Convergent synthesis of passifloricin a via a prins cyclisation and olefin cross-metathesis approach

Article abstract of DOI:10.1055/s-0030-1258253

A stereoselective and convergent approach to the total synthesis of the natural product passifloricin A is illustrated using Prins cyclisation and metathesis reactions as key steps. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258253

PAPER
3891
Convergent Synthesis of Passifloricin A via a Prins Cyclisation and Olefin
Cross-Metathesis Approach
C
onvergent
S
ynthe
o
sis of Passif
w
loricin
A
ravaram Sabitha,* Muddala Nagendra Prasad, Konatham Shankaraiah, Nandyala Mallikarjuna Reddy,
Jhillu Singh Yadav
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: gowravaramsr@yahoo.com; E-mail: sabitha@iict.res.in
Received 2 August 2010; revised 11 August 2010
O
O
Abstract: A stereoselective and convergent approach to the total
synthesis of the natural product passifloricin A is illustrated using
OH OH OH
O
OH OH
O
Prins cyclisation and metathesis reactions as key steps.
( )
( )
12
12
Key words: passifloricin A, Prins cyclisation, cross-metathesis,
ring-closing metathesis, lithium aluminum hydride–lithium iodide
OH
passifloricin A (1)
revised structure
passifloricin A (1a)
proposed structure
Figure 1
Passifloricin A (1), a 6-substituted a,b-unsubstituted d-
lactone (Figure 1), was isolated from Passiflora foetida,1
a species from the family Passifloraceae which grows in
tropical zones of America. It was found to show very in-
teresting leishmanicidal2 and antiprotozoal3 activities.
The relative configuration of passifloricin A has been es-
tablished based purely on spectroscopic findings and the
structure was proposed to be 1a (Figure 1). Several
syntheses4 of the proposed structure 1a of passifloricin A
were reported; however, it was realised that the NMR data
of the synthetic products did not match the data of the nat-
ural product and that they were different compounds.
Quantum mechanical 13C NMR GIAO chemical shift cal-
culations,5 as well as fluorous tagging en route,6 also
proved that the proposed structure was incorrect. The pro-
posed structure 1a was revised to structure 1 after the syn-
thesis of several isomers7 of the natural product and
studies of their spectroscopic data. Later on, a linear syn-
thesis of 1 appeared.8
for the construction of substituted tetrahydropyran rings
of natural products.9 In continuation of our interest in the
Prins reaction10 coupled with metathesis reactions and
their exploration in the synthesis of molecules,11 we now
report a convergent synthesis of passifloricin A utilising
Prins and metathesis reactions.
In our retrosynthetic analysis (Scheme 1), we envisaged
that the target molecule 1 could be prepared through ring-
closing metathesis of compound 2 which in turn could be
made by a cross-metathesis reaction of two chiral allylic
alcohol derivatives I and II. Compound I in turn could be
obtained from tetrahydropyranol 3, prepared by a Prins
cyclisation reaction, whereas the chiral allylic acetate II
could be obtained from the readily available aldehyde 4.
The synthesis of fragment I (Scheme 2) began with the
Prins cyclisation reaction of chiral homoallylic alcohol 5
with 3-(benzyloxy)propanal in the presence of trifluoro-
acetic acid, followed by hydrolysis of the resulting trifluo-
roacetate to afford the tetrahydropyranol 3 (enantiomer of
311e). The primary hydroxy group in compound 3 was se-
lectively protected as its TBS ether 6, and the secondary
We were attracted to passifloricin A (1) because of its in-
teresting structure and important biological activities. The
Prins cyclisation has emerged as a powerful synthetic tool
O
O
O
O
O
OH OH
O
( )12
( )12
OTBDPS
OH
1
2
OH
O
O
CHO
( )
+
( )12
12
HO
OBn
OBn
O
OAc
4
II
I
3
Scheme 1 Retrosynthetic analysis for passifloricin A (1)
SYNTHESIS 2010, No. 22, pp 3891–3898
x
x.
x
x
.
2
0
1
0
Advanced online publication: 17.09.2010
DOI: 10.1055/s-0030-1258253; Art ID: Z19710SS
© Georg Thieme Verlag Stuttgart · New York

3892
G. Sabitha et al.
PAPER
OH
OH
c
d
a
HO
RO
TBSO
OH
O
OBn
g(i)
O
OBn
3 R = H
5
b
7
6 R = TBS
OMOM
OMOM
OMOM
O
OMOM
g(ii)
f
RO
I
O
OBn
O
OBn
OBn
O
OBn
12
8 R = TBS
9 R = H
11
10
e
O
O
OR OR
MOMO
OAc
k
h
i
OBn
OBn
OBn
13
14 R = MOM
15 R = H
I
j
Scheme 2 Reagents and conditions: a) (i) 3-(benzyloxy)propanal, TFA, CH2Cl2, 3 h; (ii) K2CO3, MeOH, r.t., 0.5 h, 56% (over 2 steps); b)
TBSCl, imidazole, CH2Cl2, 2 h, 92%; c) p-O2NC6H4CO2H, DEAD, Ph3P, toluene, –78 to –20 °C, 1 h, then K2CO3, MeOH, r.t., 1 h, 75%; d)
MOMCl, DIPEA, DMAP, CH2Cl2, r.t., 3 h, 92%; e) TBAF, THF, 0 °C, 8 h, 93%; f) I2, Ph3P, imidazole, MeCN–Et2O, 0 °C, 2 h, 88%; g) (i)
NaH, DMF, r.t., 6 h; (ii) silica gel rearrangement, 80%; h) (i) O3, Ph3P, CH2Cl2; (ii) Ph3P=CH2, t-BuOK, THF, –78 to 0 °C, 71% (over 2 steps);
i) K2CO3, MeOH, r.t., 2 h, 95%; j) TFA, CH2Cl2, 25 °C, 2 h, 88%; k) 2,2-dimethoxypropane, PPTS, CH2Cl2, 2 h, 95%.
hydroxy group was inverted under standard Mitsunobu the corresponding allylic alcohol 17 in 92% yield. Epoxi-
conditions12 to afford 7, which was expected to give the dation of the allylic alcohol 17 was achieved under
required syn-1,3-diol system after elaboration. Protection Sharpless conditions using (+)-diethyl tartrate to give
of the secondary alcohol in compound 7 as the methoxy- chiral epoxy alcohol 18, which was converted into the cor-
methyl ether 8, followed by removal of the silyl group, responding epoxy iodide 19 using iodine, triphenylphos-
provided primary alcohol 9 in good yield. Treatment of al- phane and imidazole in acetonitrile–diethyl ether in 90%
cohol 9 with iodine in the presence of triphenylphosphane isolated yield. The iodo compound 19 on refluxing in eth-
and imidazole in acetonitrile–diethyl ether gave the corre- anol with zinc yielded the allylic alcohol 20, from which
sponding iodo compound 10. Elimination of hydrogen the corresponding allylic acetate II was prepared, by treat-
iodide13 from 10, using sodium hydride in N,N-dimethyl- ment with acetic anhydride in the presence of triethyl-
formamide, provided enolic exocyclic alkene 11, which amine and 4-(dimethylamino)pyridine, to facilitate the
on column chromatography using silica gel gave rear- cross-metathesis reaction as shown in Scheme 4.
ranged product 12.
