Effective procedure for the oxidative cleavage of olefins by OsO4-NaIO4

Article abstract of DOI:10.3987/COM-09-11689

Oxidative cleavage of olefins by OsO₄-NaIO₄ sometimes suffers from low yields due to the formation of side products. It is reported that the addition of pyrimidine can suppress the side reactions and dramatically improve the yield of

Full text of DOI:10.3987/COM-09-11689

HETEROCYCLES, Vol. 78, No. 7, 20091837
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HETEROCYCLES, Vol. 78, No. 7, 2009, pp. 1837 - 1846. © The Japan Institute of Heterocyclic Chemistry
Received, 25th February, 2009, Accepted, 19th March, 2009, Published online, 23rd March, 2009
DOI: 10.3987/COM-09-11689
EFFECTIVE PROCEDURE FOR THE OXIDATIVE CLEAVAGE OF
OLEFINS BY OsO4-NaIO4
Hong Woo Lee,* Sung Kwon Kang, Choong Leol Yoo, and Seung Uk Lee
Chemical Research Group, Chong Kun Dang Research Institute, Chonan P.O.
Box 74, Chonan, 330-831, South Korea
Abstract – Oxidative cleavage of olefins by OsO4-NaIO4 sometimes suffers from
low yields due to the formation of side products. It is reported that the addition of
pyrimidine can suppress the side reactions and dramatically improve the yield of
this classic reaction.
Phosphodiesterase (V) inhibitors (PDE5 inhibitors) are an important class of pharmaceutical compounds.
The first clinical use of these compounds was in the treatment of male erectile dysfunction (MED).1
Further uses are being proposed and investigated, including pulmonary hypertension. There are currently
three commercial PDE5 inhibitors which have been approved by the FDA, that is, Viagra (Pfizer), Cialis
(Eli-Lilly), and Levitra (Bayer). In the course of synthesis of novel quinazoline derivatives, we needed to
convert olefin 1 to aldehyde 2 via an oxidative cleavage reaction (Scheme 1). Due to the presence of the
qninazoline moiety, ozonolysis did not give satisfactory results. Therefore we decide to apply the well-
known OsO4-NaIO4 protocol. The oxidative cleavage of the double bond of compound 1 under the
standard literature conditions of OsO4-NaIO4 gave the desired aldehyde 2 in only 58-62% moderate yield
(Table entry 1).2 We found that the relatively low yield was due to the formation of 25-30% α-hydroxy
ketone 3, presumably formed via the over-oxidation of the diol intermediate. Others also have reported
the formation of α-hydroxy ketones as side products under the standard literature conditions.3 Although
we did not find many example that actually reported α- hydroxyl ketones as the side product, we noticed
that the tedious two-step procedure (dihydroxylation employing OsO4-NMO or Sharpless asymmetric
dihydro-oxidation followed by oxidative cleavage with NaIO4 was employed more often than the one-step
protocol (OsO4-NaIO4).4-5

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O
O
N
O2N
HO
O2N
HO
NH
NH
OsO4-NaIO4
N
O
pyrimidine, 6-7 h, rt,
dioxane-H2O (3:1)
H
1
2
Scheme 1
Recently, Jin et al. reported an improved procedure for the oxidative cleavage of OsO4-NaIO4 using
basic condition.6 Since the reaction media was acidic (pH = 3.5) condition, we thought that buffering the
reaction might change the outcome of the reaction. Deionized water was replaced with the phosphate
buffer (about pH = 7.0-7.2). But the reaction appeared to be very slow and no selectivity was
observed (Table 1, entry 2). We next examined the effect of the addition of pulverized K2CO3 (3.5 equiv).
Interestingly, TLC and HPLC7 showed very good selectivity, and only a trace amount of compound 3 was
formed (Table 1, entry 3). However, the reaction was still very slow and never went to completion even
after 36 h, and gave several other unknown impurities. This experiment indicated that it was possible to in
hibit the formation of compound 3 by the addition of a weak base. Nevertheless, more experiments were
needed to search for the good matched base that could prevent the formation of compound 3 at a
reasonable reaction rate. It is known that the rate of formation of osmium (VI) ester complex could be
dramatically increased by the addition of an excess of tertiary amine such as triethylamine, Hünig base,
NMO, pyridine, 2,6-lutidine, pyrazine, and pyridazine (Table 1, entry 4-10).8-9 Especially, when 2,6-
lutidine was added, the reaction was indeed faster, and the selectivity was excellent (Table1, entry 8).
