The concise synthesis of a key intermediate for the total synthesis of fumagillin, TNP-470, and ovalicin

Article abstract of DOI:10.1055/s-2008-1067030

The facile synthesis of a key intermediate for the total synthesis of the antiangiogenic compound fumagillin, its semisynthetic analogue TNP-470, and ovalicin is described. The methodology employs a Diels-Alder strategy and a zinc-mediated ring-opening reaction to realize the cyclohexane backbone. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067030

1460
PAPER
The Concise Synthesis of a Key Intermediate for the Total Synthesis of
Fumagillin, TNP-470, and Ovalicin
S
ynthesis
h
of
a
K
ey Inte
i
rmedia
l
te for
t
l
he Tota
u
l
S
ynthesis of Fum
S
agillin,
T
N
P-4
.
70, and
OvaY
licin adav,*a Pamu Sreedhar,a Pabbaraja Srihari,a Ganti Dattatreya Sarma,b Bharatam Jagadeeshb
a
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
b
Centre for Nuclear Magnetic Resonance, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 27 December 2007; revised 21 January 2008
mal total synthesis of ovalicin, an angiogenesis
inhibitor.14 Because of the vast research oriented toward
the biological properties of fumagillin for its enhanced ac-
tivities, we became interested in the total synthesis of
fumagillin. The three compounds fumagillin (1), TNP-
470 (2), and ovalicin (3) have a similar carbocyclic back-
bone (Scheme 1). Therefore, we targeted a key intermedi-
ate that could be used further for the total synthesis of
these three molecules; herein, we describe the synthesis of
this potential key intermediate. The retrosynthetic analy-
sis of fumagillin (1), TNP-470 (2), and ovalicin (3) is
shown Scheme 1. We envisaged that the target molecules
could be easily synthesized from the key intermediate 4,
which in turn could be formed from the bicyclic com-
pound 6 using a zinc-mediated ring-opening reaction and
further manipulations. Compound 6 could be easily ob-
tained via a Diels–Alder reaction of protected furfuryl al-
cohol 7 with methyl bromopropiolate (8).
Abstract: The facile synthesis of a key intermediate for the total
synthesis of the antiangiogenic compound fumagillin, its semisyn-
thetic analogue TNP-470, and ovalicin is described. The methodol-
ogy employs a Diels–Alder strategy and a zinc-mediated ring-
opening reaction to realize the cyclohexane backbone.
Key words: angiogenesis inhibitors, Diels–Alder reaction, syn re-
duction, dihydroxylation, HIV
Abnormal angiogenesis has been recognized as the most
prevalent feature of many proliferative diseases, including
diabetic retinopathy, psoriasis, and rheumatoid arthritis.1
Because tumor metastasis is highly dependent upon an-
giogenesis, the inhibition of angiogenesis has become in-
creasingly important as an alternative promising method
for cancer therapy.2 Toward this goal, large efforts have
been made to develop specific antiangiogenic drugs,
which starve and thus reduce the tumor cells by eliminat-
ing their blood supplies, and these investigations have re-
sulted in the discovery of various antiangiogenic
compounds, such as fumagillin,3 RK-805,4 endostatin,5
angiostatin,6 ovalicin,7 and the synthetic analogue TNP-
470.8 Thus, these compounds and the synthesis of their
more potent and stable derivatives have become challeng-
ing targets for chemists. Initially, fumagillin was found to
be an effective antibiotic and antiparasitic agent, as well
as a potential drug for the treatment of malaria and leish-
maniasis;9 later, it was used for the treatment of intestinal
microsporidiosis in HIV-infected patients.10 More recent-
ly, fumagillin has been found to reverse the growth inhib-
itory activity of Vpr in yeast and human cells, and to
inhibit the HIV-1 infection of human macrophages.11 This
significant property may make it a lead compound for the
development of AIDS therapeutic drugs that target Vpr
activity. The profound activity of fumagillin has attracted
chemists and culminated in several synthetic approaches
to give the compound and its analogues, from Corey and
Snider’s first elegant total synthesis12 to various other for-
mal and total syntheses of both the racemic and enantio-
meric forms.13
We started with readily available furfuryl alcohol, which
was protected as the 4-methoxybenzyl (PMB) ether 7 us-
ing 4-methoxybenzyl bromide and sodium hydride. Com-
mercially available methyl propiolate was brominated
using the known protocol15 to give dienophile 8. The
Diels–Alder reaction of diene 7 and dienophile 8 provided
adduct 9 in 57% yield with the required regiospecificity
(Scheme 2).16 To realize the hydroxy group at C-2, bro-
mide 9 was converted into dimethoxy ketal 10 on reaction
with sodium methoxide in methanol.17 Treatment of the
unsaturated bicyclic compound 10 with hydrogen and pal-
ladium on carbon resulted in one-pot hydrogenation and
also PMB deprotection to give the primary alcohol 6.18
Alcohol 6 was then converted into iodo compound 11 us-
ing iodine, triphenylphosphine, and 1H-imidazole, and
product 11 was further subjected to a zinc-mediated ring-
opening reaction,19 by applying the known protocol, to
give olefinic alcohol 12 (Scheme 2).
To reduce the number of steps involved, the dimethoxy
ketal deprotection was attempted at this stage; the reaction
resulted in the aromatization of compound 12. To over-
come this problem, olefin 12 was converted into diol 13
and then was protected as acetonide 14. However, com-
pound 14 was not stable under any of the reaction condi-
tions employed for either the protection of the C-3 alcohol
or the deprotection of the dimethoxy ketal,20 and the start-
ing material always decomposed (Scheme 3).
