A simple spiroepoxide as methionine aminopeptidase-2 inhibitor: Synthetic problems and solutions

Article abstract of DOI:10.1016/j.tetlet.2005.07.136

The preparation of a simple 1-oxa-spiro[2.4]heptane derivative is described. Observations made in the course of the synthesis show again that apparently minor structural modifications of the dienic substrate exert a strong influence on the ring-closing me

Full text of DOI:10.1016/j.tetlet.2005.07.136

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6691–6695
A simple spiroepoxide as methionine aminopeptidase-2 inhibitor:
synthetic problems and solutions
*
´
Vincent Rodeschini, Pierre Van de Weghe, Celine Tarnus and Jacques Eustache
Laboratoire de Chimie Organique et Bioorganique associe´ au CNRS, Universite´ de Haute-Alsace, Ecole Nationale Supe´rieure
de Chimie de Mulhouse, 3, rue Alfred Werner, F-68093 Mulhouse Cedex, France
Received 6 July 2005; revised 25 July 2005; accepted 26 July 2005
Available online 10 August 2005
Abstract—The preparation of a simple 1-oxa-spiro[2.4]heptane derivative is described. Observations made in the course of the syn-
thesis show again that apparently minor structural modifications of the dienic substrate exert a strong influence on the ring-closing
metathesis outcome and that the efficient construction of even simple but highly substituted systems by RCM may constitute a syn-
thetic challenge.
Ó 2005 Elsevier Ltd. All rights reserved.
In a previous work on angiogenesis inhibitors based on
the fumagillin structure (1),1 we showed that the parent
molecule could be simplified without loss of biological
activity, as measured by MetAP-2 inhibition. In these
studies, however, the overall structure of fumagillin
was still conserved (2) (Fig. 1).
dowed with MetAP-2 inhibition properties, we decided
to perform drastic changes on the parent molecule ske-
leton. From the literature data and our earlier work,
we knew that certain features such as an exo epoxide
O
O
O
O
In an attempt to bypass lengthy structure–activity rela-
tionship (SAR) studies towards simple molecules en-
a
R
R
O
N
N
O
OH
4
Ph
5
Ph
Critical
1
2
O
O
MeO
O
O
8
3
N
4
O
OMe
b, c
d
R
7
5
OMe
6O
COOH
4
OMe
OMe
O
OMe
O
6
7
O
Modulatory
role
1
2
O
1
2
O
e
3
7
8
4
R = i-pentyl
OMe
5 OMe
6
Scheme 1. Reagents and conditions: (a) (i) n-Bu2BOTf (1 M in
CH2Cl2, 1.2 equiv), Et3N (1.3 equiv), CH2Cl2, ꢀ78 °C (30 min) then
0 °C (20 min); (ii) acrolein (5 equiv), ꢀ78 °C (1 h) ! 0 °C (1 h), then
MeOH, pH 7 buffer and 30% H2O2, 27%; (b) Me(MeO)NHÆHCl,
AlMe3 (2 M in toluene, 3.5 equiv), THF, 0 °C, 14 h; (c) MeI (excess),
3
Figure 1.
˚
Ag2O, mol. sieves 4 A, Et2O, 40 °C, 8 h, 50%; (d) CH2@CH–MgBr
Keywords: RCM; MetAP-2; Inhibition; Fumagillin.
Corresponding author. Tel.: +33 3 89 33 6858; fax: +33 3 89 33
6860; e-mail: jacques.eustache@uha.fr
*
(1 M in THF, 5 equiv), 6, THF, 0 ! 20 °C, 12 h, THF, then NH4Cl,
50%; (e) [Ru]-2 (10 mol %), toluene, 70 °C, 4 h, 60%.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.136

6692
V. Rodeschini et al. / Tetrahedron Letters 46 (2005) 6691–6695
lein. Standard conversion to the a,b-unsaturated ketone
7 followed by RCM using [Ru]-2 (Fig. 2) as catalyst
afforded cyclopentenone 8.