Although we observed only a trace amount of compound 3 by using 2,6-lutidine, we found the formation
of several unknown impurities, instantaneously.
Table 1. Effect of various bases on the rate of reaction and product distribution.a)
conditionsb)
no base
desired product
entry
1
aldehyde
substrates
O
O
O
O2N
O2N
O2N
HO
NH
NH
NH
HO
N
HO
N
N
O
H
O
OH
58-62%d)
25-30%
3
2
1
very slow rxn
over 36 h
no selectivity
2
3
1
1
buffer = 7.0-7.2
K2CO3 (3.5 equiv)
trace, other impurities

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31-42%d)
36-40%d)
Et3N (2.0 equiv)
4
5
1
1
1
1
trace, other impurities
trace, other impurities
trace, other impurities
trace, other impurities
(i-Pr)2NEt (2.0 equiv)
NMOc) (2.0 equiv)
pyridine (2.0 equiv)
40-45%d)
32-42%d)
75-81%d)
6
7
8
9
1
1
2,6-lutidine (2.0 equiv)
pyrazine (2.0 equiv)
3-5%, other impurities
trace, other impurities
57-62%d)
45-51%d)
10
1
pyridazine (2.0 equiv)
trace, other impurities
no effecte)
85-90%d)
76-80%d)
11
12
13
1
1
1
2,6-di-t-butylpyridine (2.0 equiv)
pyrimidine (2.0 equiv)
3-5%
2-chloropyrimidine (2.0 equiv)
6-9%, other impurities
a) All of the reactions was monitored by HPLC or TLC. b) Reaction conditions: OsO4 (2-5 mol% equiv), NaIO4
(4.0 equiv), dioxane-water (3:1, v:v). c) N-Methyl morpholine. d) Isolated yields. e) Desired product was not
dectected.
Further trial with 2,6-di-tert-butylpyridine, which is very similar to 2,6-lutidine except bulky tert-butyl
part, had no effect on the reaction (Table 1, entry 11). This finding led us to investigate the use of
pyrimidine as a base. To our delight, we found that 2.0 equivalent of pyrimidine effectively suppressed
the formation of compound 3 and improved the yield of the desired aldehyde 2 to 85-90% with 3-5% of
the side product 3 (Table 1, entry 12). Furthermore, the reaction went fast and was completed in 6-7 h
without any significant impurity. 2-Chloropyrimidine, derivative of pyrimidine, gave a good result with
76-80% yield of the desired aldehyde 2. However, the reaction gave 6-9% of the side product 3 and
several other unknown impurities (Table 1, entry 13). With this result in hand, we set out to explore the
effect of pyrimidine on a variety of substrates in OsO4-NaIO4 reaction (Table 2).
In the absence of pyrimidine, the reaction of compound 4 and compound 6 with OsO4-NaIO4 gave only
58-66% yield of the desired product 5 and 7 (Table 2, entry 1 and 2). Although compound 4 and 6 are
structurally very similar to compound 1, we have observed that the oxidative cleavage reaction of
compound 4 and 6 under the classic condition (without pyrimidine as base) gave complex side products.10
Surprisingly, the yields of the desired aldehyde product 5 and 7 were improved to 88-90% with the
addition of pyrimidine. It appeared that pyrimidine inhibited several uncharacterized side products. The
reactions of compound 8 and 12 under the classic condition were quite slow and gave only 46-48% yields
of the desired products 9 and 13 along with 20-25% recovery of the starting materials (Table 2, entry 3
and 5). It was noteworthy that prolonged reaction times gave even lower yields due to cleavage of the
quinazoline moiety under basic condition. In the presence of pyrimidine base, the same reactions were

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HETEROCYCLES, Vol. 78, No. 7, 20091840
completed in 8-10 h and afforded 82-72% yields of desired products 9 and 13. Substrate 12, which has an
internal olefin moiety, exhibited a little bit lower yield and long reaction time compared to terminal olefin
substrate 6 for both classical condition and pyrimidine base condition (Table 2, entry 2 and 5).
Compound 10, branched olefin, gave about 85% yield, and this case showed similar result compared to
compound 6 (Table 2, entry 2). In the case of ring open compound, substrate 14 gave only 52% yield of
the aldehyde compound 15 under classical condition. Again, the yield was improved to 80% after the
addition of pyrimidine base (Table 2, entry 6). In the course of the synthesis of novel fumagillol
derivatives in our other project, we tried to apply this oxidative cleavage reaction to convert fumagillol
compounds 16 and 18 to corresponding aldehyde fumagillol compounds 17 and 19 (Table 2, entry 7 and
8). Particularly, fumagillol substrate 16, having two epoxides and α,β-unsaturated ester at C-6 position,
needed cautious approach of choosing oxidizing condition.