In continuation of our research on the synthesis of biolog-
ically active compounds, we recently accomplished a for-
SYNTHESIS 2008, No. 9, pp 1460–1466
x
x
.
x
x
.2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1067030; Art ID: Z29807SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of a Key Intermediate for the Total Synthesis of Fumagillin, TNP-470, and Ovalicin
1461
R
O
OMe
O
O
Me
O
OH
R =
O
1
Fumagillin
O
OH
O
OMe
OMe
O
O
OMe
Cl
O
OMe
OH
OH
R =
N
H
O
O
COOMe
2
TNP- 470
O
OH
5
4
6
OMe
OH
+
Br
COOMe
OPMB
O
O
O
Me
8
7
3
Ovalicin
Scheme 1 Retrosynthesis of fumagillin, TNP-470, and ovalicin
OMe
OMe
Br
8
Br
COOMe
benzene, reflux,
H2, Pd/C
NaOMe, MeOH
30 min, 78%
O
O
O
COOMe
COOMe
MeOH, 12 h, 93%
OPMB
48 h, 57%
PMBO
PMBO
10
9
7
OH
OMe
OMe
OMe
OMe
OMe
Zn, EtOH
reflux, 6 h, 87%
I2, Ph3P, 1H-imidazole
toluene, reflux, 2 h, 93%
OMe
O
O
COOMe
11
COOMe
COOMe
I
HO
12
6
Scheme 2
OH
OH
OH
OMe
OMe
COOMe
OMe
OMe
OMe
OMe
OsO4, NMO
CSA, acetone
decomposition
acetone–H2O
24 h, 65%
r.t., 30 min, 65%
COOMe
COOMe
OH
O
O
OH
14
12
13
Scheme 3
Next, the ester functionality in compound 12 was reduced epoxide product was not stable to any of the reaction con-
to alcohol 5 using DIBAL-H at low temperature ditions applied for proceeding further with either the pro-
(Scheme 4). Because all three target molecules, i.e. fum- tection of the alcohol or the deprotection of the dimethoxy
agillin (1), TNP-470 (2), and ovalicin (3), have an epoxide ketal (Scheme 5).20 Hence, we returned to using dihydrox-
moiety at C-6, we decided to perform an epoxidation on ylation as a method for forming a product that could be
the olefin moiety of 5. Thus, olefin 5 was converted into converted into the desired epoxide at a later stage. Thus,
the corresponding epoxide using 2-chloroperoxybenzoic dihydroxylation of compound 5 yielded tetrol 15, which
acid at 0 °C in 80% yield.21 Although the epoxidation was was subjected to isopropylidene protection with acetone
successful, further manipulations were not possible as the in the presence of 10-camphorsulfonic acid (Scheme 4).
Synthesis 2008, No. 9, 1460–1466 © Thieme Stuttgart · New York

1462
J. S. Yadav et al.
PAPER
OH
OH
OH
OH
OH
OMe
OMe
OMe
OH
OMe
OMe
OH
O
OsO4, NMO
DIBAL-H
OMe
CSA, acetone
r.t., 3 h, 65%
CH2Cl2, –78 °C
70%
COOMe
acetone–H2O (8:2)
24 h, 70%
OH
O
O
OH
12
16
5
15
OH
OH
O
OH
O
O
Et3B, NaBH4
THF, r.t., 3 h, 84%
TBSCl, 1H-imidazole
CH2Cl2, 2 h, 73%
CSA, acetone
OTBS
OTBS
2,2-DMP, r.t.,
30 min, 67%
OTBS
O
O
O
O
O
O
17
18
19
O
TBAF, THF
30 min, 88%
O
OH
O
O
4
Scheme 4
OH
OH
OMe
OMe
OMe
OH
MCPBA
OMe
OH
alcohol protection
ketal deprotection
X
CH2Cl2, 0 °C
80%
O
5
Scheme 5
16
Interestingly, during this reaction simultaneous
dimethoxy ketal deprotection occurred to give the keto
compound 16. The primary hydroxy group was then pro-
tected as the tert-butyldimethylsilyl (TBS) ether to give
17 using tert-butyldimethylsilyl chloride in the presence
of 1H-imidazole.
15
CH3
CH3
O
H
H
2
4
OH
O
1
H
10
C3
The selective syn reduction of a-hydroxy ketone 17 was
successfully achieved with sodium borohydride in the
presence of triethylborane to give the required diastere-
omer 18 exclusively.22 This compound was further treated
with 2,2-dimethoxypropane (2,2-DMP) to yield the ace-
tonide-protected product 19 (Scheme 5). Thus, the re-
quired geometry at C-2 was realized in a practical manner.
H
C1
6
H
C2
H
11
3
C5
H
7
C4
H
C6
O
H
5
H
9
12
H
8
O
To confirm the exact stereochemistry at all of the stereo-
centers of the product, we tried to simplify its structure by
removing the TBS protecting group which was also essen-
tial for further proceedings. Thus, deprotection of com-
pound 19 with tetrabutylammonium fluoride afforded the
key intermediate 4 in 88% yield (Scheme 5). At this stage,
14
CH3
CH3
13
Figure 1 Structure of compound 4 showing the observed NOE
interactions
1
the compound was fully characterized by H and 13C
formation. The nuclear Overhauser effect (NOE) cross
peaks between H-4–H-10, H-11–H-4, H-2–H-4, H-12–H-
9, and H-6–H-9 confirmed this molecular conformation
(Figure 1). The acetonide moiety makes the C-2–C-3 sin-
NMR spectroscopy and mass spectrometry. Further de-
tailed spectral studies of this molecule (i.e., 1D proton de-
coupling experiments, gDQCOSY, TOCSY, NOESY,
and gHSQC) revealed that it adopts a deformed chair con-
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Synthesis of a Key Intermediate for the Total Synthesis of Fumagillin, TNP-470, and Ovalicin
1463
13C NMR (200 MHz, CDCl3): d = 51.5, 55.1, 66.2, 73.2, 84.1, 88.4,
gle bond rigid, resulting in the H-5 (3.98) and H-8 (2.21)
protons having a distance greater than 5 angstroms, which
96.8, 113.6, 129.4, 129.7, 142.5, 143.4, 148.9, 159.1, 163.2.
could be the reason for not observing the NOE between H- LCMS: m/z = 403 (M+ + 23).