N
Cl
Cl
N
Mes
Mes
PCy3
Ru
PCy3
Cl
Cl
Ru
PCy3
Mes =
Unfortunately, while the RCM worked reasonably well,
the Evans aldolization proceeded only in poor yield to
afford a single aldol (27%, optimized), to which the
expected structure shown in Scheme 1 was attributed.
This contrasts with the fair-to-good yields reported for
the few similar condensations that have been published.5
[Ru]-1
[Ru]-2
Figure 2.
and a 1,5-dimethyl-hex-1-enyl side chain were required
for activity2 and it is known that modification of the
substituent at C-6 modulates, but does not suppress
activity.3 Even replacement of the C-6 substituent by
H seems to be compatible with significant biological
activity.4 The above considerations led us to select the
simple spiroepoxide 3 (Fig. 1), which in our view, repre-
sented the minimal structure required for biological
activity, as our target molecule.
Following this disappointing result, we modified our
approach as shown in Scheme 2. The Evans aldoliza-
tion was now performed using crotonaldehyde instead
of acrolein to afford in excellent overall yield a 75:25
mixture of two aldols, which could be separated by chro-
matography. The absolute configurations in the major
aldol 9 are again assumed to be those predicted by the
rules applying to the Evans reaction using boron eno-
lates. While the overall sequence leading to 13 was satis-
factory, the RCM reaction (catalyst: [Ru]-2) was very
sluggish, affording cyclopentenone 8 in low (30%) yield.
The latter problem could be solved by a slight modifica-
tion of our synthetic scheme: Luche reduction of ketone
13 afforded the corresponding allylic alcohol 14, which
as expected, smoothly ring-cyclized to cyclopentenol
15.6 Oxidation using Dess–Martin periodinane led to
Considering the structural simplicity of 3, we anticipated
its synthesis to present no serious problem. Our initial
approach, shown in Scheme 1, takes advantage of a reli-
able Evans aldolization/RCM sequence that we had
used successfully in a previous work. The required
Evans (S)-oxazolidinone 4 was prepared as previously
described for the (R)-enantiomer and coupled with acro-
MeO
O
PMPO
O
Xc
O
O
N
a
R
R
R
O
N
b
d
a
O
11
OH
+
4
10
OMOM
OMOM
Ph
16
17
MeO
O
PMPO
HO
PMPO
HO
N
Xc
b
R
R
R
R
O
R
OR'
11: R' = H
12: R' = Me
9
8
OH
OMOM
c
OMOM
20
18
c
+
O
PMPO
HO
PMPO
HO
d
R
e
R
R
R
13
OMe
f
d
f
S
OMOM
h
OMOM
21
19
OH
HO
PMPO
HO
R
PMPO
HO
g
R
14
OMe
15
e
18
OMe
OH
R = i-pentyl
OH
22
23
Scheme 2. Reagents and conditions: (a) (i) n-Bu2BOTf (1 M in
CH2Cl2, 1.1 equiv), Et3N (1.3 equiv), CH2Cl2, ꢀ78 °C, 30 min; (ii)
crotonaldehyde (1.5 equiv), ꢀ78 °C (1 h) ! ꢀ20 °C (20 h), then
MeOH, pH 7 buffer and 30% H2O2, 62% (9) and 22% (10); (b)
Me(MeO)NHÆHCl (3.5 equiv), AlMe3 (2 M in toluene, 3.5 equiv),
PMP = p-methoxyphenyl, R = i-pentyl
Scheme 3. Reagents and conditions: (a) MOM-Cl (2 equiv), iPr2NEt
(4 equiv), CH2Cl2, 20 °C, 16 h, 81%; (b) (i) tributyl-(4-methoxy-
phenoxymethyl)-stannane (2.8 equiv), BuLi (2.75 equiv), THF,
ꢀ78 °C, 30 min; (ii) 16, ꢀ78 °C, 30 min, 64%; (c) CH2@CH–MgBr
(1 M in THF, 3 equiv), THF, ꢀ78 °C, 2 h, 51%; (d) [Ru]-2 (15 mol %),
CH2Cl2, 40 °C, 30 h, 42% (20), 48% (21); (e) BF3ÆMe2S (6 equiv),
CH2Cl2, Me2S, ꢀ78 °C, 3 h, 10–45%; (f) [Ru]-2 (5 mol %), CH2Cl2,
40 °C, 1 h, 80%.
