Stereoselective synthesis of (S,S)-palythazine from D-mannitol

Article abstract of DOI:10.1016/j.tetasy.2010.05.002

Exploiting the symmetry element, an asymmetric synthesis of (S,S)-palythazine was accomplished with (R)-glyceraldehyde acetonide as the chiral precursor. The prominent steps involved stereoselective Barbier allylation, ring-closing metathesis, regioselect

Full text of DOI:10.1016/j.tetasy.2010.05.002

Tetrahedron: Asymmetry 21 (2010) 885–889
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of (S,S)-palythazine from D-mannitol
Kommu Nagaiah a, , Khandregula Srinivasu a,b, S. Praveen Kumar a, Jeelani Basha c, Jhillu Singh Yadav a
*
a Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Indian Institute of Chemical Technology, An Associate Institution of University of Hyderabad, Hyderabad 500 046, India
c Centre for Nuclear Magnetic Resonance, Indian Institute of Chemical Technology, Hyderabad, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Exploiting the symmetry element, an asymmetric synthesis of (S,S)-palythazine was accomplished with
(R)-glyceraldehyde acetonide as the chiral precursor. The prominent steps involved stereoselective Bar-
bier allylation, ring-closing metathesis, regioselective nucleophilic opening of epoxide, and auto-conden-
sation of aminoketone moiety.
Received 20 April 2010
Accepted 4 May 2010
Available online 2 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
atives are effective medicines for skin disease caused by the prolifer-
ation of keratinocytes.6b The intriguing architecture of palythazine,
Nature provides a rich source of bioactive compounds with sig-
nificant biological activity and has, therefore, received considerable
attention from the synthetic organic and medicinal chemistry com-
munities. Fused pyran rings are widely present in the natural prod-
ucts. The marine products, adorned with fused pyran skeleton,
have attracted considerable synthetic interest due to their promis-
ing anti-tumor properties.1
endowed with a tricyclic ring with a center of symmetry with two
stereogenic centers, presents an attractive target to synthetic chem-
ists. To the best of our knowledge, only one synthesis of 1 has been
reported to date.3 Herein, we report a new synthetic route of (S,S)-
palythazine 1 from D-mannitol by extending the scheme, developed
previously for the synthesis of (S)-clavulazine in our laboratory.7
2. Results and discussion
Yoshimasa et al. reported the isolation of palythazine 1, isopa-
lythazine 13, and similar alkoloids from Palythoa tuberculosa in
1979.2 The absolute stereochemistry of palythazine was conclu-
2.1. Retrosynthetic analysis
sively established through total synthesis of palythazine from D-glu-
cose in 1982.3a The simple clavulazine 14 was isolated from the
Okinawan soft coral Clavularia viridis.4 Furazano[3,4-b]pyrazine
derivatives show a wide spectrum of biological activity as antimi-
crobials,5a herbicides, plant growth regulators,5b and anti-bacteri-
als.5c In 2003, Kashman et al. isolated two cytotoxic alkaloids,
barrenazine A 15 and B 16, which were adorned with all nitrogen
atoms in the tricyclic ring.6a Tetrahydropyrido[3,4-b]pyrazine deriv-
The foremost disconnection involves desymmetrifying pyrida-
zine ring, exploiting the symmetry element. This leads to the
3-amino-4-oxotetrahydropyran unit 12, which in the synthetic
direction could lead to 1 on auto-condensation. The aminoketone
was envisaged to derive from the corresponding epoxide 9, which
could easily be derived from the three-carbon chiral synthon,
D-glyceraldehyde, through a series of manipulations (Scheme 1).
N
N
N
O
O
O
OH
O
OH
HO
O
HO
OH
N
N
N
Isopalythazine 13
(S)-clavulazine 14
(S,S)-Palythazine 1
N
N
N
HN
HN
NH
NH
N
Barrenazine A 15
Barrenazine B 16
* Corresponding author.
E-mail address: nagaiah@iict.res.in (K. Nagaiah).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.002

886
K. Nagaiah et al. / Tetrahedron: Asymmetry 21 (2010) 885–889
syn = 9:1) to afford the predominant homoallylic alcohol 3a.9 The
minor diastereomer 3b was not separable at this stage.