5–H-8.
HRMS: m/z calcd C17H17O5BrNa: 403.0157; found: 403.0167.
In conclusion, we have described a concise synthetic route
for the synthesis of the potential key intermediate 4, which
can be used further for the synthesis of various biological-
ly active compounds, such as fumagillin (1), TNP-470 (2),
and ovalicin (3). Moreover, the free primary alcohol
present in this intermediate allows for extensive deriva-
tions of the side chain to give more-potent molecules. Fur-
ther studies toward the total synthesis of fumagillin (1)
and its derivatives using this key intermediate are current-
ly being investigated.
Methyl 3,3-Dimethoxy-1-[(4-methoxybenzyl)oxymethyl]-
7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylate (10)
To Diels–Alder adduct 9 (380 mg, 1.0 mmol) in MeOH (10 mL)
was added dropwise 1 M NaOMe (10 mL). During the addition, the
temperature was kept below 20 °C. After completion of the reaction
(30 min), the solvent was removed in vacuo and the residue was di-
rectly purified by column chromatography (EtOAc–hexane, 1:4) to
give product 10 as a yellow liquid. Yield: 283 mg (78%).
IR (neat): 2925, 1735, 1611, 1512, 1245, 1174, 1069, 1029, 986
cm–1.
1H NMR (200 MHz, CDCl3): d = 3.20 (s, 3 H), 3.21 (s, 1 H), 3.41
(s, 3 H), 3.62 (s, 3 H), 3.80 (s, 5 H), 4.51 (ABq, J = 6.4, 12.9 Hz, 2
H), 4.70 (s, 1 H), 6.38 (dd, J = 3.8, 5.1 Hz, 1 H), 6.62 (d, J = 5.1 Hz,
1 H), 6.80 (d, J = 9.0 Hz, 2 H), 7.20 (d, J = 9.0 Hz, 2 H).
All solvents were dried and distilled prior to use. Melting points
were measured on a Buchi R-535 apparatus and are uncorrected.
Column chromatography was performed using silica gel 60–120
mesh. Infrared spectra were recorded on a Perkin-Elmer IR spectro-
13C NMR (200 MHz, CDCl3): d = 29.6, 50.9, 51.85, 51.81, 53.8,
55.2, 67.7, 73.1, 78.3, 84.5, 90.7, 113.7, 129.3, 131.8, 135.0, 138.3.
1
photometer. H and 13C NMR spectra were recorded on Varian
LCMS: m/z = 387 (M+ + 23).
Gemini 200, Bruker Avance 300, or Varian Unity 400 MHz instru-
ments using TMS as an internal standard. Mass spectra were record-
ed on a Micromass VG 7070H mass spectrometer for EI MS, a VG
Autospec mass spectrometer for FAB MS, and a Micromass Quatro
LC triple quadrupole mass spectrometer for ESI MS analysis.
HRMS data were obtained on an AB Systems QSTAR plus mass
spectrometer following ESI-QTOF high-resolution technique.
HRMS: m/z calcd C19H24O7Na: 387.1419; found: 387.1414.
Methyl 1-(Hydroxymethyl)-3,3-dimethoxy-7-oxabicy-
clo[2.2.1]heptane-2-carboxylate (6)
To dimethoxy compound 10 (148 mg, 0.6 mmol) in MeOH (5 mL)
was added 10% Pd/C (10 mg). The mixture was kept under H2 at 1
atm for 12 h. After completion of the reaction, the mixture was fil-
tered through a small pad of Celite, washed with MeOH (5 mL), and
the solvent was evaporated in vacuo. The residue was purified by
column chromatography (EtOAc–hexane, 2:3) to give product 6 as
a white solid. Yield: 239 mg (93%); mp 79–81 °C.
2-[(4-Methoxybenzyl)oxymethyl]furan (7)
To a mixture of NaH (57.6 mg, 2.4 mmol) in Et2O (2 mL) under a
N2 atmosphere was added dropwise furfuryl alcohol (98.0 mg, 1.0
mmol) in dry Et2O (3 mL) at 0 °C, and the mixture was stirred for
30 min. To this stirred solution, PMBBr (201 mg, 1.0 mmol) in dry
Et2O (3 mL) was added dropwise, and the resulting mixture was
stirred for a further 6 h. After completion of the reaction, the excess
NaH was quenched with ice flakes, and the resulting ethereal layer
was washed with brine solution (3 × 10 mL), dried (Na2SO4), fil-
tered, and concentrated. The crude product was purified by column
chromatography (EtOAc–hexane, 5:95) to give product 7 as a yel-
low liquid. Yield: 230 mg (98%).
IR (KBr): 3448, 2952, 1734, 1440, 1314, 1203, 1147, 1073, 1039,
761 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.33–1.48 (m, 1 H), 1.63–1.81 (m,
1 H), 1.86–1.90 (m, 1 H), 2.60–2.73 (m, 1 H), 3.17 (s, 1 H), 3.18 (s,
3 H), 3.33 (s, 3 H), 3.68 (s, 3 H), 3.75 (d, J = 2.9 Hz, 2 H), 4.35 (d,
J = 5.0 Hz, 1 H).