˚
THF, 0 °C, 14 h, 80%; (c) MeI (excess), Ag2O, mol. sieves 4 A, Et2O,
40 °C, 8 h, 90%; (d) CH2@CH–MgBr (1 M in THF, 5 equiv), 12, THF,
0 ! 20 °C, 12 h, THF, then NH4Cl, 52%; (e) [Ru]-2 (15 mol %),
toluene, 70 °C, 4 h, 30%; (f) NaBH4, CeCl3Æ7H2O, MeOH, 0 °C,
30 min; (g) [Ru]-2 (15 mol %), CH2Cl2, 40 °C, 1 h (quantitative); (h)
Dess–Martin periodinane, CH2Cl2, 20 °C, 1 h, 55% (three steps).

V. Rodeschini et al. / Tetrahedron Letters 46 (2005) 6691–6695
6693
arated by chromatography. Both isomers underwent
slow ring closure, using [Ru]-2 as catalyst to furnish
the corresponding cyclopentenols in modest (42% and
48%, respectively), yield.
NOE
H
PMPO
HO
PMPO
HO
NOE
R
R
H
3
3
H
H
OMOM
OMOM
The absolute configuration at C-3 in 20 and 21 was
determined from the observed NOEs (Fig. 3).
20
21
Figure 3.
In an attempt to improve the yields at the RCM step, the
MOM protecting group was removed (Scheme 3). This
seemingly simple operation proved to be quite trouble-
some. Under classical conditions (cat. p-toluenesulfonic
acid in methanol), only a transposed allylether 24 was
obtained in 80% yield from 18.
cyclopentenone 8. The overall yield from 13 to 8 via 14
was a satisfactory, unoptimized 55%, the best result
being the quantitative RCM step.
Unfortunately, it rapidly became clear that cyclopente-
none 8 was very unstable and readily eliminated metha-
nol upon basic treatment, jeopardizing the next steps of
the synthesis (Corey or Mattheson epoxidation of the
ketone). Thus, although we had been successful in
improving the sequence 4!8, it appeared that we had
reached a dead-end regarding the preparation of our
ultimate target molecule 3 and that we needed to more
drastically rethink our original plans.
PMPO
HO
R
OMe
24
Using the conditions developed by Gennari and co-
workers8 for cleaving sensitive MOM ethers, the desired
allylic alcohol 22 could be obtained but the yield re-
mained modest and variable (10–45%). As expected,
RCM now proceeded smoothly, affording cyclopentenol
23 in 80% yield (non-optimized).
We then turned to the alternative approach shown in
Scheme 3 that capitalizes on our previous positive
results: Evans reaction using crotonaldehyde and reactive
RCM substrate. A protected diol is introduced before
cyclization and will be converted to an epoxide towards
the end of the synthesis, thus avoiding the problematic
cyclopentenone step. With the idea of introducing vari-
ous substituents at position 5, we decided to replace the
5-methoxy group (see 3, Fig. 1 for numbering) used until
now by the readily cleavable MOM protecting group.