N
N
H2N
O
O
OH
O
HO
O
OH
Allylation was next undertaken using allyl bromide and NaH at
0 °C to afford the O-allyl diastereomers 4a and 4b,10 which were
easily separated by silica gel column chromatography. The
unmasking of the diol with 2 N HCl and the subsequent oxidative
fission11 with NaIO4 and the reduction of the intermediate alde-
hyde with NaBH4 gave the dienol 6.9a
1
12
O
The alcohol 6 was protected as a benzylic ether by using benzyl
bromide and NaH in THF, setting the stage for the construction of
the pyran ring. Metathesis of diene 7 in the presence of Grubbs’
catalyst (2 mol %; 1st generation) in dry DCM at ambient tempera-
ture delivered the pyran product 8.12 Compound 8 was subjected
to epoxidation with m-CPBA and NaHCO3 to afford a mixture of
diastereomers 9a and 9b (1:1).13 The mixture of epoxides 9a and
9b was exposed to NaN3 and NH4Cl to afford the azido alcohol
10 as a mixture of diastereomers in 79% yield in a regio- and ste-
reo-selective manner (Scheme 3). The regioselectivity of the reac-
tion can be explained by the preferred diaxial epoxide opening
(Fürst–Platter rule).14 This was confirmed with the help of double
quantum filtered correlation spectroscopy (DQF COSY)15 (see
Fig. 1). The alcohol 10 was oxidized with Dess–Martin period-
O
H
O
O
OBn
O
2
9
Scheme 1. Retrosynthetic analysis of (S,S)-palythazine.
2.2. Total synthesis of palythazine 1
The synthesis commenced from (R)-2,3-O-isopropylidene glyc-
eraldehyde 2, which was readily prepared from
-mannitol.8 As
depicted in Scheme 2, Zn-mediated allyl addition to 2 under the
Barbier protocol proceeded with good diastereoselectivity (anti/
D
O
OH
OH OH
Ref-8
b
a
HO
H
O
OH
O
O
O
OH OH
D-Mannitol
2
3a:3b
dr = 90:10(anti:syn)
O
O
O
O
c
d
OH
OH
+
O
O
O
O
OH
4a
4b
6
5
Scheme 2. Reagents and conditions: (a) Zn, THF, allyl bromide, saturated aq NH4Cl, 0 °C to rt, 3 h, 74%; (b) NaH, THF, allyl bromide, 0 °C to rt, 3 h, 86%; (c) 2 N HCl, THF, rt, 3 h,
90%; (d) NaIO4, saturated aq NaHCO3, DCM, 0 °C to rt, 8 h; then NaBH4, MeOH, 0 °C, 15 min, 91%.
O
O
O
a
b
c
OH
OBn
OBn
OBn
6
7
8
N3
O
O
O
e
d
O
O
+
OBn
OBn
HO
9a
10
9b
H2N
HCl.H2N
O
N3
O
g
O
O
O
f
OH
OH
OBn
O
11
12
N
N
O
OH
HO
O
(S,S)- Palythazine 1
Scheme 3. Reagents and conditions: (a) NaH, THF, BnBr, 0 °C to rt, 2 h, 92%; (b) Grubbs’ catalyst 1st generation, DCM, rt, 10 h, 88%; (c) m-CPBA, NaHCO3, DCM, 10 h, 78%; (d)
NaN3, NH4Cl, EtOH, H2O, 80 °C, 8 h, 80%; (e) DMP, NaHCO3, DCM, 0 °C to rt, 6 h, 70%; (f) H2, 10% Pd/C, EtOH, concd HCl, 12 h; (g) Et3N, air, 4 h, 50% (over two steps).

K. Nagaiah et al. / Tetrahedron: Asymmetry 21 (2010) 885–889
887
3 (5.4 g, 74%) as yellowish oil. Rf = 0.50 (3:7 EtOAc and hexane).