13C NMR (200 MHz, CDCl3): d = 24.3, 25.6, 49.1, 50.9, 51.5, 53.3,
63.3, 83.2, 89.6, 109.2, 169.1.
LCMS: m/z = 269 (M+ + 23).
IR (neat): 1611, 1513, 1248, 1070, 1033, 818, 743 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.80 (s, 3 H), 4.46 (s, 2 H), 4.49
(s, 2 H), 6.30–6.39 (m, 2 H), 6.90 (d, J = 8.0 Hz, 2 H), 7.30 (d, J =
8.7 Hz, 2 H), 7.42 (d, J = 2.0 Hz, 1 H).
HRMS: m/z calcd C11H18O6Na: 269.1001; found: 269.1002.
13C NMR (200 MHz, CDCl3): d = 55.2, 63.5, 109.2, 110.2, 113.8,
Methyl 1-(Iodomethyl)-3,3-dimethoxy-7-oxabicyclo[2.2.1]hep-
tane-2-carboxylate (11)
129.5, 130.0, 142.7, 151.9, 159.3.
LCMS: m/z = 241 (M+ + 23).
To a solution of hydroxy compound 6 (246 mg, 1.0 mmol) in dry
toluene (15 mL) was added Ph3P (393 mg, 1.5 mmol), 1H-imidazole
(238 mg, 3.5 mmol), and I2 (379.5 mg, 1.5 mmol). The mixture was
refluxed for 2 h, after which the solvent was removed in vacuo. The
residue was purified by column chromatography (EtOAc–hexane,
1:4) to give product 11 as a yellow-white solid. Yield: 331 mg
(93%); mp 87–89 °C.
HRMS: m/z calcd for C13H14O3Na: 241.0840; found: 241.0835.
Methyl 3-Bromo-1-[(4-methoxybenzyl)oxymethyl]-7-oxabicy-
clo[2.2.1]hepta-2,5-diene-2-carboxylate (9)
Methyl bromopropiolate (8) (164 mg, 1.0 mmol) and PMB-protect-
ed furfuryl alcohol 7 (218 mg, 1 mmol) were added to benzene (10
mL), and the mixture was refluxed for 48 h. The solvent was re-
moved in vacuo and the residue was subjected to column chroma-
tography (EtOAc–hexane, 1:9) to give product 9 as a viscous liquid.
Yield: 216 mg (57%).
IR (KBr): 2950, 1732, 1438, 1350, 1319, 1199, 1139, 1066, 1028,
946 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.54–1.89 (m, 2 H), 1.95–2.08 (m,
1 H), 2.79–2.92 (m, 1 H), 3.05 (s, 1 H), 3.20 (s, 2 H), 3.34 (s, 3 H),
3.50 (s, 3 H), 3.71 (s, 3 H), 4.38 (d, J = 5.1 Hz, 1 H).
IR (neat): 2952, 1712, 1610, 1513, 1248, 1111, 1033, 824 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.75 (s, 3 H), 3.80 (s, 3 H), 4.20
(ABq, J = 11.7, 20.4 Hz, 2 H), 4.52 (s, 2 H), 5.29 (s, 1 H), 6.85 (d,
J = 8.7 Hz, 2 H), 7.01 (d, J = 5.1 Hz, 1 H), 7.10–7.28 (m, 3 H).
13C NMR (200 MHz, CDCl3): d = 8.2, 25.5, 28.3, 49.1, 50.8, 51.7,
57.8, 83.1, 86.0, 109.6, 168.6.
LCMS: m/z = 379 (M+ + 23).
Synthesis 2008, No. 9, 1460–1466 © Thieme Stuttgart · New York

1464
J. S. Yadav et al.
PAPER
HRMS: m/z calcd C11H17O5INa: 379.0018; found: 379.0022.
× 10 mL) and brine (3 × 10 mL), and dried (Na2SO4). Evaporation
of the solvent followed by purification by column chromatography
(EtOAc–hexane, 1:1) yielded product 16 as a colorless liquid.
Yield: 149 mg (65%).
Methyl 3-Hydroxy-2,2-dimethoxy-6-methylenecyclohexanecar-
boxylate (12)
To a solution of iodo compound 11 (357 mg, 1 mmol) in EtOH (10
mL) was added Zn (2.6 g, 40 mmol), and the mixture was refluxed
for 6 h. After completion of the reaction, the mixture was filtered
through a small pad of Celite, washed with EtOH (35 mL), and all
the solvent was evaporated. The residue was directly used for col-
umn chromatography (EtOAc–hexane, 3:7) to give product 12 as a
white solid. Yield: 200 mg (87%); mp 83–85 °C.
IR (neat): 3519, 2946, 1714, 1119, 1048, 927, 754 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.34 (s, 3 H), 1.38 (s, 3 H), 1.86–
2.08 (m, 4 H), 2.18–2.25 (m, 1 H), 2.80–2.92 (m, 1 H), 3.49 (br s, 1
H), 3.80 (d, J = 6.7 Hz, 2 H), 3.90 (d, J = 9.0 Hz, 1 H), 4.06 (d, J =
6.7 Hz, 1 H), 4.17–4.25 (m, 1 H).
13C NMR (200 MHz, CDCl3): d = 26.4, 27.5, 29.9, 30.2, 60.9, 61.6,
71.3, 73.1, 84.5, 109.8, 210.7.
IR (KBr): 3405, 2933, 1719, 1375, 1254, 1214, 1046, 860 cm–1.
LCMS: m/z = 253 (M+ + 23).
1H NMR (200 MHz, CDCl3): d = 1.39–1.60 (m, 1 H), 1.80–2.01 (m,
1 H), 2.12–2.27 (m, 1 H), 2.50–2.70 (m, 1 H), 3.30 (s, 3 H), 3.34 (s,
3 H), 3.64 (s, 1 H), 3.66 (s, 3 H), 4.39 (dd, J = 5.2, 11.7 Hz, 1 H),
4.84 (d, J = 10.4 Hz, 2 H).