In this case of substrate 16 having two epoxides (spiro-epoxide and the one on C-4 olefin side chain) and
the α,β-unsaturated ester at C-6 position, it exhibited only 32 % yield of the aldehyde fumagillol
derivative under the classical condition. However, the yield was increased to 51% after the addition of
pyrimidine base (Table 2, entry 7). Fumagillol compound 18 without C-6 side chain, that is N,N-dimethyl
aminocinnamoyl moiety, showed about 38% yield of the aldehyde fumagillol 19 under no base condition.
The yield also dramatically improved to 53% after the addition of pyrimidine base (Table 2, entry 8). The
reaction of compound 20 under classical conditions gave only 42% yield of the desired product 21 after
the reaction was stirred at rt for 10 h (Table 2, entry 9). In the presence of pyrimidine, the same reaction
was completed in 7 h and afforeded 74% yield of compound 21. Both inhibiting and rate acceleration
effects by pyrimidine were quite obvious in this instance. Similar effects were also observed in compound
22 (Table 2, entry 10). Compound 24, a terminal olefin, gave only 43% yield of the aldehyde 25 under the
classic conditions. However, the yield was improved to 81% after the addition of pyrimidine (Table 2,
entry 11). Compound 26, which has a terminal olefin , gave improved result as a compound 24 (Table 2,
entry 12).
Table 2. Dramatic improvement of the oxidative cleavage of olefinsa)
time, yield
(without base)
time, yield
(with pyrimidine)
substrateb)
entry
desired product
OMe
OMe
O2N
O2N
N
N
18 h, 58%
12 h, 66%
6 h, 88%
1
MeO
MeO
N
N
H
O
4
5
OEt
OEt
N
O2N
EtO
O2N
EtO
N
2
6 h, 90%
N
N
H
O
7

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OMe
OMe
O
O
N
O
O
O2N
O
O2N
N
N
24 h, 46%c)
10 h, 82%
7 h, 85%
3
MeO
MeO
O
N
H
O
O
O
8
9
OEt
N
OEt
N
O2N
EtO
O2N
15 h, 62%
4
5
N
H
EtO
N
O
10
11
OEt
N
OEt
N
O2N
EtO
O2N
EtO
24 h, 48%c)
17 h, 52%
8 h, 72%
7 h, 80%
N
O
N
12
14
13
OMe
OMe
O
O2N
O
O
O2N
MeO
MeO
NH
O
6
7
NH
O
H
O
O
15
O
O
H
O
O
OMe
O
OMe
10 h, 32%
12 h, 38%
6h, 51%
7 h, 53%
O
O
O
N
N
O
O
O
O
16
17
O
H
8
O
OMe
O
O
OMe
OH
OH
18
19
H
O
10 h, 42%
18 h, 23%
7 h, 74%
9
N
N
20
21
H
O
O
MeO
MeO
MeO
MeO
12 h, 41%
10
N
N
22
23
O
O
O
O
O
12 h, 43%
3 h, 31%
6 h, 81%
3 h, 73%
CN
CN
11
12
H
24
25
O
O
O
O
O
OTBS
OTBS
26
27
a) All of the reactions was monitorized by HPLC and TLC, b) Reaction conditions: OsO4 (3-5 mol% equiv), NaIO4
(4.0 equiv), pyrimidine (1.5 equiv), dioxane-water 3:1, v/v), c) Starting materials (20-25%) were recovered, respectively.
In conclusion, we have successfully developed an improved procedure for the classic OsO4-NaIO4
mediated oxidative cleavage reaction. Addition of pyrimidine effectively suppressed the formation of α-
hydroxy ketone side product 3, accelerated the rate of the desired reaction, and dramatically improved the
reaction yields. In addition, these results indicated that pyrimidine base can also be used as a weak base to
neutralize the acid generated in the reaction. Furthermore, we have noted that pyrimidine can suppress
some other side reactions that are not characterized at the present time. We are certain that this new

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procedure will find wide application in organic synthesis. The mechanistic explanation of the inhibiting
effect of pyrimidine is currently under investigation and will be reported in due course.