Thus the Weinreb amide 11 was treated with MOMCl
to afford the corresponding ether 16 in good yield, which
was converted to ketone 17 in 64% yield by treatment
with 4-methoxy-phenoxymethyllithium.7 The reaction
of ketone 17 with vinylmagnesium bromide gave a 7:3
mixture of two isomers (18 and 19), which could be sep-
Taking into account the observations made during this
work, a final, optimized synthetic route that eventually
led to our target molecule 3 was devised (Scheme 4).9
Table 1. MetAP-2 inhibition by fumagillin and analogues 2 and 3
Compound
IC50 (nM)
Fumagillin
2
3
10
15
3000
PMPO
HO
PMPO
HO
MeO
N
O
b
R
PMPO
R
R
R
R
a
c
R
O
+
11
S
OTBDMS
OTBDMS
OH
R
OH
25
26
27
22
d
R1O
HO
R1O
R2O
PMPO
HO
O
R
R
h
OR'
OTBDMS
OTBDMS
OR'
31
e
g
32: R' = TBDMS
33: R' = H
29: R1 = PMP, R2 = Ac
30: R1 = R2 = H
i
j
23: R' = H
28: R' = TBDMS
f
a
R = i-pentyl
3: R' = Me
Scheme 4. (a) TBDMSOTf (2 equiv), 2,6-lutidine (2 equiv), CH2Cl2, ꢀ78 °C, 1 h, 98% (25) and 96% (28); (b) p-methoxyphenoxymethyl(tributyl)tin
(2.9 equiv), BuLi (2.8 equiv), THF, ꢀ78 °C, 30 min; (c) CH2@CH–MgBr (1 M in THF, 3 equiv), THF, ꢀ78 °C, 2 h, 24% (27) and 33% (22) (two
steps); (d) [Ru]-2 (5 mol %), CH2Cl2, 40 °C, 1 h, 95%; (e) Ac2O (2 equiv), DMAP (cat.), pyridine, 40 °C, 24 h, 54%; (f) (i) CAN (2 equiv), CH3CN/
pH 7 phosphate buffer, 0 °C, 30 min; (ii) K2CO3, MeOH, 1 h, 0 °C, 66%; (g) Rh(PPh3)3Cl (10 mol %), H2, toluene, 14 h, 80 °C; (h) (i) MsCl
(1.2 equiv), Et3N (3 equiv), CH2Cl2, 0 °C, 1 h; (ii) NaOH (0.25 M in MeOH, 5 equiv), 20 °C, 30 min; (i) NBu4F (1 M in THF, 5 equiv), mol. Sieves
˚
˚
4 A, THF, 13% (from 30); (j) MeI (10 equiv), Ag2O (5 equiv), mol. sieves 4 A, diethyl ether, reflux, 2 h, 50%.

6694
V. Rodeschini et al. / Tetrahedron Letters 46 (2005) 6691–6695
Table 2. RCM to form cyclopentenols or cyclopentenones
Substrate
Conditions
Time (h)
Yield (%)
13
[Ru]-2 (15 mol %), toluene, 70 °C
[Ru]-1 (15 mol %), Ti(OiPr)4 (30%), toluene, 70 °C
[Ru]-2 (10 mol %), toluene, 70 °C
[Ru]-2 (7 mol %), CH2Cl2, 40 °C
[Ru]-2 (15 mol %), CH2Cl2, 40 °C
[Ru]-2 (5 mol %), CH2Cl2, 40 °C
4
4
4
1
30
1
30
<5
60
7
14
18
22
Quantitative
50% conversion
95
Protection of the free hydroxyl by a tert-butyldimethyl-
silyl group in Weinreb amide 11 was followed by
sequential addition of p-methoxyphenoxymethyl lithium
and vinyl magnesium bromide. The crude mixture of
carbinols was desilylated to afford a nearly 1:1 mixture
of the desired R-diol 22 and its 3-epi-isomer 27 in good
yield. The two compounds were separated and 22 was
submitted to RCM conditions to afford 23. The second-
ary and tertiary alcohols in 23 were protected as the
corresponding tert-butyldimethylsilyl ether and acetate,
respectively, and the PMP was removed by CAN-
induced oxidative cleavage.10 The final steps include
deacetylation, selective reduction of the allylic double
bond11 and mesylation/epoxide formation, then removal
of the TBDMS group and methylation of the second-
ary alcohol to afford 3. The compound was evaluated
in our MetAP-2 assay.1b Despite its considerably
simplified structure as compared to fumagilline or fum-
agillol, the compound exhibited moderate MetAP-2
inhibitory activity (300 times less than fumagillin)
(Table 1).12
Acknowledgements
´
We thank Drs. Didier Le Nouen and Stephane Bourg
for help with NMR recording and interpretation. We
thank the CNRS and Galderma R&D for a fellowship
to V.R. Financial support for this project by Galderma
R&D is gratefully acknowledged.
