
2
concentrated. Silica gel column chromatography of the crude
residue obtained after evaporation of the solvent, with petroleum
ether/EtOAc (4:1) as eluent, gave 16 (0.44 g, 96%, dr = 85:15) as
To a solution of the crude aldehyde (obtained above), in toluene
(10 mL) was added the ylide Ph PCHCHO 17 (0.39 g, 1.28
3
mmol) and the resulting mixture was refluxed for 2 h. After the
reaction was complete (TLC), most of the solvent was evaporated
off and the residue thus obtained was purified by column
chromatography using petroleum ether/EtOAc (4:1) as eluent to
obtain the unsaturated aldehyde 18 (0.23 g, 71% over 2 steps) as
24
colorless oil. R 0.5 (25% EtOAc/ Petroleum ether); [α] +9.2 (c
f
D
-
1
1
4
.4, CHCl ); IR (neat) 3467, 2957, 2859, 1371 cm ; H NMR
3
(
400 MHz, CDCl ) δ 5.90 (ddd, J = 17.2, 10.4, 5.2 Hz, 1H),
3 H
5
1
1
0
1
1
.35 (d, J = 17.2 Hz, 1H), 5.21 (d, J = 10.4 Hz, 1H). 4.19, (brs,
H), 3.95 (m, 1H), 3.80-3.78 (m, 2H), 2.35 (d, J = 9.6 Hz, 1H),
.41 (s, 3H), 1.36 (s, 3H), 1.22 (d, J = 5.2 Hz, 3H), 0.86 (s, 9H),
2
4
colorless oil. R 0.5 (20% EtOAc/ Petroleum ether); [α] −47.8
f
D
-
1 1
(c 1.1, CHCl ); IR (neat) 2934, 2894, 2728, 1700, 1254 cm ; H
3
13
.07 (s, 3H), 0.05 (s, 3H); C NMR (100 MHz, CDCl ) δ 137.8,
NMR (400 MHz, CDCl ) δ 9.59 (d, J = 8.0 Hz, 1H), 6.82 (dd, J
3
C
3
H
16.1, 109.5, 81.7, 81.2, 71.7, 70.6, 27.4, 27.3, 25.8 (3C), 21.9,
7.9, −4.2, −4.4; HRMS: [M+Na] found 339.1966.
= 16.0, 6.8 Hz, 1H), 6.27 (dd, J = 16.0, 6.8 Hz, 1H). 4.66 (s, 2H),
4.44 (dd, J = 6.8, 2.8 Hz, 1H), 4.04 (dd, J = 6.8, 2.8 Hz, 1H),
3.88 (t, J = 6.8 Hz, 1H), 3.81 (quint, J = 6.0 Hz, 1H), 3.39 (s,
C H O Si+Na requires 339.1968.
16
32
4
3
H), 1.43 (s, 3H), 1.37 (s, 3H), 1.23 (d, J = 6.0 Hz, 3H), 0.88 (s,
13
Preparation
methoxymethoxy)allyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)ethoxy)dimethylsilane (8): To a pre-cooled (0 °C) solution of
6 (0.43 g, 1.35 mmol), in CH Cl2 (5 mL) was added
of
tert-butyl((S)-1-((4R,5S)-5-((R)-1-
9H), 0.08 (s, 3H), 0.05 (s, 3H); C NMR (100 MHz, CDCl ) δ
3 C
(
193.3, 153.3, 133.7, 109.9, 95.1, 81.1, 80.6, 75.0, 70.5, 56.0,
27.6, 26.8, 25.8 (3C), 21.4, 17.9, −4.2, −4.3; HRMS: [M+Na]
found 411.2161. C H O Si+Na requires 411.2179.
1
2
19 36
6
diisopropylethyl amine (0.7 mL, 4.06 mmol), followed by
MOMCl (0.2 mL, 2.71 mmol) under argon atmosphere. The
reaction mixture was stirred at room temperature for 12 h and
after completion of the reaction (TLC), it was poured into cold
water (15 mL) and extracted with EtOAc (2 × 10 mL). The
combined organic layers were washed with brine (5 mL) and
dried over anhydrous Na SO The residue obtained after
evaporation of the solvent was purified by silica gel column
chromatography using petroleum ether/EtOAc (9:1) as eluent to
yield the corresponding MOM ether 8 (0.44 g, 90%, major
Preparation
of
(4R,7R,E)-7-((4S,5R)-5-((S)-1-((tert-
butyldimethylsilyl)oxy)ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-
7-(methoxymethoxy)hepta-1,5-dien-4-ol (19): To a pre-cooled
(−78 °C) solution of (+)-Ipc B-allyl (0.7 mL, 0.66 mmol) in ether
2
(3 mL) was added 18 (0.21 g, 0.54) dissolved in ether (3 mL)
under argon atmosphere. The reaction mixture was stirred at −78
°C for 1.5 h and was quenched with a solution of phosphate
buffer (pH =7) solution (1 mL), MeOH (1 mL), followed by 30%
H O (0.5 mL). After stirring for 30 min, the reaction mixture
2
4.
2
2
diastereomer 0.36 g, 74%) as colorless oil. R 0.8 (5% EtOAc/
was poured into saturated NaHCO solution and extracted with
