The stereoselective synthesis of the C6-C18 fragment of scytophycin C employing a novel synthetic methodology

Article abstract of DOI:10.1055/s-2008-1067219

A novel synthetic approach towards the stereoselective synthesis of the C6-C18 fragment of the biologically active antitumor agent scytophycin C is described. The synthesis involves Marouka allylation, base-catalyzed intramolecular conjugate addition, Wit

Full text of DOI:10.1055/s-2008-1067219

PAPER
2933
The Stereoselective Synthesis of the C6–C18 Fragment of Scytophycin C
Employing a Novel Synthetic Methodology
S
tereosele
h
ctive
S
ynthe
i
sis of th
l
e
C6–C
l
18 Fra
u
gment of Scytophy
S
cin C . Yadav,* V. Sunitha, Basi V. Subba Reddy, E. Gyanchander
Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 13 May 2008; revised 28 May 2008
Until now, an elegant total synthesis of scytophycin C has
been reported by Paterson using stereoselective aldol re-
actions.7a,9 The total synthesis of swinholide A has also
been accomplished by Paterson and Nicolaou.8a,10,11 The
promising biological activity and its structural beauty
make it an attractive synthetic target.
Abstract: A novel synthetic approach towards the stereoselective
synthesis of the C6–C18 fragment of the biologically active anti-
tumor agent scytophycin C is described. The synthesis involves
Marouka allylation, base-catalyzed intramolecular conjugate addi-
tion, Wittig olefination, and a tandem allylation.
Key words: scytophycin, allylation, olefination, trans-2,6-disub-
stituted dihydropyran
In continuation of our interest in the total synthesis of bi-
ologically active macrolide, scytophycin C,12 we herein
report a stereoselective synthesis of the C6–C18 fragment
of scytophycin C. Retrosynthetic analysis of scytophycin
C is outlined in Scheme 1.
The scytophycins, a group of highly functionalized poly-
oxygenated 22-membered macrolides isolated from the
terrestrial blue-green algae Scytonema pseudohofmanni,
were first reported by Moore et al. in 1986.1 They exhibit
potent cytotoxicity and antifungicidal activity.2–4 Apart
from scytophycin C (1), four related polyketide-derived4
macrolides, scytophycins A, B, D, and E, were also isolat-
ed.5 All the scytophycins (Figure 1) have a characteristic
C21 side chain terminating in an unusual N-methylform-
amide group, whereas scytophycins A–E differ from each
other with regard to the substituents at C16 and C27. The
potent cytotoxicity6 associated with scytophycin C7 and a
closely related complex polyketide macrolide swinholide
A8 make these compounds attractive targets for synthetic
organic chemists.
OMe
O
O
OMe OMe
N
H
O
OH
O
OMe
Me
OH
O
1
scytophycin C
OMe
O
O
Me
OP
Me
Me
Me
OMe
O
Me
Me
OMe
+
O
O
Me
OP
16
OMe
O
O
O
O
OMe OMe
27
O
Me
N
H
3
2
O
OH
OMe
Me
Scheme 1
OH
O
scytophycin C (1)
The natural product scytophycin C could be cleaved ret-
rosynthetically into two fragments 2 and 3. The synthesis
of the C1–C18 fragment of scytophycin C 2 could be
achieved via the stereoselective construction of a key in-
termediate 4. The retrosynthesis of the C6–C18 fragment
of scytophycin C 4 is depicted in Scheme 2.
Scytophycin
A
C16
O
C 27
OH
O
B
D
E
O
O
The synthesis of fragment 4 began with the known alde-
hyde 9, which was prepared using the literature proce-
dure.13 The aldehyde 9 was used as a precursor to
introduce chirality at C15 by a catalytic asymmetric ally-
lation. According to a recent report on the modified Keck
allylation by Marouka et al., higher enantiomeric excess
was observed.14 Thus, the Marouka allylation of (S)-3-
(benzyloxy)-2-methylpropanal (9) gave homoallylic alco-
hol 815 in 78% yield with 95% de. Dihydroxylation of the
alkene 8 and subsequent oxidation of the resulting diol
OH
OH
O
Figure 1 Scytophycins A–E
SYNTHESIS 2008, No. 18, pp 2933–2938
Advanced online publication: 11.08.2008
DOI: 10.1055/s-2008-1067219; Art ID: Z10608SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8