13C NMR (200 MHz, CDCl3): d = 29.3, 31.0, 49.4, 50.7, 51.8, 56.1,
71.7, 96.3, 114.0, 142.1, 170.3.
HRMS: m/z calcd C11H18O5Na: 253.1051; found: 253.1060.
6-[(tert-Butyldimethylsiloxy)methyl]-8-hydroxy-2,2-dimethyl-
1,3-dioxaspiro[4.5]decan-7-one (17)
To a solution of compound 16 (230 mg, 1.0 mmol) in CH2Cl2 (3
mL) was added 1H-imidazole (102 mg, 1.5 mmol) at 0 °C, and the
mixture was stirred for 10 min. Then, TBSCl (180 mg, 1.1 mmol)
was added and the mixture was stirred for a further 2 h. The mixture
was then diluted with CH2Cl2 (5 mL), washed with H2O (3 × 10
mL), and dried (Na2SO4). Evaporation of the solvent and purifica-
tion of the residue by column chromatography (EtOAc–hexane,
1:9) gave product 17 as a light-yellow liquid. Yield: 251 mg (73%).
LCMS: m/z = 253 (M+ + 23).
HRMS: m/z calcd C11H18O5Na: 253.1051; found: 253.1059.
3-(Hydroxymethyl)-2,2-dimethoxy-4-methylenecyclohexanol
(5)
A solution of 20 wt% DIBAL-H in toluene (1.5 mL, 2.2 mmol) was
added dropwise at –78 °C through a syringe to ester 12 (231 mg, 1.0
mmol) dissolved in dry CH2Cl2 (5 mL). After completion of the re-
action, the excess reagent was quenched with sat. aq sodium potas-
sium tartrate. The resulting CH2Cl2 layer was washed with brine (3
× 10 mL) and dried (Na2SO4), and all the solvent was removed un-
der reduced pressure. The residue was purified by column chroma-
tography (EtOAc–hexane, 1:1) to give product 5 as a colorless
liquid. Yield: 141 mg (70%).
IR (neat): 3429, 2929, 1720, 1254, 1215, 1103, 839, 762 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.06 (s, 6 H), 0.88 (s, 9 H), 1.32
(s, 3 H), 1.37 (s, 1 H), 1.83–2.08 (m, 3 H), 2.17–2.27 (m, 1 H), 2.78
(dt, J = 2.3, 6.0 Hz, 1 H), 3.51 (d, J = 3.0 Hz, 1 H), 3.75 (dd, J = 1.5,
6.0 Hz, 2 H), 3.77 (d, J = 9.0 Hz, 2 H), 3.87 (d, J = 9.0 Hz, 1 H),
4.08–4.19 (m, 1 H).
13C NMR (200 MHz, CDCl3): d = –5.23, –5.16, 18.5, 26.2, 26.9,
28.1, 30.1, 30.8, 61.5, 62.00, 71.8, 74.0, 84.9, 96.5, 109.8, 209.6.
IR (neat): 3427, 2943, 1650, 1449, 1130, 1054, 869, 753 cm–1.
LCMS: m/z = 367 (M+ + 23).
1H NMR (200 MHz, CDCl3): d = 1.50–1.64 (m, 1 H), 1.86–1.96 (m,
1 H), 2.02–2.21 (m, 2 H), 2.79–2.87 (m, 1 H), 3.32 (s, 3 H), 3.40–
3.48 (m, 4 H), 3.72–3.89 (m, 2 H), 4.84 (d, J = 11.0 Hz, 2 H).
HRMS: m/z calcd C17H32O5SiNa: 367.1916; found: 367.1934.
13C NMR (200 MHz, CDCl3): d = 29.8, 31.4, 49.0, 50.3, 52.0, 61.4,
72.3, 112.4, 144.9.
6-[(tert-Butyldimethylsiloxy)methyl]-2,2-dimethyl-1,3-dioxa-
spiro[4.5]decane-7,8-diol (18)
Into a solution of 1 M Et3B in THF (5 mL, 1.1 mmol) and compound
17 (344 mg, 1.0 mmol) was bubbled a small amount of air (3 mL),
and the solution was stirred for 3 h at r.t. under an Ar atmosphere.
Then, the solution was cooled to –100 °C and solid NaBH4 (37 mg,
1.1 mmol) was added in one portion. The mixture was stirred for 6
h at r.t. and then quenched with a mixture of 30% H2O2 (5 mL), pH
7 buffer (10 mL), and MeOH (15 mL). The organic solvents were
evaporated under reduced pressure and the residual aqueous solu-
tion was extracted with CH2Cl2 (2 × 25 mL). The organic extract
was dried (Na2SO4) and evaporated in vacuo to afford the crude
product, which was purified by column chromatography (EtOAc–
hexane, 2:8) to give product 18 as a colorless liquid. Yield: 290 mg
(84%).
LCMS: m/z = 225 (M+ + 23).
HRMS: m/z calcd C10H18O4Na: 225.1102; found: 225.1111.
1,2-Bis(hydroxymethyl)-3,3-dimethoxycyclohexane-1,4-diol
(15)
To compound 5 (193 mg, 1.0 mmol) in acetone–H2O (4:1, 5 mL)
were added NMO (292 mg, 2.5 mmol) and OsO4 (0.1 mL, 0.2
mmol), and the mixture was stirred for 24 h. After completion of the
reaction, the mixture was concentrated under reduced pressure and
the residue was passed through a small pad of silica gel to give the
crude product 15 as a white oil. Yield: 149 mg (70%).