EtOAc (2 × 10 mL). The combined organic layers were washed
with brine (5 mL) and dried over Na SO . Evaporation of solvent
f
3
24
Petroleum ether); [α]
−36.7 (c 1.8, CHCl ); IR (neat) 2985,
934, 2892, 2860, 1607, 1375, 1254, 1098, 1034, 834, 776 cm ;
H NMR (400 MHz, CDCl ) δ 5.79 (ddd, J = 16.8, 10.8, 8.4 Hz,
D
3
-
1
2
2
4
1
3
H
followed by column chromatography of the resulting residue with
1
=
4
1
3
H), 5.32 (s, 1H), 5.29 (d, J = 7.6 Hz, 1H), 4.74 and 4.59 (ABq, J
6.8 Hz, 2H), 4.15 (dd, J = 8.4, 4.0 Hz, 1H), 4.00 (dd, J = 6.4,
petroleum ether/EtOAc (7:3) as eluent afforded 19 (major
diastereomer 0.17 g, 74%) as colorless oil. R 0.3 (30% EtOAc/
f
24
.0 Hz, 1H), 3.88 (t, J = 6.4 Hz, 1H), 3.80 (quint, J = 6.0 Hz,
H), 3.39 (s, 3H), 1.44 (s, 3H), 1.39 (s, 3H), 1.22 (d, J = 6.0 Hz,
Petroleum ether); [α]
−73.0 (c 1.0, CHCl ); IR (neat) 3456,
D 3
-1 1
2893, 1603, 1372, 1093 cm ; H NMR (400 MHz, CDCl ) δ
3
H
13
H), 0.89 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); C NMR (100
5.79-5.73 (m, 2H), 5.66 (dd, J = 15.6, 8.4 Hz, 1H), 5.13 (d, J =
6.8 Hz, 1H), 5.10 (s, 1H), 4.70 and 4.54 (ABq, J = 6.8 Hz, 2H),
4.22 (brd, J = 6.0 Hz, 1H), 4.16 (dd, J = 8.0, 3.6 Hz, 1H), 3.99
(dd, J = 6.0, 4.0 Hz, 1H), 3.87 (t, J = 6.8 Hz, 1H), 3.79 (quint, J =
MHz, CDCl ) δ 134.9, 119.5, 109.5, 93.5, 81.7, 81.0, 77.0, 70.3,
5
3
C
5.6, 27.7, 27.2, 25.8 (3C) 20.9, 17.9, −4.2, −4.4; HRMS:
[
M+Na] found 383.2229. C H O Si+Na requires 383.2230.
18
36
5
6
.0 Hz, 1H), 3.37 (s, 3H), 2.31-2.29 (m, 2H), 1.75 (brs, 1H), 1.43
Minor diastereomer (8a) as colorless oil, (0.048 g, 11%), R 0.7
(s, 3H), 1.37 (s, 3H), 1.21 (d, J = 6.0 Hz, 3H), 0.88 (s, 9H), 0.07
(s, 3H), 0.05 (s, 3H); C NMR (100 MHz, CDCl ) δ 137.7,
133.8, 127.3, 118.4, 109.5, 93.3, 81.8, 80.9, 75.6, 71.0, 70.4,
55.6, 41.7, 27.7, 27.2, 25.8 (3C), 21.2, 18.0, −4.2, −4.4; HRMS:
[M+Na] found 453.2646. C H O Si+Na requires 453.2648.
f
24
13
(
5% EtOAc/ Petroleum ether); [α]
+32.5 (c 0.2, CHCl ); IR
D
3
3
C
-
1
1
(neat) 2933, 2891, 2860, 1462, 1375 cm ; H NMR (400 MHz,
CDCl ) δ 5.92-5.83 (m, 1H), 5.42 (d, J = 10.4 Hz, 1H), 5.29 (d,
3
H
J = 17.2 Hz, 1H), 4.75 (d, J = 6.8 Hz, 1H), 4.58 (d, J = 6.8 Hz,
H), 4.17 (d, J = 7.6 Hz, 2H), 3.85 (quint, J = 6.4 Hz, 1H), 3.58
t, J = 6.8 Hz, 1H), 3.38 (s, 3H), 1.39 (s, 6H), 1.22 (d, J = 6.0
22
42
6
2
(
Minor diastereomer (19a) as colorless oil, (0.03 g, 10%), R 0.4
(30% EtOAc/ Petroleum ether); [α] +16.5 (c 1.0, CHCl ); IR
(neat) 3456, 2930, 2888, 1609, 1253, 1032, 835 cm ; H NMR
f
13
24
Hz, 3H), 0.91 (s, 9H), 0.1 (s, 6H); C NMR (100 MHz, CDCl3)
D
3
-
1
1
δC 133.2, 121.4, 109.3, 93.5, 82.0, 81.1, 78.1, 70.3, 55.7, 27.4,
2
3
7.0, 25.8 (3C) 21.2, 18.0, −4.3, −4.4; HRMS: [M+Na] found
(400 MHz, CDCl ) δ 5.90-5.70 (m, 2H), 5.68 (dd, J = 15.6, 8.4
3
H
83.2231. C H O Si+Na requires 383.2230.
Hz, 1H), 5.16 (d, J = 4.4 Hz, 1H), 5.12 (brs, 1H), 4.74, 4.57
ABq, J = 6.8 Hz, 2H), 4.23 (brs, 1H), 4.17 (dd, J = 8.0, 4.0 Hz,
18
36
5
(
Preparation
butyldimethylsilyl)oxy)ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-
-(methoxymethoxy)but-2-enal (18): Ozone was bubbled
through a pre-cooled (−78 °C) CH Cl :MeOH (4:1, 10 mL)
of
(R,E)-4-((4S,5R)-5-((S)-1-((tert-
1H), 4.05 – 3.93 (m, 1H), 3.86 (t, J = 6.4 Hz, 1H), 3.80 (quint, J
= 6.0 Hz, 1H), 3.39 (s, 3H), 2.44-2.20 (m, 2H), 1.78 (br s, 1H),
1.44 (s, 3H), 1.39 (s, 3H), 1.22 (d, J = 6.0 Hz, 3H), 0.89 (s, 9H),
4
13
2
2
0.09 (s, 3H), 0.07 (s, 3H);
C NMR (100 MHz, CDCl ) δC
3