References and notes
1. (a) Boiteau, J.-G.; Van de Weghe, P.; Eustache, J. Org.
Lett. 2001, 3, 2737–2740; (b) Rodeschini, V.; Boiteau,
J.-G.; Van de Weghe, P.; Tarnus, C.; Eustache, J. J. Org.
Chem. 2004, 69, 357–373.
2. Griffith, E. C.; Su, Z.; Turk, B. E.; Chen, S.; Chang, Y.-H.;
Wu, Z.; Bieman, K.; Liu, J. O. Chem. Biol. 1997, 4, 461–
471.
3. Han, C. K.; Ahn, S. K.; Choi, N. S.; Hong, R. K.; Moon,
S. K.; Chun, H. S.; Lee, S. J.; Kim, J. W.; Hong, C. I.;
Kim, D.; Yoon, J. H.; No, K. T. Bioorg. Med. Chem. Lett.
2000, 10, 39–43.
4. Ohashi, N.; Fukui, M.; Yamaoka, T.; Hirota, F.; Nakajo,
E.; Imazaki, N.; Kurimoto, A. Sumitomo Pharmaceuticals
Co., Ltd., Japan, Jpn. Kokai Tokkyo Koho JP 08 183,752,
16 July 1996, Appl. 94/340,108, 30 Aug 1994; [C.A. 125:
247602].
5. (a) Kuang, R.; Ganguly, A. K.; Chan, T. M.; Pramanik, B.
N.; Blythin, D. J.; McPhail, A. T.; Saksena, A. K.
Tetrahedron Lett. 2000, 41, 9575–9579; (b) Xiao, D.; Vera,
The results of our metathesis experiments (Table 2)
show again the crucial role of substituents on (or close
to) the dienic system and illustrate how these can be
optimized for maximal efficacy. Initially, we worked
with electron-poor systems in which one of the olefins
carried an a-keto group. In this case acceptable yields
were only obtained with monosubstituted olefins (com-
pare 7 and 13). Replacement of the keto group by a
secondary alcohol (14) restored reactivity and led to
quantitative yields of cyclized product. This reactivity
was again strongly decreased for 18, featuring a ter-
tiary allylic alcohol, probably reflecting the difficulty
for the catalyst to reach the now hindered coordination
site. Simply providing a new site of coordination for
the catalyst again restored the reactivity towards
metathesis conditions (22). This demonstrates once
again how the nature of substituents can drastically al-
ter the reactivity of dienic systems in RCM and shows
that simple manipulation of protective groups may
provide an answer to the problems posed by difficult
metatheses.13
´
M. D.; Liang, B.; Joullie, M. J. Org. Chem. 2001, 66,
2734–2742.
6. It is known that allylic alcohols are excellent substrates for
the RCM reaction: Hoye, T. R.; Zhao, H. Org. Lett. 1999,
1, 1123–1125.
7. (a) Go¨res, J.; Winterfeldt, E. J. Chem. Soc., Perkin Trans.
1 1994, 3525–3531; (b) Ahman, J.; Somfai, R. Synth.
Commun. 1994, 24, 1117–1120.