2934
J. S. Yadav et al.
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O
OBn
OMe
H
OH
H
BnO
H
O
CHO
O
H
OH OH
6
5
4
BnO
COOEt
BnO
H
BnO
O
O
O
OH
7
8
9
Ph
Scheme 2
with sodium periodate afforded a b-hydroxyaldehyde that in dichloromethane gave the key intermediate 6, a d-hy-
was then subjected to Wittig olefination16 with a stable droxy-a,b-unsaturated aldehyde, which was immediately
ylide, (ethoxycarbonylmethylene)triphenylphosphorane, converted into the trans-2,6-disubstituted 3,6-dihydropy-
in benzene at room temperature to provide d-hydroxy-a,b- ran 5 using novel methodology recently developed in our
unsaturated ester 10 (Scheme 3). Subsequent conversion laboratory (Scheme 4).18
of 10 into benzylidene acetal 11 was achieved in 70%
The formation of the trans-2,6-disubstituted dihydropy-
ran ring is the key step, which typically involves the
yield with a diastereomeric ratio syn/anti 9:1 by base-cat-
alyzed intramolecular conjugate addition17 (oxy-Michael
Lewis acid catalyzed and nucleophile-induced tandem cy-
addition) using benzaldehyde and potassium tert-butoxide
clization of a d-hydroxy-a,b-unsaturated aldehyde. This
tandem approach was utilized to introduce chirality at C9.
Accordingly, treatment of d-hydroxy-a,b-unsaturated al-
in tetrahydrofuran at 0 °C. The separation of the syn- and
anti-isomers was achieved by column chromatography.
The reduction of ester 11 with lithium aluminum hydride
dehyde 6 with allyltrimethylsilane in the presence of 10
in tetrahydrofuran gave alcohol 12 in 90% yield
mol% of indium(III) bromide in dichloromethane at room
temperature gave trans-2,6-disubstituted dihydropyran 5
(Scheme 3).
The alcohol 12 was oxidized with 2-iodoxybenzoic acid in 83% yield with a diastereomeric ratio cis/trans 2:8. The
(IBX) in tetrahydrofuran–dimethyl sulfoxide at room separation of the cis- and trans-isomers was achieved by
1
temperature to give the corresponding aldehyde, which column chromatography. H NMR spectra revealed the
was treated with (ethoxycarbonylmethylene)triphe- presence of olefinic protons at d = 5.94–5.69 and 5.21–
nylphosphorane under Wittig conditions to afford the re- 5.01 as multiplets. A signal for the C9 proton appeared at
quired (E)-ester derivative 7 in 92% yield. The ester 7 was d = 4.32–4.24 as multiplet and also a signal for the C13
reduced regioselectively to alcohol 13 using diisobutyl- proton appeared at d = 4.01–3.88 as a multiplet. The pres-
aluminum hydride in dichloromethane at –78 °C. The hy- ence of allylic protons between d = 2.54–1.97 confirmed
drolysis of benzylidene acetal 13 using catalytic 4- the structure of compound 5.
toluenesulfonic acid in methanol gave the corresponding
triol. The rate of hydrolysis of the benzylidene acetal was
very slow and required a long reaction time. The regiose-
lective oxidation of the triol using manganese(IV) oxide
The secondary hydroxy group in compound 5 was protect-
ed as its methyl ether using sodium hydride and methyl io-
dide in dry tetrahydrofuran to give 14 in 92% yield.
Deprotection of the benzyl group in 14 using lithium and
a
b, c, d
BnO
OEt
BnO
H
BnO
OH
O
O
OH
9
8
10
BnO
OEt
e
BnO
OH
f
O
O
O
O
O
Ph
Ph
11
12
Scheme 3 Reagents and conditions: (a) TiCl4, Ti(Oi-Pr)4, (R)-BINOL, Ag2O, 12 h, –15 to 0 °C, 78%, 95% de; (b) OsO4, NMO, acetone–H2O;
(c) NaIO4, THF, H2O, r.t.; (d) Ph3P=CHCO2Et, benzene, r.t., 4 h, 85%; (e) PhCHO, t-BuOK, 0 °C, 2 h, 70%; (f) LiAlH4, THF, 0 °C, 90%.
Synthesis 2008, No. 18, 2933–2938 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of the C6–C18 Fragment of Scytophycin C
2935
BnO
BnO
OEt
OH
a, b
c
12
O
O
O
O
O
13
Ph
Ph
7
OBn
OH
BnO
H
d, e
f
O
OH OH
O
5
6
Scheme 4 Reagents and conditions: (a) IBX, DMSO, THF, r.t., 89%; (b) Ph3P=CHCO2Et, benzene, r.t., 92%; (c) DIBAL-H, CH2Cl2, –78 °C,
2 h, 87%; (d) PTSA, MeOH, r.t., 12 h., 76%; (e) MnO2, CH2Cl2, r.t., 3 h, 87%; (f) allyltrimethylsilane, InBr3, CH2Cl2, r.t., 1 h, 83%.