5
1
7
37.7, 133.8, 127.3, 118.4, 109.6, 93.4, 81.9, 81.0, 75.8, 70.8,
0.4, 55.6, 41.7, 27.8, 27.2, 25.8 (3C), 21.1, 18.0, −4.2, −4.4;
residue obtained after evaporation of the solvent was purified
ACCEPTED MANUSCRIPT
by a short pad silica gel column chromatography using
EtOAc/MeOH (4:1) as eluent to furnish the tetrol, which was
used as such in the next step without further characterization.
To a pre-cooled (0 °C) solution of the tetrol obtained above in
HRMS: [M+Na] found 453.2645. C H O Si+Na requires
4
22
42
6
53.2648.
CH Cl (1 mL) were added DMAP (0.001 g, 0.009 mmol), Et N
Preparation
butyldimethylsilyl)oxy)ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-
-(methoxymethoxy)hepta-1,5-dien-4-yl cinnamate (20): To a
pre-cooled (0 °C) solution of 19 (0.07 g, 0.16 mmol) in CH Cl2
of
(4R,7R,E)-7-((4S,5R)-5-((S)-1-((tert-
2
2
3
(
0.1 mL, 0.68 mmol) followed by Ac O (0.04 mL, 0.34 mmol)
2
under argon atmosphere. The reaction mixture was stirred at
room temperature for 1 h. After completion of the reaction
7
2
(
(
TLC), it was poured into cold water and extracted with EtOAc
2 × 10 mL). The combined organic layers were washed with
(
3 mL) was added Et N (0.07 mL, 0.48 mmol), DMAP (0.002 g,
3
0
.016 mmol) followed by cinnamoyl chloride (0.054 g, 0.32
brine (5 mL) and dried over anhydrous Na SO . Evaporation of
mmol) under argon atmosphere. The reaction mixture was
warmed up to room temperature and was stirred at rt for 2 h.
After completion of the reaction (TLC), it was poured into cold
water and extracted with ether (2 × 10 mL). The combined
ethereal layers were washed with brine (5 mL) and dried over
Na SO . Evaporation of solvent followed by column
2
4
solvent followed by silica gel column chromatography of the
resultant residue using petroleum ether/EtOAc (1:1) as eluent
furnished (+)-anamarine (1) (8 mg, 44% yield over 2 steps) as a
2
4
gummy mass. R 0.6 (50% EtOAc/ Petroleum ether); [α] +16.2
f
D
1d
24
(
c 0.4, CHCl ); Lit [α] +17.0 (c 0.3, CHCl ); IR (neat) 3471,
926, 2855, 1738, 1638, 1374, 1044 cm ; H NMR (400 MHz,
3
D
3
2
4
-
1
1
2
chromatography of the residue with petroleum ether/EtOAc (9:1)
CDCl ) δ 6.89 (ddd, J = 9.2, 5.2, 3.6 Hz, 1H), 6.06 (d, J = 9.6
as eluent furnished the cinnamate ester 20 (0.085 g, 95% yield)
3
H
2
4
Hz, 1H), 5.87-5.77 (m, 2H), 5.36 (dd, J = 7.2, 6.0 Hz, 1H), 5.31
dd, J = 7.2, 3.6 Hz, 1H), 5.18 (dd, J = 6.8, 3.6 Hz, 1H), 4.98-
as colorless oil. R 0.6 (20% EtOAc/ Petroleum ether); [α]
f
D
-
1 1
(
−
54.9 (c 2.1, CHCl ); IR (neat) 2934, 2860, 1730, 1454 cm ; H
3
4
2
.88 (m, 2H), 2.47-2.43 (m, 2H), 2.13 (s, 3H), 2.08 (s, 3H × 2),
.03 (s, 3H), 1.18 (d, J = 6.4 Hz, 3H); C NMR (100 MHz,