EXPERIMENTAL
Commercial available reagents used without further purification. NaBH4 (98% Aldrich Co.) was used
without further purification. Anion exchange resin (Amberlite IRA-400) was used supporting the polymer
of borohydride exchange resin (BER). All reactions were conducted under anhydrous condition in
solvents dried over molecular sieves type 4Å under nitrogen atmosphere and performed using oven dried
glassware. Melting points were determined on a Büchi 510 capillary apparatus and are uncorrected. IR
spectra were recorded on a Bruker Vector 22 FT-IR spectrophotometer. NMR spectra were recorded on a
Bruker DPX 400 MHz instrument operating at 400 MHz for proton and 100 MHz carbon NMR and were
performed in CDCl3 solution using tetramethylsilane as the internal reference and chemical shift (δ) is
reported in ppm downfield from internal tetramethylsilane. The coupling constants (J) is reported in Hz.
MS spectra were recorded on a HP 5989B instrument. Flash chromatography was performed using Merck
silica gel 60 (230-400 mesh) according to the published procedure.11 TLC was performed on glass backed
plates pre-coated with silica (0.2 mm, 60 F254) and developed using standard visualizing agents UV
fluorescence (254 and 365 nm), potassium permanganate and iodine. Fumagillol substrate 16 and 18
having cinnamoyl moiety compounds were synthesized and purified according to in house procedures.12
General Procedure: 2-(7-Hydroxy-6-nitro-4-oxo-3,4-dihydroquinazolin-8-yl)acetaldehyde (2). To a
solution of compound 1 (296 mg, 0.812 mmol) in dioxane-water (10 mL, 3:1, v/v) was added pyrimidine
(0.189 mL, 1.62 mmol), OsO4 (3.0 mol% in 2-methylpropanol, 180 mg, 0.016 mmol), and NaIO4 (695
mg, 3.25 mmol). The reaction was stirred at rt and monitored by HPLC and TLC. After the reaction was
complete, water (10 mL) and CH2Cl2 (20 mL) were added. The organic layer was separated, and the water
layer was extracted by CH2Cl2 (10 mL) three times. The combined organic layer was washed with brine
and dried over Na2SO4. The solvent was removed, and the product was purified with silica gel column
o
chromatography to afford aldehyde compound 2 (268 mg, 88%) as a white powder. mp 112-115 C. IR
(KBr) νmax cm-1: 3581, 2852, 1521, 1431. 1H NMR (400 MHz, CDCl3) δ: 3.78-3.95 (m, 2H), 7.47 (s, 1H),
13
8.84 (s, 1H), 9.65-9.71 (m, 1H), 9.82 (br, 1H), 12.38 (s, 1H). C NMR (100 MHz, CDCl3) δ: 38.32,
114.85, 117.68, 122.74, 136.15, 145.52, 149.51, 159.02, 160.77, 199.91. Anal. Calcd for C10H7N3O5
(249.18): C, 48.20; H, 2.83; N, 16.86; O, 32.10. Found: C 48.11; H 2.88; N 16.99; O 32.01.
2-(4,7-Dimethoxy-6-nitroquinazolin-8-yl)acetaldehyde (5). Yield: 0.82 g, 88% as yellowish solid. mp
o
113-116 C. IR (KBr) νmax cm-1: 3101, 2869, 2837, 1508. 1H NMR (400 MHz, CDCl3) δ: 3.55-3.68 (m,
2H), 3.76 (s, 3H), 3.84 (s, 3H), 8.61 (s, 1H), 8.91 (s, 1H), 9.82 (br, 1H). 13C NMR (100 MHz, CDCl3) δ:

HETEROCYCLES, Vol. 78, No. 7, 20091843
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38.80, 55.10, 56.28, 111.55, 113.47, 117.69, 140.57, 153.20, 159.83, 160.08, 185.35, 199.91. Anal. Calcd
for C12H11N3O5 (277.23): C, 51.99; H, 4.00; N, 15.06; O, 28.86. Found: C 51.85; H 4.03; N 15.16; O
28.97.
2-(4,7-Diethoxy-6-nitroquinazolin-8-yl)acetaldehyde (7). Yield: 0.86 g, 90% as yellowish solid. mp
122-125 oC. IR (KBr) νmax cm-1: 2869, 2833, 1511, 1382. 1H NMR (400 MHz, CDCl3) δ: 1.16 (t, 3H, J =
7.6 Hz), 1.22 (t, 3H, J = 7.3 Hz), 3.63-3.69 (m, 2H), 3.72-3.78 (m, 2H), 3.83-3.92 (m, 2H), 8.64 (s, 1H),
13
8.89 (s, 1H), 9.94 (br, 1H). C NMR (100 MHz, CDCl3) δ: 14.85, 14.98, 38.87, 63.90, 65.02, 111.50,
113.42, 116.28, 138.25, 154.78, 160.25, 161.38, 185.48, 198.58. Anal. Calcd for C14H15N3O5 (305.29): C,
55.08; H, 4.95; N, 13.76; O, 26.20. Found: C 55.00; H 4.92; N 14.01; O 26.06.