8. Beumer, R.; Bayon, P.; Bugada, P.; Ducki, S.; Mongelli,
N.; Sirton, F. R.; Tesler, J.; Gennari, C. Tetrahedron 2003,
59, 8803–8820.
20
9. Analytical data for selected compounds: 9. ½aꢁD +28 (c 1,
1
CHCl3). H NMR (400 MHz, CDCl3): 7.18–7.27 (m, 5H,
ArH), 5.77 (m, 1H, CH@CH–CHOH), 5.60 (t, J = 7.0,
1H, C@CH–CH2), 5.50 (dd, J = 15.4, 5.8, 1H, CH@CH–
CHOH), 4.69 (m, 1H, CH–CH2–Phe), 4.51 (m, 2H, CH–
OH and (C@O)–CH), 4.13 (m, 2H, N–CO2CH2), 3.22 (dd,
J = 13.3, 3.5, 1H, CHH–Phe), 2.65 (dd, J = 13.3, 9.8, 1H,
CHH–Phe), 2.20 (d, J = 2.3, 1H, CH–OH), 2.10 (q,
J = 7.0, 2H, CH2–CH@C), 1.80 (s, 3H, CH3–C@CH),
1.68 (br d, J = 6.5, 3H, Me–CH@CH), 1.56 (m, 1H,
CH(Me)2), 1.27 (m, 2H, CH2–CH(Me)2), 0.88 (d, J = 6.5,
6H (CH3)2CH). 13C NMR (100 MHz, CDCl3): 172.1
((CO)CH), 152.8 (O–(C@O)–N), 135.2 (HC@C(Me)),
133.7 ((Me)C@CH), 130.9 (CH@CH–CH(OH), 129.4
In conclusion, the synthesis of a simple, chiral spiro-
epoxide, which initially appeared to be a simple task,
required careful adjustment of the synthetic intermedi-
ates at nearly all steps. Noteworthy is, in our case, the
strong difference between acrolein and crotonaldehyde
as electrophilic partner in the Evans reaction and the
very strong influence of the 1,6-diene substitution pat-
tern on the RCM outcome.

V. Rodeschini et al. / Tetrahedron Letters 46 (2005) 6691–6695
6695
20
(Ar), 128.9 (Ar), 128.8 (CH@CH–CH(OH)), 127.6 (Ar),
127.4 (Ar), 71.6 (CH(OH)), 65.9 ((C@O)–O–CH2), 57.6
((C@O)–CH), 54.9 (CH–CH2–Phe), 38.6 (CH2–
CH(CH3)), 37.7 (CH2–Phe), 27.8 (CH–(CH3)2), 26.2
(CH2–CH@C), 22.6 ((CH3)2), 17.8 (CH3–CH@CH), 15.1
(CH3–C@CH). Anal. Calcd for C24H33NO4: C, 72.15; H,
8.33; N, 3.51. Found: C, 71.82; H, 8.64; N, 3.37.
Compound 33. ½aꢁD ꢀ36 (c 0.25, CHCl3). 1H NMR
(400 MHz, CDCl3): 5.18 (t, J = 6.6, 1H, C@CH), 4.37 (dt,
J = 8.8, 6.4, 1H, CHOH), 2.70 and 2.66 (2 d, AB, J = 5.2,
´
2H, CH2-epoxyde), 2.49 (d, J = 8.8, 1H, CH–C(Me)@C),
2.25–2.20 (m, 1H, CHH–CHOH), 2.20–2.10 (m, 1H,
CHH–CH2–CHOH), 2.00 (m, 2H, C@CH–CH2), 1.80
(m, 1H, CHH–CH2–CHOH), 1.66 (s, 3H, (Me)C@C),
1.56–1.48 (m, 3H, CHH–CHOH, CH(Me)2 and OH), 1.22
(q, J = 7.4, 2H, CH2–CH(Me)2), 0.87 (d, J = 6.8, 6H,
(CH3)2). 13C NMR (100 MHz, CDCl3): 131.4, 129.7, 74.1,
63.0, 60.4, 50.1, 38.9, 31.9, 29.7, 27.7, 25.9, 22.6, 22.5, 14.5.
