MetAP-2 Inhibitors Based on the Fumagillin Structure. Side-Chain Modification and Ring-Substituted Analogues

Article abstract of DOI:10.1021/jo035065+

The preparation of a series of new fumagillin-derived MetAP-2 inhibitors is described. The synthetic approach was designed so as to permit modification of the fumagillin backbone at sites inaccessible through semisynthesis or previously existing total syntheses. An Evans aldolization and a ring-closing metathesis allowed the preparation of a pivotal intermediate which could then be functionalized in various ways using already established or newly developed methodologies.

Full text of DOI:10.1021/jo035065+

MetAP -2 In h ibitor s Ba sed on th e F u m a gillin Str u ctu r e.
Sid e-Ch a in Mod ifica tion a n d Rin g-Su bstitu ted An a logu es
Vincent Rodeschini, J ean-Guy Boiteau, Pierre Van de Weghe, Ce´line Tarnus, and
J acques 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
j.eustache@uha.fr
Received J uly 23, 2003
The preparation of a series of new fumagillin-derived MetAP-2 inhibitors is described. The synthetic
approach was designed so as to permit modification of the fumagillin backbone at sites inaccessible
through semisynthesis or previously existing total syntheses. An Evans aldolization and a ring-
closing metathesis allowed the preparation of a pivotal intermediate which could then be
functionalized in various ways using already established or newly developed methodologies.
In tr od u ction
On the basis of inspection of the MetAP-2-fumagillin
complex, Clardy et al. determined several sites of the
fumagillin molecule important for binding to MetAP-2.
In particular, the spiroepoxide moiety (see Figure 1) plays
a crucial role by creating a covalent bond with an
histidine residue (His231) of the enzyme. The side chain
appeared to be involved in the recognition process in two
ways: in addition to establishing hydrophobic interac-
tions with several lipophilic amino acids, it interacts with
the protein via the 1′-2′ epoxide which functions as an
H-bond acceptor for a defined water molecule within the
enzyme’s recognition site. This latter hypothesis served
as a rationale for targeted modification of the fumagillin
structure as recently reported by Baldwin et al.6 The role
of the side chain with respect to binding to MetAP-2 and
inhibition of endothelial cell proliferation is still unclear,
however: Liu et al. observed that removal of the side
chain epoxide in biotinyl esters of fumagillol did not
result in significant loss of activity in a MetAP-2 binding
assay.7 Additional data, from the patent literature,
suggested that modification of the C1′-C8′ side chain was
possible while maintainingsat least in partsbiological
activity.8 Inspection of the fumagillin structure bound to
MetAP-2 reveals a pocket in the vicinity of the C7-C8
(see Figure 1 for numbering) part of the molecule (see
Angiogenesis is believed to play an important role in
tumor development as well as in certain inflammatory
diseases such as rheumatoid arthritis or psoriasis. As
early as 1971,1 inhibition of angiogenesis has been
suggested as a potential new therapeutic approach to the
above disorders, and over the years, evidence supporting
this earlier proposal has accumulated. The potential of
antiangiogenic agents as new antitumor agents, alone or
combined with other drugs, is currently widely accepted
and several molecules structurally quite different (pro-
teins, low molecular weight compounds) are undergoing
extensive biological testing.2 Among small molecular
weight antiangiogenic agents, certain semisynthetic ana-
logues of fumagillin have reached the stage of advanced
preclinical or even clinical studies for cancer treatment.2
Until recently, however, the mode of action of this class
of molecules remained obscure.
In 1998, the identification of a biological target for
fumagillin, the enzyme methionine aminopeptidase 2
(MetAP-2), and the publication of the X-ray structure of
a MetAP-2-fumagillin complex3 provided a starting point
for the rational design of fumagillin analogues and
triggered a renewed interest from synthetic chemists.
Following the first total synthesis of fumagillin (1, Figure
1) by Corey et al. in 1972,4 little (chemical) research
activity in the area had been reported, but, within the
past 7 years, eight total syntheses or approaches to
fumagillin and analogues have been described.5
(5) (a) Kim, D.; Ahn, S. K.; Bae, H.; Choi, W. J . Kim, H. S.