O
O
Me
OMe
OBn
OMe
Me
OMe
O
OMe
HO
a
b, c, d
O
O
O
OP
ref. 7b
5
14
4
2
Scheme 5 Reagents conditions: (a) NaH, MeI, THF, 0 °C, 92%; (b) Li, naphthalene, THF, –78 °C, 83%; (c) DMP, CH2Cl2, r.t., 1 h, 90%;
(d) ref. 7b.
dropwise and this was followed by the addition of allyltributylstan-
nane (36.4 mmol) and the mixture was then stirred at –15 °C for 30
min. The mixture was allowed to warm to 0 °C and stirred at this
temperature for 12 h. When the reaction was complete, it was
quenched with sat. NaHCO3 soln and Et2O was added. The organic
layer was separated and the aqueous layer was extracted with Et2O
(3 × 50 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated under reduced pressure. The res-
idue was further purified by column chromatography (silica gel, 8%
EtOAc–hexane) to give 8 (78% yield) as a pale yellow oil.
naphthalene followed by oxidation of the alcohol gave an
aldehyde, which was further subjected to methylation us-
ing cerium(III) chloride and methyllithium in tetrahydro-
furan furnished the target intermediate 4 by the route
outlined in Scheme 5. The structure of the fragment 4 was
established with the aid of spectral data, which was found
to be identical in all respects with the reported values.7b
In conclusion, the synthesis of the C6–C18 fragment of
scytophycin C has been achieved in a stereocontrolled
manner employing a sequence of reactions that include
Marouka allylation, base-catalyzed intramolecular oxy-
Michael reaction, and a nucleophile-induced tandem cy-
clization. This synthetic sequence provides easy access to
the construction of a key fragment of scytophycin C. Fur-
ther work towards the total synthesis of scytophycin C by
employing fragment 4 is in progress.
[a]D20 +5.74 (c 1.05, CHCl3).
IR (KBr): 3449, 2921, 2857, 1640, 1454, 1363, 1094, 913, 740, 698
cm–1.
1H NMR (300 MHz, CDCl3): d = 0.92 (d, J = 6.9 Hz, 3 H), 1.85 (dq,
J = 4.5, 6.9, 11.5, 13.9 Hz, 1 H), 2.09–2.21 (m, 1 H), 2.26–2.37 (m,
1 H), 2.98 (d, J = 3.5 Hz, 1 H, OH), 3.44 (dd, J = 6.7, 9.0 Hz, 1 H),
3.56 (dd, J = 6.7, 9.0 Hz, 2 H), 4.5 (s, 2 H), 5.03–5.12 (m, 2 H),
5.77–5.94 (m, 1 H), 7.21–7.35 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 13.8, 37.9, 39.3, 73.4, 74.7, 74.9,
Melting points were recorded on Buchi R-535 apparatus and are un-
corrected. IR spectra were recorded on a Perkin-Elmer FT-IR
240-c spectrophotometer using KBr optics. H NMR spectra were
recorded on Varian-unity 300 spectrometer in CDCl3 using TMS as
internal standard. Mass spectra were recorded on a Finnigan MAT
1020 mass spectrometer operating at 70 eV.
117.2, 127.6, 127.7, 128.4, 135.2, 137.8.
MS (EI): m/z = 243 [M + Na]+, 220 [M]+.
HRMS (ESI): m/z [M + Na]+ calcd for C14H20O2Na: 243.1360.
1
Found: 243.1366.
Ethyl (E)-(5S,6S)-7-(Benzyloxy)-5-hydroxy-6-methylhept-2-
enoate (10)
(2S,3S)-1-(Benzyloxy)-2-methylhex-5-en-3-ol (8)
To a stirred suspension of NMO (34.0 mmol) in acetone (16 mL)
and H2O (4 mL), was added OsO4 (5 mg, 1.02 mmol) in THF (100
mL) followed by addition of a soln of 8 (20.4 mmol) in acetone at
25 °C. The mixture was stirred for 3 h then solid Na2S was added
and the mixture was stirred for 30 min. The acetone was evaporated
under reduced pressure and H2O was added to the residue and this
was stirred for 30 min. The organic layer was separated and the
aqueous layer was extracted with EtOAc (3 × 50 mL). The com-
To a stirred soln of 1 M TiCl4 in CH2Cl2 (1.4 mmol) in anhyd
CH2Cl2 was added Ti(Oi-Pr)4 (4.2 mmol) at 0 °C and the mixture
was stirred at r.t. for 1 h. The round-bottomed flask was wrapped
with carbon paper and added Ag2O (2.8 mmol) was added at 25 °C
and the mixture was allowed to stir at r.t. for 5 h. Then (R,R)-
BINOL (5.6 mmol) was added to the mixture at 25 °C and it was
stirred for 2 h. The mixture was cooled to –15 °C and freshly pre-
pared 9 (28 mmol) in anhyd CH2Cl2 (15 mL) was added slowly
Synthesis 2008, No. 18, 2933–2938 © Thieme Stuttgart · New York

2936
J. S. Yadav et al.
PAPER
bined organic layers were washed with brine, dried (Na2SO4), and
concentrated under reduced pressure to afford the diol as a colorless
oil, which was used for next step without purification. To a soln of
the diol (16.5 mmol) in THF (24 mL) and H2O (6 mL) at 0 °C was
added NaIO4 (33.0 mmol) and the mixture was stirred at 25 °C for
30 min. When the reaction was complete, THF was added and the
mixture was filtered through a pad of Celite with the aid of EtOAc.