After several trial reactions of the cross-metathesis reac-
Compound 12 was subjected to ozonolysis to give the cor- tion between two fragments with different protecting
responding acetoxy aldehyde, which without purification groups, we succeeded in obtaining high yields using allyl-
was treated with methylene(triphenyl)phosphorane to fur- ic alcohol derivatives I and II, as shown in Scheme 4.
nish alkene 13.14 Hydrolysis of the acetate and removal of
Accordingly, the chiral benzyl ether I was subjected to a
the MOM group resulted in diol 15, which was protected
cross-metathesis reaction with the allylic acetate II in the
as the acetonide, using 2,2-dimethoxypropane and pyri-
presence of Grubbs II catalyst in refluxing dichloro-
dinium p-toluenesulfonate, to provide the desired chiral
benzyl ether fragment I.
methane to furnish the desired cross-coupled product 21
(78%, based on conversion of I) along with trace amounts
The synthesis of fragment II (Scheme 3) began from the of homodimerised product (detected by MS). After hy-
commercially available aldehyde 4 by subjecting it to a drolysis of the acetate group, the secondary hydroxy
Wittig reaction using ethyl (triphenylphosphoranyl- group was protected as the TBDPS ether 23, which was
idene)acetate to give the a,b-unsaturated ester 16, which followed by catalytic hydrogenation using palladium on
was reduced using diisobutylaluminum hydride to give
O
a
c
e
CHO
( )12
R
( )12
( )12
R
( )12
OR
4
18 R = OH
19 R = I
16 R = COOEt
17 R = CH2OH
20 R = H
II R = Ac
b
d
f
Scheme 3 Reagents and conditions: a) Ph3P=CHCO2Et, benzene, r.t., 1 h, 95%; b) DIBAL-H, CH2Cl2, –15 °C to r.t., 2 h, 92%; c) t-BuOOH,
4 Å MS, Ti(Oi-Pr)4, (+)-DET, CH2Cl2, –20 ºC, 10 h, 92%; d) I2, Ph3P, imidazole, MeCN–Et2O, 0 °C, 1.5 h, 90%; e) Zn, EtOH, reflux, 2 h, 95%;
f) Ac2O, Et3N, DMAP, CH2Cl2, 0 °C to r.t., 96%.
Synthesis 2010, No. 22, 3891–3898 © Thieme Stuttgart · New York

PAPER
Convergent Synthesis of Passifloricin A
3893
O
O
O
O
e
d
a
I
II
+
( )12
OH
( )12
OBn
OTBDPS
OR
21 R = Ac
22 R = H
24
b
c
23 R = TBDPS
O
O
O
O
O
OH
g
f
( )12
( )12
OTBDPS
OTBDPS
25
26
O
O
O
O
O
O
O
O
h
i
1
( )12
( )12
OTBDPS
OTBDPS
2
27
Scheme 4 Reagents and conditions: a) 4 mol% Grubbs II catalyst, CH2Cl2, 40 °C, 10 h, 78%; b) K2CO3, MeOH, r.t., 1 h, 95%; c) TBDPSCl,
imidazole, CH2Cl2, 4 h, 90%; d) H2, Pd/C, EtOAc, r.t., 95%; e) (i) DMP, CH2Cl2, r.t., 1 h; (ii) allyl bromide, Zn, THF, 0 °C to r.t., 4 h, 88%
(over 2 steps); (iii) DMP, CH2Cl2, r.t., 1.5 h, 85%; f) LAH–LiI (1:1), Et2O, –100 to 0 °C, 1 h, 86%; g) acryloyl chloride, Et3N, DMAP, CH2Cl2,
0 °C to r.t., 1 h, 92%; h) Grubbs II catalyst, CH2Cl2, 40 °C, 3 h, 75%; i) 5 N aq HCl, THF, r.t., 8 h, 92%.
an internal standard. Optical rotations were measured with a
JASCO DIP-370 polarimeter. IR spectra were recorded neat or as
KBr pellets on a Thermo-Nicolet Nexus 670 FT-IR spectrophotom-
eter. Mass spectra were recorded under EI conditions at 70 eV on
LC/MSD (Agilent Technologies) spectrometers. Column chroma-
tography was performed on silica gel (60–120 mesh) supplied by
Acme Chemical Co., India. TLC was performed on Merck 60 F254
silica gel plates.
carbon in ethyl acetate to give the primary alcohol 24 in
95% yield.
Oxidation of the resulting alcohol 24 with Dess–Martin
periodinane (DMP) in dichloromethane afforded the alde-
hyde, which on further treatment with allyl bromide and
zinc in tetrahydrofuran gave carbinol as a diastereomeric
mixture which, without characterisation, was subjected to
oxidation to give ketone 25. Ketone 25 was further sub-
jected to a syn-stereoselective 1,3-asymmetric reduction
using lithium aluminum hydride–lithium iodide15 in dieth-
yl ether at –100 °C to provide the desired homoallylic al-
cohol 26 in 86% yield (syn/anti = 95:5). The homoallylic
alcohol 26 was esterified with acryloyl chloride to provide
the diene 2. The ring-closing metathesis reaction in re-
fluxing dichloromethane using Grubbs II catalyst fur-
nished the lactone 27, which on treatment with 5 N
hydrochloric acid in tetrahydrofuran gave the target mol-
ecule, passifloricin A (1), in 92% yield. The spectroscopic
data and optical rotation values for the synthetic material
are in agreement with those reported for the natural prod-
uct.7
(2R,4S,6R)-2-[2-(Benzyloxy)ethyl]-6-(hydroxymethyl)tetrahy-
dro-2H-4-pyranol (3)
TFA (37.5 mL, 490.1 mmol) was added slowly to a soln of homoal-
lylic alcohol 5 (2.5 g, 24.5 mmol) and 3-(benzyloxy)propanal (12.0
g, 73.5 mmol) in CH2Cl2 (90 mL) at r.t. under N2 atmosphere. The
reaction mixture was stirred for 3 h and then sat. NaHCO3 soln (200
mL) was added and the pH was adjusted to >7 by the addition of
Et3N. The layers were separated and the aqueous layer was extract-
ed with CH2Cl2 (4 × 70 mL); the organic layers were combined and
the solvent was removed under reduced pressure. The residue was
dissolved in MeOH (40 mL) and the solution was stirred with
K2CO3 (6.77 g) for 30 min. The MeOH was then removed under re-
duced pressure and H2O (30 mL) was added. The mixture was ex-
tracted with CH2Cl2 (3 × 30 mL), the combined organic layers were
dried (Na2SO4) and the solvent was removed under reduced pres-
sure. Purification of the crude product by column chromatography
(EtOAc–hexane, 8:2) yielded 3 (3.65 g, 56%) as a gummy liquid.
In conclusion, the total synthesis of passifloricin A has
been achieved in a stereocontrolled manner by the cre-
ation of chiral centres via Prins cyclisation, lithium alumi-
num hydride–lithium iodide reduction and Sharpless
asymmetric epoxidation reactions.
[a]D25 +13.1 (c 0.05, CHCl3).
IR (neat): 3410, 2922, 2854, 1736, 1453, 1368, 1244, 1096, 1029,
742, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.36–7.17 (m, 5 H), 4.47 (ABq,
J = 12.5, 14.7 Hz, 2 H), 4.02–3.66 (m, 1 H), 3.66–3.30 (m, 6 H),
1.98–1.59 (m, 3 H), 1.57–1.30 (m, including two OH, 3 H), 1.28–
1.06 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 138.2, 128.3, 127.6, 75.9, 72.8,
72.7, 67.5, 66.5, 65.5, 40.9, 36.6, 35.9.
LC–MS: m/z = 289 [M + Na]+.
Reactions were conducted under N2 in anhydrous solvents such as
CH2Cl2, THF and EtOAc. All reactions were monitored by TLC
(silica gel coated plates, visualisation under UV light). n-Hexane
(bp 60–80 °C) was used. Yields refer to chromatographically and
spectroscopically (1H and 13C NMR) homogeneous material. Air-
sensitive reagents were transferred by syringe or double-ended nee-
dle. Evaporation of solvents was performed at reduced pressure on
a Büchi rotary evaporator. 1H and 13C NMR spectra of samples in
CDCl3 were recorded on Varian FT-200 MHz (Gemini), Bruker
UXNMR FT-300 MHz (Avance) and Inova FT-400 MHz spectro-
meters. Chemical shifts (d) are reported relative to TMS (d = 0.0) as
(2R,4S,6R)-2-[2-(Benzyloxy)ethyl]-6-([(tert-butyl)dimethylsi-
lyl]oxymethyl)tetrahydro-2H-4-pyranol (6)
To a stirred soln of diol 3 (3.5 g, 13.1 mmol) in anhyd CH2Cl2 (25
mL), imidazole (1.78 g, 26.2 mmol) was added at 0 °C and the mix-
ture was stirred for 15 min. Then, TBSCl (1.97 g, 13.1 mmol) was
Synthesis 2010, No. 22, 3891–3898 © Thieme Stuttgart · New York

3894
G. Sabitha et al.
PAPER
[(2R,4R,6R)-6-[2-(Benzyloxy)ethyl]-4-(methoxymethoxy)tet-
added at 0 °C and the mixture was stirred for 2 h. After completion
of the reaction as indicated by TLC, the reaction mixture was direct-
ly concentrated under reduced pressure and the residue was purified
by column chromatography (EtOAc–hexane, 3:7) to yield the pure
product 6 (4.6 g, 92%) as a colourless liquid.