Dimethyl 2,2-[6-nitro-8-(2-oxoethyl)quinazoline-4,7-diyl]bis(oxy)diacetate (9). Yield: 0.87 g, 82% as
yellow solid. mp 139-142 oC. IR (KBr) νmax cm-1: 2911, 2835, 1733, 1514. 1H NMR (400 MHz, CDCl3) δ:
3.51-3.60 (m, 2H), 3.66 (s, 3H), 3.74 (s, 3H), 4.68 (s, 2H), 4.71 (s, 2H), 8.63 (s, 1H), 8.97 (s, 1H), 9.92
13
(br, 1H). C NMR (100 MHz, CDCl3) δ: 38.25, 50.92, 51.78, 64.32, 65.41, 110.98, 113.24, 117.25,
140.78, 153.78, 159.02, 161.38, 169.38, 184.45, 199.07. Anal. Calcd for C16H15N3O9 (393.31): C, 48.86;
H, 3.84; N, 10.68; O, 36.61. Found: C 49.06; H 3.74; N 10.67; O 36.52.
2-(4,7-Diethoxy-6-nitroquinazolin-8-yl)propanal (11). Yield: 0.83 g, 85% as yellow solid. mp 126-129
oC. IR (KBr) νmax cm-1: 2852, 2833, 1522, 1385. 1H NMR (400 MHz, CDCl3) δ: 1.16 (t, 3H, J = 7.6 Hz),
1.22 (t, 3H, J = 7.3 Hz), 1.36 (d, 3H, J = 12.3 Hz), 3.63-3.71 (m, 1H), 3.75-3.80 (m, 2H), 3.84-3.99 (m,
2H), 8.64 (s, 1H), 8.89 (s, 1H), 9.94 (br, 1H). 13C NMR (100 MHz, CDCl3) δ: 13.85, 14.57, 15.57, 45.28,
63.54, 65.17, 111.12, 112.97, 118.49, 139.27, 153.54, 159.88, 160.41, 185.20, 200.17. Anal. Calcd for
C15H17N3O5 (319.31): C, 56.42; H, 5.37; N, 13.16; O, 25.05. Found: C 56.28; H 5.45; N 13.15; O 25.12.
1-(4,7-Diethoxy-6-nitroquinazolin-8-yl)propan-2-one (13). Yield: 0.67 g, 72% as yellow solid. mp 119-
o
121 C. IR (KBr) νmax cm-1: 2836, 1689, 1508, 1378. 1H NMR (400 MHz, CDCl3) δ: 1.18 (t, 3H, J = 7.6
Hz), 1.25 (t, 3H, J = 7.3 Hz), 2.14 (s, 3H), 3.55-3.62 (m, 2H), 3.65-3.78 (m, 2H), 3.83-3.97 (m, 2H), 8.66
13
(s, 1H), 8.91 (s, 1H). C NMR (100 MHz, CDCl3) δ: 14.85, 15.02, 30.59, 42.82, 63.08, 65.75, 111.53,
113.07, 117.49, 140.27, 153.08, 159.81, 160.55, 185.86, 204.14. Anal. Calcd for C15H17N3O5 (319.31): C,
56.42; H, 5.37; N, 13.16; O, 25.05. Found: C 56.21; H 5.52; N 13.25; O 25.02.
Methyl 4-(2-methoxy-2-oxoethoxy)-5-nitro-2-(2-oxoethylamino)benzoate (15). Yield: 0.87 g, 80% as
yellow solid. mp 112-115 oC. IR (KBr) νmax cm-1: 3444, 2865, 1740, 1523. 1H NMR (400 MHz, CDCl3)
δ: 3.71 (s, 3H), 3.86 (s, 3H), 4.22-4.39 (m, 2H), 4.89 (s, 2H), 6.11 (br, 1H), 6.45 (s, 1H), 8.64 (s, 1H),
9.88 (br, 1H). 13C NMR (100 MHz, CDCl3) δ: 51.17, 51.95, 64.05, 65.27, 97.23, 100.04, 123.50, 125.87,

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156.19, 159.21, 165.35, 169.26, 199.80. Anal. Calcd for C13H14N2O8 (326.26): C, 47.86; H, 4.33; N, 8.59;
O, 39.23. Found: C 47.88; H 4.38; N 8.62; O 39.13.
