Enantiodivergent total synthesis of microcarpalide from l-tartaric acid

Article abstract of DOI:10.1016/j.tet.2011.03.102

Stereoselective approach for the synthesis of both enantiomers of bio-active decanolactone microcarpalide is described from l-tartaric acid. The synthesis of the key intermediates en route to the natural product is achieved from l-tartaric acid involving

Full text of DOI:10.1016/j.tet.2011.03.102

Tetrahedron 67 (2011) 4268e4276
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Enantiodivergent total synthesis of microcarpalide from -tartaric acid
L
*
Kavirayani R. Prasad , Kamala Penchalaiah
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective approach for the synthesis of both enantiomers of bio-active decanolactone micro-
Received 9 February 2011
Received in revised form 28 March 2011
Accepted 30 March 2011
Available online 8 April 2011
carpalide is described from
product is achieved from
tartaric acid and ring opening of an epoxide derived from tartaric acid.
L
-tartaric acid. The synthesis of the key intermediates en route to the natural
L
-tartaric acid involving the elaboration of -hydroxy amide derived from
g
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Decanolide
Microcarpalide
Tartaric acid
Total synthesis
1. Introduction
Our approach for the synthesis of natural (ꢀ)-microcarpalide 1
is based on the ring closing metathesis (RCM) of the known diene
ester 6 to yield the macrolactone. Synthesis of the acid fragment 8
required for the formation of the diene ester is anticipated by
elaboration of the
while the alcohol fragment 7 is envisaged by extrapolation of the
Microcarpalide is a 10-membered lactone isolated from the
fermentation broths of unidentified endophytic fungi by Hem-
scheidt’s group.1 Microcarpalide is structurally similar to other
decanolides herbarumin I (2), herbarumin II (3), and lethaloxin (4).
It was found to be weakly cytotoxic to mammalian cells and acts as
a microfilament disrupting agent. Since the isolation of micro-
carpalide, a handful of total syntheses of 1 were reported,2,3 ma-
jority of which involve ring closing metathesis (RCM) of a suitably
protected diene ester to install the required E-alkene. We earlier in
2007 reported a formal total synthesis of microcarpalide4 and
herein we report in detail our efforts concerning the synthesis of
g
-hydroxy amide 95 derived from tartaric acid
epoxide 10 also derived from
L-tartaric acid (Scheme 1).
OBn
OBn
OBn
OH
OH
OBn
C6H13
C6H13
C6H13
O
O
O
O
5
O
6
O
1
OBn
BnO
OBn
OH
OH
BnO
OBn
both enantiomers of microcarpalide from L-tartaric acid.
O
C6H13
C6H13
O
O
OH
10
11
O
OH
7
OH
6
+
HO
OH
O
OBn
O
O
O
MeO
OH
N
OBn
8
Me
O
OH
9
Scheme 1. Retrosynthesis for microcarpalide.
The synthetic sequence commenced with synthesis of the g-hy-
droxy amide 9 derived from tartaric acid using a procedure estab-
lished in our laboratory involving controlled addition of Grignard
reagent followed by stereoselective reduction.5 Treatment of 9 with
benzyl bromide in presence of Ag2O afforded the benzyl ether 12 in
71% yield. Ozonolysis of the olefin in 12 to the aldehyde followed by
reduction with NaBH4 resulted in the primary alcohol 13 in 58% yield
accompanied with the formation of the diol 14 in 16% yield. Pro-
tection of the primary hydroxy group in 13 as the silyl ether 15 and
* Corresponding author. Fax: þ91 80 23600529; e-mail address: prasad@org-
chem.iisc.ernet.in (K.R. Prasad).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.102

K.R. Prasad, K. Penchalaiah / Tetrahedron 67 (2011) 4268e4276
4269
further reduction of the amide with NaBH4 furnished the alcohol 16
in 85% yield. Conversion of the primary alcohol to the iodide (75%
yield) followed by reaction with zinc dust in refluxing ethanol pro-
duced the allylic alcohol 17 in 76% yield.6 Protection of the free hy-
droxy group in 17 as the benzyl ether and deprotection of the silyl
etheraffordedtheknownprimaryalcohol183j in94% yield. Oxidation
of the alcohol 18 to the aldehyde and further oxidation to the alcohol
furnished the acid 8 in 96% yield for two steps (Scheme 2).
Accordingly, alcohol 11 was transformed into the diol 28
using a procedure reported by us.8 NaIO4 mediated cleavage of
the diol 28 afforded the aldehyde, which on reduction with
NaBH4 furnished the primary alcohol 29 in 80% yield for two
steps. Elaboration of the primary alcohol 29 involving the dis-
placement of the corresponding tosylate afforded 30, which on
deprotection of the MOM ether resulted in ent-7 in quantitative
yield (Scheme 6).
1) O2/O3, NaHCO3
O
O
O
O
Ag2O, BnBr
toluene, Δ
12 h, 71 %
CH2Cl2:MeOH/Me2S
−78 °C to rt, 3 h
2) NaBH4, MeOH
− 78 °C, 1 h
MeO
OH
MeO
N
N
Me
OH
Me
O
OBn
O
9
12
O
OH
O
O
O
O
OPG
TBDPSCl, imidazole
DMAP, CH2Cl2, Δ
2 h, 99%
MeO
MeO
HO
N
N
O
OBn
(16%)
Me
O
OBn
Me
O
OBn
14
13 (58 %)
15
PG = TBDPS
i) I2, PPh3, imidazole
toluene, Δ, 2 h, 75%
ii) Zn, EtOH, Δ, 12 h
76%
OH
O
NaBH4, MeOH
Δ, 2 h, 85 %
OPG
HO
OPG
OH
OBn
17
O
OBn
16
i) IBX, DMSO, toluene, rt, 2 h
ii) NaClO2, NaH2PO4.2H2O
DMSO, H2O, 0 °C to rt, 2 h
96 % for two steps
i) NaH, BnBr, DMF
0 °C to rt, 2 h, 94 %
ii) TBAF, THF, 0 °C to rt
2 h, 94 %
OBn
OBn
O
OH
OBn
18
OBn
8
Scheme 2. Synthesis of the acid fragment 8.
For the synthesis of the homoallylic alcohol fragment 7, the
known alcohol 117 was converted to the tosylate 19, which on re-
action with n-pentylmagnesium bromide afforded 20 in 69% yield.
FeCl3 mediated deprotection of the acetonide in 20 furnished the
diol 21 in 76% yield (88% based on starting material recovery).
Following a procedure described by Sharma et.al.3l diol 21 was
transformed into the epoxide 10 using standard conditions.
Opening of the epoxide 10 with vinylmagnesium bromide afforded
the required homoallylic alcohol 7 in 88% yield (Scheme 3).
OBn
OBn
DCC, DMAP
rt, 25 h, 43%
Grubbs' catalyst
DCM, rt
C6H13
7 + 8
O
O
6
OBn
OH
OH
OBn
OBn
C6H13
C6H13
ref. 2e
O
O
O
O
OH
OBn
5
−
1
( )-microcarpalide
Scheme 4. Formal synthesis of (ꢀ)-microcarpalide.
O
OH
O
O
O
OH
C6H13
C6H13
C6H13
Scheme 3. Synthesis of the alcohol fragment 7.
O
O
O
O
O
O
OBn
OH
OBn
23
(
)-1
24
+
DCC mediated coupling of alcohol 7 and acid 8 resulted in the
ester 6. Conversion of the ester to the macrolactone 5 by RCM re-
action and further deprotection of the benzyl ether is already
reported in literature,3g hence, the present sequence constitutes
a formal synthesis of (ꢀ)-microcarpalide (Scheme 4).
O
O
O
O
O
BnO
BnO
OH
OH
L-tartaric acid
O
O
27
25
26
For the synthesis of (þ)-microcarpalide 1, RCM of the diene ester
24 is anticipated to construct the decanolactone. Synthesis of the
required acid fragment 25 is envisaged by extension of the primary
alcohol 27 while elaboration of the diol 28 is planned for the syn-
thesis of required alcohol fragment ent-7 as depicted in Scheme 5.
OBn
OBn
OH
OH
C6H13
HO
O
O
OH OMOM
OBn
ent-7
11
28
Scheme 5. Retrosynthesis for (þ)-microcarpalide.

4270
K.R. Prasad, K. Penchalaiah / Tetrahedron 67 (2011) 4268e4276
2. Experimental
2.1. (4R,5S)-5-((R)-1-(Benzyloxy)pent-4-en-1-yl)-N-methoxy-
N,2,2-trimethyl-1,3-dioxolane-4-carboxamide (12)
To a stirred solution of 9 (0.231 g, 0.84 mmol) in toluene (3 mL)
was added Ag2O (0.589 g, 2.53 mmol) at room temperature and
stirred for 1 h. Benzyl bromide (0.12 mL, 1.01 mmol) was added to
the reaction mixture at same temperature and refluxed for 12 h.
After completion of the reaction (TLC), it was filtered through
a short pad of Celite and the Celite pad was washed with CH2Cl2
(15 mL). The residue obtained after concentration of the solvent
was purified by column chromatography furnish the benzyl ether
12 (0.217 g) in 71% yield as a colorless oil. Rf 0.6 (petroleum ether/
Scheme 6. Synthesis of ent-7.
For the synthesis of the acid fragment 25, benzyloxy alcohol 27
was elaborated to the alkene 26 using a known procedure.9 Ozo-
nolysis of 26 resulted in the aldehyde, which on reduction with
NaBH4 afforded the primary alcohol 31 in 76% yield for two steps.
Protection of the primary alcohol in 31 as the TBS ether followed by
deprotection of the benzyl ether afforded 33 in 88% yield. IBX ox-
idation of 33 produced the aldehyde which on Wittig olefination
followed by TBS deprotection with TBAF furnished the alkenol 34 in
56% yield for three steps. Primary alcohol in 34 was transformed
into the acid using standard conditions to yield the required acid
fragment in 87% yield for two steps (Scheme 7).