½
a 2D5
ꢀ
¼ þ11:5 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): d 5.91–
5.79 (m, 1H), 5.20–5.10 (m, 2H), 4.06–3.91 (m, 3H), 3.82–3.74
(m, 1H), 2.38–2.15 (m, 2H), 1.73 (br s, OH, 1H), 1.43 (s, 3H), 1.37
(s, 3H); 13C NMR (CDCl3, 75 MHz): d 133.9, 118.3, 109.0, 78.0,
70.3, 65.1, 35.5, 26.5, 25.2; IR (KBr, neat): 3460, 2988, 2895,
1375, 1215, 1065 cmꢁ1; ESIMS (m/z): 195 (M+Na)+; HRMS (ESIMS):
m/z calcd for C9H16O3Na (M+Na)+ 195.0997, found 195.0998.
H
H
7
O
H
6
N3
H
H
4
5
O
H
H
1
H
2
3
H
OH
H
H
4.3. (R)-4-((S)-1-(Allyloxy)but-3-enyl)-2,2-dimethyl-1,3-dioxolane
4a
Figure 1.
To a stirred solution of NaH (3.49 g, 87.2 mmol) in dry THF
(20 mL) was added a solution of alcohol 3 (7.5 g, 43.6 mmol) in
anhydrous THF (30 mL) at 0 °C under nitrogen atmosphere. The
mixture was stirred at room temperature for 30 min. The resulting
solution was again cooled to 0 °C followed by the slow addition of
allyl bromide (5.7 mL, 65.8 mmol). After being stirred for 3 h at
room temperature, the excess NaH was destroyed by the addition
of 15 mL methanol. The solvent was removed under vacuum and
the residue was partitioned between water and ethyl acetate.
The organic layer was washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The crude residue was purified
by column chromatography (hexane/EtOAc = 20:1) to afford the re-
quired compound 4a (8.0 g, 86%) as a pale yellowish oil. Rf = 0.47
inane16 (DMP) and NaHCO3 to furnish the corresponding ketone
11. The compound 11, which was relatively less stable, was hydro-
genated in the presence of Pd/C and HCl under hydrogen atmo-
sphere to give the salt 12. Neutralization with Et3N, which paved
the way for self-condensation, culminated in the target molecule
117 (Scheme 3). The physical and spectroscopic data of synthetic
compound 1 were in excellent agreement with the earlier report.3
3. Conclusion
In conclusion, we have achieved a stereoselective total synthe-
sis (S,S)-palythazine from the common carbohydrate precursor.
The prominent steps involved the diastereoselective allylic addi-
tion, construction of pyran unit by RCM, and finally auto-condensa-
tion. The synthesis of other natural products of this family and
their analogs is underway and will be reported in due course.
(1:9 EtOAc and hexane). ½a D25
ꢀ
¼ þ27:8 (c 1.0, CHCl3); 1H NMR
(CDCl3, 600 MHz): d 5.94–5.83 (m, 2H), 5.29–5.07 (m, 4H), 4.16–
4.10 (m, 1H), 4.09–4.01 (m, 3H), 3.90 (t, J = 6.8 Hz, 1H), 3.48 (q,
J = 5.6 Hz, 1H), 2.41–2.35 (m, 1H), 2.33–2.26 (m, 1H), 1.42 (s, 3H),
1.35 (s, 3H); 13C NMR (CDCl3, 75 MHz): d 134.8, 134.1, 117.4,
116.9, 109.0, 78.6, 77.0, 71.5, 66.2, 35.5, 26.5, 25.3; IR (KBr, neat):
3077, 2985, 2927, 1642, 1456, 1374, 1254, 1074 cmꢁ1; ESIMS (m/
z): 235 (M+Na)+; HRMS (ESIMS): m/z calcd for C12H20O3Na
(M+Na)+ 235.1310, found 235.1314.
4. Experimental
4.1. General experimental
All reagents were purchased from Aldrich (Sigma–Aldrich, Ban-
galore, India). Reactions were monitored by TLC, performed on sil-
ica gel glass plates containing 60 F-254. Column chromatography
was performed with Merck 60–120 mesh silica gel. IR spectra were
recorded on a Perkin–Elmer RX-1 FT-IR system. 1H NMR spectra
were recorded on Varian Gemini 200, Bruker 300, Varian unity
400, Inova-500, and Bruker 600 MHz spectrometer. 13C NMR
(75 MHz) spectra were recorded on Bruker Avance-300 MHz spec-
trometer. Chemical shifts (d) are reported in parts per million
(ppm) downfield from internal TMS standard. Peaks are labeled
as singlet (s), doublet (d), triplet (t), quartet (q), and multiplet
(m). ESI spectra were recorded on Micro mass, Quattro LC using
ESI+ software with a capillary voltage of 3.98 kV and ESI mode po-
sitive ion trap detector. Optical rotations were measured with a
Horiba-SEPA-300 digital polarimeter.