HRMS m/z found 224.1763, calcd for C14H24O2 m/z
224.1776.
20
Compound 11. ½aꢁD ꢀ124 (c 0.5, CHCl3). 1H NMR
(400 MHz, CDCl3): 5.75 (m, 1H, CH@CH–CHOH), 5.48
(ddd, J = 13.6, 6.6, 1.8, 1H, CH@CH–CHOH), 5.40 (t,
J = 6.4, 1H, C@CH–CH2), 4.47 (t, J = 6.6, 1H, CH–OH),
3.64 (s, 3H, Me–O–N), 3.46 (m, 1H, (C@O)–CH), 3.16 (s,
3H, Me–N), 2.98 (br s, 1H, CH–OH), 2.09 (m, 2H, CH2–
CH@C), 1.74 (s, 3H, CH3–C@CH), 1.68 (d, J = 6.3, 3H,
Me–CH@CH), 1.55 (m, 1H, CH(Me)2), 1.24 (m, 2H,
CH2–CH(Me)2), 0.88 (d, J = 6.5, 6H (CH3)2CH). 13C
NMR (100 MHz, CDCl3): 132.2 (HC@C(Me)), 131.9
((Me)C@CH), 131.0 (CH@CH–H(OH), 127.8 (CH@CH–
CH(OH)), 71.8 (CH(OH)), 61.3 (Me–O–N), 56.2 ((C@O)–
CH), 38.7 (CH2–CH(CH3)), 31.9 (Me–N), 27.7 (CH–
(CH3)2), 26.0 (CH2–CH@C), 22.5 ((CH3)2), 17.8 (CH3–
CH@CH), 15.2 (CH3–C@CH). Anal. Calcd for
C16H29NO3: C, 67.81; H, 10.31; N, 4.94. Found: C,
67.98; H, 10.27; N, 4.91.
20
Compound 3. ½aꢁD ꢀ27 (c 0.1, CHCl3). 1H NMR
(400 MHz, CDCl3): 5.15 (t, J = 6.8, 1H, C@CH), 3.97
(m, 1H, CHOMe), 3.36 (s, 3H, OMe), 2.70 and 2.57 (2 d,
´
J = 5.2, AB, 2H, CH2(epoxyde)), 2.61 (d, J = 8.0, 1H,
CH–C(Me)@CH), 2.15 (m, 2H, CH2), 2.01 (m, 2H,
C(Me)@CH–CH2), 1.80-1.50 (m, 3H, CH(Me)2 and
CH2), 1.64 (s, 3H, Me), 1.20 (m, 2H, CH2–CH(Me)2),
0.87 (d, J = 6.8, 6H, CH(Me)2). 13C NMR (100 MHz,
CDCl3): 130.1, 127.4, 83.2, 61.4, 57.9, 57.0, 49.9, 38.8, 29.9,
29.3, 27.8, 25.9, 22.6, 22.5, 14.8. HRMS m/z 238 (M+).