EtOAc 1:1); [
a
]
24 þ11.8 (c 0.8, CHCl3); IR (neat) 2985, 2935, 1667,
D
1449, 1384, 1070 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.39e7.19 (m,
5H), 5.79 (ddt, J¼16.9, 10.1, 6.7 Hz, 1H), 4.99 (dd, J¼18.9, 10.3 Hz,
2H), 4.75 (br s, 2H), 4.65, 4.58 (ABq, J¼11.3 Hz, 2H), 3.64 (br s, 4H),
3.18 (br s, 3H), 2.32e2.04 (m, 2H), 1.68 (q, J¼7.4 Hz, 2H), 1.48 (s, 3H),
1.47(s, 3H); 13C NMR (100 MHz, CDCl3) 170.2 (Cq), 138.4 (Cq), 138.2
i) ozonolysis
ii) NaBH4, MeOH
0 °C, 1 h
O
O
O
Ref. 9
OH
OH
BnO
BnO
BnO
O
O
O
76 % for two steps
31
26
27
O
O
TBSCl, imidazole
DMAP, CH2Cl2
rt, 10 h, 94 %
Pd-C/H2, EtOAc
rt, 3 h, 88 %
OTBS
OH
OTBS
HO
BnO
O
O
33
32
i) PCC, 4Å MS, celite
CH2Cl2, rt, 1 h
ii) NaClO2, NaH2PO4.2H2O
DMSO, H2O, 0 °C to rt
87 % for two steps
i) IBX, EtOAc, Δ, 5 h
ii) CH3PPh3Br, LHMDS
THF, 0 °C to rt, 2 h
iii) TBAF, THF, 0 °C to rt, 1 h
56 % for three steps
O
O
O
O
O
OH
25
34
Scheme 7. Synthesis of the acid fragment 25.
DCC mediated coupling of ent-7 and acid 25 produced the
known ester 24 in 96% yield. Ring closing metathesis of 24 with
Grubbs first generation catalyst produced the Z and E lactones 23a
and 23 in 26% and 49% yield after chromatography.10 (E)-Lactone 23
was treated with TiCl4 to afford microcarpalide in 62% yield
(Scheme 8).
(CH), 128.2 (CH), 127.9 (CH), 127.5 (CH), 114.9 (CH2), 111.1 (Cq), 78.9
(CH), 77.2 (CH), 72.5 (CH), 72.3 (CH2), 61.7 (CH3), 32.2 (CH3), 29.8
(CH2), 29.3 (CH2), 27.0 (CH3), 26.1 (CH3); HRMS MþþNa found
386.1934; C20H29NO5þNa requires 386.1943.
2.2. (4R,5S)-5-((R)-1-(Benzyloxy)-4-hydroxybutyl)-N-
methoxy-N,2,2-trimethyl-1,3-sdioxolane-4-carboxamide (13)
In conclusion, facile synthesis of microcarpalide in both en-
antiomeric forms has been accomplished starting from
acid. Main feature of the synthesis include the elaboration of
-hydroxy amide and -threotol derivatives derived from tartaric
L-tartaric
Ozone was bubbled through a pre-cooled (ꢀ78 ꢁC) solution of 12
(0.173 g, 0.47 mmol) in a mixture of CH2Cl2/MeOH (4:1, 10 mL),
containing solid NaHCO3 (0.010 g) until the pale blue color per-
sisted. Excess ozone was flushed off with oxygen and Me2S (0.5 mL)
was added. The reaction mixture was warmed to 0 ꢁC and stirred
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.
g
L
acid and ring closing metathesis to construct the 10-membered
lactone ring.
O
O
Grubbs 1st gen cat
DCC, DMAP
CH2Cl2, rt
1 2h, 96%
25 + ent-7
C6H13
CH2Cl2, Δ, 48 h
O
O
24
OBn
O
To a pre-cooled solution (ꢀ78 ꢁC) of the aldehyde prepared
above in MeOH (3 mL) was added NaBH4 (0.036 g, 0.95 mmol)
portion wise. The reaction mixture was stirred at same temperature
for 1 h. After the reaction was completed (TLC), it was quenched by
addition of cold water at ꢀ78 ꢁC. The reaction mixture was
extracted with EtOAc (2ꢂ15 mL) and the combined EtOAc extracts
were washed with brine (5 mL) and dried over Na2SO4. Residue
obtained after evaporation of solvent was purified by column
O
OH
O
O
O
OH
TiCl4/CH2Cl2
0°C, 2h, 62%
+
O
C6H13
O
C6H13
O
O
O
OH
OBn
C6H13
OBn
23
(49%)
23a
(
) 26%
Scheme 8. Synthesis of (þ)-microcarpalide.

K.R. Prasad, K. Penchalaiah / Tetrahedron 67 (2011) 4268e4276
4271
chromatography to obtain 13 (0.101 g) in 58% overall yield for two
1.3 Hz, 4H), 7.48e7.22 (m, 11H), 4.62, 4.57 (ABq, J¼11.4 Hz, 2H), 4.0
(t, J¼3.3 Hz, 2H), 3.74e3.51 (m, 5H), 2.32 (br s, 1H), 1.88e1.51 (m,
4H), 1.41 (s, 6H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3) 139.4 (Cq),
137.0 (CH), 135.3 (Cq), 131.0 (CH), 129.8 (CH), 129.5 (CH), 129.3 (CH),
129.0 (CH), 110.2 (Cq), 80.0 (CH), 79.4 (CH), 76.6 (CH), 74.3 (CH2),
65.0 (CH2), 64.1 (CH2), 30.4 (CH2), 28.53 (CH3), 28.46 (CH3), 28.3
(CH3), 27.9 (CH2), 20.6 (Cq); HRMS MþþNa found 571.2859;
C20H29NO5þNa requires 571.2856.
steps as a colorless oil. Rf 0.4 (EtOAc); [
a
]
24 þ12.2 (c 1.7, CHCl3); IR
D
(neat) 3445, 2987, 2936, 2873,1663,1451,1385,1067 cmꢀ1; 1H NMR
(400 MHz, CDCl3)
d 7.51e7.20 (m, 5H), 4.74 (br s, 2H),4.66, 4.58
(ABq, J¼11.4 Hz, 2H), 3.64 (s, 3H), 3.78e3.54 (m, 3H), 3.17 (br s, 3H),
2.02 (br s, 1H), 1.76e1.52 (m, 4H), 1.47 (s, 3H), 1.45 (s, 3H); 13C NMR
(100 MHz, CDCl3) 170.1 (Cq), 138.2 (Cq), 128.2 (CH), 128.0 (CH),
127.6 (CH), 111.1 (Cq), 78.9 (CH), 77.8 (CH), 72.6 (CH), 72.2 (CH2),
62.5 (CH2), 61.7 (CH3), 32.2 (CH3), 28.8 (CH2), 27.0 (CH3), 26.4 (CH2),
26.1 (CH3); HRMS MþþNa found 390.1892; C20H29NO5þNa requires
390.1893.
2.6. (3R,4R)-4-(Benzyloxy)-7-((tert-butyldiphenylsilyl)oxy)
hept-1-en-3-ol (17)
2.3. (R)-4-(Benzyloxy)-4-((4S,5S)-5-(hydroxymethyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)butan-1-ol (14)
To a solution of 16 (0.115 g, 0.2 mmol) in dry toluene (3 mL)
were added triphenylphosphine (0.165 g, 0.62 mmol), imidazole
(0.043 g, 0.62 mmol), and iodine (0.106 g, 0.41 mmol) at room
temperature and the reaction mixture was stirred under reflux for
2 h. After the reaction was completed (TLC), it was cooled to room
temperature and poured into water (10 mL). It was then extracted
with ether (3ꢂ20 mL) and the combined organic layers were
washed with brine (30 mL), satd sodium thiosulfate (5 mL), and
dried over Na2SO4. Silica gel column chromatography of the res-
idue obtained after evaporation of the solvent, gave the iodide
Diol 14 (0.024 g) yield 16%. Rf 0.3 (EtOAc); [
a
]
24 þ14.7 (c 2.4,
D
CHCl3); IR (neat) 3417, 2934, 2874, 1454, 1372, 1250, 1214,
1058 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 7.39e7.21 (m, 5H), 4.68,
4.61 (ABq, J¼11.4 Hz, 2H), 4.01 (dt, J¼12.4, 8.4 Hz, 2H), 3.80 (dd,
J¼8.4, 3.1 Hz, 1H), 3.70e3.55 (m, 4H), 2.28 (br s, 2H), 1.79e1.53 (m,
4H), 1.42 (s, 3H), 1.41 (s, 3H); 13C NMR (100 MHz, CDCl3) 137.8 (Cq),
128.4 (CH), 128.1 (CH), 127.9 (CH), 108.9 (Cq), 78.5 (CH), 78.0 (CH),
77.3 (CH), 72.9 (CH2), 62.6 (CH2), 62.5 (CH2), 28.9 (CH2), 27.0 6
(CH3), 27.01 (CH3), 26.6 (CH2); HRMS MþþNa found 333.1682;
C20H29NO5þNa requires 333.1678.
(0.081 g, 75%) as a colorless oil. Rf 0.6 (petroleum ether/ether 9:1);
24
[
a
]
ꢀ15.9 (c 0.6, CHCl3); IR (neat) 2931, 2858, 1109, 1020,
D
701 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.66 (dd, J¼7.6, 1.2 Hz, 4H),
7.46e7.23 (m, 11H), 4.62, 4.57 (ABq, J¼11.4 Hz, 2H), 3.91 (dd, J¼7.5,
4.4 Hz, 1H), 3.87e3.74 (m, 1H), 3.67 (t, J¼5.6 Hz, 2H), 3.54 (dt,
J¼7.3, 3.1 Hz, 1H), 3.32 (dd, J¼10.7, 4.1 Hz, 1H), 3.20 (dd, J¼10.7,
5.2 Hz, 1H), 1.83e1.69 (m, 2H), 1.67e1.55 (m, 2H), 1.46 (s, 3H), 1.41
(s, 3H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3) 138.2 (Cq), 135.6
(CH), 133.9 (Cq), 129.6 (CH), 128.4 (CH), 128.07 (CH), 127.8 (CH),
127.6 (CH), 109.3 (Cq), 81.8 (CH), 77.7 (CH), 75.5 (CH), 72.7 (CH2),
63.6 (CH2), 28.8 (CH2), 27.5 (CH3), 27.3 (CH3), 26.9 (CH3), 26.6
(CH2), 19.2 (Cq), 7.5 (CH2); HRMS MþþNa found 681.1878;
C20H29NO5þNa requires 681.1873.