[a]D25 +15.4 (c 1.0, CHCl3).
IR (neat): 3403, 2926, 2859, 1451, 1367, 1096, 1028, 744 cm–1.
rahydro-2H-2-pyranyl]methanol (9)
To a stirred soln of compound 8 (3.0 g, 7.07 mmol) in anhyd THF
(15 mL), TBAF (1 M in THF; 7.1 mL, 7.1 mmol) was added slowly
at 0 °C. After completion of the reaction as indicated by TLC, the
reaction mixture was concentrated under reduced pressure and the
residue was purified by column chromatography (EtOAc–hexane,
3:7) to yield the pure product 9 (2.04 g, 93%) as a colourless liquid.
1H NMR (200 MHz, CDCl3): d = 7.33–7.19 (m, 5 H), 4.46 (s, 2 H),
3.80–3.72 (m, 1 H), 3.67–3.43 (m, 5 H), 3.38–3.30 (m, 1 H), 2.0–
1.86 (m, 2 H), 1.83–1.69 (m, 2 H), 1.41 (br s, 1 H), 1.17–1.04 (m, 2
H), 0.89 (s, 9 H), 0.04 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 138.4, 128.2, 127.5, 127.4, 76.1,
72.9, 72.4, 68.0, 66.5, 66.2, 41.2, 37.7, 36.0, 25.8, –5.2.
[a]D25 +8.9 (c 1.0, CHCl3).
IR (neat): 3455, 2923, 2876, 1102, 1037, 740 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.36–7.19 (m, 5 H), 4.63 (s, 2 H),
4.48 (ABq, J = 12.0, 4.5 Hz, 2 H), 4.05–3.99 (m, 1 H), 3.96–3.77
(m, 2 H), 3.60–3.47 (m, 3 H), 3.44–3.34 (m, 1 H), 3.33 (s, 3 H),
1.83–1.58 (m, 4 H), 1.51–1.29 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 138.3, 128.2, 127.5, 127.4, 94.8,
72.9, 72.5, 69.4, 69.2, 66.5, 66.0, 55.2, 36.4, 36.3, 32.0.
LC–MS: m/z = 333 [M + Na]+.
LC–MS: m/z = 403 [M + Na]+.
(2R,4R,6R)-2-[2-(Benzyloxy)ethyl]-6-([(tert-butyl)dimethylsi-
lyl]oxymethyl)tetrahydro-2H-4-pyranol (7)
To a stirred soln of alcohol 6 (4.5 g, 11.8 mmol) in toluene (30 mL)
was added Ph3P (6.2 g, 23.6 mmol) and p-nitrobenzoic acid (3.95 g,
23.6 mmol). The mixture was brought to –78 °C and DEAD (6.1
mL, 35.4 mmol) was slowly added. The mixture was slowly brought
to –20 °C and stirred for 1 h. Then, the mixture was concentrated
under reduced pressure. To the residue, MeOH (30 mL) and K2CO3
(2.76 g, 20 mmol) were added and the mixture was stirred for 1 h.
Then, the reaction mixture was filtered through a plug of Celite®
and washed with EtOAc. The combined organic layers were con-
centrated under reduced pressure and the residue was purified by
column chromatography (EtOAc–hexane, 3:7) to yield the pure
product 7 (3.37 g, 75%) as a colourless liquid.
(2R,4R,6R)-2-[2-(Benzyloxy)ethyl]-6-(iodomethyl)-4-(meth-
oxymethoxy)tetrahydro-2H-pyran (10)
To a soln of primary alcohol 9 (1.9 g, 6.1 mmol) in anhyd MeCN–
Et2O (1:1; 20 mL) were added imidazole (1.04 g, 15.2 mmol), Ph3P
(3.9 g, 15.2 mmol) and I2 (2.32 g, 9.15 mmol) at 0 °C. The mixture
was allowed to warm to r.t. and was stirred for 2 h. The reaction was
quenched with sat. aq Na2SO3 (8 mL). The resultant mixture was di-
luted with EtOAc (20 mL), washed with H2O (10 mL) and brine (10
mL), dried (Na2SO4) and concentrated under reduced pressure. Pu-
rification of the residue by column chromatography (EtOAc–hex-
ane, 1:9) gave iodide 10 (2.26 g, 88%) as a colourless, clear liquid.
[a]D25 +9.7 (c 1.0, CHCl3).
IR (neat): 3435, 2928, 2859, 1462, 1117, 1074, 837, 777 cm–1.
[a]D25 +2.2 (c 1.0, CHCl3).
IR (neat): 2945, 2856, 1450, 1364, 1144, 1098, 1037, 739 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.32–7.20 (m, 5 H), 4.47 (s, 2 H),
4.24–4.20 (m, 1 H), 3.95–3.86 (m, 1 H), 3.81–3.73 (m, 1 H), 3.62–
3.43 (m, 4 H), 1.77–1.57 (m, 4 H), 1.51–1.40 (m, 2 H), 0.88 (s, 9 H),
0.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 136.6, 128.3, 127.6, 127.4, 72.9,
72.2, 68.5, 66.8, 66.6, 64.4, 36.4, 35.1, 26.0, 18.4, –5.1.
1H NMR (300 MHz, CDCl3): d = 7.33–7.22 (m, 5 H), 4.63 (s, 2 H),
4.49 (s, 2 H), 3.77–3.60 (m, 2 H), 3.59–3.48 (m, 2 H), 3.38–3.27 (m,
1 H), 3.33 (s, 3 H), 3.13 (d, J = 6.0 Hz, 2 H), 2.21–2.14 (m, 1 H),
1.94–1.84 (m, 1 H), 1.82–1.72 (m, 2 H), 1.26–1.09 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 138.4, 128.2, 127.6, 127.4, 94.4,
74.9, 72.9, 72.6, 72.4, 66.3, 55.2, 38.1, 36.0, 8.7.
LC–MS: m/z = 403 [M + Na]+.
LC–MS: m/z = 443 [M + Na]+.
([(2R,4R,6R)-6-[2-(Benzyloxy)ethyl]-4-(methoxymethoxy)tet-
rahydro-2H-2-pyranyl]methoxy)(tert-butyl)dimethylsilane (8)
To a soln of alcohol 7 (3.2 g, 8.4 mmol) in anhyd CH2Cl2 (30 mL)
at 0 °C were added DIPEA (9.7 mL, 56.6 mmol), DMAP (cat.) and
MOMCl (1.4 mL, 16.8 mmol) successively and the mixture was
stirred at r.t. for 3 h. The reaction was quenched by adding H2O (20
mL) and the mixture was extracted with CH2Cl2 (3 × 15 mL). The
organic extracts were washed with brine (15 mL), dried (Na2SO4, 2
g) and concentrated under reduced pressure. The crude residue was
purified by column chromatography (EtOAc–hexane, 2:8) to afford
the MOM ether 8 (3.28 g, 92%) as a colourless liquid.
(2R,4R)-2-[2-(Benzyloxy)ethyl]-4-(methoxymethoxy)-6-methyl-
3,4-dihydro-2H-pyran (12)
To a soln of iodide 10 (2.2 g, 5.23 mmol) in DMF (100 mL) at 0 °C
was added 60% NaH in oil (1.04 g, 26.15 mmol). After being stirred
at r.t. for 6 h, the reaction mixture was quenched with H2O (10 mL)
at 0 °C. The resultant mixture was diluted with EtOAc (50 mL),
washed with H2O (25 mL) and brine (20 mL), dried (Na2SO4), fil-
tered and concentrated under reduced pressure. Purification of the
residue by column chromatography (EtOAc–hexane, 2:8) gave exo-
cyclic enol ether 11 which on column chromatography provided the
rearranged product 12 (1.22 g, 80%) as a colourless, clear liquid.