The resulting filtrate was extracted with EtOAc (3 × 30 mL) and the
combined organic layers were washed with brine, dried (Na2SO4),
and concentrated in vacuo to give the aldehyde. The crude aldehyde
(15.3 mmol) was taken up in anhyd benzene (40 mL) and to this was
added Ph3P=CHCO2Et (30.6 mmol) and the mixture was stirred at
r.t. for 4 h. The solvent was removed and the resulting crude product
was further purified by column chromatography (silica gel, EtOAc–
hexane, 1:9) to give 10 (85% yield over 3 steps) as a colorless oil.
4 h then cooled to 0 °C and quenched by the dropwise addition of
sat. Na2SO4 soln, stirred for 1 h, and filtered through Celite. To the
filtrate was added H2O, the organic layer was separated, and the
aqueous layer was extracted with EtOAc (3 × 50 mL). The com-
bined organic layers were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The crude product was purified by column
chromatography (silica gel, 15% EtOAc–hexane) to give 12 (90%
yield) as a colorless oil.
[a]D20 –17.5 (c 1.0, CHCl3).
IR (KBr): 3424, 3032, 2915, 2860, 1453, 1345, 1103, 1023, 752,
699 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.01 (d, J = 7.5 Hz, 3 H), 1.46–
1.58 (t, J = 7.5 Hz, 2 H), 1.71–1.90 (m, 2 H), 1.92–2.05 (m, 1 H),
3.49 (d, J = 5.28 Hz, 2 H), 3.73–3.85 (m, 3 H), 3.97–4.07 (m, 1 H),
4.48 (s, 2 H), 5.49 (s, 1 H), 7.19–7.40 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 12.9, 14.2, 33.6, 38.1, 38.4, 60.4,
71.5, 73.0, 100.5, 126.0, 127.5, 128.2, 128.3, 128.6, 138.6.
MS (EI): m/z = 379 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C22H28O4Na: 379.1885.
[a]D20 +11.9 (c 1.0, CHCl3).
IR (KBr): 3446, 2968, 2920, 2858, 1734, 1631, 1453, 1257, 1100,
1023, 757, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.91 (d, J = 6.9 Hz, 3 H), 1.29 (t,
J = 6.7 Hz, 3 H), 1.86 (dq, J = 3.7, 6.9, 11.3, 14.3 Hz, 1 H), 2.21–
2.45 (m, 2 H), 3.30 (d, J = 3.7 Hz, 1 H), 3.43 (dd, J = 3.7, 9.0 Hz, 1
H), 3.59 (dd, J = 7.5, 9.0 Hz, 1 H), 3.65 (m, 1 H), 4.16 (q,
J = 7.5,15.8 Hz, 2 H), 4.5 (s, 2 H), 5.84 (d, J = 15.8 Hz, 1 H), 6.99
(dt, J = 7.5, 15.8 Hz, 1 H), 7.23–7.36 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 13.8, 14.2, 37.7, 37.9, 60.1, 65.2,
73.5, 74.8, 74.9, 123.4, 127.8, 128.5, 128.9, 137.5, 145.7, 166.3.
MS (EI): m/z = 315 [M + Na]+, 292 [M]+.
HRMS (ESI): m/z [M + Na]+ calcd for C17H24O4Na: 315.1572.
Found: 379.1881.
Ethyl (E)-4-{(4S,6S)-6-[(S)-2-(Benzyloxy)-1-methylethyl]-2-
phenyl-1,3-dioxan-4-yl}but-2-enoate (7)
To a suspension of IBX (10.9 mmol) in DMSO (5 mL) at 0 °C was
added dropwise a soln of 12 (7.3 mmol) in THF (25 mL) and the
mixture was stirred 25 °C for 2 h. When the reaction was complete,
the mixture was poured into Et2O and filtered through Celite. The
resulting filtrate was washed with sat. NaHCO3 soln (3 ×) and ex-
tracted with Et2O (3 × 20 mL). The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated under reduced
pressure to yield the aldehyde as yellow oil in 89% yield, which was
used in the next step without purification. The crude aldehyde (5.6
mmol) was taken up in anhyd benzene (30 mL) and to this was add-
ed Ph3P=CHCO2Et (11.2 mmol) and the mixture was stirred at 25
°C for 4 h. The solvent was removed and the resulting crude product
was further purified by column chromatography (silica gel, EtOAc–
hexane, 1:9) to give 7 (92% yield) as a colorless oil.