4.4. (2R,3S)-3-(Allyloxy)-hex-5-ene-1,2-diol 5
To a stirred solution of acetonide 4a (10.0 g, 47.2 mmol) in THF
(50 mL) was added 2 N HCl (6 mL) at 0 °C. The solution was al-
lowed to warm to room temperature, stirred for 3 h, and cooled
again to 0 °C. Then solid Na2CO3 was added in portion to neutralize
the reaction mixture. The solvent was removed under vacuum and
the residue partitioned between water and ethyl acetate. The or-
ganic layer was washed with aqueous sodium bicarbonate solution
and brine and dried over Na2SO4. The filtrate was concentrated un-
der vacuum and purified by column chromatography (hexane/
EtOAc = 7:3) to afforded the diol compound 5 (7.3 g, 90%) as a pale
yellowish liquid. Rf = 0.27 (5:5 EtOAc and hexane). ½a D25
¼ þ28:4 (c
ꢀ
1.0, CHCl3); 1H NMR (CDCl3, 600 MHz): d 5.93–5.80 (m, 2H), 5.30–
5.08 (m, 4H), 4.13 (dd, J = 5.6, 12.6 Hz, 1H), 4.02 (dd, J = 6.0,
12.6 Hz, 1H), 3.77–3.68 (m, 3H), 3.52 (q, J = 5.8 Hz, 1H), 3.13 (br
s, OH, 1H), 2.94 (br s, OH, 1H), 2.44–2.38 (m, 1H), 2.35–2.30 (m,
1H); 13C NMR (CDCl3, 75 MHz): d 134.5, 134.1, 117.6, 117.2, 80.2,
77.3, 71.3, 63.2, 34.9; FTIR (KBr, neat): 3403, 2924, 1641, 1426,
1340, 1079 cmꢁ1; ESIMS (m/z): 195 (M+Na)+; HRMS (ESIMS): m/z
calcd for C9H16O3Na (M+Na)+ 195.0997, found 195.0991.
4.2. (S)-1-(2,2-Dimethyl-1,3-dioxolan-4-yl)-but-3-en-1-ol 3
To a stirred suspension of activated zinc (5.53 g, 84.6 mmol) in
30 mL of dry THF was added a solution of (R)-glyceraldehyde 2
(5.5 g, 42.3 mmol) in 25 mL of dry THF under nitrogen at 0 °C. After
15 min, allyl bromide (7.32 mL, 84.6 mmol) was added dropwise
over 15 min at 0 °C. The reaction mixture was stirred for 3 h at
room temperature. After completion of the reaction (monitored
by TLC), the reaction was quenched by the slow addition of satu-
rated aqueous NH4Cl solution (17 mL) at 0 °C over 15 min. After
being stirred for 1 h, the mixture was filtered through Celite pad.
The filtrate was concentrated under reduced pressure. The crude
product was partitioned between water and ethyl acetate. The
combined organic layer was washed with brine, dried over anhy-
drous Na2SO4, and evaporated. The residue was purified by column
chromatography (hexane/EtOAc, 9:1) to afford the pure compound
4.5. (S)-2-(Allyloxy)pent-4-en-1-ol 6
To a stirred solution of diol 5 (4.0 g, 23.25 mmol) in DCM (30 mL)
was added 3.0 mL of aqueous sodium bicarbonate at 0 °C. Then
NaIO4 (10.0 g, 46.5 mmol) was added portionwise over 15 min,
and the resulting reaction mixture was gradually warmed to
ambient temperature and stirred for 8 h. The reaction mixture was
filtered. The filtrate was washed with brine solution and concen-
trated under reduced pressure to afford the crude aldehyde, which

888
K. Nagaiah et al. / Tetrahedron: Asymmetry 21 (2010) 885–889
was dissolved in 35 mL methanol. Then NaBH4 (0.88 g 23.26 mmol)
was added at 0 °C, and the resulting mixture was stirred for 15 min.