[a]D25 +12.6 (c 1.0, CHCl3).
IR (neat): 2928, 2858, 1464, 1104, 1040, 838, 777 cm–1.
[a]D25 +24.6 (c 1.0, CHCl3).
IR (neat): 2960, 2832, 1622, 1510, 1428, 1389, 1102, 745 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32–7.21 (m, 5 H), 4.63 (s, 2 H),
4.48 (s, 2 H), 4.04–3.98 (m, 1 H), 3.91–3.80 (m, 1 H), 3.77–3.67 (m,
1 H), 3.62–3.42 (m, 4 H), 3.33 (s, 3 H), 1.82–1.62 (m, 3 H), 1.43–
1.30 (m, 3 H), 0.88 (s, 9 H), 0.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 138.5, 128.2, 127.5, 127.3, 94.8,
72.9, 72.8, 69.8, 69.1, 66.8, 66.7, 55.2, 36.8, 36.5, 32.9, 26.0, 18.5,
–5.0.
1H NMR (300 MHz, CDCl3): d = 7.36–7.20 (m, 5 H), 4.72 (s, 1 H),
4.61 (s, 2 H), 4.53 (s, 2 H), 4.28 (m, 1 H), 3.61–3.51 (m, 2 H), 3.43–
3.29 (m, 1 H), 3.36 (s, 3 H), 2.12–1.9 (m, 1 H), 1.9–1.2 (br m, 6 H).
LC–MS: m/z = 315 [M + Na]+.
(1R,3R)-1-[2-(Benzyloxy)ethyl]-3-(methoxymethoxy)-4-penten-
yl Acetate (13)
Ozone was bubbled through a soln of 12 (1.2 g, 4.1 mmol) in
CH2Cl2 (12 mL) at –78 °C until no unreacted starting material was
observed on TLC. The reaction mixture was purged with N2 to re-
LC–MS: m/z = 447 [M + Na]+.
Synthesis 2010, No. 22, 3891–3898 © Thieme Stuttgart · New York

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Convergent Synthesis of Passifloricin A
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move the excess ozone and cooled to 0 °C. Ph3P (2.1 g, 8.2 mmol)
was added and the mixture was stirred for 2 h and then concentrated
under reduced pressure. After hexane (20 mL) was added, the mix-
ture was filtered through a Celite® pad and the residue was washed
with hexane. The filtrate was dried (Na2SO4) and concentrated un-
der reduced pressure. The resulting crude aldehyde was subjected to
the next reaction without further purification. To the ylide generated
from methylene(triphenyl)phosphorane (4.9 g, 11.9 mmol) and t-
BuOK (2.2 g, 20.5 mmol) in anhyd THF (30 mL), a soln of the al-
dehyde in anhyd THF (12 mL) was added at 0 °C. The mixture was
stirred for 2 h at that same temperature. After completion of the re-
action, the reaction mixture was quenched with sat. NH4Cl soln (25
mL) and extracted with EtOAc (2 × 15 mL). The combined extracts
were dried (Na2SO4) and concentrated under reduced pressure. Pu-
rification of the residue by column chromatography (EtOAc–hex-
ane, 2:8) afforded 13 (0.94 g, 71%, over 2 steps) as a colourless oil.
[a]D25 +8.7 (c 1.0, CHCl3).
IR (neat): 2926, 2887, 1735, 1641, 1240, 1096, 1029, 742 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34–7.18 (m, 5 H), 5.70–5.53 (m,
1 H), 5.27–5.05 (m, 3 H), 4.66–4.60 (m, 1 H), 4.49–4.42 (m, 3 H),
4.01 (q, J = 6.7 Hz, 1 H), 3.52–3.41 (m, 2 H), 3.32 (s, 3 H), 1.97 (s,
3 H), 1.96–1.82 (m, 3 H), 1.81–1.65 (m, 1 H).
(4R,6R)-4-[2-(Benzyloxy)ethyl]-2,2-dimethyl-6-vinyl-1,3-diox-
ane (I)
To a stirred soln of diol 15 (0.82 g, 3.3 mmol) in anhyd CH2Cl2 (8
mL) was added 2,2-dimethoxypropane (15 mL) and a catalytic
amount of PPTS, and the mixture was stirred at r.t. for 2 h. Et3N (1
mL) was added to the mixture which was then stirred for 10 min.
The solvent was evaporated under reduced pressure and the residue
was purified by column chromatography (EtOAc–hexane, 2:8) to
yield compound I (0.91 g, 95%) as a colourless liquid.
[a]D25 +11.3 (c 1.0, CHCl3).
IR (neat): 2990, 2860, 1647, 1375, 1200, 1102, 739, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.36–7.17 (m, 5 H), 5.83–5.69 (m,
1 H), 5.19 (td, J = 17.3, 1.5 Hz, 1 H), 5.06 (td, J = 10.5, 1.5 Hz, 1
H), 4.47 (ABq, J = 12.0, 2.0 Hz, 2 H), 4.36–4.25 (m, 1 H), 4.11–
3.97 (m, 1 H), 3.61–3.45 (m, 2 H), 1.79–1.63 (m, 2 H), 1.54–1.20
(m, 2 H), 1.43 (s, 3 H), 1.37 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 138.8, 138.5, 128.3, 127.6, 127.5,
118.2, 98.5, 72.9, 70.1, 66.0, 65.6, 36.4, 30.1, 19.7.
LC–MS: m/z = 299 [M + Na]+.
Ethyl (E)-2-Heptadecenoate (16)
To aldehyde 4 (5 g, 22.1 mmol) was added benzene (50 mL) fol-
lowed by the two-carbon Wittig ylide (9.2 g, 26.5 mmol) and the
mixture was stirred at r.t. for 1 h. After completion of the reaction,
the reaction mixture was diluted with CH2Cl2 (40 mL) and washed
with brine (15 mL) and H2O (10 mL). The organic layer was dried
(Na2SO4) and concentrated under reduced pressure. The crude com-
pound was eluted on a silica gel column (EtOAc–hexane, 1:9) to af-
ford the pure ester 16 (6.2 g, 95%) as a colourless solid.
13C NMR (75 MHz, CDCl3): d = 170.4, 138.2, 137.4, 128.3, 127.7,
127.5, 118.1, 93.6, 74.4, 73.0, 69.1, 66.5, 55.5, 40.0, 34.4, 21.2.
LC–MS: m/z = 345 [M + Na]+.
(3R,5R)-1-(Benzyloxy)-5-(methoxymethoxy)-6-hepten-3-ol (14)
Compound 13 (1.5 g, 4.6 mmol) was dissolved in MeOH (10 mL)
and K2CO3 (1.27 g, 9.2 mmol) was added. The mixture was stirred
at r.t. for 2 h, then filtered through a plug of Celite® and concentrat-
ed under reduced pressure. Flash chromatography (EtOAc–hexane,
3:7) of the residue afforded 14 (1.23 g, 95%) as a colourless liquid.
[a]D25 +5.8 (c 1.0, CHCl3).
IR (neat): 3345, 2944, 2863, 1630, 1445, 1132, 1045, 740 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.39–7.19 (m, 5 H), 5.87–5.79 (m,
1 H), 5.21–5.02 (m, 2 H), 4.72–4.6 (m, 2 H), 4.49 (s, 2 H), 4.39–4.2
(m, 1 H), 3.92–3.86 (m, 1 H), 3.52–3.49 (m, 2 H), 3.35 (s, 3 H), 2.9
(br s, 1 H), 1.9–1.6 (m, 4 H).
IR (KBr): 2925, 2854, 1723, 1654, 1179, 1043, 719 cm–1.
1H NMR (200 MHz, CDCl3): d = 6.97–6.84 (m, 1 H), 5.81–5.72 (m,
1 H), 4.16 (q, J = 14.3 Hz, 2 H), 2.19 (dq, J = 1.5, 8.3 Hz, 2 H),
1.52–1.38 (m, 2 H), 1.36–1.16 (m, 25 H), 0.88 (t, J = 7.5 Hz, 3 H).