2.4. (4R,5S)-5-((R)-1-(Benzyloxy)-4-((tert-butyldiphenylsilyl)
oxy)butyl)-N-methoxy-N,2,2-trimethyl-1,3-dioxolane-4-
carboxamide (15)
To a stirred solution of the alcohol 13 (0.101 g, 0.27 mmol), im-
idazole (0.037 g, 0.55 mmol), and DMAP (0.007 g, 0.055 mmol) in
CH2Cl2 (3 mL) was added TBDPSCl (0.08 mL, 0.33 mmol), at room
temperature and refluxed for 2 h. After completion of the reaction
(TLC), it was poured into water (5 mL) and extracted with diethyl
ether (2ꢂ10 mL). The combined organic extracts were washed with
brine (5 mL) and dried over Na2SO4. Evaporation of the solvent
followed by column chromatography of the resulting residue yiel-
ded 15 (0.164 g) in quantitative yield as a colorless oil. Rf 0.5 (pe-
To a solution of the iodide (0.081 g, 0.15 mmol) prepared above
in absolute ethanol (2 mL) was added zinc dust (0.78 g, 1.20 mmol)
at room temperature and refluxed for 5 h. Progress of the reaction
was followed by TLC. After the reaction was completed it was fil-
tered through a short pad of Celite and the Celite pad was washed
with ether (2ꢂ10 mL). Silica gel column chromatography of the
residue obtained after evaporation of the solvent, furnished the
allylic alcohol 17 (0.054 g, 76%) as a colorless oil. Rf 0.5 (petroleum
troleum ether/EtOAc 7:3); [
a
]
24þ8.7 (c 0.8, CHCl3); IR (neat) 2933,
D
2858, 1669, 1109, 1020, 702 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.65
(d, J¼6.8 Hz, 4H), 7.46e7.20 (m, 11H), 4.75 (br s, 2H), 4.62, 4.55
(ABq, J¼11.4 Hz, 2H), 3.70e3.56 (m, 3H), 3.61 (s, 3H), 3.16 (br s, 3H),
1.81e1.70 (m, 2H), 1.69e1.56 (m, 2H), 1.48 (s, 3H), 1.46 (s, 3H), 1.04
(s, 9H); 13C NMR (100 MHz, CDCl3) 170.2 (Cq), 138.4 (Cq), 135.5
(CH), 134.8 (CH), 133.9 (Cq), 129.5 (CH), 128.2 (CH), 127.9 (CH), 127.6
(CH), 111.1 (Cq), 79.0 (CH), 77.8 (CH), 72.51 (CH), 72.16 (CH2), 63.7
(CH2), 61.6 (CH3), 32.2 (CH3), 28.8 (CH2), 27.05 (CH3), 26.8 (CH3),
26.4 (CH2), 26.1 (CH3), 19.2 (Cq); HRMS MþþNa found 628.3069;
C20H29NO5þNa requires 628.3070.
ether/EtOAc 9:1); [
a
]
24 ꢀ5.5 (c 1.2, CHCl3); IR (neat) 3456, 3071,
2932, 2859, 1111, 701 Dcmꢀ1
; d 7.68 (dd,
1H NMR (400 MHz, CDCl3)
J¼7.6, 1.1 Hz, 4H), 7.47e7.21 (m, 11H), 5.88 (ddd, J¼17.0, 10.4, 6.3 Hz,
1H), 5.37 (d, J¼16.6 Hz, 1H), 5.23 (d, J¼10.5 Hz, 1H), 4.63, 4.53 (ABq,
J¼11.3 Hz, 2H), 4.10 (t, J¼6.3 Hz, 1H), 3.68 (t, J¼5.8 Hz, 2H),
3.47e3.33 (m, 1H), 1.87e1.56 (m, 4H), 1.07 (s, 9H); 13C NMR
(100 MHz, CDCl3) 138.1 (Cq),137.4 (CH),135.5 (CH),133.9 (Cq),129.6
(CH), 128.4 (CH), 127.85 (CH), 127.81 (CH), 127.6 (CH), 117.0 (CH2),
81.9 (CH), 74.4 (CH), 72.3 (CH2), 63.8 (CH2), 27.8 (CH2), 26.8 (CH3),
26.4 (CH2), 19.2 (Cq); HRMS MþþNa found 497.2473;
C20H29NO5þNa requires 497.2488.
2.5. ((4S,5S)-5-((R)-1-(Benzyloxy)-4-((tert-butyldiphenylsilyl)
oxy)butyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (16)
To a pre-cooled solution (0 ꢁC) of the Weinreb amide 15 (0.164 g,
0.27 mmol) prepared above in MeOH (3 mL) was added NaBH4
(0.031 g, 0.81 mmol) portion wise. The reaction mixture was slowly
allowed to warm up to room temperature and refluxed for 2 h. After
the reaction was completed (TLC), it was quenched by addition of
cold water at 0 ꢁC. The reaction mixture was extracted with EtOAc
(2ꢂ15 mL) and the combined EtOAc extracts were washed with
brine (5 mL) and dried over Na2SO4. Residue obtained after evap-
oration of solvent was purified by column chromatography to ob-
tain 16 (0.126 g) in 85% yield as a colorless oil. Rf 0.3 (petroleum
2.7. (4R,5R)-4,5-Bis(benzyloxy)hept-6-en-1-ol (18)
To a stirred solution of the allylic alcohol 17 (0.103 g, 0.21 mmol)
in DMF (2 mL) was added NaH (0.013 g, 0.32 mmol) portion wise at
0 ꢁC and stirred it for 45 min at the same temperature. Benzyl
bromide (0.038 mL, 0.32 mmol) was added to the reaction mixture
at 0 ꢁC and stirred at room temperature for 2 h. After the reaction
was completed (TLC), it was cooled to room temperature and
poured into water (10 mL). It was then extracted with ether
(2ꢂ15 mL) and the combined organic layers were washed with
brine (5 mL), and dried over Na2SO4. Silica gel column
ether/EtOAc 7:3); [
a
]
;
24 þ4.8 (c 1.2, CHCl3); IR (neat) 3447, 2931,
D
2858, 1109, 701 cmꢀ1
1H NMR (400 MHz, CDCl3)
d
7.65 (dd, J¼7.7,

4272
K.R. Prasad, K. Penchalaiah / Tetrahedron 67 (2011) 4268e4276
chromatography of the residue obtained after evaporation of the
30.3 (CH2), 25.9 (CH2); HRMS MþþNa found 379.1308;
C20H29NO5þNa requires 379.1312.
solvent, gave the bis benzyl ether (0.113 g), 94% as a colorless oil. Rf
0.6 (petroleum ether/EtOAc 9:1); [
a
]
24þ3.07 (c 1.3, CHCl3); IR (neat)
3069, 2929, 2857, 1641, 1111, 699 cmDꢀ1
;
1H NMR (300 MHz, CDCl3)
2.9. (S)-2-(Benzyloxy)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)
d
7.64 (dd, J¼8.1, 1.8 Hz, 4H), 7.45e7.17 (m, 16H), 5.83 (ddd, J¼18.6,
ethyl 4-methylbenzenesulfonate (19)
10.8, 7.5 Hz, 1H), 5.28 (dd, J¼18.0, 10.4 Hz, 2H), 4.71, 4.52 (ABq,
J¼11.1 Hz, 2H), 4.63, 4.39 (ABq, J¼11.7 Hz, 2H), 3.87 (t, J¼6.6 Hz,1H),
3.62 (t, J¼5.7 Hz, 2H), 3.47 (ddd, J¼8.1, 4.8, 3.3 Hz, 1H), 1.79e1.64
(m, 2H), 1.62e1.41 (m, 2H), 1.03 (s, 9H); 13C NMR (75 MHz, CDCl3)
138.8 (Cq), 138.6 (Cq), 135.5 (CH), 135.4 (CH), 134.0 (Cq), 129.5 (CH),
128.26 (CH), 128.21 (CH), 127.9 (CH), 127.7 (CH), 127.5 (CH), 127.42
(CH), 127.40 (CH), 118.6 (CH2), 82.8 (CH), 81.1 (CH), 73.1 (CH2), 70.5
(CH2), 63.8 (CH2), 28.6 (CH2), 27.1 (CH2), 26.8 (CH3),19.2 (Cq); HRMS
MþþNa found 587.2951; C20H29NO5þNa requires 587.2957.
To a stirred solution of alcohol 11 (0.5 g, 1. 98 mmol) in CH2Cl2
(4 mL) was added DMAP (0.726 g, 5.95 mmol), followed by p-TsCl
(0.754 g, 3.96 mmol) at room temperature under argon atmo-
sphere. The reaction mixture was stirred for 12 h at the same
temperature. After completion of the reaction (TLC), it was poured
into water (15 mL) and extracted with diethyl ether (2ꢂ20 mL). The
combined organic extracts were washed with brine (10 mL) and
dried over Na2SO4. Evaporation of the solvent followed by column
chromatography of the resulting residue yielded 19 (0.666 g) in 83%
To a pre-cooled (0 ꢁC) solution of the bis benzyl ether (prepared
above) (0.176 g, 0.31 mmol) in THF (3 mL) was added TBAF (0.5 mL,
0.46 mmol) and stirred at room temperature and stirred for 2 h.
After the reaction was completed (TLC), it was poured into cold
water (15 mL) and extracted with EtOAc. The organic layer was
washed with brine (5 mL) and dried over Na2SO4. Evaporation of
the solvent and purification of the resulting residue by column
chromatography furnished the alcohol 18 (0.095 g) in 94% yield as
yield as colorless oil. Rf 0.8 (petroleum ether/EtOAc 1:1); [
a
]
2D4þ13.1
(c 1.0, CHCl3); IR (neat) 2936, 2866, 1686, 1542, 1365, 1177 cmꢀ1; 1H
NMR (400 MHz, CDCl3)
d
7.75 (d, J¼8.2 Hz, 2H), 7.20e7.36 (m, 7H),
4.66, 4.58 (ABq, J¼11.8 Hz, 2H), 4.23e4.12 (m, 2H), 4.08 (dd, J¼10.5,
6.2 Hz, 1H), 3.91 (dd, J¼8.4, 6.8 Hz, 1H), 3.73 (dd, J¼8.3, 6.6 Hz, 1H),
3.67 (dt, J¼10.5, 5.2 Hz,1H), 2.42 (s, 3H),1.33 (s, 3H),1.28 (s, 3H); 13C
NMR (100 MHz, CDCl3) 145.0 (Cq), 137.6 (Cq), 132.6 (Cq), 129.9 (CH),
128.4 (CH), 128.0 (CH), 127.9 (CH), 109.5 (Cq), 76.3 (CH), 75.2 (CH),
73.2 (CH2), 69.4 (CH2), 65.1 (CH2), 26.1 (CH3), 25.1 (CH3), 21.6 (CH3);
HRMS MþþNa found 429.1349; C20H29NO5þNa requires 429.1348.
a colorless oil. Rf 0.3 (petroleum ether/EtOAc 7:3); [
a
]
24 þ7.08 (c
D
1.23, CHCl3); lit.3j
[
a
]
24 þ10.4 (c 1.3, CHCl3); IR (neat) 3405, 2925,
D
2867, 1088, 1063, 736, 697 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.41e7.21 (m, 10H), 5.83 (ddd, J¼17.5, 10.4, 7.5 Hz, 1H), 5.33 (dd,
J¼17.4, 10.0 Hz, 2H), 4.77, 4.57 (ABq, J¼11.4 Hz, 2H), 4.66, 4.42
(ABq¼11.9 Hz, 2H), 3.96 (t, J¼6.7 Hz, 1H), 3.57 (t, J¼5.8 Hz, 2H),
3.45e3.55 (m, 1H), 1.92 (br s, 1H), 1.81e1.63 (m, 2H), 1.62e1.46 (m,
2H); 13C NMR (100 MHz, CDCl3) 138.5 (2ꢂCq), 135.2 (CH), 128.4
(2ꢂCH), 128.1 (CH), 127.8 (CH), 127.7 (CH), 127.6 (CH), 119.0 (CH2),
82.4 (CH), 81.0 (CH), 73.2 (CH2), 70.6 (CH2), 62.8 (CH2), 29.0 (CH2),
27.2 (CH2); HRMS MþþNa found 349.1792; C20H29NO5þNa requires
349.1780.