The solvent was removed under reduced pressure. The residue was
taken in water (40 mL) and extracted with ethyl acetate (3 ꢂ 50 mL).
The organic layer was washed with brine and dried over anhydrous
Na2SO4. The filtrate was concentrated under vacuum followed by
flash column chromatography (hexane/EtOAc = 8:2) to afford the
mono hydroxyl product 6 (3.0 g, 91%). Rf = 0.39 (3:7 EtOAc and hex-
0 °C. The resulting reaction mixture was stirred at room tempera-
ture for 10 h; after completion of the reaction, the reaction was
quenched with aqueous Na2CO3 (6 mL) at 0 °C. The reaction mass
was filtered on Celite and washed with DCM. The organic layer
was washed with brine and dried over anhydrous Na2SO4. The fil-
trate was concentrated under reduced pressure and the crude was
purified by column chromatography (hexane/EtOAc = 8:2) to pro-
vide the mixture of required products 9 (1.6 g, 78%). 1H NMR
(CDCl3, 300 MHz): d 7.33–7.20 (m, 5H), 4.52 (s, 2H), 4.21 (dd,
J = 4.5, 13.6 Hz, 1H), 3.91 (d, J = 13.6 Hz, 1H), 3.60–3.51 (m, 1H),
3.38–3.31 (m, 3H), 3.20 (t, J = 4.5 Hz, 1H), 1.98 (dt, J = 15.1,
2.2 Hz, 1H), 1.81 (ddd, J = 2.2, 10.6, 14.3 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d 138.0, 128.2, 127.57, 127.51, 73.2, 72.4, 69.2, 65.6,
50.9, 50.5, 27.5; FTIR (KBr, neat): 3508, 3002, 2912, 2855, 1724,
1453, 1359, 1259, 1208, 1095, 1033, 808, 740, 699 cmꢁ1; ESIMS
(m/z): 243 (M+Na)+; HRMS (ESIMS): m/z calcd for C13H16O3Na
(M+Na)+ 243.0997, found 243.0991.
ane). ½a 2D5
ꢀ
¼ þ29:2 (c 1.0, CHCl3); 1H NMR (CDCl3, 600 MHz): d 5.97–
5.89 (m, 1H), 5.84–5.76 (m, 1H), 5.32–5.27 (m, 1H), 5.21–5.18 (m,
1H), 5.14–5.06 (m, 2H), 4.14 (dd, J = 5.6, 12.6 Hz, 1H), 4.04 (dd,
J = 5.8, 12.6 Hz, 1H), 3.69–3.64 (m, 1H), 3.55–3.48 (m, 2H), 2.39–
2.33 (m, 1H), 2.30–2.24 (m, 1H), 2.18 (br s, OH, 1H); 13C NMR (CDCl3,
75 MHz): d 134.7, 133.9, 117.5, 117.1, 78.9, 70.4, 63.9, 35.2; FTIR
(KBr, neat): 3428, 2926, 2871, 1642, 1426, 1342, 1080, 1047, 966,
919 cmꢁ1; ESIMS (m/z): 165 (M+Na)+; HRMS (ESIMS): m/z calcd
for C8H14O2Na (M+Na)+ 165.0891, found 165.0896.