LC–MS: m/z = 319 [M + Na]+.
(E)-2-Heptadecen-1-ol (17)
To a soln of ester 16 (4.5 g, 15.1 mmol) in anhyd CH2Cl2 (50 mL)
cooled to –15 °C, 1 M DIBAL-H in CH2Cl2 (31.9 mL, 31.9 mmol)
was added dropwise and the mixture was stirred at that temperature
for 2 h. The reaction mixture was then quenched by the slow addi-
tion of anhyd MeOH (10 mL) and was brought to r.t. Sat. aq sodium
potassium tartrate (30 mL) was added to the mixture which was
stirred until two layers separated. The solvent was evaporated under
reduced pressure and the remaining aqueous layer was extracted
with EtOAc (2 × 50 mL). The combined organic extracts were
washed with brine (25 mL), dried (Na2SO4) and concentrated under
reduced pressure. Purification of the residue by column chromatog-
raphy (EtOAc–hexane, 2:8) afforded pure 17 (3.55 g, 92%) as a co-
lourless solid.
LC–MS: m/z = 303 [M + Na]+.
(3R,5R)-7-(Benzyloxy)-1-heptene-3,5-diol (15)
Compound 14 (1.1 g, 3.92 mmol) was dissolved in CH2Cl2 (10 mL)
and TFA (1.19 mL, 15.6 mmol) was added dropwise at 25 °C. The
reaction mixture was stirred at that same temperature for 2 h, then
was quenched with sat. NaHCO3 soln (8 mL) and extracted with
CH2Cl2 (2 × 15 mL). The combined organic extracts were washed
with brine (8 mL) and concentrated under reduced pressure. The
residue was subjected to column chromatography (EtOAc–hexane,
6:4) to afford the pure diol 15 (0.81 g, 88%) as a colourless, gummy
oil.
IR (KBr): 3417, 2919, 2852, 1636, 1459, 756 cm–1.
IR (neat): 3399, 2929, 2863, 1642, 1445, 1090, 995, 739 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.69–5.56 (m, 2 H), 4.04 (d,
J = 4.5 Hz, 2 H), 2.06–2.00 (m, 2 H), 1.45–1.20 (m, 24 H), 0.88 (t,
J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 133.5, 128.7, 63.8, 32.1, 31.8, 29.6
(several overlapped peaks), 29.4, 29.3, 29.1, 27.4, 14.0.
1H NMR (300 MHz, CDCl3): d = 7.37–7.23 (m, 5 H), 5.89–5.75 (m,
1 H), 5.23 (td, J = 17.3, 1.5 Hz, 1 H), 5.04 (td, J = 10.5, 1.5 Hz, 1
H), 4.50 (s, 2 H), 4.38–4.29 (m, 1 H), 4.16–4.0 (m, 1 H), 3.76–3.58
(m, 2 H), 3.57–3.38 (br s, 1 H), 1.91–1.53 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 140.7, 140.5, 128.3, 127.7, 127.6,
114.1, 73.2, 73.0, 71.5, 68.4, 43.0, 36.8.
LC–MS: m/z = 277 [M + Na]+.
[(2S,3S)-3-Tetradecyl-2-oxiranyl]methanol (18)
LC–MS: m/z = 237 [M + H]+.
To a suspension of powdered, activated 4 Å molecular sieves (0.2
g) in anhyd CH2Cl2 (15 mL), Ti(Oi-Pr)4 (0.69 mL, 2.3 mmol) and
(+)-DET (0.4 mL, 2.3 mmol) were added sequentially at –20 °C and
the mixture was stirred for 30 min. Allylic alcohol 17 (3 g, 11.8
mmol) in anhyd CH2Cl2 (20 mL) was added and stirring was con-
Synthesis 2010, No. 22, 3891–3898 © Thieme Stuttgart · New York

3896
G. Sabitha et al.
PAPER
tinued for another 30 min at that same temperature. Then, 5 M t-
BuOOH in toluene (4.7 mL, 23.6 mmol) was added and, after being
stirred for another 10 h at that same temperature, the reaction mix-
ture was quenched by the addition of H2O (10 mL). The mixture
was allowed to remain at r.t. with stirring for 30 min. After recool-
ing to 0 °C, aq NaOH soln (30% w/v, 10 mL, saturated with brine)
was added and the mixture was stirred at 0 °C for 1 h. The solvent
was removed under reduced pressure and the residue was extracted
with Et2O (3 × 10 mL). The combined organic extracts were washed
with brine (15 mL), dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by column chromatography
(EtOAc–hexane, 3:7) to afford pure 18 (2.93 g, 92%) as a colourless
solid.
[a]D25 –8.9 (c 1.0, CHCl3).
IR (KBr): 3285, 2919, 2847, 1461, 1021, 721 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.95–3.83 (m, 1 H), 3.66–3.55 (m,
1 H), 2.97–2.85 (m, 2 H), 1.77 (br s, 1 H), 1.64–1.40 (m, 4 H), 1.36–
1.18 (m, 22 H), 0.88 (t, J = 6.7 Hz, 3 H).
(S)-1-Tetradecyl-2-propenyl Acetate (II)
To allylic alcohol 20 (1.5 g, 5.9 mmol) dissolved in CH2Cl2 (10 mL)
was added Et3N (2.4 mL, 17.7 mmol), Ac2O (1.1 mL, 11.8 mmol)
and DMAP (cat.) at 0 °C, and the mixture was stirred at r.t. for 2 h.
The mixture was diluted with CH2Cl2 (4 mL), washed with H2O (8
mL) and brine (5 mL), dried (Na2SO4) and concentrated under re-
duced pressure. The crude product was purified by column chroma-
tography (EtOAc–hexane, 1:9) to obtain II (1.67 g, 96%) as a
colourless liquid.
[a]D25 –5.5 (c 1.0, CHCl3).
IR (neat): 2925, 2854, 1741, 1461, 1237, 719 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.82–5.68 (m, 1 H), 5.27–5.11 (m,
3 H), 2.05 (s, 3 H), 1.69–1.43 (m, 2 H), 1.36–1.19 (m, 24 H), 0.88
(t, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 170.3, 136.6, 116.4, 74.8, 34.1,
31.9, 29.6 (several overlapped peaks), 29.3, 25.0, 22.6, 21.2, 14.0.
LC–MS: m/z = 319 [M + Na]+.
13C NMR (75 MHz, CDCl3): d = 61.7, 58.4, 55.9, 31.8, 31.5, 29.6
(1S,2E)-3-((4R,6R)-6-[2-(Benzyloxy)ethyl]-2,2-dimethyl-1,3-di-
oxan-4-yl)-1-tetradecyl-2-propenyl Acetate (21)
(several overlapped peaks), 29.5, 29.3, 25.9, 22.6, 14.0.
LC–MS: m/z = 293 [M + Na]+.
A mixture of compound I (1.2 g, 4.3 mmol), compound II (1.5 g,
5.2 mmol) and Grubbs II catalyst (5 mol%) in CH2Cl2 (10 mL) was
stirred at 40 °C for 10 h. After completion of the reaction, the reac-
tion mixture was concentrated under reduced pressure and the resi-
due was subjected to column chromatography (EtOAc–hexane, 2:8)
to give pure 21 (1.84 g, 78%) as a gummy liquid.
[a]D25 –11.9 (c 1.0, CHCl3).
IR (neat): 2925, 2854, 1737, 1458, 1372, 1238, 1099, 738 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.33–7.22 (m, 5 H), 5.67–5.51 (m,
2 H), 5.23–5.13 (dd, J = 6.0, 12.8 Hz, 1 H), 4.48 (ABq, J = 12.0,
14.2 Hz, 2 H), 4.35–4.25 (m, 1 H), 4.09–3.95 (m, 1 H), 3.61–3.44
(m, 2 H), 2.03 (s, 3 H), 1.80–1.07 (br m, 30 H), 1.42 (s, 3 H), 1.36
(s, 3 H), 0.87 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 170.3, 138.4, 133.0, 128.9, 128.3,
127.6, 127.5, 98.6, 73.9, 72.9, 69.0, 66.0, 65.7, 37.0, 36.4, 34.2,
31.8, 30.1, 29.6 (several overlapped peaks), 29.3, 25.0, 22.6, 21.2,
19.7, 14.0.