Tetrahedron Lett. 1997, 38, 4437-4440. (b) Taber, D. F.; Christos, T.
E.; Rheingold, A. L.; Guzei, I. A. J . Am. Chem. Soc. 1999, 121, 5589-
5590. (c) Vosburg, D. A.; Weiler, S.; Sorensen, E. J . Angew. Chem.,
Int. Ed. 1999, 38, 971-974. (d) Picoul, W.; Urchegui, R.; Haudrechy,
A.; Langlois, Y. Tetrahedron Lett. 1999, 40, 4797-4800. (e) Moffat,
D.; Simpkins, N. S. Synlett 2001, 63-64. (f) Boiteau, J .-G.; Van de
Weghe, P.; Eustache, J . Org. Lett. 2001, 3, 2737-2740. (g) Vosburg,
D. A.; Weiler, S.; Sorensen, E. J . Chirality 2003, 15, 156-66. (h) Picoul,
W.; Bedel, O.; Haudrechy, A.; Langlois, Y. Pure Appl. Chem. 2003, 75,
235-249.
(6) Baldwin, J . E.; Bulger, P. G.; Marquez, R. Tetrahedron 2002,
58, 5441-5452.
(7) (a) Griffith, E. C.; Su, Z.; Niwayama, S.; Ramsay, C. A.; Chang,
Y.-H.; Liu, J . O. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 15183-15188.
(8) Lamothe, S.; Attardo, G.; Labrecque, D.; Courchesne, M.; Wang,
W.; Li, T. WO 99/61142, 1999.
(1) Folkman, J . N. Engl. J . Med. 1971, 285, 1182-1185.
(2) For reviews on the clinical potential of antiangiogenic agents,
see: (a) Norrby, K. APMIS 1997, 105, 417-437. (b) Liekens, S.; De
Clercq, E.; Neyts, J . Biochem. Pharmacol. 2001, 61, 253-270.
(3) (a) Liu, S.; Widom, J .; Kemp, C. W.; Crews, C. M.; Clardy, J .
Science 1998, 282, 1324-1327. (b) Sin, N.; Meng, L.; Wang, M. Q. W.;
Wen, J . J .; Bornmann, W. G.; Crews, C. M. Proc. Natl. Acad. Sci. U.S.A.
1997 94, 6099-6103.
(4) Corey, E. J .; Snider, B. B. J . Am. Chem. Soc. 1972, 94, 2549-
2550.
10.1021/jo035065+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/23/2003
J . Org. Chem. 2004, 69, 357-373
357

Rodeschini et al.
F IGURE 1. Active MetAP-2 inhibitors based on the fumagillin structure.
F IGURE 2. Stereoview of TNP 470 bound to Met-AP2 (only relevant amino acids are shown).
Figure 2), which we thought might be exploited for the
design of improved fumagillin analogues. This informa-
tion led us to target two sites of the fumagillin structure
for our exploratory studies: the side chain and the C7-
C8 (close to the cobalt binding site) “western” part of the
fumagillin. This latter area of the molecule is not readily
accessible: it bears no functionality which could serve
as a starting point for derivatization, which precluded
semi synthetic approaches, and the reported total syn-
theses were of little help for solving our problem. This
F IGURE 3. Fumagillol p-methoxycinnamyl ester: areas
led us to develop our own approach to the fumagillin
skeleton, specially aimed at providing an advanced,
versatile synthetic intermediate, from which a palette of
analogues, modified at the C7-C8 carbons could be
prepared. We recently described a synthesis of fumagillol
based on this approach5f and we now disclose the suc-
cessful application of this strategy to the preparation of
novel fumagillin analogues.
targeted for modification.
compared to fumagillin or TNP-4709 and therefore may
be considered as “the state of the art” in this research
area. The p-methoxycinnamyl ester 3, the most active
representative of the series, was chosen as parent
molecule for our studies. The planned transformations
are shown in Figure 3. While the synthesis of modified
side chains did not appear to constitute a major problem,
the introduction of substituents at positions C7 and C8
was far from obvious and dictated our strategy depicted
in Scheme 1.