3. (S)-4-((S)-1-(Benzyloxy)heptyl)-2,2-dimethyl-1,3-dioxolane
(20)
To a stirred solution of CuBr (0.351 g, 2.43 mmol) in THF (2 mL)
was added n-pentylmagnesiun bromide (10 mL, 8.0 mmol 0.8 M
solution in THF) at 0 ꢁC and stirred for 15 min. A solution of the
tosylate 19 (0.66 g,1.62 mmol) was added to the reaction mixture at
0 ꢁC. The reaction mixture was slowly warmed to room tempera-
ture and stirred for 2 h. After completion of the reaction (TLC), it
was poured into satd NH4Cl solution (15 mL) and extracted with
diethyl ether (2ꢂ20 mL). The combined organic extracts were
washed with brine (10 mL) and dried over Na2SO4. Evaporation of
the solvent followed by column chromatography of the resulting
residue yielded 20 (0.344 g) in 69% yield as colorless oil. Rf 0.7
2.8. (4R,5R)-4,5-Bis(benzyloxy)hept-6-enoic acid (8)
To a stirred solution of the alcohol 18 (0.037 g, 0.11 mmol) in
DMSO/toluene (1:0.5 mL) was added IBX (0.095 g, 0.34 mmol) at
room temperature and stirred for 2 h. After the reaction was
completed (TLC), water (0.2 mL) was added. Reaction mixture was
filtered through a short pad of Celite and the Celite pad was washed
with ether (2ꢂ5 mL). The organic layer was diluted with ether
(20 mL) and washed with water (10 mL).Combined ethereal ex-
tracts were washed with brine and dried over Na2SO4. Evaporation
of the solvent yielded the crude aldehyde, which was subjected to
the next reaction without further purification.
(petroleum ether/EtOAc 95:5); [
a
]
24 ꢀ39.5 (c 1.4, CHCl3); IR (neat)
D
2931, 2863, 1651, 1545, 1069 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.41e7.19 (m, 5H), 4.75, 4.60 (ABq, J¼11.6 Hz, 2H), 4.19 (dt, J¼17.4,
6.7 Hz, 1H), 3.96 (t, J¼6.6 Hz, 1H), 3.66 (t, J¼7.7 Hz, 1H), 3.48e3.33
(m, 1H), 1.43 (s, 3H), 1.36 (s, 3H), 1.48e1.18 (m, 10H), 0.86 (t,
J¼6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) 138.8 (Cq), 128.2 (CH),
127.9 (CH), 127.5 (CH), 109.2 (Cq), 79.7 (CH), 78.5 (CH), 72.8 (CH2),
66.0 (CH2), 31.7 (CH2), 30.7 (CH2) 29.3 (CH2), 26.5 (CH3), 25.5 (CH2),
25.4 (CH3), 22.6 (CH2), 14.0 (CH3); HRMS MþþNa found 329.2090;
C20H29NO5þNa requires 329.2093.
To a pre-cooled solution (0 ꢁC) of the aldehyde prepared above
in DMSO/H2O (0.5:0.5 mL) was added NaH2PO4$2H2O (0.177 g,
1.13 mmol) at room temperature and stirred it for 5 min NaClO2
(0.051 g, 0.56 mmol) was added at 0 ꢁC and stirred at room tem-
perature for 2 h. After the reaction was completed (TLC), water
(10 mL) was added and extracted with EtOAc (2ꢂ15 mL). Combined
EtOAc extracts were washed with brine (5 mL) and dried over
Na2SO4. Residue obtained after evaporation of solvent was purified
by column chromatography to obtain 8 (0.034 g) in 96% overall
yield in two steps as a colorless oil. Rf 0.4 (petroleum ether/EtOAc
3.1. (2S,3S)-3-(Benzyloxy)nonane-1,2-diol (21)
To a stirred solution of 20 (0.15 g, 0.49 mmol) in CH2Cl2 (2 mL)
was added FeCl3.6H2O (0.397 g, 1.47 mmol) at room temperature
and stirred for 2 h. After completion of the reaction (TLC), the re-
action mixture was diluted with CH2Cl2 (5 mL) and solid NaHCO3
(0.5 g) and water (0.1 mL) were added and stirred it for 15 min. The
reaction mixture was filtered through a short pad of Celite and the
Celite pad was washed with CH2Cl2 (30 mL). The residue obtained
after concentration of the solvent was purified by column chro-
matoghaphy to furnish the diol 21 (0.099 g) in 76% yield as a col-
1:1); [
a
]
24 þ15.5 (c 0.71, CHCl3); lit.3j
[
a]
24 þ16.8 (c 0.7, CHCl3); IR
D
D
(neat) 3420, 3030, 2921, 2871, 1710, 1071, 737 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d
7.44e7.24 (m, 10H), 5.88 (ddt, J¼17.5, 10.5,
7.6 Hz, 1H), 5.40 (dd, J¼14.1, 4.9 Hz, 2H), 4.82, 4.59 (ABq, J¼11.4 Hz,
2H), 4.71, 4.46 (ABq, J¼11.9 Hz, 2H), 3.98 (t, J¼6.5 Hz, 1H), 3.61 (ddd,
J¼9.3, 5.7, 3.6 Hz, 1H), 2.59e2.45 (m, 2H), 2.06e1.91 (m, 1H),
1.87e1.73 (m, 1H), 13C NMR (100 MHz, CDCl3) 179.8 (Cq), 138.4
(2ꢂCq), 134.9 (CH), 128.4 (CH), 128.1 (CH), 127.8 (CH), 127.7 (CH),
127.6 (CH), 119.3 (CH2), 82.5 (CH), 79.8 (CH), 73.4 (CH2), 70.6 (CH2),
orless oil. Rf 0.4 (petroleum ether/EtOAc 1:1); [
a]
24 þ34.1 (c 1.0,
CHCl3); IR (neat) 3370, 2930, 2863, 1653, 1545, 1085,D1046 cmꢀ1; 1H
NMR (400 MHz, CDCl3)
d 7.42e7.20 (m, 5H), 4.65, 4.46 (ABq,
J¼11.3 Hz, 2H), 3.70e3.52 (m, 3H), 3.45 (dt, J¼10.8, 5.5 Hz, 1H), 2.64

K.R. Prasad, K. Penchalaiah / Tetrahedron 67 (2011) 4268e4276
4273
(br s, 1H), 2.28 (br s, 1H), 1.65e1.49 (m, 2H), 1.43e1.25 (m, 8H), 0.87
(t, J¼7 Hz, 3H); 13C NMR (100 MHz, CDCl3) 138.0 (Cq) 128.5 (CH),
127.9 (CHꢂ2), 79.7 (CH), 72.7 (CH), 72.1 (CH2), 64.0 (CH2), 31.7
(CH2), 30.0 (CH2), 29.5 (CH2) 25.0 (CH2), 22.6 (CH2), 14.0 (CH3);
HRMS MþþNa found 289.1779; C20H29NO5þNa requires 289.1780.
J¼16.8, 6.3 Hz, 2H), 4.64, 4.50 (ABq, J¼11.3 Hz, 2H), 3.63 (td, J¼9.8,
4.9 Hz, 1H), 3.32 (q, J¼5.5 Hz, 1H), 2.41e2.17 (m, 3H), 1.72e1.49 (m,
2H),1.43e1.23 (br m, 8H), 0.89 (t, J¼6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) 138.4 (Cq), 135.0 (CH), 128.4 (CH), 127.8 (CH), 127.7 (CH),
117.2 (CH2), 81.4 (CH), 72.3 (CH2), 78.0 (CH), 38.1 (CH2), 31.8 (CH2),
30.1 (CH2), 29.5 (CH2), 25.1 (CH2), 22.6 (CH2), 14.1 (CH3); HRMS
MþþNa found 299.1987; C20H29NO5þNa requires 299.1987.
3.2. (2S,3S)-3-(Benzyloxy)-2-hydroxynonyl
4-methylbenzenesulfonate (22)
3.5. (4R,5R)-(4S,5S)-5-(Benzyloxy)undec-1-en-4-yl 4,5-
To a stirred solution of the diol 21 (0.06 g, 0.22 mmol) in CH2Cl2
(1 mL) was added Et3N (0.1 mL, 0.67 mmol), followed by p-TsCl
(0.086 g, 0.45 mmol) at 0 ꢁC under argon atmosphere. The reaction
mixture was stirred for 12 h at room temperature. After completion
of the reaction (TLC), it was poured into water (5 mL) and extracted
with diethyl ether (2ꢂ5 mL). The combined organic extracts were
washed with brine (5 mL) and dried over Na2SO4. Evaporation of
the solvent followed by column chromatography of the resulting
residue yielded 22 (0.062 g) in 67% yield as a colorless oil. Rf 0.5
bis(benzyloxy)hept-6-enoate (6)
To a stirred solution of acid 8 (0.016 g, 0.047 mmol), in CH2Cl2
(0.5 mL) were added alcohol 7 (0.011 g, 0.039 mmol, in 0.5 mL
CH2Cl2), DCC (0.017 g, 0.079 mmol), and DMAP (0.002 g,
0.0079 mmol), at room temperature and stirred for 25 h. After
completion of the reaction (TLC), it was filtered through a short pad
of silica gel and the silica gel pad was washed with diethyl ether
(20 mL). Evaporation of the solvent and purification of the resulting
residue by column chromatography furnished the ester 6 (0.013 g)
in 43% yield as a colorless oil. Rf 0.7 (petroleum ether/ether 4:1);
(petroleum ether/EtOAc 4:1); [
a]
24 þ3.3 (c 1.0, CHCl3); IR (neat)
D
3422, 2927, 2858, 1598, 1362, 1176, 1097, 975, 814 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d
7.78 (d, J¼8.0 Hz, 2H), 7.38e7.18 (m, 7H), 4.57,
[a
]
24þ2.0 (c 1.5, CHCl3); lit.3g
[
a]
24þ1.9 (c 1.4, CHCl3); IR (neat) 2928,
D
D
4.39 (ABq, J¼11.3 Hz, 2H), 4.03 (qd, J¼10.0, 5.4 Hz, 2H), 3.79 (td,
J¼9.6, 6.7 Hz, 1H), 3.46 (td, J¼9.5, 5.8 Hz, 1H), 2.42 (s, 3H), 2.33 (d,
J¼7.1 Hz, 1H), 1.65e1.46 (m, 2H), 1.38e1.20 (br m, 8H), 0.87 (t,
J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) 145 (Cq), 137.8 (Cq), 132.6
(Cq), 129.9 (CH), 128.4 (CH), 128.0 (CH), 127.9 (CH), 77.9 (CH), 72.4
(CH2), 70.5 (CH2), 70.1 (CH), 31.7 (CH2), 29.9 (CH2), 29.3 (CH2), 25.2
(CH2), 22.5 (CH2), 21.6 (CH3), 14.0 (CH3); HRMS MþþNa found
443.2038; C20H29NO5þNa requires 443.1868.