(E)-[(3R, 5S, 6R)-5-Methoxy-4-[(2R,3R)-2-methyl-3-(2-oxoethyl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-
yl] 3-[4-[2-(dimethylamino)ethoxy]phenyl]acrylate (17). Yield: 0.37 g, 51% as yellow oil. mp 145-149
oC. IR (KBr) νmax cm-1: 3429, 2928, 1603, 1512. 1H NMR (CDCl3) δ: 1.06-1.18 (m, 1H), 1.24 (s, 3H),
1.81-2.20 (m, 6H), 2.37 (s, 6H), 2.56 (d, 1H, J = 4.3 Hz), 2.58 (t, 1H, J = 6.4 Hz), 2.79 (t, 2H, J = 5.6 Hz),
3.01 (d, 1H, J = 4.3 Hz), 3.45 (s, 3H), 3.71 (dd, 1H, J = 2.8 Hz), 4.12 (t, 2H, J = 5.6 Hz), 5.73-5.95 (m,
1H), 6.36 (d, 1H, J = 15.9 Hz), 6.91 (d, 2H, J = 8.7 Hz), 7.46 (d, 2H, J = 8.7 Hz), 7.62 (d, 1H, J = 15.9
Hz), 9.72 (br, 1H). 13C NMR (100 MHz, CDCl3) δ: 18.80, 21.08, 29.47, 42.08, 43.51, 45.18, 45.73, 52.07,
54.01, 54.58, 57.55, 58.49, 59.66, 66.22, 77.16, 77.68, 114.02, 114.53, 116.69, 126.80, 127.51, 128.67,
145.50, 156.79, 166.50, 202.11. Anal. Calcd for C26H35NO7 (473.56): C, 65.94; H, 7.45; N, 2.96; O, 23.65.
Found: C 65.55; H 7.62; N 3.04; O 23.79.
2-[(2R,3R)-3-[(3R,5S,6R)-6-Hydroxy-5-methoxy-1-oxaspiro[2.5]octan-4-yl]-3-methyloxiran-2-yl]-
o
acetaldehyde (19). Yield: 0.42 g, 53% as yellow oil. mp 119-121 C. IR (KBr) νmax cm-1: 3424, 2924,
1632, 1170. 1H NMR (CDCl3) δ: 1.03-1.12 (m, 1H), 1.14 (s, 3H), 1.78-2.27 (m, 7H), 2.30-2.37 (m, 1H),
2.40-2.48 (m, 1H), 2.52 (d, 1H, J = 4.4 Hz), 2.70 (dd, 1H, J = 7.1 and 5.9 Hz), 2.86 (d, 1H, J = 4.4 Hz),
4.21-4.38 (m, 1H), 9.66 (s, 1H). 13C NMR (100 MHz, CDCl3) δ:18.84, 24.32, 29.28, 41.85, 43.51, 52.44,
54.26, 55.09, 57.78, 58.81, 72.91, 80.64, 202.13. Anal. Calcd for C13H20O5 (256.29): C, 60.92; H, 7.87; O,
31.21. Found: C 61.25; H 7.81; O 30.94.
o
1-Benzylpiperidine-4-carbaldehyde (21). Yield: 0.66 g, 74% as yellow oil. mp 145-149 C. IR (KBr)
νmax cm-1: 3046, 2865, 1725,. 1H NMR (400 MHz, CDCl3) δ: 1.55-1.65 (m, 2H), 1.88-1.95 (m, 2H), 2.22-
2.33 (m, 4H), 2.38 (m, 1H), 3.66 (s, 2H), 7.10 (m, 2H), 7.22-7.38 (m, 3H), 9.68 (m, 1H). 13C NMR (100
MHz, CDCl3) δ: 26.43, 26.49, 50.06, 51.59, 51.77, 60.05, 126.51, 128.16, 128.98, 129.28, 130.22, 136.27,
202.83. Anal. Calcd for C13H17NO (203.13): C, 76.81; H, 8.43; N, 6.89; O, 7.87. Found: C, 76.97; H,
8.60; N, 6.85; O, 7.58.