NMR (400 MHz, CDCl ) δ 7.68 (d, J = 16.0 Hz, 1H), 7.54-7.51
3
H
13
(m, 2H), 7.39-7.38 (m, 3H), 6.44 (d, J = 16.0 Hz, 1H), 5.81-5.73
(m, 3H), 5.50 (q, J = 6.0 Hz, 1H), 5.14-5.08 (m, 2H), 4.72, 4.56
(ABq, J = 6.8 Hz, 2H), 4.20 (dd, J = 7.6, 3.6 Hz, 1H), 4.02 (dd, J
CDCl ) δ 169.9, 169.8, 169.77, 169.70, 163.4, 144.4, 132.9,
3
C
1
2
25.4, 121.4, 75.7, 71.8, 71.5, 70.3, 67.2, 29.0, 20.9, 20.86,
0.80, 20.5, 15.7; HRMS: [M+Na] found 449.1425.
=
6.0, 3.6 Hz, 1H), 3.88 (t, J = 6.8 Hz, 1H), 3.81 (q, J = 6.0 Hz,
C H O +Na requires 449.1424.
20 26 10
1
3
3
1
9
H), 3.38 (s, 3H), 2.48 (q, J = 6.4 Hz, 2H), 1.43 (s, 3H), 1.39 (s,
H), 1.22 (d, J = 6.0 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 3H), 0.06 (s,
13
Acknowledgments
H). C NMR (100 MHz, CDCl ) δ 165.9, 144.9, 134.4, 133.5,
3
C
32.9, 130.3, 128.8 (2C), 128.5, 128.0 (2C), 118.2, 118.1, 109.5,
3.4, 81.4, 81.0, 75.5, 72.6, 70.3, 55.6, 39.0, 27.7, 27.2, 25.9
We thank the Department of Science and Technology (DST),
New Delhi for funding. KRP is a Swarnajayanthi fellow of DST,
New Delhi. SMK thanks Council of Scientific and Industrial
Research (CSIR), New Delhi for a senior research fellowship.
(3C), 21.1, 18.0, −4.2, −4.4; HRMS: [M+Na] found 583.3068.
C H O Si+Na requires 583.3067.
31
48
7
References and notes
Preparation
butyldimethylsilyl)oxy)ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-
-(methoxymethoxy)prop-1-en-1-yl)-5,6-dihydro-2H-pyran-2-
one (21): To a stirred solution of the cinnamate ester 20 (0.038 g,
.067 mmol) in CH Cl2 (10 mL) was added Grubbs’ 2nd
generation catalyst (0.006 g, 0.0067 mmol) under argon
atmosphere and refluxed for 12 h. After completion of the
reaction, the solvent was evaporated off and the residue thus
obtained was purified by silica gel column chromatography using
petroleum ether/EtOAc (3:2) as eluent to furnish the lactone 21
of
(R)-6-((R,E)-3-((4S,5R)-5-((S)-1-((tert-
1
2
.
.
For a reviw on
J. A.; Carda, M.; Murga, J.; Falomir, E. Tetrahedron 2007, 63,
929.
For a general approach to the synthesis of γ-keto amides by
addition of alkyl or aryl Grignard reagents to tartaric acid derived
amides see: (a) Prasad, K. R.; Chandrakumar, A. Tetrahedron
δ-pyrone containing natural products see: Marco,
3
2
0
2
2
007, 63, 1798. For recent application of γ-keto amides derived
from tartaric acid in natural product synthesis from our group see:
b) Prasad, K. R.; Kumar, S. M. Synthesis 2013, 785. (c) Prasad,
(
K. R.; Metri, P. K. Chem. Asian J. 2013, 8, 488. (d) Prasad, K. R.;
Pawar, A. B. Chem.-Eur. J. 2012, 18, 15202 (e) Prasad, K. R.;
Kumar, S. M. Synlett 2011, 1602. (f) Prasad, K. R.; Swain, B. J.