2858, 1732, 1071, 734, 697 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
7.37e7.20 (m, 15H), 5.87e5.63 (m, 2H), 5.30 (dd, J¼17.4, 9.6 Hz,
2H), 5.15e5.05 (m, 2H), 5.03e4.93 (m, 1H), 4.72, 4.51 (ABq,
J¼11.4 Hz, 2H), 4.62, 4.38 (ABq, J¼11.7 Hz, 2H), 4.56 (s, 2H), 3.88 (t,
J¼6.3 Hz, 1H), 3.51 (ddd, J¼9.0, 5.7, 3.6 Hz, 1H), 3.42 (dt, J¼7.2,
4.2 Hz, 1H), 2.54e2.37 (m, 2H), 2.36e2.18 (m, 2H), 2.03e1.83 (m,
1H), 1.81e1.61 (m, 1H), 1.55e1.32 (br m, 2H), 1.23 (br m, 8H), 0.86 (t,
J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) 173.1 (Cq), 138.5 (CH),
138.4 (CH), 135.0 (CH), 134.1 (CH), 128.3 (CH),128.0 (CH), 127.8 (CH),
127.7 (CH), 127.6 (CH), 127.5 (CH), 119.1 (CH2), 117.5 (CH2), 82.5 (CH),
80.1 (CH), 78.9 (CH), 73.4 (CH2), 73.2 (CH), 72.3 (CH2), 70.5 (CH2),
34.3 (CH2), 31.7 (CH2), 30.6 (CH2), 29.9 (CH2), 29.3 (CH2), 26.2 (CH2),
25.6 (CH2), 22.6 (CH2), 14.1 (CH3); HRMS MþþNa found 621.3556;
C20H29NO5þNa requires 621.3556.
3.3. (S)-2-((S)-1-(Benzyloxy)heptyl)oxirane (10)
To a stirred solution of 22 (0.085 g, 0.20 mmol) in MeOH
(1.5 mL) was added K2CO3 (0.056 g, 0.40 mmol) at room tempera-
ture and stirred for 2 h. After completion of the reaction (TLC), it
was filtered through a short pad of Celite and the Celite pad was
washed with CH2Cl2 (15 mL). The residue obtained after concen-
tration of the solvent was purified by column chromatography to
furnish epoxide 10 (0.045 g) in 91% yield as a colorless oil. Rf 0.5
3.6. (2R,3R)-2-(Benzyloxy)-3-(methoxymethoxy)hex-5-en-
1-ol (29)
(petroleum ether/EtOAc 9:1); [
a]
24 ꢀ30.2 (c 1.0, CHCl3); IR (neat)
To a stirred solution of 28 (0.218 g, 0.73 mmol) in CH3CN/H2O
(3:1 mL) was added NaIO4 (0.315 g, 1.47 mmol) at room tempera-
ture and stirred for 1 h. After completion of the reaction (TLC), it
was filtered through a short pad of Celite and the Celite pad was
washed with EtOAc (15 mL). The EtOAc layer was washed with
water (10 mL) followed by brine (5 mL) and dried over Na2SO4.
Evaporation of the solvent yielded the crude aldehyde, which was
subjected to the next reaction without further purification.
D
2927, 2857, 1608, 1093, 737 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.42e7.19 (m, 5H), 4.82, 4.57 (ABq, J¼11.8 Hz, 2H), 3.10e2.94 (m,
2H), 2.77 (t, J¼4.1 Hz, 1H), 2.48 (dd, J¼4.6, 0.8 Hz, 1H), 1.74e1.60 (m,
1H), 1.59e1.40 (m, 2H), 1.39e1.20 (m, 7H), 0.87 (t, J¼6.9 Hz, 3H); 13C
NMR (100 MHz, CDCl3) 138.6 (Cq), 128.2 (CH), 127.8 (CH), 127.4
(CH), 80.5 (CH), 71.6 (CH2), 55.1 (CH), 43.1 (CH2), 32.3 (CH2), 31.7
(CH2), 29.2 (CH2), 25.4 (CH2), 22.6 (CH2), 14.0 (CH3); HRMS MþþNa
found 271.1673; C20H29NO5þNa requires 271.1674.
To a pre-cooled solution (0 ꢁC) of the aldehyde prepared above
in MeOH (3 mL) was added NaBH4 (0.055 g, 0.73 mmol) portion
wise. The reaction mixture was slowly allowed to warm to room
temperature and stirred for 1 h. After the reaction was completed
(TLC), it was quenched by addition of cold water at 0 ꢁC. The re-
action mixture was extracted with EtOAc (2ꢂ15 mL) and the com-
bined EtOAc extracts were washed with brine (5 mL) and dried over
Na2SO4. Residue obtained after evaporation of solvent was purified
by column chromatography to obtain 29 (0.155 g) in 80% overall
yield in two steps as a colorless oil. Rf 0.5 (petroleum ether/EtOAc
3.4. (4S,5S)-5-(Benzyloxy)undec-1-en-4-ol (7)
To a stirred solution of CuCN (0.006 g, 0.058 mmol) in THF
(0.5 mL) was added vinylmagnesium bromide (0.7 mL, 0.70 mmol
1 M solution in THF) at ꢀ78 ꢁC and stirred for 15 min. A solution of
the epoxide 10 (0.036 g, 0.14 mmol) in THF (1 mL) was added to the
reaction mixture at ꢀ78 ꢁC. The reaction mixture was slowly
warmed up to room temperature and stirred overnight. After
completion of the reaction (TLC), it was poured into satd NH4Cl
solution (5 mL) and extracted with diethyl ether (2ꢂ10 mL). The
combined organic extracts were washed with brine (5 mL) and
dried over Na2SO4. Evaporation of the solvent followed by column
chromatography of the resulting residue yielded 7 (0.034 g) in 88%
6:4); [
a]
24 ꢀ21.5 (c 1.5, CHCl3); IR (neat) 3454, 2933, 2890, 1099,
D
1035, 915 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.40e7.23 (m, 5H),
5.80 (ddt, J¼17.1, 10.1, 7.1 Hz, 1H), 5.08 (dd, J¼16.9, 9.3 Hz, 2H), 4.68
(s, 2H), 4.64 (s, 2H), 3.89e3.72 (m, 2H), 3.68 (dd, J¼11.5, 5.8 Hz, 1H),
3.58 (dd, J¼10.0, 5.3 Hz, 1H), 3.39 (s, 3H), 2.54e2.25 (m, 3H); 13C
NMR (100 MHz, CDCl3) 138.2 (Cq), 134.6 (CH), 128.4 (CH), 127.9
(CH), 127.8 (CH), 117.5 (CH2), 96.9 (CH2), 79.9 (CH), 77.3 (CH), 72.9
(CH2), 61.2 (CH2), 55.9 (CH3), 35.2 (CH2); HRMS MþþNa found
389.1416; C20H29NO5þNa requires 389.1418.
yield as colorless oil. Rf 0.4 (petroleum ether/EtOAc 9:1); [
a
]
2D4þ19.3
(c 1.5, CHCl3); lit.3g
[
a]
24 þ17.4 (c 1.5, CHCl3); IR (neat) 3450, 2930,
2860, 1591, 1444, 109D3, 1071 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.42e7.22 (m, 5H), 5.86 (ddt, J¼17.3, 10.6, 7.0 Hz, 1H), 5.11 (dd,

4274
K.R. Prasad, K. Penchalaiah / Tetrahedron 67 (2011) 4268e4276
3.7. ((((4R,5R)-4-(Methoxymethoxy)undec-1-en-5-yl)oxy)
methyl)benzene (30)
containing solid NaHCO3 (20 mg) until the pale blue color persisted.
Excess ozone was flushed off with oxygen and Me2S (1 mL) was
added. The reaction mixture was warmed to 0 ꢁC and stirred 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.
To a stirred solution of alcohol 29 (0.12 g, 0.45 mmol) in CH2Cl2
(2 mL) was added DMAP (0.165 g, 1.35 mmol), followed by p-TsCl
(0.171 g, 0.90 mmol) at room temperature under argon atmosphere.
The reaction mixture was stirred for 12 h at the same temperature.
After completion of the reaction (TLC), it was poured into water
(15 mL) and extracted with diethyl ether (2ꢂ20 mL). The combined
organic extracts were washed with brine (5 mL) and dried over
Na2SO4. Evaporation of the solvent yielded the crude tosylate,
which was subjected to the next reaction without further
purification.
To a pre-cooled solution (0 ꢁC) of the aldehyde prepared above
in MeOH (4 mL) was added NaBH4 (0.2 g, 5.24 mmol) portion wise.