An R,â-unsaturated ketone was chosen as advanced
intermediate. R,â-Unsaturated ketones are highly reac-
tive and can be easily converted to a range of function-
alized molecules. As can be seen in Scheme 1, our
approach to this intermediate relied on two key reac-
tions: an Evans aldolization to establish the absolute
configurations at C4 and C5, and a ring-closing metath-
Resu lts a n d Discu ssion
Str a tegy for Str u ctu r a l Mod ifica tion s. When this
work was initiated, most biologically active fumagillin
analogues only differed from the parent molecule (fum-
agillin) in the nature of the ester at position 6 (Figure
1). This is the case for TNP-470 (2)sthe most studied
fumagillin analoguesand also for a recently described
series of cinnamyl esters of fumagillol which showed a
strongly increased cell proliferation inhibitory activity as
(9) 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.
(10) The validity of this approach has already been demonstrated
in a preliminary communication (ref 5f).
358 J . Org. Chem., Vol. 69, No. 2, 2004

MetAP-2 Inhibitors Based on the Fumagillin Structure
SCHEME 1
SCHEME 3 a
a
Key: (a) (i) PhSeNa (1.8 equiv), 18-crown-6 (0.05 equiv), THF,
SCHEME 2 a
20 °C, 2 h, (ii) HCl (1 M), then extract with AcOEt, (iii) CH2N2
(excess), Et2O, 20 °C; (b) PMBOC(CCl3)dNH, camphorsulfonic acid
(0.2 equiv), 20 °C, 20 h; (c) DIBAL-H, toluene, -78 °C, 20 min.
SCHEME 4 a
a
Key: (a) (i) isopentylZnCl (2.1 equiv), Pd(PPh3)4 (0.02 molar
equiv), THF, 20 °C, 16 h, (ii) NBu4F (1.1 equiv), THF, 20 °C, 2 h;
(b) CrO3 (3 equiv), H2SO4/H2O/acetone, 0 °C, 15 min; (c) (i) (COCl)2,
DMF (cat.), CH2Cl2, 0 °C, 1 h f 20 °C, 3 h, (ii) (R)-(+)-4-benzyl-
2-oxazolidinone (Li salt) (1 equiv), -78 °C, 20 min.
a
Key: (a) p-methoxycinnamic acid (8-10 equiv), DCC (8-10
12. Although the reduction was always clean as judged
equiv), DMAP (8-10 equiv), CH2Cl2, 20 °C, 5 h.
1
by TLC and H NMR, we observed RD’s ranging from +6°
esis (RCM) to form the cyclohexenyl ring. The configu-
ration at C6 was secured using a chiral R-alkoxyalde-
hyde10 at the aldolization step.
to +30° in different experiments, an obvious sign that
racemization had occurred, further confirmed by 1H NMR
studies using the chiral shift reagent Eu(hfc)3.
1. Syn th esis of p-Meth oxycin n a m yl Ester (3) a n d
Its (1′S,2′S)-Isom er (4). Our first task was to prepare
the p-methoxycinnamyl ester of fumagillol 3 as the best
available standard according to the literature. For this
we needed fumagillol, which was conveniently prepared
as recently described in a preliminary communication
(Scheme 2).5f Briefly, the aldol obtained by condensation
of the chiral isogeranyl-derived oxazolidine 5 and the
chiral aldehyde 12 was converted in a few steps to the
key intermediate 6. RCM of 6 yielded a substituted
cyclohexenone which was functionalized, eventually lead-
ing to fumagillol 7 and its (1′S,2′S)-isomer 8. Treatment
of fumagillol with p-methoxycinnamic acid and DCC/
DMAP afforded our target molecule 3 in excellent yield.
For comparison purposes, the (1′S,2′S)-isomer 4 was
prepared from 8 in the same way.