IR (neat): 3413, 2950, 1734, 1440, 1136, 1066, 1030, 762 cm–1.
LCMS: m/z = 259 (M+ + 23).
IR (neat): 3448, 2924, 1462, 772 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.10 (s, 6 H), 0.90 (s, 9 H), 1.37
(s, 3 H), 1.38 (s, 3 H), 1.48–1.62 (m, 1 H), 1.81–2.07 (m, 3 H), 2.14–
2.26 (dt, J = 4.6, 8.2 Hz, 1 H), 2.56 (br s, 1 H), 3.61–3.82 (m, 4 H),
3.87 (d, J = 8.9 Hz, 1 H), 3.93–4.06 (m, 1 H), 4.48 (br s, 1 H).
13C NMR (200 MHz, CDCl3): d = –5.35, 18.3, 22.9, 26.0, 26.3, 27.3,
29.5, 29.9, 31.2, 31.6, 67.7, 70.2, 73.5, 82.4, 108.8.
HRMS calculated for C10H20O6Na: calcd 259.1157; found
259.1147.
8-Hydroxy-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxa-
spiro[4.5]decan-7-one (16)
The crude tetrol 15 (236 mg, 1 mmol) obtained from the above re-
action was taken up in acetone (3 mL), and CSA (cat.) was added at
0 °C. The mixture was stirred for 3 h at r.t., then solid NaHCO3 (84
mg, 1 mmol) was added, and all the solvent was removed in vacuo.
The mixture was diluted with CH2Cl2 (5 mL), washed with H2O (3
LCMS: m/z = 369 (M+ + 23).
HRMS: m/z calcd C17H34O5SiNa: 369.2073; found: 369.2076.
Synthesis 2008, No. 9, 1460–1466 © Thieme Stuttgart · New York

PAPER
Synthesis of a Key Intermediate for the Total Synthesis of Fumagillin, TNP-470, and Ovalicin
1465
4-[(tert-Butyldimethylsiloxy)methyl]-2,2-dimethylhexahydro-
benzo-1,3-dioxole-5-spiro-4¢-(2,2-dimethyl-1,3-dioxolane) (19)
To a solution of compound 18 (346 mg, 1 mmol) in acetone (1 mL)
was added 2,2-DMP and CSA at 0 °C, and the mixture was stirred
at r.t. for 30 min. After completion of the reaction, solid NaHCO3
(84 mg, 1 mmol) was added and the mixture was stirred for a further
10 min. After all the acetone was removed, the mixture was diluted
with CH2Cl2 (7 mL), washed with H2O (3 × 10 mL) and brine (3 ×
10 mL), and dried (Na2SO4). The crude product 19 was obtained as
a yellow liquid and was used as such for further reaction. Yield: 258
mg (67%).
1H NMR (200 MHz, CDCl3): d = 0.06 (s, 6 H), 0.90 (s, 9 H), 1.31
(s, 3 H), 1.36 (s, 3 H), 1.39 (s, 3 H), 1.42 (s, 3 H), 1.52–1.79 (m, 4
H), 2.08–2.20 (m, 1 H), 3.59 (d, J = 8.0 Hz, 1 H), 3.76 (dd, J = 3.6,
10.2 Hz, 1 H), 4.03–4.17 (m, 3 H), 4.30 (d, J = 8.8 Hz, 1 H).
13C NMR (200 MHz, CDCl3): d = –5.46, –5.39, 18.4, 24.0, 26.1,
26.2, 26.7, 27.8, 28.7, 29.9, 32.5, 47.7, 57.8, 67.5, 72.5, 74.1, 82.8,
107.9, 108.3.
(4) (a) Asami, Y.; Kakeya, H.; Onose, R.; Chang, Y.-H.; Toi,
M.; Osada, H. Tetrahedron 2004, 60, 7085. (b) Yamaguchi,
J.; Toyoshima, M.; Shoji, M.; Kakeya, H.; Osada, H.;
Hayashi, Y. Angew. Chem. Int. Ed. 2006, 45, 789.
(5) (a) O’Reilly, M. S.; Boehm, T.; Shing, Y.; Fukai, N.; Vasios,
G.; Lane, W. S.; Flynn, E.; Birkhead, J. R.; Olsen, B. R.;
Folkman, J. Cell 1997, 88, 277. (b) Oh, S. P.; Warman, M.
L.; Seldin, M. F.; Cheng, S. D.; Knoll, J. H. M.; Timmons,
S.; Olsen, B. R. Genomics 1994, 19, 494.
(6) (a) O’Reilly, M. S.; Holmgren, L.; Shing, Y.; Chen, C.;
Rosenthal, R. A.; Moses, M.; Lane, W. S.; Cao, Y.; Sage, E.
H.; Folkman, J. Cell 1994, 79, 315. (b) Gately, S.;
Twardowski, P.; Stack, M. S.; Patrick, M.; Boggio, L.;
Cundiff, D. L.; Schnaper, H. W.; Madison, L.; Volpert, O.;
Bouck, N.; Enghild, J.; Kwaan, H. C.; Soff, G. A. Cancer
Res. 1996, 56, 4887.
(7) (a) Sigg, H. P.; Weber, H. P. Helv. Chim. Acta 1968, 51,
1395. (b) Sassa, T.; Kaise, H.; Munata, K. Agric. Biol.
Chem. 1970, 34, 649. (c) Corey, E. J.; Dittami, J. P. J. Am.
Chem. Soc. 1985, 107, 256. (d) Tiefenbacher, K.; Arion, V.
B.; Mulzer, J. Angew. Chem. Int. Ed. 2007, 46, 1.
LCMS: m/z = 409 (M+ + 23).