2-[3-(1-Benzylpiperidin-4-yl)-2-oxopropyl]-4,5-dimethoxybenzaldehyde (23). Yield: 0.72 g, 41% as
yellow solid. mp 188-191 oC. IR (KBr) νmax cm-1: 3381, 3037, 2870, 1240. 1H NMR (400 MHz, CDCl3) δ:
1.42-1.50 (m, 4H), 1.68-1.72 (m, 1H), 2.22-2.29 (m, 4H), 2.41 (d, 2H, J = 5.1 Hz), 3.62 (s, 2H), 3.74 (s,
13
2H), 3.77 (s, 3H), 3.84 (s, 3H), 7.01 (s, 1H), 7.05-7.12 (m, 3H), 7.24-7.32 (m, 3H), 10.12 (s, 1H). C
NMR (100 MHz, CDCl3) δ: 29.61, 29.99, 31.84, 47.64, 49.75, 51.12, 51.48, 56.15, 56.28, 60.08, 114.02,
115.42, 127.01, 128.11, 128.45, 128.49, 128.87, 129.08, 129.63, 125.51, 148.07, 156.25, 192.47, 206.67.

HETEROCYCLES, Vol. 78, No. 7, 20091845
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Anal. Calcd for C24H29NO4 (395.21): C, 72.89; H, 7.39; N, 3.54; O, 16.18. Found: C, 72.85; H, 7.49; N,
3.64; O, 16.02.
2-[(4S,6S)-2,2-Dimethyl-6-(2-oxoethyl)-1,3-dioxan-4-yl]acetonitrile (25). Yield: 0.65 g, 81% as yellow
oil. mp 148-153 oC. IR (KBr) νmax cm-1: 3042, 1682, 1328. 1H NMR (400 MHz, CDCl3) δ: 1.19 (s, 3H),
1.23 (s, 3H), 1.44-1.50 (m, 1H), 1.78-1.84 (m, 1H), 2.41-2.52 (m, 2H), 2.62-2.69 (m, 2H), 3.80-3.88 (m,
13
1H), 4.02-4.10 (m, 1H), 9.71 (s, 1H). C NMR (100 MHz, CDCl3) δ: 23.04, 26.77, 26.98, 37.66, 50.20,
61.32, 65.77, 95.28, 117.45, 201.23. Anal. Calcd for C10H15NO3 (197.11): C, 60.90; H, 7.67; N, 7.10; O,
24.34. Found: C, 60.80; H, 7.62; N, 7.18; O, 24.41.
(R)-3-(tert-Butyldimethylsilyloxy)-3-((R)-1,4-dioxaspiro[4.5]decan-2-yl)propanal (27). Yield: 0.77 g,
1
73% as yellow oil. IR (KBr) νmax cm-1: 3402, 3003, 1654, 1388. H NMR (400 MHz, CDCl3) δ: 0.06 (s,
6H), 0.90 (s, 9H), 1.42-1.60 (m, 10H), 2.17-2.22 (m, 2H), 3.31-3.42 (m, 1H), 3.62-3.72 (m, 1H), 3.90-
4.08 (m, 2H), 9.76 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 4.52, 5.24, 16.11, 16.25, 18.44, 25.78, 25.99,
26.45, 28.41, 35.47, 36.29, 47.10, 62.25, 65.52, 83.57, 111.36, 201.02. Anal. Calcd for C17H32O4Si
(328.21): C, 62.15; H, 9.82; O, 19.48; Si, 8.55. Found: C, 61.87; H, 9.91; O, 19.99.
ACKNOWLEDGEMENTS
The authors would like to thank for the Research Grant (A08-1022-B91801-08N1-00010A) from
Ministry of Health and Welfare, Korea for financial support.
REFERENCE AND NOTES
1. M. Boolell, M. J. Allen, S. A. Ballard, S. Gepi-Attee, G. J. Muirhead, G. J. A. M. Naylor, I. H.
Osterloh, and J. C. Gingell, Clin. J. Impot. Res., 1996, 8, 47; H. Wilkens, A. Guth, J. Koning, N.
Forestier, B. Gremers, B. Hennen, M. Bohm, and G. W. Sybrecht, Circulation, 2001, 104, 1218.
2. R. Paper, D. S. Alen, R. U. Jr. Lemieux, and W. S. Johnson, J. Org. Chem., 1956, 21, 487.
3. P. K. Grant, L. R. Hanton, G. P. Lynch, W. T. Robinson, and G. Wong, Aust. J. Chem., 1994, 47, 71; B.
B. Lohray, V. Bhushan, and R. K. Kumar, J. Org. Chem., 1994, 59, 1357.
4. There are numerous examples of using the two-step procedure to cleave olefins. The following are
some of the recent applications: C. Francavilla, W. Chen, and F. R. Jr. Kinder, Org. Lett., 2003, 5,
1233; Z. Wang and M. G. Moloney, Tetrahedron Lett., 2002, 43, 9629; R. E. Taylor, Y. Chen, and A.
Beatty, J. Am. Chem. Soc., 2003, 125, 26; W. R. Roush, T. D. Bannister, M. D. Wendt, J. A.