Two minor modifications of our original protocol proved
to be beneficial (Scheme 3). In the original procedure,
opening of lactone 9 was effected by treatment with
NaBH4/PhSeSePh. Although this method generally pro-
vided good yields of ester 10, we sometimes had disap-
pointing results when performing large-scale prepara-
tions, resulting in material loss and formation of side
products. Reliability could be greatly improved using
“naked” NaSePh obtained by cleavage of PhSeSePh by
NaH in THF. A more annoying phenomenon was the high
sensitivity of aldehyde 12 to basic or acidic conditions
which manifested itself during the reduction step 11 f
The reaction workup involves the formation of a gel
by careful addition of methanol to the reaction mixture.
This was supposed to facilitate removal of inorganic
aluminum species by filtration but the result was quite
disappointing. In fact this procedure led to partial
racemization whose extent could be linked to the time
taken for filtering-off the gel. Switching to a more
classical workup (addition of methanol at -78 °C, then
brine, and rapid extraction with non polar solvents such
as cyclohexane) partly solved the problem, reducing
racemization to an acceptable level (77% ee as measured
1
by H NMR), the corresponding RD being +50°.
2. Sid e-Ch a in Mod ifica tion . We did not intend to
embark on extensive structure-activity relationship
studies of the fumagillin side chain. Our aim, in this part
of the work, was limited to: (a) clarifying the role of the
side-chain epoxide and (b) identifying an alternative side
chain compatible with biological activity but easier to
work with than the unstable 1,4-dienic system used in
our previous work on fumagillol (see Scheme 2). Our
synthesis commences with the preparation of oxazolidine
16 (Scheme 4). The known vinyl iodide 1311 was treated
with isopentyl zinc chloride in the presence of tetrakis-
triphenylphosphine palladium and subsequently with
TBAF to afford alcohol 14.12 Oxidation with CrO3 gave
(11) Rand, C. L.; Van Horn, D. E.; Moore, M. W.; Negishi, E. J . Org.
Chem. 1981, 46, 4093-4096.
J . Org. Chem, Vol. 69, No. 2, 2004 359

Rodeschini et al.
SCHEME 5 a
a
Key: (a) (i) LDA (1 equiv), THF, -78 °C, 30 min, (ii) 12 (1.1 equiv), -78 °C, 1.5 h, (iii) evaporate, (iv) NBu4IO4 (2 equiv), CHCl3, 60
°C, 2 h; (b) AlMe3 (3.5 equiv), N,O-dimethylhydroxylamine hydrochloride (3.5 equiv), THF, 20 °C, 24 h; (c) MeI (18 equiv), Ag2O (5 equiv),
Et2O, reflux, 8 h; (d) CH2dCHMgBr (5 equiv), THF, 20 °C, 12 h; (e) Grubbs II (0.10 molar equiv), toluene, 70 °C, 45 min.
SCHEME 6 a
a
Key: (a) RaNi, THF, 0 °C, 20 min; (b) Me3S+OI- (15 equiv), NaH (10 equiv), LiI (12 equiv), DMSO/THF (1:1), 0 °C f 20 °C, 30 min;
(c) m-CPBA (1.5 equiv), NaHCO3 (6 equiv), CH2Cl2, 0 °C, 1 h, separate; (d) DDQ (1.1 equiv), CH2Cl2/H2O, 20 °C, 1 h; (e) p-methoxycinnamic
acid (10 equiv), DCC (10 equiv), DMAP (10 equiv), CH2Cl2, 20 °C, 48 h.
attributed on the basis of our earlier work on fumagillol.5f
Cleavage of the chiral auxiliary by N,O-dimethylhy-
droxylamine/AlMe3 and sequential treatment of the
resulting N,O-dimethylhydroxylamide with vinylmagne-
sium bromide afforded the R,â-unsaturated ketone 20
which was submitted to RCM. Using the conditions
developed earlier (Grubbs type I catalyst, Ti(OiPr)4),
cyclohexenone 21 was obtained in 48% yield, a value close
to the 53% obtained in our fumagillol synthesis. In the
F IGURE 4. Structure of Ru-based RCM catalysts.
the corresponding carboxylic acid which was converted
to oxazolidine 16 (Scheme 4).