Found: 315.1578.;
Ethyl {(4R,6S)-6-[(S)-2-(Benzyloxy)-1-methylethyl]-2-phenyl-
1,3-dioxan-4-yl}acetate (11)
To a well-stirred soln of 10 (13.6 mmol) in THF (30 mL) at 0 °C was
added t-BuOK (4.1 mmol) in THF (2 mL) followed by freshly dis-
tilled benzaldehyde (41.0 mmol) and the resulting yellow soln was
stirred at 0 °C for 15 min. This addition sequence was repeated (2 ×)
and the mixture was quenched with pH 7 phosphate buffer (10 mL).
Et2O was added to the mixture, the layers were separated, and the
aqueous layer was extracted with Et2O (3 × 50 mL). The combined
organic layers were washed with brine, dried (Na2SO4), and concen-
trated under reduced pressure. The residue was further purified by
column chromatography (silica gel, EtOAc–hexane, 1:9) to give 11
(70% yield) as a colorless liquid.
[a]D20 –6.36 (c 1.1, CHCl3).
IR (KBr): 2920, 2852, 1717, 1655, 1454, 1316, 1269, 1105 1024,
754, 699 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.00 (d, J = 7.3 Hz, 3 H), 1.29 (t,
J = 7.3 Hz, 3 H), 1.42 (t, J = 6.5 Hz, 1 H), 1.56 (tt, J = 6.5, 12.4 Hz,
1 H), 1.99 (m, 1 H), 2.32–2.67 (m, 2 H), 3.50 (d, J = 5.1 Hz, 2 H),
3.72–4.01 (m, 2 H), 4.18 (q, J = 7.3, 14.6 Hz, 2 H), 4.48 (s, 2 H),
5.46 (s, 1 H), 5.88 (d, J = 15.3 Hz, 1 H), 6.85–7.06 (m, 1 H), 7.19–
7.44 (m, 10 H).
[a]D20 –19.2 (c 1.0, CHCl3).
IR (KBr): 2920, 2854, 1735, 1454, 1346, 1212, 1100, 1023, 751,
698 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.01 (d, J = 6.9 Hz, 3 H), 1.27 (d,
J = 7.5 Hz, 3 H), 1.45 (t, J = 11.3 Hz, 2 H), 2.01 (m, 1 H), 2.45 (dd,
J = 6.0, 15.1 Hz, 1 H), 2.69 (dd, J = 6.0, 15.1 Hz, 1 H), 3.52 (d,
J = 5.2 Hz, 2 H), 3.85 (dddd, J = 2.2, 7.5, 9.8, 11.3 Hz, 1 H), 4.16
(q, J = 7.5, 14.3 Hz, 2 H), 4.26 (m, 1 H), 4.49 (s, 2 H), 5.50 (s, 1 H),
7.21–7.33 (m, 8 H), 7.34–7.41 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 30.8, 32.2, 37.3, 39.1, 67.4, 72.4,
117.0, 124.4, 125.9, 128.5, 128.6, 29.4, 135.3, 142.5.
MS (EI): m/z = 421 [M + Na]+, 398 [M]+.
HRMS (ESI): m/z [M + Na]+ calcd for C24H30O5Na: 421.1990.
13C NMR (75 MHz, CDCl3): d = 12.8, 14.1, 33.3, 38.4, 38.6, 60.1,
71.3, 72.9, 75.2, 76.5, 100.3, 123.6, 125.9, 127.3, 127.4, 128.2,
128.4, 138.5, 144.1, 166.2.
MS (EI): m/z = 447 [M + Na]+, 424 [M]+.
HRMS (ESI): m/z [M + Na]+ calcd for C26H32O5Na: 447.2147.
Found: 447.2167.
(E)-4-{(4S,6S)-6-[(S)-2-(Benzyloxy)-1-methylethyl]-2-phenyl-
1,3-dioxan-4-yl}but-2-en-1-ol (13)
A soln of 7 (4.22 mmol) in anhyd CH2Cl2 (30 mL) was stirred and
cooled to –78 °C and then 20% DIBAL-H soln (5.07 mmol) was
added dropwise over a period of 15 min. The mixture was stirred for
30 min at this temperature and then quenched with sat. sodium po-
tassium tartrate soln and stirred for 1 h. The organic layer was sep-
arated and the aqueous layer was extracted with CH2Cl2 (3 × 50
mL). The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated under reduced pressure. The residue
Found: 421.2000
2-{(4S,6S)-6-[(S)-2-(Benzyloxy)-1-methylethyl]-2-phenyl-1,3-
dioxan-4-yl}ethanol (12)
To a well-stirred suspension of LiAlH4 (13.1 mmol) in THF (30
mL) was added 11 (3.5 g, 8.79 mmol) in THF (20 mL) at 0 °C. The
mixture was allowed to come up to 25 °C and it was stirred at r.t. for
Synthesis 2008, No. 18, 2933–2938 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of the C6–C18 Fragment of Scytophycin C
2937
was purified by column chromatography (silica gel, EtOAc–hex-
ane, 1:9) to give 13 (87% yield) as a colorless oil.