4.6. (S)-((2-(Allyloxy)pent-4-enyloxy)methyl)benzene (7)
4.9. (2S)-5-Azido-2-(benzyloxymethyl)-tetrahydro-2H-pyran-4-
ol 10
To a stirred solution of NaH (1.69 g, 42.25 mmol) in dry THF
(30 mL) was added a solution of alcohol 6 (3.0 g, 21.13 mmol) in
dry THF (10 mL) by dropwise under nitrogen atmosphere at 0 °C
and stirred for 15 min. Then benzyl bromide (3.8 mL, 31.69 mmol)
was added to the reaction mixture at 0 °C and stirred for 4 h at
room temperature. Then the reaction was quenched with aqueous
NH4Cl (5 mL) at 0 °C and concentrated under reduced pressure. The
residue was diluted with H2O (30 mL), extracted with ethyl acetate
(2 ꢂ 100 mL), and the combined extracts were dried over anhy-
drous Na2SO4. The filtrate was concentrated and residue was puri-
fied by flash column chromatography (hexane/EtOAc = 9.5:0.5) to
afford the required product 7 (4.5 g, 92%). Rf = 0.5 (1:9 EtOAc and
A mixture of epoxide compound 9 (1.7 g, 7.7 mmol), NaN3
(1.0 g, 15.45 mmol), and NH4Cl (0.83 g, 15.45 mmol) in EtOH/H2O
(40 mL, 3:1) was refluxed at 80 °C for 8 h. After completion of the
reaction, monitored by TLC, the reaction mixture was concentrated
under reduced pressure and the crude was taken in water and ex-
tracted with ethyl acetate (2 ꢂ 100 mL). The organic layer was
washed with aqueous NaHCO3 and brine and dried over anhydrous
Na2SO4. The filtrate was concentrated under reduced pressure fol-
lowed by column chromatography (hexane/EtOAc, 7:3) to provide
the required product 10 (1.6 g, 79%). 1H NMR (CDCl3, 300 MHz): d
7.36–7.22 (m, 5H), 4.53 (s, 2H), 3.87–3.70 (m, 4H), 3.51–3.40 (m,
3H), 2.04 (ddd, J = 3.7, 11.2, 14.5 Hz, 1H), 1.64–1.55 (m, 1H); 13C
NMR (CDCl3, 75 MHz): d 137.7, 128.3, 127.7, 73.4, 72.4, 71.4,
67.4, 66.0, 58.6, 27.1 FTIR (KBr, neat): 3432, 3030, 2920, 2856,
2103, 1451, 1264, 1070, 995, 745, 698 cmꢁ1; ESIMS (m/z): 286
(M+Na)+; HRMS (ESIMS): m/z calcd for C13H17N3O3Na (M+Na)+
286.1167, found 286.1162.
hexane). ½a 2D5
ꢀ
¼ ꢁ1:8 (c 1.0, CHCl3); 1H NMR (CDCl3, 200 MHz): d
7.40–7.22 (m, 5H), 6.00–5.70 (m, 2H), 5.33–5.00 (m, 4H), 4.54 (s,
2H), 4.13–4.06 (m, 2H), 3.63–3.45 (m, 3H), 2.38–2.27 (m, 2H);
13C NMR (CDCl3, 75 MHz): d 138.3, 135.2, 134.5, 128.2, 127.5,
116.9, 116.4, 77.5, 73.2, 72.0, 70.7, 36.2; FTIR (KBr, neat): 3073,
2916, 2859, 1642, 1452, 1361, 1095, 996, 917, 738, 697 cmꢁ1
;
ESIMS (m/z): 255 (M+Na)+; HRMS (ESIMS): m/z calcd for
15H20O2Na (M+Na)+ 255.1360, found 255.1349.
C
4.10. (2S)-5-Azido-2-(benzyloxymethyl)-tetrahydro pyran-4-
one 11
4.7. (S)-2-(Benzyloxymethyl)-3,6-dihydro-2H-pyran 8
To a solution of mixture of alcohols 10 (0.6 g, 2.28 mmol) in
CH2Cl2 (10 mL) were added NaHCO3 (0.958 g, 11.4 mmol) and
Dess–Martin periodinane (1.94 g, 4.56 mmol) at 0 °C. After stirring
for 6 h at 0 °C, the reaction was quenched with aqueous Na2SO3
(20 mL) and the resultant mixture was then extracted with CH2Cl2
(2 ꢂ 50 mL). The extracts were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The resultant
residue 11 (0.417 g, 70%) was used for the next reaction without
further purification. 1H NMR (CDCl3, 300 MHz): d 7.36–7.25 (m,
5H), 4.56 (ABq, J = 12.8, 14.3 Hz, 2H), 4.29 (dd, J = 7.0, 10.6 Hz,
1H), 4.03 (dd, J = 6.8, 10.6 Hz, 1H), 3.85–3.76 (m, 1H), 3.57–3.48
(m, 2H), 3.38 (t, J = 10.6 Hz, 1H), 2.63 (dd, J = 10.6, 14.3 Hz, 1H),
2.52 (dd, J = 3.0, 14.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d 201.6,
137.5, 128.5, 127.89, 127.73, 77.9, 73.6, 71.5, 69.8, 63.8, 43.8; FTIR
(KBr, neat): 3425, 2924, 2855, 2113, 1727, 1456, 1267, 1219, 1099,
To a solution of diene compound 7 (4.5 g, 19.4 mmol), in dry
DCM (100 mL), was added Grubbs’ 1st generation catalyst
(0.32 g, 0.39 mmol) and the resulting purple-colored solution was
stirred at room temperature for 10 h. After completion of the reac-
tion, the brown-colored solution was concentrated under reduced
pressure and subjected to column chromatography (hexane/
EtOAc = 9.5:0.5) to afford the cyclized compound 8 (3.5 g, 88%).