Org. Chem. 2011, 76, 2029. (g) Prasad, K. R.; Gandi, V. R.;
Nidhiry, J. E.; Bhat, K. S. Synthesis 2010, 2521. (h) Prasad, K. R.;
Gholap, S. L. J. Org. Chem. 2008, 73, 2. (i) Prasad, K. R.; Gholap,
S. L. J. Org. Chem. 2008, 73, 2916. (j) Prasad, K. R.;
Chandrakumar, A. J. Org. Chem. 2007, 72, 6312. (k) Prasad, K.
(
0.022 g, 72% yield) as a brown colored oil. R 0.5 (40% EtOAc/
f
24
Petroleum ether); [α]
−13.2 (c 1.4, CHCl ); IR (neat) 2934,
3
-1 1
D
2
6
=
894, 1730, 1454, 1251 cm ; H NMR (400 MHz, CDCl ) δ
3 H
.88 (dt, J = 9.2, 4.0 Hz, 1H), 6.05 (d, J = 9.8 Hz, 1H), 5.89 (d, J
15.6 Hz, 1H), 5.84 (d, J = 15.6 Hz, 1H), 4.96 (td, J = 9.6, 3.2
Hz, 1H), 4.69, 4.57 (ABq, J = 6.8 Hz, 2H), 4.21 (d, J = 3.2 Hz,
H), 3.99 (dd, J = 6.4, 3.2 Hz, 1H), 3.87 (t, J = 6.8 Hz, 1H), 3.80
quint, J = 6.0 Hz, 1H), 3.38 (s, 3H), 2.50-2.44 (m, 2H), 1.42 (s,
1
(
R.; Gholap, S. L. J. Org. Chem. 2006, 71, 3643.
3. For earlier syntheses of Anamarine see: (a) Valverde, S.;
Hernandez, A.; Herradon, B.; Rabanal, R. M.; Martin-Lomas, M.
Tetrahedron 1987, 43, 3499. (b) Lorenz, K.; Lichtenthaler, F. W.
Tetrahedron Lett. 1987, 28, 6437. (c) Diaz-Oltra, S.; Murga, J.;
Falomir, E.; Carda, M.; Marco, J. A. Tetrahedron 2004, 60, 2979.
(d) Gao, D.; O’Doherty, G. A. J. Org. Chem. 2005, 70, 9932. (e)
Gao, D.; O’Doherty, G. A. Org. Lett. 2005, 7, 1069. (f) Sabitha,
G.; Reddy, C. N.; Gopal, P.; Yadav, J. S. Tetrahedron Lett. 2010,
3
3
1
5
H), 1.37 (s, 3H), 1.22 (d, J = 5.9 Hz, 3H), 0.89 (s, 9H), 0.08 (s,
13
H), 0.06 (s, 3H); C NMR (100 MHz, CDCl ) δ 163.7, 144.5,
3
C
31.4, 130.7, 121.6, 109.5, 93.7, 81.6, 80.7, 77.1, 75.1, 70.5,
5.7, 29.6, 27.6, 27.1, 25.8 (3C), 21.3, 17.9, −4.2, −4.3; HRMS:
[
M+Na] found 479.2441. C H O Si+Na requires 479.2441.
23 40 7
5
7
2
1, 5736. (g) Prasad, K. R.; Penchalaiah, K. J. Org. Chem. 2011,
6, 6889. (h) Ramesh, P.; Meshram, H. M. Tetrahedron Lett.
012, 53, 4008. (i) Kumar, K. S.; Reddy, C. S. Org. Biomol.
Sythesis of (+)-Anamarine (1): To a stirred solution of 21 (0.02
g, 0.044 mmol) in a mixture of MeOH/water (9:1, 2 mL) was
added PPTS (0.067 g, 0.26 mmol) at room temperature and the
reaction mixture was refluxed for 12 h. After completion of the
Chem. 2012, 10, 2647. (j) Reddy, S. B. V.; Reddy, V. V.;
Praneeth, K. Tetrahedron Lett. 2014, 55, 1398.
Reduction of 11 with Zn(BH
mixture of diasteromers (dr 11:9) in 86% yield, whereas
o
4
.
4
)
2
at −78 C gave an inseparable
reaction (TLC), NaHCO (0.1 g) was added and stirred for 5 min.
3
The reaction mixture was then filtered through a short pad of
o
4
reduction of 11 with NaBH at −78 C gave a mixture of
celite and the celite pad was washed with CHCl (15 mL). The
3