(2R,3S)-2-(Iodomethyl)-3-tetradecyloxirane (19)
To a soln of epoxy alcohol 18 (2.5 g, 9.2 mmol) in anhyd MeCN–
Et2O (1:1; 25 mL) were added imidazole (1.32 g, 19.4 mmol), Ph3P
(5.3 g, 20.3 mmol) and I2 (3.2 g, 12.9 mmol) at 0 °C. The mixture
was allowed to warm to r.t. and was stirred for 1.5 h. The reaction
was quenched with sat. aq Na2S2O3 (25 mL). The resultant mixture
was diluted with EtOAc (30 mL), washed with H2O (20 mL) and
brine (25 mL), dried (Na2SO4) and concentrated under reduced
pressure. Purification of the residue by column chromatography
(EtOAc–hexane, 1:9) gave iodide 19 (3.16 g, 90%) as a colourless
solid.
[a]D25 +4.2 (c 1.0, CHCl3).
IR (KBr): 2916, 2849, 1467, 1170, 882, 718 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.30–3.24 (m, 1 H), 2.96–2.90 (m,
2 H), 2.74–2.70 (m, 1 H), 1.59–1.40 (m, 4 H), 1.33–1.22 (m, 22 H),
0.89 (t, J = 6.8 Hz, 3 H).
LC–MS: m/z = 567 [M + Na]+.
13C NMR (75 MHz, CDCl3): d = 62.5, 58.2, 31.9, 31.6, 29.6 (sever-
al overlapped peaks), 29.3, 25.8, 22.6, 14.1, 5.0.
LC–MS: m/z = 403 [M + Na]+.
(1E,3S)-1-((4R,6R)-6-[2-(Benzyloxy)ethyl]-2,2-dimethyl-1,3-di-
oxan-4-yl)-1-heptadecen-3-ol (22)
Compound 21 (1.0 g, 1.8 mmol) was dissolved in MeOH (10 mL)
and K2CO3 (0.5 g, 3.6 mmol) was added. After the mixture was
stirred at r.t. for 1 h, it was filtered through a plug of Celite®. Re-
moval of the solvent under reduced pressure followed by flash chro-
matography (EtOAc–hexane, 3:7) of the residue afforded alcohol
22 (0.87 g, 95%) as a pale yellow liquid.
[a]D25 +10.1 (c 1.5, CHCl3).
IR (neat): 3422, 2922, 2852, 1462, 1378, 1103, 738 cm–1.
(S)-1-Heptadecen-3-ol (20)
To a soln of iodide 19 (3 g, 7.8 mmol) in EtOH (20 mL), commer-
cial Zn dust (10.3 g, 157.7 mmol) was added. The mixture was re-
fluxed for 2 h and then cooled to 25 °C. NH4Cl (4.0 g) was added
and the mixture was filtered through a plug of Celite®. The filtrate
was concentrated under reduced pressure. Purification of the resi-
due by flash chromatography (EtOAc–hexane, 2:8) gave allylic al-
cohol 20 (1.90 g, 95%) as a colourless solid.
1H NMR (300 MHz, CDCl3): d = 7.33–7.20 (m, 5 H), 5.72–5.54 (m,
2 H), 4.47 (ABq, J = 2.2, 12.0 Hz, 2 H), 4.35–4.25 (m, 1 H), 4.10–
3.96 (m, 2 H), 3.60–3.44 (m, 2 H), 1.79–1.62 (m, 2 H), 1.55–1.22
(br m, 28 H), 1.43 (s, 3 H), 1.36 (s, 3 H), 0.88 (t, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 138.4, 134.2, 131.0, 128.3, 127.6,
127.5, 98.7, 73.0, 72.2, 69.3, 66.0, 65.7, 37.0, 36.5, 31.9, 30.2, 29.6
(several overlapped peaks), 29.5, 29.3, 25.4, 22.7, 19.8, 14.1.
[a]D25 +3.5 (c 1.0, CHCl3).
IR (KBr): 3350, 2922, 2852, 1468, 922, 718 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.88–5.79 (m, 1 H), 5.20 (d,
J = 17.3 Hz, 1 H), 5.08 (d, J = 12.8 Hz, 1 H), 4.10–4.04 (m, 1 H),
1.78 (br s, 1 H), 1.56–1.43 (m, 2 H), 1.36–1.19 (m, 24 H), 0.89 (t,
J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 140.8, 114.9, 36.8, 31.9, 29.6, 29.5
(several overlapped peaks), 29.3, 25.3, 22.6, 14.1.
LC–MS: m/z = 525 [M + Na]+.
LC–MS: m/z = 277 [M + Na]+.
Synthesis 2010, No. 22, 3891–3898 © Thieme Stuttgart · New York

PAPER
Convergent Synthesis of Passifloricin A
3897
([(1S,2E)-3-((4R,6R)-6-[2-(Benzyloxy)ethyl]-2,2-dimethyl-1,3-
dioxan-4-yl)-1-tetradecyl-2-propenyl]oxy)(tert-butyl)diphenyl-
silane (23)
Na2S2O3–sat. aq NaHCO3 soln (1:1; 5 mL). The aqueous layer was
extracted with Et2O (2 × 15 mL). The combined organic extracts
were washed once with brine (4 mL), dried (MgSO4) and concen-
trated under reduced pressure. The residue was purified by column
chromatography (EtOAc–hexane, 2:8) to yield ketone 25 (0.508 g,
85%) as a light yellow liquid.
[a]D25 +12.1 (c 1.0, CHCl3).
IR (neat): 2926, 2855, 1718, 1462, 1108, 1056, 703, 610 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.70–7.56 (m, 6 H), 7.44–7.26 (m,
4 H), 5.98–5.77 (m, 1 H), 5.20–4.99 (m, 2 H), 4.29–4.10 (m, 1 H),
3.75–3.55 (m, 2 H), 3.15 (d, J = 6.9 Hz, 2 H), 2.62 (dd, J = 6.6, 16.0
Hz, 1 H), 2.34 (dd, J = 6.8, 16.0 Hz, 1 H), 1.45–1.08 (br m, 32 H),
1.36 (s, 3 H), 1.29 (s, 3 H), 1.04 (s, 9 H), 0.89 (t, J = 6.8 Hz, 3 H).
To a stirred soln of compound 22 (0.8 g, 1.59 mmol) in anhyd
CH2Cl2 (10 mL), imidazole (0.21 g, 3.1 mmol) was added at 0 °C,
and the mixture was stirred for 15 min. Then, TBDPSCl (0.45 mL,
1.75 mmol) was added at 0 °C and the mixture was stirred for 4 h.
After completion of the reaction as indicated by TLC, the reaction
mixture was directly concentrated under reduced pressure and the
residue was column chromatographed (EtOAc–hexane, 2:8) to
yield the pure product 23 (1.06 g, 90%) as a pale yellow liquid.
[a]D25 +18.4 (c 1.0, CHCl3).
IR (neat): 2982, 2846, 1472, 1110, 1034, 728 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.68–7.54 (m, 4 H), 7.42–7.17 (m,
11 H), 5.53 (dd, J = 7.9, 15.2 Hz, 1 H), 5.16 (dd, J = 5.8, 15.2 Hz, 1
H), 4.47 (ABq, J = 2.6, 12.2 Hz, 2 H), 4.18–4.01 (m, 2 H), 4.0–3.85
(m, 1 H), 3.59–3.39 (m, 2 H), 1.75–1.57 (m, 2 H), 1.53–1.11 (br s,
28 H), 1.38 (s, 3 H), 1.31 (s, 3 H), 1.04 (s, 9 H), 0.88 (t, J = 6.9 Hz,
3 H).
13C NMR (75 MHz, CDCl3): d = 206.8, 135.9, 135.8, 134.7, 129.3,
127.3, 118.9, 73.0, 69.0, 65.6, 48.8, 48.7, 38.7, 36.6, 36.2, 31.9,
30.1, 29.7 (several overlapped peaks), 29.5, 29.3, 27.0, 23.7, 22.7,
19.4, 14.1.