(8) (a) Ingber, D.; Fujita, T.; Kishimoto, S.; Sudo, K.;
Kanamaru, T.; Brem, H.; Folkman, J. Nature 1990, 348,
555. (b) Figg, W. D.; Kruger, E. A. Expert Opin. Invest.
Drugs 2000, 9, 1383. (c) Kwon, J.; Jeong, H.; Kang, K.;
Hang, Y.; Bae, K.; Choi, J.; Lee, U.; Son, K.; Kown, B.
J. Antibiot. 2000, 53, 799.
(9) (a) See also ref. 3b. (b) See also ref. 3a. (c) Zhang, P.;
Nicholson, D. E.; Bujnicki, J. M.; Su, X.; Brendle, J. J.;
Ferdig, M.; Kyle, D. E.; Milhous, W. K.; Chiang, P. K.
J. Biomed. Sci. 2002, 9, 34.
4-(Hydroxymethyl)-2,2-dimethylhexahydrobenzo-1,3-dioxole-
5-spiro-4¢-(2,2-dimethyl-1,3-dioxolane) (4)
To a solution of compound 19 (386 mg, 1.0 mmol) in THF (1 mL)
was added 1 M TBAF in THF (1.2 mL, 1.2 mmol), and the mixture
was stirred for 30 min. After completion of the reaction, all the THF
was removed, and the mixture was diluted with CH2Cl2 (7 mL),
washed with H2O (3 × 10 mL) and brine (3 × 10 mL), and dried
(Na2SO4). The crude product was purified by column chromatogra-
phy (EtOAc–hexane, 3:7) to give product 4 as a colorless liquid.
Yield: 239 mg (88%).
(10) (a) Molina, J. M.; Derouin, F. PCT Int. Appl. WO 9630010,
1996; Chem. Abstr. 1996, 125, 309073. (b) Coyle, C.; Kent,
M.; Tanowitz, H. B.; Wittner, M.; Weiss, L. M. J. Infect. Dis.
1998, 177, 515. (c) Molina, J. M.; Goguel, J.; Sarfati, C.;
Michiels, J.-F.; Desportes-Livage, I.; Balkan, S.; Chastang,
C.; Cotte, L.; Maslo, C.; Struxiano, A.; Derouin, F.; Decazes,
J.-M. AIDS 2000, 14, 1341.
(11) Watanabe, N.; Nishihara, Y.; Yamaguchi, T.; Koito, A.;
Miyoshi, H.; Kakeya, H.; Osada, H. FEBS Lett. 2006, 580,
2598.
IR (neat): 3446, 2925, 1214, 760 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.32 (s, 3 H), 1.39 (s, 3 H), 1.45
(s, 3 H), 1.49 (s, 3 H), 1.59–1.66 (m, 2 H), 1.86 (td, J = 4.6, 10.5 Hz,
1 H), 1.93–2.00 (m, 1 H), 2.17–2.23 (m, 1 H), 3.55 (br s, 1 H), 3.66
(d, J = 8.9 Hz, 1 H), 3.86 (dd, J = 4.6, 11.7 Hz, 1 H), 3.93 (dd, J =
4.6, 11.7 Hz, 1 H), 3.97 (dd, J = 4.6, 10.5 Hz, 1 H), 3.99 (d, J = 8.9
Hz, 1 H), 4.15 (dt, J = 4.6, 1.1 Hz, 1 H).
13C NMR (200 MHz, CDCl3): d = 26.4, 26.6, 26.8, 28.7, 29.6, 54.1,
60.3, 67.7, 69.6, 72.3, 76.5, 82.9, 108.8, 108.9.
(12) Corey, E. J.; Snider, B. B. J. Am. Chem. Soc. 1972, 94, 2549.
(13) For the total synthesis of fumagillin and the synthesis of its
key intermediate fragments and some other analogues, see:
(a) Camara, F.; Angarita, J.; Mootoo, D. R. J. Org. Chem.
2005, 70, 6870. (b) Ciampini, M.; Perlmutter, P.; Watson,
K. Tetrahedron: Asymmetry 2007, 18, 243. (c) Bedel, O.;
Haudrechy, A.; Pouilhes, A.; Langlois, Y. Pure Appl. Chem.
2005, 77, 1139. (d) Manitschek, R.; Huwe, A.; Giannis, A.
Org. Biomol. Chem. 2005, 3, 2150. (e) Vosburg, D. A.;
Weiler, S.; Sorensen, E. Chirality 2003, 15, 156. (f) Picoul,
W.; Bedel, O.; Haudrechy, A.; Langlois, Y. Pure Appl.
Chem. 2003, 75, 235. (g) Fardis, M.; Pyun, H. J.; Tario, J.;
Jin, H. L.; Kim, C. U.; Ruckman, J.; Lin, Y.; Green, L.;
Hicke, B. Bioorg. Med. Chem. 2003, 11, 5051. (h) Picoul,
W.; Urchequi, R.; Haudrechy, A.; Langlois, Y. Tetrahedron
Lett. 1999, 40, 4797. (i) Taber, D. F.; Christos, T. E.;
Rheingold, A. L.; Guzei, I. A. J. Am. Chem. Soc. 1999, 121,
5589. (j) Hutchings, M.; Moffat, D.; Simpkins, N. S. Synlett
2001, 661. (k) Kim, D.; Ahn, S. K.; Bae, H.; Choi, W. J.;
Kim, H. S. Tetrahedron Lett. 1997, 38, 4437. (l) Vosburg,
D. A.; Weiler, S.; Sorensen, E. J. Angew. Chem. Int. Ed.
1999, 38, 971. (m) Bedel, O.; Haudrechy, A.; Langlois, Y.
Eur. J. Org. Chem. 2004, 3813. (n) Boiteau, J.-G.; Van de
Weghe, P.; Eustache, J. Org. Lett. 2001, 3, 2737.