Rf = 0.37 (1:9 EtOAc and hexane). ½a D25
ꢀ
¼ ꢁ66:5 (c 1.0, CHCl3); 1H
NMR (CDCl3, 300 MHz): d 7.32–7.19 (m, 5H), 5.83–5.75 (m, 1H),
5.73–5.66 (m, 1H), 4.56 (ABq, J = 12.1, 18.9 Hz, 2H), 4.21–4.17 (m,
2H), 3.78–3.68 (m, 1H), 3.50 (dd, J = 6.0, 10.6 Hz, 1H), 3.42 (dd,
J = 3.8, 10.6 Hz, 1H), 2.16–2.01 (m, 1H), 1.99–1.88 (m, 1H); 13C
NMR (CDCl3, 75 MHz): d 138.0, 128.1, 127.5, 127.4, 126.1, 123.4,
73.2, 72.7, 72.5, 65.6, 27.1; FTIR (KBr, neat): 3436, 3032, 2923,
2854, 1650, 1451, 1369, 1183, 1092, 1012, 738, 697, 653 cmꢁ1
;
770 cmꢁ1
.
ESIMS (m/z): 227 (M+Na)+; HRMS (ESIMS): m/z calcd for
C13H16O2Na (M+Na)+ 227.1047, found 227.1049.
4.11. (S,S)-Palythazine 1
4.8. (4S)-4-(Benzyloxymethyl)-3,7-dioxa-bicyclo[4.1.0]heptane 9
To a solution of crude keto compound 10 (0.417 g, 1.6 mmol) in
EtOH (5 mL) were added conc. HCl (0.54 mL, 6.4 mmol) and 0.7 g
10% Pd/C at room temperature. The resulting mixture was stirred
under hydrogen atmosphere for 12 h. Then the reaction mixture
was filtered over Celite and washed with methanol (2 ꢂ 10 mL).
To a stirred solution of olefin compound 8 (1.9 g, 9.3 mmol) and
solid NaHCO3 (0.94 g, 11.17 mmol) in 20 mL of dry DCM was added
a solution of m-CPBA (1.93 g, 11.17 mmol) in dry DCM (20 mL) at

K. Nagaiah et al. / Tetrahedron: Asymmetry 21 (2010) 885–889
889
7. Praveen Kumar, S.; Nagaiah, K.; Chorghade, M. S. Tetrahedron Lett. 2006, 47,
7149–7151.
8. (a) Marton, D.; Stivanello, D.; Tagliavini, G. J. Org. Chem. 1996, 61, 2731–2737;
(b) Christian, P.; Jean, L. L. J. Org. Chem. 1985, 50, 910–912; (c) Petrier, C.;
Einhorn, J.; Luche, J. L. Tetrahedron Lett. 1985, 26, 1449–1452; (d) Cathy, E.;
Jean, L. L. J. Organomet. Chem. 1987, 322, 177–183.
9. (a) Yong, X.; Glenn, D. P. J. Org. Chem. 2002, 67, 7158–7160; (b) Jackson, D. Y.
Synth. Commun. 1988, 18, 337–341; (c) Janusz, J.; Stanislaw, P.; Tomasz, B.