(13) Although aldehyde 12 is a 7.7: 1 mixture of (R) and (S)
enantiomers, we could isolate only one aldol product, after deseleny-
lation. This unexpected result has also been observed in the course of
our fumagillol synthesis (see ref 5f) as well as with other similar
condensations using aldehyde 12 and oxazolidinones bearing branched,
â,γ-unsaturated acyl groups (unpublished results). A possible explana-
tion is that of preferential condensation of these oxazolidinones with
(S)-12 possibly due to “matched” double-asymmetric induction, whereas
reaction with (R)-12 would be kinetically strongly disfavoured. Al-
though we are not aware of literature reports fully supporting our
We next proceeded to the preparation of the key
cyclohexenone 21 (Scheme 5), from which all analogues
modified in the side chain or the C7-C8 region were to
be prepared. Condensation between oxazolidine 16 and
aldehyde 12 afforded a single adduct 17 in fair yield,13
to which the configuration shown in Scheme 5 was
tentative explanation,
a related behavior of oxazolidinone boron
enolates was described: Sibi, M. P.; Lu, J .; Talbacka, C. L. J . Org.
Chem. 1996, 61, 7848-7855. In this report, however, the differences
in yields were not as marked as in the present work.
(12) Weissberger, E.; Stockis, A.; Carr, D. D.; Gienfried, J . Bull. Soc.
Chim. Belg. 1980, 89, 281-288.
360 J . Org. Chem., Vol. 69, No. 2, 2004

MetAP-2 Inhibitors Based on the Fumagillin Structure
TABLE 1. Com p a r ison of 1H NMR Sign a ls for Cin n a m yl Ester s 3, 4, 28, a n d 29
(1′R,2′R)-3
(1′S,2′S)-4
(1′R,2′R)-28
(1′S,2′S)-29
H-2′
H-2a
H-2b
H-5
δ 2.62 (t, J ) 6.4 Hz)
δ 2.54 (d, J ) 4.3 Hz)
δ 3.00 (d, J ) 4.3 Hz)
δ 3.70 (dd, 11.1, 2.8 Hz)
δ 2.70 (t, J ) 6.5 Hz)
δ 2.66 (d, J ) 4.5 Hz)
δ 3.34 (d, J ) 4.5 Hz)
δ 3.54 (dd, 11.5, 2.8 Hz.)
δ 2.59 (dd, J ) 8, 4.4 Hz)
δ 2.61 (d, J ) 4.3 Hz)
δ 2.91 (d, J ) 4.3 Hz)
δ 3.71 (dd, 11.1, 2.8 Hz.)
δ 2.62 (m)
δ 2.66 (d, J ) 4.5)
δ 3.30 (d, J ) 4.5)
δ 3.55 (dd, 11.3, 2.7 Hz)
TABLE 2. MetAP -2 In h ibition by F u m a gillin a n d
Sid e-Ch a in -Mod ified An a logu es
present case, however, considering the central role of 21
in our synthetic strategy, higher yields were highly
desirable. In this respect, switching to Grubbs type II
catalyst (Figure 4) proved to be very beneficial, raising
the RCM yield to a satisfactory 78%. This very good result
almost came as a surprise, considering the complete lack
of success of these RCM conditions when applied to the
synthesis of fumagillol itself. We hypothesize that the
increased reactivity of Grubbs type II catalyst as com-
pared to Grubbs type I allowed the trisubstituted (4′,5′)
double bond in the fumagillol series to participate to the
RCM process, either via RCM or cross-metathesis.
2
3
4
24
28
29
IC50 (nM) 10 ( 2 35 ( 10 .2500 15 ( 5 17 ( 3 .2500
The synthesis of 28, as compared to that of the
standard molecule 3 offers several distinct advantages:
(a) The highly efficient Grubbs II catalyst could be used
for the RCM of 20, leading to shorter reaction times and
improved yields (78% yield as compared to 53% for 6).