LC–MS: m/z = 714 [M + Na]+.
LC–MS: m/z = 763 [M + Na]+.
(2R)-1-((4R,6S)-6-[(3S)-3-([(tert-Butyl)diphenylsilyl]oxy)hepta-
decyl]-2,2-dimethyl-1,3-dioxan-4-yl)-4-penten-2-ol (26)
2-((4R,6S)-6-[(3S)-3-([(tert-Butyl)diphenylsilyl]oxy)heptade-
cyl]-2,2-dimethyl-1,3-dioxan-4-yl)ethanol (24)
To a soln of ketone 25 (0.4 g, 0.57 mmol) in anhyd Et2O (10 mL) at
r.t. under N2 was added LiI (0.232 g, 1.7 mmol) and the mixture was
stirred at –40 °C for 30 min. The resulting mixture was then cooled
to –100 °C, LAH (0.06 mg, 1.59 mmol) was added and the mixture
was stirred for 30 min. The reaction mixture was then allowed to
reach 0 °C, diluted with Et2O (10 mL) and quenched by the drop-
wise addition of sat. aq Na2SO4 (10 mL). The solid material was col-
lected by filtration and washed thoroughly with hot EtOAc several
times. The combined organic layers were dried (Na2SO4). The sol-
vent was removed under reduced pressure and the residue was puri-
fied by column chromatography (EtOAc–hexane, 3:7) to afford
alcohol 26 (0.34 g, 86%) as a light yellow, gummy liquid.
To a stirred soln of 23 (0.9 g, 1.21 mmol) in EtOAc (15 mL) was
added 10% Pd/C (0.2 g) and the mixture was stirred under H2 atmo-
sphere for 12 h. The mixture was filtered through Celite® and the fil-
trate was concentrated under reduced pressure. The residue was
purified by column chromatography (EtOAc–hexane, 3:7) to obtain
24 (0.754 g, 95%) as a pale yellow liquid.
[a]D25 +4.2 (c 1.0, CHCl3).
IR (neat): 3423, 2926, 2855, 1463, 1108, 1054, 703 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.73–7.59 (m, 4 H), 7.45–7.27 (m,
6 H), 4.06–3.9 (m, 1 H), 3.78–3.56 (m, 4 H), 2.39–2.21 (br s, 1 H),
1.71–1.56 (m, 2 H), 1.44–1.08 (br m, 32 H), 1.39 (s, 3 H), 1.32 (s, 3
H), 1.04 (s, 9 H), 0.89 (t, J = 6.9 Hz, 3 H).
[a]D25 +6.4 (c 1.0, CHCl3).
IR (neat): 3452, 2926, 2855, 1378, 1107, 703 cm–1.
13C NMR (75 MHz, CDCl3): d = 135.9, 134.7, 129.4, 127.4, 98.4,
77.4, 73.1, 69.1, 60.8, 38.1, 36.6, 36.3, 32.0, 31.7, 30.3, 29.7 (sev-
eral overlapped peaks), 29.4, 27.2, 24.9, 22.7, 19.5, 14.2.
1H NMR (300 MHz, CDCl3): d = 7.70–7.61 (m, 4 H), 7.46–7.29 (m,
6 H), 5.94–5.75 (m, 1 H), 5.18–5.05 (td, J = 11.1, 5.2 Hz, 2 H),
4.20–3.98 (m, 1 H), 3.97–3.78 (m, 1 H), 3.77–3.52 (m, 2 H), 2.32–
2.15 (m, 2 H), 1.64–1.52 (m, 2 H), 1.45–1.10 (br m, 32 H), 1.39 (s,
3 H), 1.35 (s, 3 H), 1.05 (s, 9 H), 0.88 (t, J = 6.8 Hz, 3 H).
LC–MS: m/z = 654 [M + 1]+.
1-((4S,6S)-6-[(3S)-3-([(tert-Butyl)diphenylsilyl]oxy)heptadec-
yl]-2,2-dimethyl-1,3-dioxan-4-yl)-4-penten-2-one (25)
13C NMR (75 MHz, CDCl3): d = 136.1, 135.8, 133.9, 129.3, 127.4,
119.4, 98.2, 77.6, 72.2, 70.3, 58.2, 38.2, 36.2, 35.4, 32.3, 30.6, 29.7
(several overlapped peaks), 29.3, 27.0, 24.5, 22.4, 20.2, 14.5.
To a soln of DMP (0.68 g, 1.6 mmol) in CH2Cl2 (8 mL) at r.t. was
added a soln of alcohol 24 (0.7 g, 1.07 mmol) in CH2Cl2 (6 mL). Af-
ter being stirred for 1 h, the mixture was diluted with Et2O (10 mL)
and washed once with 10% Na2S2O3–sat. aq NaHCO3 soln (1:1; 5
mL). The aqueous layer was extracted with Et2O (2 × 15 mL). The
combined organic extracts were washed once with brine (5 mL),
dried (MgSO4) and concentrated under reduced pressure. The resi-
due was directly used for the next reaction. To a stirred soln of this
aldehyde (0.6 g, 0.91 mmol) in THF (10 mL) at 0 °C was added ac-
tivated Zn (0.120 g, 1.82 mmol) and dropwise allyl bromide (0.15
mL, 1.82 mmol). After being stirred at r.t. for 4 h, the reaction mix-
ture was quenched with sat. NH4Cl soln (5 mL), and the product was
extracted into EtOAc (2 × 10 mL). The combined organic phases
were washed with H2O (2 × 10 mL) and brine (2 × 10 mL), dried
(Na2SO4) and concentrated, and the crude product was purified by
column chromatography (EtOAc–hexane, 3:7) to obtain a diastereo-
meric mixture of secondary alcohol (0.65 g, 88%) as a pale yellow
liquid. This alcohol was used for the next reaction without any fur-
ther characterisation. To a soln of DMP (0.437 g, 1.29 mmol) in
CH2Cl2 (8 mL) at r.t. was added a soln of the above alcohol (0.6 g,
0.86 mmol) in CH2Cl2 (6 mL). After being stirred for 1 h, the mix-
ture was diluted with Et2O (10 mL) and washed once with 10%
LC–MS: m/z = 693 [M+].
(1R)-1-[((4S,6S)-6-[(3S)-3-([(tert-Butyl)diphenylsilyl]oxy)hepta-
decyl]-2,2-dimethyl-1,3-dioxan-4-yl)methyl]-3-butenyl Acry-
late (2)
Acryloyl chloride (0.02 mL, 0.31 mmol) was added dropwise under
N2 to a soln of alcohol 26 (0.18 g, 0.25 mmol), Et3N (0.1 mL, 0.64
mmol) and DMAP (cat.) in anhyd CH2Cl2 (5 mL) at 0 °C. The mix-
ture was allowed to reach r.t. and stirred for 1 h. After completion
of the reaction, the reaction mixture was diluted with CH2Cl2 (5
mL), washed with brine (3 mL) and extracted with CH2Cl2 (2 × 3
mL). The organic phases were washed with 1 M aq HCl (2 mL) and
brine (3 mL), dried (Na2SO4) and concentrated under reduced pres-
sure. The crude product was purified by column chromatography
(EtOAc–hexane, 2:8) to give the pure acrylate 2 (0.178 g, 92%) as
a pale yellow liquid.
[a]D25 +11.8 (c 1.0, CHCl3).
IR (neat): 2883, 1726, 1644, 1488, 1143, 1092, 734 cm–1.
Synthesis 2010, No. 22, 3891–3898 © Thieme Stuttgart · New York

3898
G. Sabitha et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 7.72–7.59 (m, 4 H), 7.45–7.28
(m, 6 H), 6.42 (dd, J = 16.4, 1.4 Hz, 1 H), 6.10 (dd, J = 16.4, 8.2 Hz,
1 H), 5.90–5.72 (m, 2 H), 5.12–5.02 (m, 3 H), 3.95–3.79 (m, 1 H),
3.80–3.56 (m, 2 H), 2.45–2.29 (m, 2 H), 1.49–1.09 (m, 34 H), 1.40
(s, 3 H), 1.37 (s, 3 H), 1.03 (s, 9 H), 0.88 (t, J = 6.9 Hz, 3 H).