Tetrahedron 1986, 42, 447–488; (d) Mulzer, J.; Angermann, A.; Munch, W.
Liebigs Ann. Chem. 1986, 825–838.
10. Satoshi, S.; Kazuya, T.; Yoshihito, U.; Akira, M. J. Org. Chem. 1998, 24, 8815–
8824.
11. Jiantao, G.; Frost, J. W. J. Am. Chem. Soc. 2002, 124, 10642–10643.
12. (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446–452; (b)
Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29; (c) Lebrun, S.;
Couture, A.; Deniau, E.; Grandclaudon, P. Org. Lett. 2007, 9, 2473–2476; (d)
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5471–5473.
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14. Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley-
Interscience: New York, 1994. p 730.
15. The resonance assignments were made with the help of double quantum
filtered correlation spectroscopy (DQF COSY) and 3JHH coupling constants were
measured from resolution-enhanced one dimensional proton NMR spectrum.
The stereochemistry at C2 and C3 carbon atoms is determined with the help of
NOE and J-coupling constants. The downfield shift of H3 proton when
compared to H2 proton clearly shows that OH group is attached to C3 carbon
and N3 group is attached C2. The large coupling between H5 and one of the H4
protons indicates that these two protons are in diaxial position of a chair
conformation and the other H4 proton showing small J-coupling with H5
indicates that this proton is in equatorial position. The presence of small J-
coupling between H3 and H4 protons clearly indicates that H3 proton is in
equatorial position and OH is in axial position. Similarly, the small J-coupling of
The filtrate volume was reduced to 3 mL and neutralized with Et3N
(0.8 mL) and stirred in air for 4 h at room temperature. Then the
reaction mixture was directly concentrated under reduced pressure
and the crude was purified by column chromatography using
MeOH and CH2Cl2 (0.5:9.5 ratio) to give the final compound 1
(0.20 g, 50%) as white crystalline powder Rf = 0.27 (1:9 MeOH/
DCM). ½a 2D5
¼ ꢁ197:5 (c 0.3, MeOH); melting point: 220–223 °C
ꢀ
(upon sublimation from 190 °C on); 1H NMR (CDCl3, 600 MHz): d
4.94 (d, J = 15.5 Hz, 2H), 4.83 (d, J = 15.5 Hz, 2H), 3.96 (oct, 2H),
3.87 (dd, J = 2.6, 11.8 Hz, 2H), 3.76 (dd, J = 7.0, 11.8 Hz, 2H), 3.00
(dd, J = 11.4, 16.5 Hz, 2H), 2.80 (dd, J = 2.4, 16.5 Hz, 2H), 2.35 (t,
J = 7.6 Hz, OH, 2H); 1H NMR (DMSO-d6, 400 MHz): d 4.92 (t,
J = 5.7 Hz, OH, 2H), 4.74 (ABq, J = 15.3, 24.7 Hz, 4H), 3.84 (oct, 2H),
3.56 (t, J = 5.9 Hz, 4H), 2.79 (d, J = 14.3 Hz, 4H); 13C NMR (DMSO-
d6, 75 MHz): d 148.1, 146.3, 75.6, 68.7, 65.6, 32.3; FTIR (KBr, neat):
3480, 2909, 2870, 1452, 1385, 1348, 1258, 1161, 1062, 1020, 835,
584 cmꢁ1; ESIMS (m/z): 253 (M+H)+; HRMS (ESIMS): m/z calcd for
C
12H16N2O4Na (M+Na)+ 275.1007, found 275.1009.
Acknowledgment
K.S. thanks CSIR, New Delhi, for the award of fellowship.
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displayed in Figure 1.
Chemical shifts: H1a: 3.85 (1H, dd, 1.7, 12.4), H1e: 3.74 (1H, td, 2.0, 2.0, 12.4),
H
H
2e: 3.52 (1H, b), H3e: 3.84 (1H, overlap), H4a: 2.02 (1H, ddd, 3.7, 11.2, 14.5),
4e: 1.64 (1H, td, 3.0, 3.0, 14.5), H5a: 3.78 (1H, overlap), H6: 3.43 (1H, dd, 4.2,
0
0
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