[a]D20 –35.3 (c 1.25, CHCl3).
13C NMR (75 MHz, CDCl3): d = 14.0, 30.9, 31.9, 38.7, 39.9, 64.5,
71.5, 72.5, 73.3, 74.2, 116.8, 124.5, 127.5, 128.3, 128.9, 135.3,
138.1.
MS (EI): m/z = 339 [M + Na]+, 317 [M + 1]+.
HRMS (ESI): m/z [M + Na]+ calcd for C20H28O3Na: 339.1936.
IR (KBr): 3416, 3032, 2922, 2854, 1689, 1453, 1345, 1211, 1105,
1021, 974, 753, 699 cm–1.
Found: 339.1946.
1H NMR (300 MHz, CDCl3): d = 1.00 (d, J = 6.6 Hz, 3 H), 1.21–
1.63 (m, 2 H), 1.86–2.07 (m, 1 H), 2.17–2.51 (m, 2 H), 3.50 (d,
J = 5.1 Hz, 2 H), 3.72–3.88 (m, 2 H), 4.06 (d, J = 4.4 Hz, 2 H), 4.2
(br, 1 H), 4.48 (s, 2 H), 5.44 (s, 1 H), 5.68–5.76 (m, 2 H), 7.21–7.44
(m, 10 H).
13C NMR (75 MHz, CDCl3): d = 13.1, 33.5, 38.7, 39.0, 63.7, 71.8,
73.2, 76.6, 78.0, 100.6, 126.2, 127.6, 127.7, 128.3, 128.7, 132.0,
138.9, 139.0.
(2S,6R)-6-Allyl-2-[(2S,3S)-4-(benzyloxy)-2-methoxy-3-methyl-
butyl]-3,6-dihydro-2H-pyran (14)
To a soln of 5 (1.7 mmol) in anhyd THF (20 mL), NaH (60% dis-
persion in mineral oil, 6.1 mmol) was added at 0 °C and the mixture
was stirred at this temperature for 15 min. Then MeI (2.5 mmol) was
added dropwise followed by a catalytic amount of TBAI and the
mixture was stirred at 25 °C for 4 h. The mixture was quenched with
aq NH4Cl soln and extracted with EtOAc (3 × 20 mL). The com-
bined organic layers were washed with brine, dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, 5% EtOAc–hexane) to give 14
(92% yield) as a pale yellow oil.
MS (EI): m/z = 405 [M + Na]+, 228 [M]+.
HRMS (ESI): m/z [M + Na]+ calcd for C24H30O4Na: 405.2041.
Found: 405.2049.
(E)-(5S,7S,8S)-9-(Benzyloxy)-5,7-dihydroxy-8-methylnon-2-
enal (6)
[a]D20 –62.5 (c 1.15, CHCl3).
IR (KBr): 2924, 2854, 1641, 1456, 1368, 1090, 912, 737, 700 cm–1.
To a soln of 13 (3.4 mmol) in MeOH (20 mL) at 25 °C was added
catalytic PTSA (5 mol%) and the mixture was stirred for 12 h.
When the reaction was complete, the solvent was removed in vacuo
and the crude product was washed with NaHCO3 and extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were washed
with brine, dried (Na2SO4), and concentrated under reduced to af-
ford the triol (76% yield), which was used in the next step without
purification. To a soln of triol (2.5 mmol) in anhyd CH2Cl2 (20 mL)
at 25 °C was added activated MnO2 (5 mmol) and the mixture was
allowed to stir for 2 h. When the reaction was complete, the solvent
was removed under reduced pressure at low temperature and the
crude product was purified by flash column chromatography
(EtOAc–hexane, 3:7) to give pure aldehyde 6 (87% yield) as a col-
orless oil.
1H NMR (200 MHz, CDCl3): d = 0.94 (d, J = 6.5 Hz, 3 H), 1.45–
1.62 (m, 3 H), 1.89–2.02 (m, 2 H), 2.19–2.42 (m, 2 H), 3.30 (s, 3 H),
3.34–3.38 (m, 1 H), 3.44–3.57 (m, 2 H), 3.66–3.76 (m, 1 H), 4.16–
4.21 (m, 1 H), 4.50 (s, 2 H), 4.97–5.13 (m, 2 H), 5.69–5.90 (m, 3 H),
7.32–7.36 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 11.3, 31.7, 35.4, 36.2, 38.6, 57.5,
65.2, 71.1, 72.3, 73.6, 78.2, 116.0, 124.3, 127.2, 127.5, 128.1,
129.3, 135.6, 138.9.