The reaction mixture was slowly allowed to warm up to room
temperature and stirred for 1 h. After the reaction was completed
(TLC), it was quenched by addition of cold water at 0 ꢁC. The re-
action mixture was extracted with EtOAc (2ꢂ20 mL) and the
combined EtOAc extracts were washed with brine (5 mL) and dried
over Na2SO4. Residue obtained after evaporation of the solvent was
purified by column chromatography to obtain 31 (0.559 g) in 76%
overall yield for two steps as a colorless oil. Rf 0.4 (petroleum ether/
To a stirred solution of CuBr (0.097 g, 0.65 mmol) in THF (1 mL)
was added n-pentylmagnesiun bromide (2.8 mL, 2.2 mmol 0.8 M
solution in THF) at 0 ꢁC and stirred for 15 min. A solution of the
tosylate (prepared above) was dissolved in THF (2 mL) and was
added to the reaction mixture at 0 ꢁC. The reaction mixture was
slowly warmed to room temperature and stirred for 4 h. After
completion of the reaction (TLC), it was poured into satd NH4Cl
solution (15 mL) and extracted with diethyl ether (2ꢂ20 mL). The
combined organic extracts were washed with brine (5 mL) and
dried over Na2SO4. Evaporation of the solvent followed by column
chromatography of the resulting residue yielded 30 (0.089 g) in 62%
overall yield for two steps as a colorless oil. Rf 0.5 (petroleum ether/
EtOAc 7:3); [
a
]
24 ꢀ9.9 (c 1.8, CHCl3); IR (neat) 3450, 2986, 2935,
D
2868, 1376, 1245, 1216, 1088, 739 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.41e7.20 (m, 5H), 4.59, 4.56 (ABq, J¼12.8 Hz, 2H), 3.83 (br, d,
J¼3.6 Hz, 2H), 3.64 (br s, 2H), 3.57 (ddd, J¼14.3, 10.4, 3.8 Hz, 2H),
2.20 (br s, 1H), 1.81e1.91 (m, 4H), 1.41 (s, 3H), 1.39 (s, 3H); 13C NMR
(100 MHz, CDCl3) 137.8 (Cq), 128.3 (CH), 127.64 (CH), 127.61 (CH),
108.8 (Cq), 79.9 (CH), 78.3 (CH), 73.5 (CH2), 70.3 (CH2), 62.5 (CH2),
29.7 (CH2), 29.3 (CH2), 27.2 (CH3), 26.9 (CH3); HRMS MþþNa found
303.1572; C20H29NO5þNa requires 303.1572.
Ether 9:1); [
a]
24þ4.0 (c 1.5, CHCl3); IR (neat) 2928, 2858, 1100, 1041,
D
915 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.39e7.20 (m, 5H), 5.82 (ddt,
J¼17.1, 10.1, 7.0 Hz, 1H), 5.06 (dd, J¼17.0, 9.6 Hz, 2H), 4.68 (s, 2H),
4.60, 4.56 (ABq, J¼11.5 Hz, 2H), 3.70 (dt, J¼8.6, 4.4 Hz, 1H), 3.44 (dt,
J¼7.5, 3.4 Hz, 1H), 3.37 (s, 3H), 2.53e2.36 (m, 1H), 2.33e2.16 (m,
1H), 1.66e1.54 (m, 1H), 1.53e1.36 (m, 2H), 1.27 (br s, 7H), 0.88 (t,
J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) 138.6 (Cq), 135.3 (CH),
128.2 (CH), 127.9 (CH), 127.5 (CH), 116.8 (CH2), 96.5 (CH2), 80.1 (CH),
78.0 (CH), 72.5 (CH2), 55.6 (CH3), 34.8 (CH2), 31.7 (CH2), 29.6 (CH2),
29.3 (CH2), 25.8 (CH2), 22.5 (CH2), 14.01 (CH2); HRMS MþþNa found
343.2249; C20H29NO5þNa requires 343.2249.
4. (3-((4S,5S)-5-((Benzyloxy)methyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)propoxy)(tert-butyl)dimethylsilane (32)
To a pre-cooled (0 ꢁC) solution of 31 (0.082 g, 0.29 mmol) in
CH2Cl2 (2 mL) were added DMAP (0.007 g, 0.058 mmol) and imid-
azole (0.039 g, 0.58 mmol) followed by TBSCl (0.065 g, 0.43 mmol)
under argon atmosphere. The reaction mixture was stirred at room
temperature for 12 h. After the reaction is complete (TLC), it was
poured into cold water (5 mL) and extracted with diethyl ether
(2ꢂ10 mL). The ethereal layer was washed with brine (5 mL) and
dried over Na2SO4. Evaporation of the solvent and purification of
the resulting residue by column chromatography furnished the TBS
ether (0.108 g) in 94% yield as colorless oil. Rf 0.6 (petroleum ether/
3.8. Preparation of (4R,5R)-5-(benzyloxy)undec-1-en-4-ol
(ent-7)
To a stirred solution of 30 (0.089 g, 0.27 mmol) in MeOH (2 mL)
was added PPTS (0.070 g, 0.27 mmol) at room temperature and
refluxed for 12 h. After completion of the reaction (TLC), solid
NaHCO3 (0.1 g) was added and stirred for 10 min. Reaction mixture
was filtered through a short pad of Celite and the Celite pad was
washed with CH2Cl2 (15 mL). The residue obtained after concen-
tration of the solvent was purified by column chromatography to
furnish the homoallylic alcohol ent-7 (0.075 g) in quantitative yield
ether 9:1); [
a
]
24 ꢀ11.3 (c 1.0, CHCl3); IR (neat) 2930, 2858, 1253,
1094, 834, 775Dcmꢀ1
; d 7.38e7.21 (m,
1H NMR (400 MHz, CDCl3)
5H), 4.59, 4.55 (ABq, J¼12.2 Hz, 2H), 3.91e3.74 (m, 2H), 3.68e3.58
(m, 2H), 3.55 (d, J¼4.2 Hz, 2H), 1.76e1.51 (m, 4H), 1.40 (s, 3H), 1.38
(s, 3H), 0.87 (s, 9H), 0.026 (s, 6H); 13C NMR (100 MHz, CDCl3) 138.0
(Cq), 128.3 (CH), 127.6 (2ꢂCH), 108.7 (Cq), 80.1 (CH), 78.1 (CH), 73.5
(CH2), 70.6 (CH2), 62.8 (CH2), 29.5 (CH2), 29.1 (CH2), 27.3 (CH3), 27.0
(CH3), 25.9 (CH3), 18.1 (Cq), ꢀ5.3 (CH3); HRMS MþþNa found
417.2436; C20H29NO5þNa requires 417.2437.
as a colorless oil. Rf 0.4 (petroleum ether/EtOAc 9:1); [
a
]
2D4ꢀ19.0 (c
1.1, CHCl3); lit.3g
[
a
]
24 þ17.4 (c 1.5, CHCl3 for the enantiomer); IR
D
(neat) 3460, 2927, 2857, 1606, 1450, 1090, 1070, 912 cmꢀ1; 1H NMR
(400 MHz, CDCl3)
d
7.43e7.25 (m, 5H), 5.86 (ddt, J¼17.4,10.5, 7.0 Hz,
4.1. ((4S,5S)-5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-2,2-
dimethyl-1,3-dioxolan-4 yl)methanol (33)
1H), 5.10 (dd, J¼16.6, 5.98 Hz, 2H), 4.66, 4.51 (ABq, J¼11.3 Hz, 2H),
3.64 (dt, J¼9.9, 5.0 Hz,1H), 3.33 (q, J¼5.5 Hz,1H), 2.39e2.19 (m, 3H),
1.69e1.51(m, 2H), 1.44e1.21 (br m, 8H), 0.87 (t, J¼6.9 Hz, 3H); 13C
NMR (100 MHz, CDCl3) 138.4 (Cq), 135.0 (CH), 128.4 (CH), 127.8
(CH), 127.7 (CH), 117.2 (CH2), 81.4 (CH), 72.3 (CH2), 72.0 (CH), 38.0
(CH2), 31.7 (CH2), 30.1 (CH2), 29.5 (CH2), 25.1 (CH2), 22.6 (CH2), 14.0
(CH3); HRMS MþþNa found 299.1988; C20H29NO5þNa requires
299.1987.
TBS protected benzyl ether 32 (0.050 g, 0.12 mmol) was dis-
solved in MeOH (2 mL) and degassed. Pd/C (0.01 g) was added to
the reaction mixture and stirred under hydrogen atmosphere
(balloon) for 3 h. After completion of the reaction (TLC), it was fil-
tered through a short pad of Celite and the Celite pad was washed
with CH2Cl2 (15 mL). The residue obtained after concentration of
the solvent was purified by column chromatography to furnish the
alcohol 33 (0.032 g) in 88% yield as a colorless oil. Rf 0.5 (petroleum
3.9. 3-((4S,5S)-5-((Benzyloxy)methyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)propan-1-ol (31)
ether/EtOAc 7:3); [
a
]
24 ꢀ11.3 (c 1.0, CHCl3); IR (neat) 3448, 2932,
D
2859, 1254, 1097, 834, 775 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
Ozone was bubbled through a pre-cooled (ꢀ78 ꢁC) solution of
26 (0.724 g, 2.62 mmol) in a mixture of CH2Cl2/MeOH (4:1, 20 mL),
d
3.95e3.80 (m, 1H), 3.79e3.67 (m, 2H), 3.66e3.50 (m, 3H), 2.22 (br
s, 1H), 1.76e1.50 (m, 4H), 1.38 (s, 3H), 1.37 (s, 3H), 0.85 (s, 9H), 0.016

K.R. Prasad, K. Penchalaiah / Tetrahedron 67 (2011) 4268e4276
4275
(s, 6H); 13C NMR (100 MHz, CDCl3) 108.6 (Cq), 81.5 (CH), 76.7 (CH),
62.8 (CH2), 62.0 (CH2), 29.3 (CH2), 29.0 (CH2), 27.3 (CH3), 27.0 (CH3),
25.9 (CH3), 18.3 (Cq), ꢀ5.3 (CH3); HRMS MþþNa found 327.1966;
C20H29NO5þNa requires 327.1968.
of the resulting residue by column chromatography furnished the
acid 25 (0.145 g) in 87% overall yield for two steps as a colorless oil.
Rf 0.4 (petroleum ether/EtOAc 1:1); [
a
]
24 ꢀ6.3 (c 0.7, CHCl3); lit.12
D
24
[a
]
þ6.8 (c 0.59, CHCl3 for the enantiomer); IR (neat) 3457,
D
3225, 2987, 2933, 1712, 1376, 1241, 1067 cmꢀ1
;
1H NMR (400 MHz,
5.78 (ddd, J¼17.3, 10.2, 7.6 Hz, 1H), 5.36 (d, J¼17.1 Hz, 1H),
4.2. 3-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)
propan-1-ol (34)
CDCl3)
d
5.25 (d, J¼10.2 Hz, 1H), 4.0 (t, J¼7.8 Hz, 1H), 3.69 (dt, J¼8.2, 3.4 Hz,
1H), 2.64e2.37 (m, 2H), 2.0e1.89 (m, 1H), 1.87e1.73 (m, 1H), 1.39 (s,
6H); 13C NMR (100 MHz, CDCl3) 178.5 (Cq), 134.8 (CH), 119.3 (CH2),
108.9 (Cq), 84.4 (CH2), 79.3 (CH), 30.3 (CH2), 27.1 (CH3), 26.9 (CH3),
26.4 (CH2); HRMS MþþNa found 223.0945; C20H29NO5þNa re-
quires 223.0946.
To a stirred solution of 33 (0.454 g, 1.49 mmol) in EtOAc (7 mL)
was added IBX (1.463 g 5.22 mmol) and refluxed for 5 h. After the
reaction is complete (TLC), it was filtered through a short pad of
Celite and the Celite pad was washed with EtOAc (30 mL). The or-
ganic layer was washed with water (10 mL), brine (10 mL), and
dried over Na2SO4. The residue obtained after evaporation of the
solvent afforded the crude aldehyde, which was used in the next
step without further purification.