6
Tetrahedron
ACCEPTED MANUSCRIPT
diastereomers in a ratio of 2:3 with 85% yield. Reduction with other
reducing agents was not attempted.
stereochemistry of the major diastereoemer is further corroborated
by its conversion to anamarine. For a review on nucleophilic
addition reaction of structurally similar carbonyl compounds see:
Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191.
5
.
Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2008, 73, 2916.
Addition of 2-lithio-1,3-dithiane to the diamide 10 to produce 13
should be performed strictly under oxygen-free conditions.
Contamination in the argon or nitrogen with oxygen or presence of
oxygen in the reaction medium mitigates the yield of the reaction
and the product 13 is obtained only in 41% yield with a substantial
amount of side products resulting from 1,3-dithiane. For a
cautionary note on the effect of oxygen on the autooxidation of 2-
lithio-1,3-dithiane, see: Wade, P. A.; D’Ambrosio, S. G.; Murray
Jr., J. K. J. Org. Chem. 1995, 60, 4258.
8. Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
Supplementary Material
1
General experimental procedures and copies of H NMR and
13
6
7
.
.
Luche, J. L.; Gemal, A. L. J. Am. Chem. Soc. 1981, 103, 5454.
Stereochemistry of the major diastereomer can be explained based
on the Felkin-Ahn model proposed for the addition of
nucleophiles to 2,3-isopropylideneglyceraldehyde. Also, the
C NMR spectra for all the new compounds synthesized are
provided.