MS (EI): m/z = 353 [M + Na]+, 330 [M]+.
HRMS (ESI): m/z [M + Na]+ calcd for C21H30O3Na: 353.2092.
Found: 353.2096.
[a]D20 –59.3 (c 0.65, CHCl3).
(3R,4S)-5-[(2S,6R)-6-Allyl-3,6-dihydro-2H-pyran-2-yl]-4-meth-
oxy-3-methylpentan-2-one (4)
IR (KBr): 3423, 2920, 2858, 1722, 1685, 1454, 1381, 1067, 740,
698 cm–1.
To a stirred soln of naphthalene (7.5 mmol) in anhyd THF, was add-
ed Li (7.5 mmol) at 25 °C and the mixture was stirred for 30 min.
After the mixture turned a dark green color, compound 14 (1.5
mmol) was added dropwise at –78 °C, and the mixture was stirred
for 2 h at the same temperature. When the reaction was complete,
the reaction was quenched with sat. NH4Cl soln and extracted with
Et2O (3 × 10 mL). The organic layer was washed with brine, dried
(Na2SO4), and concentrated under reduced pressure to afford the
primary alcohol (83% yield). The crude alcohol (1.16 mmol) in an-
hyd CH2Cl2 (10 mL) was added DMP (1.39 mmol) at r.t. and the
mixture was stirred for 10 min. The solid materials were filtered
through a sintered funnel. The resulting filtrate was washed with
hypo solution (Na2S2O3⋅5H2O) and sat. NaHCO3 soln and extracted
with CH2Cl2 (3 × 20 mL). The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated under reduced
pressure to obtain the aldehyde. To a suspension of CeCl3 (0.84
mmol) in THF (10 mL) was added 1.04 M MeLi in Et2O (0.84
mmol) at –78 °C and the mixture was stirred for 30 min at this tem-
perature. The crude aldehyde (0.84 mmol) in THF (5 mL) was add-
ed dropwise and the mixture was stirred at –78 °C for 1 h. Sat.
NH4Cl was added and the mixture was filtered through Celite and
the aqueous layer was extracted with Et2O (5 × 20 mL). The com-
bined organic layers were washed with brine, dried (Na2SO4), and
concentrated in vacuo to obtain the crude alcohol. To a soln of the
alcohol (0.47 mmol) in anhyd CH2Cl2 (20 mL) was added DMP
(0.56 mmol) at r.t. and the mixture was stirred for 10 min. The mix-
ture was filtered through Celite. The filtrate was washed with hypo
solution and sat. NaHCO3 soln and extracted with CH2Cl2 (3 × 20
mL). The combined organic layers were washed with brine, dried
1H NMR (200 MHz, CDCl3): d = 0.87 (d, J = 7.0 Hz, 3 H), 1.36–
1.73 (m, 2 H), 1.74–1.94 (m, 1 H), 2.36–2.58 (m, 2 H), 3.42 (t,
J = 4.0 Hz, 1 H), 3.63 (dd, J = 4.0, 9.1 Hz, 1 H), 3.69–3.84 (m, 1 H),
3.92–4.10 (m, 1 H), 4.25 (br s, 2 H), 4.51 (s, 2 H), 6.12 (dd, J = 7.8,
15.6 Hz, 1 H,), 6.92 (m, 1 H), 7.20–7.40 (m, 5 H), 9.5 (d, J = 7.8 Hz,
1 H, CHO).
MS (EI): m/z = 315 [M + Na]+, 292 [M]+.
(2S,3S)-1-[(2S,6R)-6-Allyl-3,6-dihydro-2H-pyran-2-yl]-4-(ben-
zyloxy)-3-methylbutan-2-ol (5)
To a soln of a mixture of 6 (2.12 mmol) in CH2Cl2 (20 mL) was add-
ed allyltrimethylsilane (2.12 mmol) followed by addition of a cata-
lytic amount of InBr3 (5 mol%) and the mixture was stirred at 25 °C
for 1 h. When the reaction was complete (TLC), the mixture was di-
luted with H2O (10 mL) and extracted with CH2Cl2 (2 × 15 mL).
The organic layers were dried (anhyd Na2SO4) and purified by col-
umn chromatography (silica gel, EtOAc–hexane, 1:9) to afford pure
5 (83% yield) as a oil.
[a]D20 –81.2 (c 1.6, CHCl3).