4.4. (4R,5R)-5-(Benzyloxy)undec-1-en-4-yl 3-((4S,5S)-2,2-
dimethyl-5-vinyl-1,3-dioxolan-4-yl)propanoate (24)
To a stirred solution of methyl triphenyl phosphonium bromide
(2.127 g, 5.96 mmol) in THF (3 mL) was added LiHMDS (4.5 mL,
4.47 mmol, 1.0 M solution in THF) at 0 ꢁC and stirred for 45 min.
Aldehyde (prepared above) was dissolved in THF (3 mL) and added
to the reaction mixture at 0 ꢁC. Reaction mixture was warmed to
room temperature and stirred for 2 h. After completion of the re-
action (TLC), it was poured into cold water (15 mL) and extracted
with diethyl ether (2ꢂ20 mL). The ethereal layer was washed with
brine (5 mL) and dried over Na2SO4. Evaporation of the solvent
followed by purification of the resulting residue by column chro-
matography using petroleum ether/EtOAc (95:5) as eluent fur-
nished the alkene, which was subjected to next step without
further purification.
To a stirred solution of acid 25 (0.067 g, 0.33 mmol), in CH2Cl2
(0.5 mL) were added alcohol ent-7 (0.062 g, 0.22 mmol, in 0.5 mL
CH2Cl2), DCC (0.031 g, 0.15 mmol), and DMAP (0.002 g,
0.015 mmol), at room temperature and stirred for 12 h. After
completion of the reaction (TLC), it was filtered through a short pad
of silica gel and the silica gel pad was washed with diethyl ether
(20 mL). Evaporation of the solvent and purification of the resulting
residue by column chromatography furnished the ester 24 (0.030 g)
in 96% yield as a colorless oil. Rf 0.6 (petroleum ether/EtOAc 9:1);
[a
]
24þ2.3 (c 3.0, CHCl3); lit.3l
[
a]
24ꢀ1.9 (c 4.2, CHCl3) for the enan-
D
D
tiomer; IR (neat) 2931, 2860, 1736, 1370, 1243, 1070, 926 cmꢀ1
;
1H
NMR (400 MHz, CDCl3) d 7.37e7.19 (m, 5H), 5.82e5.64 (m,2H), 5.35
(d, J¼17.0 Hz,1H), 5.24 (d, J¼10.2 Hz,1H), 5.15e4.95 (m, 3H), 4.57 (s,
2H), 3.97 (t, J¼7.8 Hz,1H), 3.66 (dt, J¼8.2, 3.6 Hz,1H), 3.43 (dt, J¼7.5,
4.5 Hz, 1H), 2.55e2.23 (m, 4H), 1.97e1.72 (m, 2H), 1.44e1.30 (m,
3H), 1.39 (s, 3H), 1.37 (s, 3H), 1.23 (br s, 7H), 0.86 (t, J¼6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3) 172.7 (Cq), 138.4 (Cq), 135.0 (CH), 134.0
(CH), 128.3 (CH), 127.8 (CH), 127.6 (CH), 119.2 (CH2), 117.6 (CH2),
108.8 (Cq), 82.4 (CH), 79.4 (CH), 78.9 (CH), 73.4 (CH), 72.3 (CH2),
34.4 (CH2), 31.7 (CH2), 30.7 (CH2), 29.8 (CH2), 29.3 (CH2), 27.2 (CH3),
26.9 (CH3), 26.8 (CH2), 25.5 (CH2), 22.5 (CH2), 14.0 (CH3); HRMS
MþþNa found 481.2930; C20H29NO5þNa requires 481.2930.
To a pre-cooled (0 ꢁC) solution of alkene (prepared above) in THF
(2 mL) was added TBAF (2.2 mL, 2.23 mmol). Reaction mixture was
allowed to room temperature and stirred for 1 h. After the reaction
is complete (TLC), it was poured in to cold water (15 mL) and
extracted with EtOAc (2ꢂ10 mL). The organic layer was washed
with brine (5 mL) and dried over Na2SO4. Evaporation of the solvent
and purification of the resulting residue by column chromatogra-
phy furnished the alcohol 34 (0.156 g) in 56% overall yield for three
24
steps as a colorless oil. Rf 0.5 (petroleum ether/EtOAc 1:1); [a]
D
þ3.0 (c 2.0, CHCl3); lit.11
[
a]
24þ2.48 (c 1.61 in CHCl3); IR (neat) 3432,
D
2986, 2936, 2871, 1372, 1241, 1050 cmꢀ1; 1H NMR (400 MHz, CDCl3)
4.5. (3aS,8R,11aS,E)-8-((R)-1-(Benzyloxy)heptyl)-2,2-dimethyl-
4,5,8,9-tetrahydro-3aH-[1,3]dioxolo[4,5-e]oxecin-6(11aH)-one
(23)
d
5.76 (ddd, J¼17.3, 10.2, 7.4 Hz, 1H), 5.33 (d, J¼17.1 Hz, 1H), 5.22 (d,
J¼10.3 Hz, 1H), 3.97 (t, J¼7.9 Hz, 1H), 3.73e3.57 (m, 3H), 2.34 (br s,
1H), 1.78e1.34 (m, 4H), 1.38 (s, 6H); 13C NMR (100 MHz, CDCl3)
135.0 (CH), 119.1 (CH2), 108.7 (Cq), 82.7 (CH2), 80.5 (CH2), 62.5
(CH2), 29.4 (CH2), 28.3 (CH3), 27.2 (CH3), 26.9 (CH3); HRMS MþþNa
found 209.1157; C20H29NO5þNa requires 209.1154.
To a stirred solution of the diene ester 24 (0.081 g, 0.17 mmol) in
CH2Cl2 (176 mL) was added Grubbs’ first generation catalyst
(0.029 g, 0.035 mmol) and refluxed for 2 days. After completion of
the reaction (TLC), it was filtered through a short pad of silica gel
and the silica gel pad was washed with diethyl ether (20 mL).
Evaporation of the solvent and purification of the resulting residue
by column chromatography furnished 2:1 ratio of the E and Z-lac-
4.3. 3-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)
propanoic acid (25)
To a stirred suspension of PCC (0.9 g, 4.19 mmol), in dichloro-
methane (3 mL) was added a solution of the alcohol 34 (0.156 g,
0.83mmol) in CH2Cl2 (2 mL). The reaction mixture was stirred at
room temperature for 1 h. After completion of the reaction (TLC), it
was filtered through a short pad of silica gel and the silica gel pad
was washed with diethyl ether (30 mL). Evaporation of the solvent
and the resulting crude aldehyde was subjected to next step
without further purification.
tones 23 and 23a in (0.036 g) 49% and (0.019 g) 26% yield as
24
a brown colorless oil. Rf 0.5 (petroleum ether/EtOAc 7:3); [a]
D
þ45.0 (c 2.8, CHCl3); lit.3i
[
a
]
24ꢀ37.9 (c 3.0, CHCl3) for enantiomer;
D
IR (neat) 2929, 2859, 1730, 1235, 1064 cmꢀ1 1H NMR (400 MHz,
;
CDCl3)
d
7.35e7.20 (m, 5H), 5.83 (ddd, 1H, minor), 5.72 (ddd, J¼15.7,
11.3, 4.5 Hz, 1H), 5.65 (dd, J¼11.8, 5.3 Hz, 1H, minor), 5.26 (dd,
J¼15.5, 9.0 Hz, 1H), 5.05 (br d, J¼11.1 Hz, 1H, minor), 4.98e4.92 (br
m, 1H, minor), 4.90e4.85 (br m, 1H), 4.59, 4.50 (ABq, J¼11.6 Hz, 2H),
4.52 (d, J¼6.2 Hz,1H, minor), 3.86 (t, J¼8.6 Hz,1H), 3.80 (t, J¼6.3 Hz,
1H, minor), 3.70 (td, J¼10.8, 4.1 Hz, 1H, minor), 3.58 (t, J¼7.7 Hz,
1H), 3.46e3.32 (m, 1H), 2.64e2.39 (m, 2H), 2.36e2.15 (m, 2H),
2.06e1.89 (m, 2H), 1.62e1.45 (m, 2H), 1.35 (s, 6H), 1.23 (br envelope,
8H), 0.84 (br t, J¼6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) 173.4 (Cq,
minor), 171.9 (Cq), 138.2 (Cq), 132.8 (Cq, minor), 130.4 (CH), 130.3
(CH, minor), 129.7 (CH, minor), 129.3 (CH, minor), 129.1 (CH), 128.5
(CH, minor), 128.4 (CH), 128.04 (CH, minor), 127.97 (CH), 127.8 (CH),
To a pre-cooled (0 ꢁC) solution of the aldehyde (prepared above)
in DMSO/H2O (2:2 mL) was added NaH2PO4$2H2O (1.308 g,
8.4 mmol), and stirred it for 5 min. NaClO2 (0.38 g, 4.19 mmol) was
added to the reaction at the same temperature warmed to room
temperature and stirred for 2 h. After the reaction was completed
(TLC), it was poured in to cold water (15 mL) and extracted with
EtOAc (2ꢂ10 mL). The organic layer was washed with brine (5 mL)
and dried over Na2SO4. Evaporation of the solvent and purification

4276
K.R. Prasad, K. Penchalaiah / Tetrahedron 67 (2011) 4268e4276
108.8 (Cq), 108.4 (Cq, minor), 84.4 (CH), 82.1 (CH, minor), 80.4 (CH),
79. 8 (CH), 79.4 (CH, minor), 76.0 (CH, minor), 73.3 (CH), 72.7 (CH2,
minor), 72.5 (CH2), 35.3 (CH2, minor), 34.3 (CH2), 31.7 (CH2), 31.6
(CH2, minor), 31.0 (CH2, minor), 30.9 (CH2), 30.6 (CH2, minor), 30.0
(CH2), 29.4 (CH2), 29.1 (CH2, minor), 27.1 (CH3), 27.0 (CH3, minor),
26.9 (CH3), 25.6 (CH2), 25.3 (CH2), 24.5 (CH2, minor), 22.6 (CH2),14.1
(CH3); HRMS MþþNa found 453.2620; C20H29NO5þNa requires
453.2617.