ACCEPTED MANUSCRIPT
Supporting information
Total Synthesis of (+)-Anamarine
Kavirayani R. Prasad and S. Mothish Kumar
Department of Organic Chemistry
Indian Institute of Science, Bangalore 560 012, INDIA
E-mail: prasad@orgchem.iisc.ernet.in; FAX:0091-80-23600529
Contents
S2: General procedures
1
13
S3: H & C NMR spectrum of 11
1
13
S4: H & C NMR spectrum of 12
1
13
S5: H & C NMR spectrum of 12a
1
13
S6: H & C NMR spectrum of 9
1
13
S7: H & C NMR spectrum of 14
1
13
S8: H & C NMR spectrum of 15
1
13
S9: H & C NMR spectrum of 16
1
13
S10: H & C NMR spectrum of 8
1
13
S11: H & C NMR spectrum of 8a
1
13
S12: H & C NMR spectrum of 18
1
13
S13: H & C NMR spectrum of 19
1
13
S14: H & C NMR spectrum of 19a
1
13
S15: H & C NMR spectrum of 20
1
13
S16: H & C NMR spectrum of 21
1
13
S17: H & C NMR spectrum of 1
S1

ACCEPTED MANUSCRIPT
General Procedures: Column chromatography was performed on Acme’s silica gel, 100-200 mesh. TLC
plates were visualized either with UV, in an iodine chamber, or with phosphomolybdic acid spray. Unless
stated otherwise, all reagents were purchased from commercial sources and used without additional
purification. Dichloromethane was freshly distilled over calcium hydride before use. THF was freshly
distilled over Na-benzophenone ketyl. Petroleum ether refers to the fraction boiling in the 60-80 °C.
®
Melting points were uncorrected and recorded on Büchi Melting Point M-560 equipment. Optical
®
rotations were recorded on Rudolph Autopol IV polarimeter or Jasco P-1020 polarimeter at 24 °C and IR
®
1
spectra on Perkin Elmer Spectrum BX spectrophotometer. Unless stated otherwise, H NMR (400 MHz)
13
and C NMR (100 MHz) spectra were recorded on a Bruker 400 MHz machine in CDCl as solvent and
3
the chemical shifts were reported in ppm from the residual solvent as an internal standard. HRMS was
obtained using a Waters Micromass-QTOF operating in the electrospray ionization (ESI) mode. Unless
stated
otherwise,
all
the
reactions
were
performed
under
inert
atmosphere.
S2