References
(1) Echeverri, F.; Arango, V.; Quiñones, W.; Torres, F.;
Escobar, G.; Rosero, Y.; Archbold, R. Phytochemistry 2001,
56, 881.
(2) Cardona, W. G.; Quiñones, W. F.; Echeverri, F. L.
Molecules 2004, 9, 666.
LC–MS: m/z = 770 [M + Na]+.
(3) Passifloricin A has been found to be active against some
Plasmodium and Leishmania spp. (Echeverri, F. personal
communication).
(4) For the syntheses of regioisomers, see: (a) Murga, J.;
García-Fortanet, J.; Carda, M.; Marco, J. A. Tetrahedron
Lett. 2003, 44, 7909. (b) García-Fortanet, J.; Murga, J.;
Carda, M.; Marco, J. A. Org. Lett. 2003, 5, 1447. (c)Cossy,
J.; BouzBouz, S.; Popkin, M. C. R. Chim. 2003, 6, 547.
(d) BouzBouz, S.; Cossy, J. Tetrahedron Lett. 2003, 44,
4471.
(6R)-6-[((4S,6S)-6-[(3S)-3-([(tert-Butyl)diphenylsilyl]oxy)hepta-
decyl]-2,2-dimethyl-1,3-dioxan-4-yl)methyl]-5,6-dihydro-2H-2-
pyranone (27)
Grubbs II catalyst (8 mg, 5 mol%) dissolved in CH2Cl2 (10 mL) was
added to a soln of acrylic ester 2 (0.14 g, 0.18 mmol) in CH2Cl2 (20
mL). The mixture was stirred at 40 °C for 3 h by which time all of
the starting material was consumed (TLC). The solvent was re-
moved under reduced pressure and the crude product was purified
by column chromatography (EtOAc–hexane, 4:6) to obtain 27
(0.101 g, 75%) as a colourless, gummy liquid.
(5) Bifulco, G.; Gomez-Paloma, L.; Riccio, R. Tetrahedron
Lett. 2003, 44, 7137.
(6) Curran, D. P.; Moura-Letts, G.; Pohlman, M. Angew. Chem.
[a]D25 +0.9 (c 1.0, CHCl3).
IR (neat): 2926, 2855, 1729, 1462, 1380, 1107, 1054, 707 cm–1.
Int. Ed. 2006, 45, 2423.
1H NMR (300 MHz, CDCl3): d = 7.73–7.60 (m, 4 H), 7.43–7.30 (m,
6 H), 6.94–6.83 (m, 1 H), 6.03 (td, J = 10.0, 1.7 Hz, 1 H), 4.72–4.50
(m, 1 H), 4.20–3.96 (m, 1 H), 3.82–3.52 (m, 2 H), 2.50–2.18 (m, 2
H), 1.55–1.08 (m, 34 H), 1.39 (s, 3 H), 1.34 (s, 3 H), 1.05 (s, 9 H),
0.88 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 167.7, 145.2, 136.0, 134.7, 129.4,
127.4, 121.3, 98.5, 74.7, 72.9, 69.0, 64.5, 42.1, 40.8, 37.0, 36.1,
31.8, 30.1, 29.6 (several overlapped peaks), 29.3, 24.8, 19.9, 14.0.
(7) Murga, J.; García-Fortanet, J.; Carda, M.; Marco, J. A.
J. Org. Chem. 2004, 69, 7277; and references cited therein.
(8) Chandrasekar, S.; Rambabu, Ch.; Reddy, A. S. Tetrahedron
Lett. 2008, 49, 4476.
(9) (a) Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000, 2,
1217. (b) Yang, X.-F.; Mague, J. T.; Li, C.-J. J. Org. Chem.
2001, 66, 739. (c) Barry, C. St.J..; Crosby, S. R.; Harding, J.
R.; Hughes, R. A.; King, C. D.; Parker, G. D.; Willis, C. L.
Org. Lett. 2003, 5, 2429. (d) Crosby, S. R.; Harding, J. R.;
King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2002, 4,
3407. (e) Rychnovsky, S. D.; Hu, Y.; Ellsworth, B.
Tetrahedron Lett. 1998, 39, 7271. (f) Semeyn, C.; Blaauw,
R. H.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997,
62, 3426. (g) Cloninger, M. J.; Overman, L. E. J. Am. Chem.
Soc. 1999, 121, 1092. (h) Suginome, M.; Iwanami, T.; Ito,
Y. J. Org. Chem. 1998, 63, 6096.
LC–MS: m/z = 736 [M + NH4]+.
Passifloricin A (1)
To a soln of compound 27 (0.08 g, 0.11 mmol) in THF (4 mL) was
added 5 N aq HCl (2 mL), and the mixture was stirred at r.t. for 8 h.
After completion of the reaction, the reaction mixture was extracted
with EtOAc (2 × 5 mL) and the combined organic layers were
washed with H2O (5 mL) and brine (3 mL), dried (Na2SO4) and con-
centrated under reduced pressure. The crude product was purified
by column chromatography to afford compound 1 (0.045 g, 92%) as
a colourless solid; mp 102–105 °C (Lit.7 mp 103–106 °C).
[a]D25 +34.3 (c 1.0, CHCl3) {Lit.7 [a]D25 +33.3 (c 0.8, CHCl3)}.
IR (KBr): 3325, 2917, 1707, 1530, 1251, 1027, 740 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.95–6.87 (m, 1 H), 6.03 (d,
J = 9.8 Hz, 1 H), 4.75–4.63 (m, 1 H), 4.21–4.10 (m, 1 H), 4.02–3.91
(m, 1 H), 3.72–3.61 (m, 1 H), 2.46–2.40 (m, 1 H), 2.10–1.99 (m, 1
H), 1.83–1.37 (m, 8 H), 1.34–1.20 (m, 28 H), 0.88 (t, J = 6.7 Hz, 3
H).
(10) Sabitha, G.; Reddy, K. B.; Bhikshapathi, M.; Yadav, J. S.
Tetrahedron Lett. 2006, 47, 2807.
(11) (a) Sabitha, G.; Reddy, K. B.; Reddy, G. S. K. K.; Narjis, F.;
Yadav, J. S. Synlett 2005, 2347. (b) Sabitha, G.; Narjis, F.;
Reddy, E. V.; Yadav, J. S. Tetrahedron Lett. 2008, 49, 6087.
(c) Sabitha, G.; Narjis, F.; Gopal, P.; Reddy, C. N.; Yadav,
J. S. Tetrahedron: Asymmetry 2009, 20, 184. (d) Sabitha,
G.; Rao, A. S.; Yadav, J. S. Synthesis 2010, 504.
(e) Sabitha, G.; Prasad, M. N.; Shankaraiah, K. S.; Yadav, J.
S. Synthesis 2010, 1171. (f) Sabitha, G.; Vangala, B.;
Reddy, S. S. S.; Yadav, J. S. Helv. Chim. Acta 2010, 93, 329.
(12) Mitsunobu, O. Synthesis 1981, 1.
13C NMR (75 MHz, CDCl3): d = 164.2, 145.1, 121.1, 76.2, 72.4,
71.6, 69.6, 42.5, 42.4, 37.4, 34.2, 32.5, 32.0, 29.7 (several over-
lapped peaks), 29.4, 29.2, 25.7, 22.5, 14.0.
(13) Fuwa, H.; Okamura, Y.; Natsugari, H. Tetrahedron 2004,
60, 5341.
(14) Yadav, J. S.; Ather, H.; Gayathri, K. U.; Rao, N. V.; Prasad,
A. R. Synthesis 2008, 3945.
LC–MS: m/z = 463 [M + Na]+.
(15) (a) Ghosh, A. K.; Lei, H. J. Org. Chem. 2002, 67, 8783.
(b) Sabitha, G.; Sudhakar, K.; Reddy, N. M.; Rajkumar, M.;
Yadav, J. S. Tetrahedron Lett. 2005, 46, 6567.
Acknowledgment
M.N.P., K.S. and N.M.R. thank CSIR, New Delhi for the award of
fellowships.
Synthesis 2010, No. 22, 3891–3898 © Thieme Stuttgart · New York