1.77 (br ddd, 1H, H-3), 1.76e1.72 (m, 1H, H-3, minor), 1.45e1.38
(br m, 2H, H-11), 1.45e1.38 (br m, 2H, H-11, minor), 1.36e1.20 (br
envelope, 8H, H-12, 13, 14, 15), 1.36e1.20 (br envelope, 8H, H-12, 13,
14, 15, minor), 0.88 (t, J¼6.8 Hz, 3H, H-16); 13C NMR (100 MHz,
CDCl3) 176.3 (Cq-1), 173.5 (Cq-1, minor), 134.5 (CH-6), 133.7 (CH-6,
minor), 129.9 (CH-7, minor), 126.6 (CH-7), 79.6 (CH-9), 79.5 (CH-5,
minor), 76.9 (CH-4, minor), 76.4 (CH-9, minor), 73.7 (CH-10, minor),
73.3 (CH-4), 72.8 (CH-10), 72.4 (CH-5), 36.6 (CH2-8), 35.9 (CH2-2,
minor), 34.1 (CH2-11), 33.8 (CH2-11, minor), 32.5 (CH2-14), 32.2
(CH2-14, minor), 32.1 (CH2-8, minor), 29.9 (CH2-13), 29.0 (CH2-2),
26.4 (CH2-3), 26.1 (CH2-12), 23.3 (CH2-15), 14.3 (CH3-16); HRMS
MþþNa found 323.1835; C20H29NO5þNa requires 323.1834.
4.6. (3aS,8R,11aS,Z)-8-((R)-1-(Benzyloxy)heptyl)-2,2-dimethyl-
4,5,8,9-tetrahydro-3aH-[1,3]dioxolo[4,5-e]oxecin-6(11aH)-one
(23a)
Z-Lactone 23a (0.019 g) 26% yield. Rf 0.3 (petroleum ether/EtOAc
Acknowledgements
7:3); [
a
]
24 ꢀ3.1 (c 1.6, CHCl3); lit.3l
[
a]
24 þ4.5 (c 1.6, CHCl3) for the
D
D
enantiomer; IR (neat) 2930, 2860, 1734, 1241, 1056, 749 cmꢀ1
;
1H
We thank Department of Science and Technology (DST), New
Delhi for funding of the project. K.R.P. is a swarnajayanthi fellow of
DST. KP thanks CSIR for senior research fellowship.
NMR (400 MHz, CDCl3)
d
7.41e7.21 (m, 5H), 5.73 (dt, J¼10.2, 6.6, Hz,
1H), 5.49 (t, J¼10.2 Hz, 1H), 5.09 (dt, J¼11.9, 1.8 Hz, 1H), 4.64, 4.57
(ABq, J¼11.6 Hz, 2H), 4.64e4.43 (m, 1H), 3.65 (t, J¼8.5 Hz, 1H), 3.48
(dt, J¼8.9, 4.7 Hz, 1H), 2.77e2.54 (m, 2H), 2.42e1.95 (m,4H),
1.58e1.37 (m, 3H), 1.42 (s, 3H), 1.39 (s, 3H), 1.36e1.22 (br m, 7H),
0.88 (t, J¼6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) 170.8 (Cq), 138.3
(Cq), 130.8 (CH), 130.4 (CH), 128.4 (CH), 127.7 (2ꢂCH), 107.6 (Cq),
81.5 (CH), 79.6 (CH), 77.0 (CH), 72.8 (CH), 72.6 (CH2), 32.1 (CH2), 31.7
(CH2), 30.5 (CH2), 29.4 (CH2), 29.1 (CH2), 28.2 (CH2), 27.0 (CH3), 26.9
(CH3), 25.4 (CH2), 22.6 (CH2), 14.1 (CH3); HRMS MþþNa found
453.2610; C20H29NO5þNa requires 453.2617.
References and notes
1. Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. Org. Lett. 2001,
3, 3479.
2. For a concise review on earlier efforts on the synthesis of microcarplaide see:
Ishigami, K. Biosci. Biotechnol. Biochem. 2009, 73, 971.
3. Total synthesis of microcarplaide: (a) Murga, J.; Flomir, E.; García-Fortanet, J.;
Carda, M.; Marco, J. A. Org. Lett. 2002, 4, 3447; (b) Gurjar, M. K.; Nagaprasad, R.;
Ramana, C. V. Tetrahedron Lett. 2003, 44, 2873; (c) Banwell, M. G.; Loong, D. T. J.
Heterocycles 2004, 62, 713; (d) Ishigami, K.; Kitahara, T. Heterocycles 2004, 63,
785; (e) Kumar, P.; Naidu, S. V. J. Org. Chem. 2005, 70, 4207; (f) Ishigami, K.;
Watanabe, H.; Kitahara, T. Tetrahedron 2005, 61, 7546; (g) Davoli, P.; Fava, F.;
Morandi, S.; Spaggiari, A.; Prati, F. Tetrahedron 2005, 61, 4427; (h) Ghosh, S.;
Rao, B. V.; Shashidhar, J. Tetrahedron Lett. 2005, 46, 5479; (i) Chavan, S. P.;
Cherukupally, P. Tetrahedron Lett. 2005, 46, 1939; (j) Gurjar, M. K.; Nagaprasad,
R.; Ramana, C. V.; Karmakar, S.; Mohapatra, D. K. Arkivoc 2005, 235; (k) Marco,
J. A.; Fortanet, J. G.; Murga, J.; Falomir, E.; Carda, M. J. Org. Chem. 2005, 70, 9822;
(l) Cherukupalli, G. R.; Sharma, G. V. M. Tetrahedron: Asymmetry 2006, 17, 1081;
4.7. Microcarpalide (D)-1
To a pre-cooled (0 ꢁC) solution of 23 (0.037 g, 0.086 mmol) in
CH2Cl2 (1 mL) was added TiCl4 (0.28 mL, 0.25 mmol, 0.9 M solution
in CH2Cl2). Reaction mixture was stirred at same temperature for
2 h. After the reaction is complete (TLC), cold water (1 mL) was
added and it was filtered through a short pad of Celite and Celite
pad was washed with ethylacetate (5 mL). Filtrate was washed with
satd NaHCO3 (5 mL) and the aqueous layer was extracted with
EtOAc (2ꢂ5 mL). Combined EtOAc layer was washed with brine
(5 mL) and dried over Na2SO4. Evaporation of the solvent followed
by purification of the resulting residue by column chromatography
furnished (þ)-1 (0.016 g) in 62% yield as a colorless oil. Rf 0.5 EtOAc;
€
€
€
(m) Furstner, A.; Nagano, T.; Muller, C.; Seidel, G.; Muller, O. Chem.dEur. J. 2007,
13, 1452.
4. Prasad, K. R.; Penchalaiah, K.; Choudhary, A.; Anbarasan, P. Tetrahedron Lett.
2007, 48, 309.
5. For synthesis of 9 see: Prasad, K. R.; Anbarasan, P. Tetrahedron: Asymmetry 2006,
17, 850; For a general approach to the synthesis of
acid see: Prasad, K. R.; Chandrakumar, A. Tetrahedron 2007, 63, 1798 For recent
application of -keto amides derived from tartaric acid in natural product
g-keto amides from tartaric
g
synthesis see: (a) Prasad, K. R.; Pawar, A. B. Synlett 2010, 1093; (b) Prasad, K. R.;
Pawar, A. B. ARKIVOC 2010, 39; (c) Prasad, K. R.; Gandi, V. R.; Nidhiry, J. E.; Bhat,
K. S. Synthesis 2010, 2521; (d) Prasad, K. R.; Gandi, V. R. Synlett 2009, 2593; (e)
Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2008, 73, 2; (f) Prasad, K. R.; Gholap, S. L.
J. Org. Chem. 2008, 73, 2916; (g) Prasad, K. R.; Swain, B. Tetrahedron: Asymmetry
2008, 19, 1134; (h) Prasad, K. R.; Chandrakumar, A. J. Org. Chem. 2007, 72, 6312;
(i) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2006, 71, 3643.
6. For application of this strategy in the synthesis of allylic alcohols, see: (a)
Schneider, C.; Kazmaier, U. Synthesis 1998, 1314; (b) Ramarao, A. V.; Reddy, E. R.;
Joshi, B. V.; Yadav, J. S. Tetrahedron Lett. 1987, 28, 6497.
[
a
]
24þ26.3 (c 0.65, MeOH); lit.3l
[
a]
24ꢀ22.0 (c 0.67, MeOH) for en-
antDiomer; lit.3m
[a
]
2D4ꢀ27.28 (c 0.83,DMeOH) for the enantiomer; IR
(neat) 3417, 2928, 2857, 1713, 1436, 1224, 1156, 1064, 757 cmꢀ1; 1H
NMR (400 MHz, CDCl3; mixture of conformers)
d
5.70 (dd, J¼15.8,
2.1 Hz, 1H, H-6), 5.72e5.60 (m, 1H, H-7, minor), 5.50 (dddd, J¼15.5,
10.0, 5.1, 1.9 Hz, 1H, H-7), 5.06 (dd, J¼15.5, 9.2 Hz, 1H, H-6, minor),
4.82 (dt, J¼11.3, 4.5 Hz, 1H, H-9), 4.61 (ddd, J¼8.0, 4.3, 2.6 Hz, 1H, H-
9, minor), 4.11 (br m, 1H, H-5), 3.78 (br m, 1H, H-4), 3.64e3.57 (m,
1H, H-5, minor), 3.55 (br m, 1H, H-10), 3.37e3.28 (m, 1H, H-4,
minor), 3.13 (d, J¼3.8 Hz, 1H, 4-OH), 2.90 (d, J¼6.5 Hz, 1H,
5-OH, minor), 2.87 (d, J¼5.3 Hz, 2H, 5, 10-OH), 2.57e2.50 (br m, 2H,
H-2, minor), 2.52e2.42 (br m, 1H, H-2), 2.32e2.24 (br m, 1H, H-8),
2.32e2.24 (br m, 1H, H-8, minor), 2.20e2.05 (br m, 3H, H-2, 3, 8),
2.20e2.05 (br m, 1H, H-2, minor), 2.01e1.93 (br m, 1H, H-3, minor),
7. Al-Hakim, A. H.; Haines, A. H.; Morley, C. Synthesis 1985, 207.
8. Prasad, K. R.; Penchalaiah, K. Tetrahedron: Asymmetry 2010, 21, 2853.
9. Takahashi, S.; Ogawa, N.; Koshino, H.; Nakata, T. Org. Lett. 2005, 7, 2783.
10. It was shown by Cherukupalli and Sharma3l and by Furstner et.al.3m that esters
structurally similar to 24 yielded undesired (Z)-lactone in metathesis reaction
with Grubbs’ second generation catalyst. Hence ring closing metathesis
reaction of 24 was not investigated with other metathesis catalysts.
11. Shing, T. K. M.; Wong, W. F.; Ikeno, T.; Yamada, T. Chem.dEur. J. 2009, 15, 2693.
12. Batty, D.; Crich, D. J. Chem. Soc., Perkin Trans. 1 1992, 3193.