ACCEPTED MANUSCRIPT
1
3
H NMR spectrum (400 MHz, CDCl ) of 11
1
3
C NMR spectrum (100 MHz, CDCl ) of 11
3
S3

ACCEPTED MANUSCRIPT
OH
S
O
O
S
O
N
1
H NMR spectrum (400 MHz, CDCl ) of 12
3
OH
S
O
S
O
O
N
1
3
C NMR spectrum (100 MHz, CDCl ) of 12
3
S4

ACCEPTED MANUSCRIPT
OH
S
O
O
S
O
N
1
H NMR spectrum (400 MHz, CDCl ) of 12a
3
OH
S
O
O
S
O
N
1
3
3
C NMR spectrum (100 MHz, CDCl ) of 12a
S5

ACCEPTED MANUSCRIPT
OH
Me
O
O
O
N
1
H NMR spectrum (400 MHz, CDCl ) of 9
3
OH
O
O
Me
O
N
1
3
3
C NMR spectrum (100 MHz, CDCl ) of 9
S6

ACCEPTED MANUSCRIPT
OTBS
O
O
Me
O
N
1
H NMR spectrum (400 MHz, CDCl ) of 14
3
OTBS
O
O
Me
O
N
1
3
3
C NMR spectrum (100 MHz, CDCl ) of 14
S7

ACCEPTED MANUSCRIPT
OTBS
Me
O
O
O
1
H NMR spectrum (400 MHz, CDCl ) of 15
3
OTBS
O
Me
O
O
1
3
3
C NMR spectrum (100 MHz, CDCl ) of 15
S8

ACCEPTED MANUSCRIPT
OTBS
O
Me
O
OH
1
H NMR spectrum (400 MHz, CDCl ) of 16
3
OTBS
O
Me
O
OH
1
3
3
C NMR spectrum (100 MHz, CDCl ) of 16
S9

ACCEPTED MANUSCRIPT
OTBS
Me
O
O
OMOM
1
H NMR spectrum (400 MHz, CDCl ) of 8
3
OTBS
O
O
Me
OMOM
1
3
3
C NMR spectrum (100 MHz, CDCl ) of 8
S10

ACCEPTED MANUSCRIPT
1
H NMR spectrum (400 MHz, CDCl ) of 8a
3
1
3
3
C NMR spectrum (100 MHz, CDCl ) of 8a
S11

ACCEPTED MANUSCRIPT
OTBS
Me
O
O
O
OMOM
1
H NMR spectrum (400 MHz, CDCl ) of 18
3
OTBS
O
Me
O
O
OMOM
1
3
3
C NMR spectrum (100 MHz, CDCl ) of 18
S12

ACCEPTED MANUSCRIPT
OTBS
O
O
Me OH
OMOM
1
H NMR spectrum (400 MHz, CDCl ) of 19
3
OTBS
O
Me OH
O
OMOM
1
3
3
C NMR spectrum (100 MHz, CDCl ) of 19
S13

ACCEPTED MANUSCRIPT
OTBS
O
O
Me OH
OMOM
1
H NMR spectrum (400 MHz, CDCl ) of 19a
3
OTBS
O
Me OH
O
OMOM
1
3
3
C NMR spectrum (100 MHz, CDCl ) of 19a
S14

ACCEPTED MANUSCRIPT
OTBS
Me
O
O
O
O
Ph
OMOM
1
H NMR spectrum (400 MHz, CDCl ) of 20
3
OTBS
O
O
O
Me
O
Ph
OMOM
1
3
3
C NMR spectrum (100 MHz, CDCl ) of 20
S15

ACCEPTED MANUSCRIPT
OTBS
Me
O
O
O
O
OMOM
1
H NMR spectrum (400 MHz, CDCl ) of 21
3
OTBS
Me
O
O
O
O
OMOM
1
3
3
C NMR spectrum (100 MHz, CDCl ) of 21
S16

ACCEPTED MANUSCRIPT
O
OAc OAc
O
Me
OAc OAc
1
H NMR spectrum (400 MHz, CDCl ) of 1
3
O
OAc OAc
O
Me
OAc OAc
1
3
3
C NMR spectrum (100 MHz, CDCl ) of 1
S17