IR (KBr): 3445, 2924, 2855, 1455, 1218, 1075, 701 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.97 (d, J = 6.9 Hz, 3 H), 1.44–
1.69 (m, 2 H), 1.85–1.96 (m, 1 H), 1.97–2.04 (m, 2 H), 2.26–2.38
(m, 1 H), 2.41–2.54 (m, 1 H), 3.36–3.60 (m, 2 H), 3.72–3.84 (m, 1
H), 3.88–4.01 (m, 1 H), 4.26 (br s, 1 H), 4.23–4.32 (m, 1 H) 4.53 (s,
2 H), 5.10–5.21 (m, 2 H), 5.69–5.94 (m, 3 H), 7.24–7.37 (m, 5 H).
Synthesis 2008, No. 18, 2933–2938 © Thieme Stuttgart · New York

2938
J. S. Yadav et al.
PAPER
(6) (a) Patterson, G. M. L.; Smith, C. D.; Kimura, L. H.;
(Na2SO4), and concentrated under reduced pressure to yield the ke-
tone, which was further purified by column chromatography (silica
gel, EtOAc–hexane, 1:9) to afford 4 (90% yield) as a yellow oil.
[a]D20 –98 (c 0.5, CHCl3).
Brittern, B.; Carmeli, S. Cell Motil. Cytoskeleton 1993, 24,
39. (b) Smith, C. D.; Carmeli, S.; Moore, R. E.; Patterson, G.
M. L. Cancer Res. 1993, 53, 1343.
(7) For a total synthesis of scytophycin C: (a) Paterson, I.;
Watson, C.; Yeung, K. S.; Wallace, P. A.; Ward, R. A.
J. Org. Chem. 1997, 62, 452. (b) Nakamura, R.; Tanino, K.;
Miyashita, M. Org. Lett. 2003, 5, 3579. (c) Nakamura, R.;
Tanino, K.; Miyashita, M. Org. Lett. 2003, 5, 3583.
(8) For syntheses of swinholide A, see: (a) Paterson, I.; Yeung,
K. S.; Ward, R. A.; Smith, J. D.; Cumming, J. G.; Lamboley,
S. Tetrahedron 1995, 51, 9467. (b) Paterson, I.; Yeung, K.
S.; Ward, R. A.; Smith, J. D.; Cumming, J. G. J. Am. Chem.
Soc. 1994, 116, 9391. (c) Nicolaou, K. C.; Ajito, K.; Patron,
A. P.; Khatuya, H.; Richter, P. K.; Bertinato, P. J. J. Am.
Chem. Soc. 1996, 118, 3059.
(9) (a) Paterson, I.; Yeung, K. S.; Wallace, P. A.; Ward, R. A.
Tetrahedron 1998, 54, 11935. (b) Paterson, I.; Yeung, K. S.;
Wallace, P. A.; Ward, R. A. Tetrahedron 1998, 54, 11955.
(10) Nicolaou, K. C.; Patron, A. P.; Ajito, K.; Richter, P. K.;
Khatuya, H.; Bertinato, P.; Miller, R. A.; Tomaszewski, M.
J. Chem.–Eur. J. 1996, 2, 847.
(11) The synthesis of preswinholide A has also been
accomplished by Nakata and co-workers: Nagasawa, K.;
Shimizu, I.; Nakata, T. Tetrahedron Lett. 1996, 37, 6885.
(12) Yadav, J. S.; Ahmed, M. M. Tetrahedron Lett. 2002, 43,
7147.
(13) Paquette, L. A.; Guevel, R.; Sakamoto, S.; Kim, I. H.;
Crawford, J. J. Org. Chem. 2003, 68, 6096.
(14) (a) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem.
Soc. 2003, 125, 1708. (b) Keck, G. E.; Tarbet, H.; Geraci, L.
S. J. Am. Chem. Soc. 1993, 115, 8467.
(15) Brown, C. H.; Krishna, S. B.; Ramnarayan, S. R. J. Org.
Chem. 1989, 54, 1570.
IR (KBr): 2924, 2856, 1715, 1635, 1451, 1279, 1082, 765 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.92 (d, J = 7.0 Hz, 3 H), 1.20 (d,
J = 7.0 Hz, 3 H), 1.35–1.65 (m, 2 H), 1.65–1.89 (m, 2 H), 1.91–2.23
(m, 2 H), 2.83 (m, 1 H), 3.48 (s, 3 H), 3.58–3.62 (m, 1 H), 3.85–3.93
(m, 1 H), 4.28 (br s, 1 H), 4.95–5.28 (m, 2 H), 5.68–5.97 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 10.8, 29.5, 30.8, 36.4, 37.9, 39.1,
49.8, 57.4, 64.7, 72.3, 78.4, 116.0, 124.4, 123.9, 128.5, 135.3,
210.7.
MS (EI): m/z = 275 [M + Na]+, 252 [M]+.
HRMS (ESI): m/z [M]+ calcd for C15H24O3: 252.1402. Found:
252.1411.
References
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Patterson, G. M. L.; Mynderse, J. S.; Barchi, J. Jr.; Norton,
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(3) (a) Moore, R. E. In Marine Natural Products Chemical and
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(5) Scytophycins isolated from other species of Scytonema and
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Synthesis 2008, No. 18, 2933–2938 © Thieme Stuttgart · New York