LCMS: m/z = 295 (M+ + 23).
HRMS: m/z calcd C14H24O5Na: 295.1521; found: 295.1525.
Acknowledgment
P.S. and G.D.S. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi, for financial assistance.
References
(1) (a) Hanahan, D.; Folkman, J. Cell 1996, 86, 353.
(b) Folkman, J. Nat. Med. 1995, 1, 27. (c) Folkman, J.;
Klagsbrun, M. Science 1987, 235, 442. (d) McCowen, M.
C.; Callender, M. E.; Lawlis, J. F. Science 1951, 113, 202.
(2) (a) Powell, D.; Skotnicki, J.; Upeslacis, J. Annu. Rep. Med.
Chem. 1997, 32, 161. (b) Giannis, A.; Rubsam, F. Angew.
Chem., Int. Ed. Engl. 1997, 36, 588. (c) Auerbach, W.;
Auerbach, R. Pharmacol. Ther. 1994, 63, 265.
(d) Folkman, J. N. Engl. J. Med. 1971, 285, 1182.
(3) (a) Killough, J. H.; Magill, G. B.; Smith, R. C. Science 1952,
115, 71. (b) Katznelson, H.; Jamieson, C. A. Science 1952,
115, 70. (c) See also ref. 1d. (d) Eble, T. E.; Hanson, F. R.
Antibiot. Chemother. (Washington, D.C.) 1951, 1, 54.
Synthesis 2008, No. 9, 1460–1466 © Thieme Stuttgart · New York

1466
J. S. Yadav et al.
PAPER
prolonged reaction time with Pd/C also resulted in the
(14) (a) Yadav, J. S.; Sreedhar, P.; Bhunia, D. C.; Srihari, P.
Synlett 2007, 992. For our other contributions toward the
synthesis of biologically active natural products, see:
(b) Yadav, J. S.; Chetia, L. Org. Lett. 2007, 9, 4587.
(c) Yadav, J. S.; Pratap, T. V.; Rajender, V. J. Org. Chem.
2007, 72, 5882. (d) Srihari, P.; Prem Kumar, B.;
Subbarayudu, K.; Yadav, J. S. Tetrahedron Lett. 2007, 48,
6977. (e) Yadav, J. S.; Prathap, I.; Tadi, B. P. Tetrahedron
Lett. 2006, 47, 3773. (f) Yadav, J. S.; Srinivas, R.; Sathaiah,
K. Tetrahedron Lett. 2006, 47, 1603. (g) Yadav, J. S.; Raju,
A. K.; Rao, P. P.; Rajaiah, G. Tetrahedron: Asymmetry 2005,
16, 3283. (h) Yadav, J. S.; Prakash, S. J.; Gangadhar, Y.
Tetrahedron: Asymmetry 2005, 16, 2722. (i) Yadav, J. S.;
Reddy, M. S.; Prasad, A. R. Tetrahedron Lett. 2005, 46,
2133.
saturated PMB-deprotected product.
(19) (a) Bernet, B.; Vasella, A. Helv. Chim. Acta 1979, 62, 1990.
For applications and modified procedures, see: (b) Ferrier,
R. J.; Furneaux, R. H.; Prasit, P.; Tyler, P. C.; Brown, K. L.;
Gainsford, G. J.; Diehl, W. J. Chem. Soc., Perkin Trans. 1
1983, 1621. (c) Ferrier, R. J.; Prasit, P. J. Chem. Soc., Perkin
Trans. 1 1983, 1645. (d) Ferrier, R. J.; Schmidt, P.; Tyler, P.
C. J. Chem. Soc., Perkin Trans. 1 1985, 301. (e) Nicolaou,
K. C.; Duggan, M. E.; Ladduwahetty, T. Tetrahedron Lett.
1984, 25, 2069. (f) Yadav, J. S.; Reddy, B. V. S.; Srinivasa
Reddy, K. Tetrahedron 2003, 59, 5333. (g) See also ref.
14a.
(20) The reaction conditions employed for the attempted
protection of the alcohol were (a) TBDPSCl, 1H-imidazole,
CH2Cl2; (b) MOMCl, DIPEA, CH2Cl2; (c) BzCl, py,
CH2Cl2, and those employed for the attempted ketal
deprotection were (a) PTSA (cat.), acetone–H2O; (b) CSA,
acetone–H2O; (c) PPTS, acetone–H2O; (d) TMSOTf,
CH2Cl2.
(15) Leroy, J. Synth. Commun. 1992, 22, 567.
(16) Regiospecificity was determined by comparing the
corresponding reactions of furfuryl alcohols with different
protecting groups and studying their stereochemistry by
NMR spectroscopic methods. When TBS protection was
used, a mixture of isomers was formed; however, with a
PMB protecting group, only one regioisomer was
synthesized, see: Nelson, W. L.; Allen, D. R. Heterocycl.
Chem. 1972, 9, 561.
(17) Leroy, J. Tetrahedron Lett. 1992, 33, 2969.
(18) Initially, we isolated the double-bond-reduced product with
the PMB group intact and then proceeded with PMB
deprotection using DDQ in CH2Cl2/H2O. However, a
(21) Molecules with a similar core including an epoxide moiety
were found to be biologically active, see: Mazitschek, R.;
Huwe, A.; Giannis, A. Org. Biomol. Chem. 2995, 3, 2150.
(22) 1,2-Asymmetric syn reduction was achieved by following a
known protocol used for the stereoselective reduction of b-
hydroxy ketone, see: Narasaka, K.; Pai, F.-C. Tetrahedron
1984, 40, 2233.
Synthesis 2008, No. 9, 1460–1466 © Thieme Stuttgart · New York