Jablonowski, and K. A. Scheidt, J. Org. Chem., 2002, 67, 4275.
5. W. Yu, Y. Zhang, and Z. Jin, Org. Lett., 2001, 3, 1447.
6. W. Yu, Y. Mei, Y. Kang, Z. Hua, and Z. Jin, Org. Lett., 2004, 6, 3217.

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7. Analytical reversed-phase HPLC was performed on a Hewlett-Packard HPLC series 1100 system
with 254 nm UV detection, using Kromasil C18 (UG 100 Å, 5 ㎛, 4.6 mmØ × 15 cm). A solvent
system consisting of 0.05 M Ammonium formate (at adjusting pH 4.0) in 50% water - 30% in MeOH
and 20% acetonitrile was used. The samples volumes of 10.0 µL were injected. The column oven was
controlled at 35℃. The flow rate was 1.0 mL/min.
8. R. Criegee, B. Marchaud, and H. Wannowlus, Justus Liebigs Ann. Chem., 1942, 550, 99 and their
references therein.
9. M. Schroder, Chem. Rev., 1980, 80, 187 and references therein.
10. We did not try to characterize each side products.
11. W. C. Still, M. Khan, and A. Mitra, J. Org. Chem., 1978, 43, 2923.
12. N,N-Dimethyl cinnamoylfumagillol substrate 16 was prepared as follow: To a stirred suspension of a
N,N-dimethylaminocinnamic acid (386 mg, 1.64 mmol) in toluene was added SOCl2 (390 mg, 3.28
mmol) and the mixture was refluxed for 2 h. Toluene was removed under vacuum evaporation, and
the residue was used without further purification for the next step. To the residue in DMF (10 mL)
was added NaH (236 mg, 3.94 mmol) at ice-water temperature. Fumagillol (185 mg, 0.66 mmol) was
added to the mixture, maintaining at that temperature. After addition, the reaction mixture was
allowed to warm to ambient temperature and stirred 2.5 h. The mixture was quenched with saturated
NH4Cl (20 mL) and washed with EtOAc (25 mL). The organic layer was washed with saturated
NH4Cl (25 mL) five times, and brine (30 mL) in sequence. The separated organic layer was dried
over MgSO4 and concentrated in reduced pressure, giving a residue, which was subjected to column
chromatography (SiO2, EtOAc-n-hexane, 1:1, v/v) to afforded the desired product (256 mg, 78%)
product was used without further purification in the next step. 1H NMR (CDCl3) δ: 1.06-1.18 (m, 1H),
1.24 (s, 3H), 1.66 (s, 3H), 1.75 (s, 3H), 1.81-2.06 (m, 6H), 2.37 (s, 6H), 2.56 (d, 1H, J = 4.3 Hz), 2.58
(t, 1H, J = 6.4 Hz), 2.79 (t, 2H, J = 5.6 Hz), 3.01 (d, 1H, J = 4.3 Hz), 3.45 (s, 3H), 3.71 (dd, 1H, J =
2.8 Hz), 4.12 (t, 2H, J = 5.6 Hz), 5.22 (br, 1H), 5.73-5.79 (m, 1H), 6.36 (d, 1H, J = 15.9 Hz), 6.91 (d,
2H, J = 8.7 Hz), 7.46 (d, 2H, J = 8.7 Hz), 7.62 (d, 1H, J = 15.9 Hz). Fumagillol substrate 18 was
prepared as follow: To fumagillin (120 mg, 0.26 mmol), 0.1 N NaOH (12 mL, 1.2 mmol) was added
and the reaction mixture was stirred at room temperature for 6.5 h. the reaction mixture was diluted
with EtOAc (50 mL) and brine (30 mL), and dried over MgSO4. After filtered, the solvent was
removed by evaporating under reduced pressure. The residue was purified by silica gel column
1
chromatography (eluent: EtOAc-n-hexane, 1:1, v/v) to obtained 51 mg (52%) as colorless oil. H
NMR (CDCl3) δ: 1.03-1.12 (m, 1H), 1.14 (s, 3H), 1.65 (s, 3H), 1.74 (s, 3H), 1.78-2.27 (m, 7H), 2.33-
2.42 (m, 1H), 2.39-2.49 (m, 1H), 2.52 (d, 1H, J = 4.4 Hz), 2.70 (dd, 1H, J = 7.1 and 5.9 Hz), 2.86 (d,
1H, J = 4.4 Hz), 4.27-4.38 (m, 1H), 5.15-5.19 (m, 1H).