10. Failure to protect the tertiary alcohol before PMP removal
led to formation of the stable quinone ketal 35. A similar
observation has been made previously: Leung, L. W.;
20
Compound 22. ½aꢁD ꢀ22 (c 0.8, CHCl3). 1H NMR
(400 MHz, CDCl3): 6.78 (m, 4H, Ar–H), 6.13 (dd, J =
17.2, 10.4, 1H, CH2@CH), 5.63 (dq, J = 15.0, 6.0, 1H,
Me–CH@CH), 5.56 (dd, J = 17.2, 1.2, 1H, CHH@CH),
5.45 (ddd, J = 15.0, 6.8, 1.2, 1H, CH@CH–CH(OH)), 5.32
(dd, J = 10.4, 1.2, 1H, CHH@CH), 5.32 (m, 1H,
(Me)C@CH), 4.64 (dd, J = 6.8, 2.8, 1H, CH–OH), 3.82 and
3.70 (2 d, AB, J = 8.8, 2H, CH2-OAr), 3.75 (s, 3H, OMe),
2.29 (d, J = 2.8, 1H, CH–C(Me)@C), 2.00 (q, J = 7.5, 2H,
C@CH–CH2), 1.67 (s, 3H (Me)C@C), 1.66 (d, J = 6.0, 3H,
CH3–CH@CH), 1.48 (m, 1H, CH(Me)2), 1.12 (q, J = 7.5,
2H, CH2–CH(Me)2), 0.82 (d, J = 6.6, 6H (CH3)2). 13C
NMR (100 MHz, CDCl3): 153.9, 152.9, 142.1, 132.6,
132.4, 131.1, 126.7, 115.5, 114.6, 114.5, 78.3, 77.2, 73.7,
56.3, 55.7, 38.7, 27.5, 25.7, 22.5, 22.4, 17.6. Anal. Calcd for
C24H36O4: C, 74.19; H, 9.34. Found: C, 74.08; H, 9.63.
`
Vilcheze, C.; Bittman, R. Tetrahedron Lett. 1998, 39,
2921–2924
O
O
O
35
OH
11. (a) Young, J. F.; Osborn, J. A.; Jardine, F. H.; Wilkinson,
G. J. Chem. Soc., Chem. Commun. 1965, 73, 131–132; (b)
Jardine, F. H.; Osborn, J. A.; Wilkinson, G. J. Chem. Soc.
(A) 1967, 1574–1578; (c) Miller, K. M.; Luanphaisam-
nont, T.; Molinaro, C.; Janison, T. F. J. Am. Chem. Soc.
2004, 126, 4130–4131.
12. While this manuscript was being prepared, the preparation
of cyclopentane analogues of fumagillol was described.
The biological activity was inferior to that of the corre-
sponding fumagillol derivatives: Jeong, B. S.; Choi, N. S.;
Ahn, S. K.; Bae, H.; Kim, H. S.; Kim, D. Bioorg. Med.
Chem. Lett. 2005, 15, 3580–3583.
20
Compound 30. ½aꢁD ꢀ87 (c 0.9, CHCl3). 1H NMR
(400 MHz, CDCl3): 5.94 (dd, J = 5.6, 2.0, 1H, CH@CH–
CHOTBS), 5.87 (d, J = 5.6, 1H, CH@CH–CHOTBS),
5.32 (t, J = 6.8, 1H, C(Me)@CH), 4.87 (br s, 1H,
CHOTBS), 3.58 (m, 2H, CH2–OH), 2.49 (d, J = 3.6, 1H,
CH–C(Me)@C), 2.31 (br s, 1H, OH), 2.16 (br s, 1H, OH),
2.06 (m, 2H, C@CH–CH2), 1.66 (s, 3H, (Me)C@C), 1.55
(m, 1H, CH(Me)2), 1.25 (q, J = 7.5, 2H, CH2–CH(Me)2),
0.89 (d, J = 6.8, 6H, (CH3)2), 0.87 (s, 9H, tBu), 0.04 (s, 6H,
(Me)2Si). 13C NMR (100 MHz, CDCl3): 137.6, 135.7,
132.7, 130.2, 84.2, 80.4, 69.3, 62.8, 38.8, 27.7, 25.9, 25.8,
22.6, 22.5, 18.1, 17.5, ꢀ4.7. HRMS m/z found 323.2408,
calcd for C19H35O2Si m/z 323.2406.
13. For general reviews about the use of metathesis in organic
chemistry see: (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah,
D. Angew. Chem., Int. Ed. 2005, 44, 4490–4527; (b)
Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043.
¨