(b) The spiroepoxide 23 was obtained in 77% yield (53%
for the corresponding spiroepoxide in the synthesis of 3).5f
(c) The presence of a single double bond in 23 allowed us
to use a simple, high yielding, stereoselective m-CPBA-
based epoxidation procedure for installing the side chain
epoxide instead of the regioselective but poorly stereo-
selective hydroxyl-directed epoxidation required for the
synthesis of 3. At this point, the inhibitory activity
against MetAP-2 of the standard molecule 3 and its
dihydro analogue 28 were compared. To our pleasure,
both molecules showed similar potencies (35 nM vs 17
nM, respectively) (Table 2).17-19
In addition, we found out that epoxide 28 and olefin
24 were equally active, supporting Han’s observations.9
The most striking finding, however, was the complete
lack of activity of compound 29 (and analogue 4) (Table
2).
Although it is too early for drawing firm conclusions,
the data derived from this work added to available
information from the literature indicate that, in addition
to being directly involved in binding with MetAP-2, the
1′-2′ epoxide may play a role in optimizing the orienta-
With cyclohexenone 21 in hand, we moved on to the
synthesis of our first series of side-chain-modified ana-
logues (Scheme 6). Selective reduction of the conjugated
double bond in 21 was very cleanly effected with Raney
nickel.14 The resulting cyclohexanone 22 was converted
in good yield to a single isolated epoxide 23 by treatment
with the ylide derived from trimethylsulfoxonium iodide,
in the presence of LiI.5f,15 Oxidative removal of the PMB
protecting group and acylation by p-methoxycinnamic
acid yielded the p-methoxycinnamate 24, our first target
molecule. It should be noted that all cinnamyl derivatives
described in this work (24, 28, 29, 32, 39, 45, 51, and
60) contain predominantly (E) isomers but are always
contaminated by small amounts (ca. 10%) of the (Z)
isomer. This is of limited relevance with regard to
biological results, however. Previous work from Han has
shown that (Z)-6-cinnamyl analogues of fumagillin are
4 orders of magnitude less active than the (E)-isomers.9
From 23, epoxidation using m-CPBA led to the formation
of two epoxides, 25 and 26. Based upon literature
precedents, we attributed the (1′R,2′R) configuration to
the major isomer 25.16 Treatment of epoxide 25 with DDQ
and acylation of the resulting alcohol by p-methoxycin-
namic acid/DCC/DMAP afforded the (1′R,2′R) cinnamyl
ester 28. Similar treatment of the minor, (1′S,2′S) epoxide
26 gave the corresponding ester 29. The 1H NMR spectra
of 28 and 29 were compared to those of their unsaturated
analogues 3 and 4 obtained from fumagillol and (1′S,2′S)-
fumagillol, respectively, thus confirming the structures
of 28 and 29 and the validity of our earlier structure
assignment to 25 and 26 (Table 1).
(17) Briefly, recombinant human MetAP-2 was obtained and purified
to homogeneity according to the method decribed by X. Li and Y.-H.
Chang (see ref 18). All the assays were performed in buffer A (10 mM
Hepes buffer-pH 7.4 containing 10% glycerol and 0.5 mM CoCl2) with
MET-ALA-SER as the substrate (Km ) 0.7 mM).1 To an appropriate
amount of each enzyme sample, the substrate solution was added at
a final concentration of 1 mM and the reaction mixture was incubated
at 37 °C for 10-30 min. The reaction was stopped by adding 100 mM
EDTA or by placing the samples in a boiling bath for 2 min. The release
of the N-terminal methionine was quantified by measuring the
absorbance at 450 nm developed by incubation with the following color
reagent (see ref 19): 10 mM Hepes buffer, pH 7.4 (buffer B) containing
70 µg/mL of amino acid oxidase, 10 µg/mL of horseradish peroxidase
and 1 mM o-dianisidine for 30-60 min at 37 °C. Activities were
expressed as µmols of methionine produced by using the conversion
factor of 1 µmol of Met per mL ) 8.6 A450. IC50 were determined by
incubating the enzyme and its substrate (following the experimental
conditions described above) with increasing concentrations of inhibitor.
(18) Li, X.; Chang, Y.-H. Biochem. Biophys. Res. Commun. 1996,
227, 152-159
(14) Barrero, A. F.; Alvarez-Manzaneda, E. J .; Chahboun, R.;
Meneses, R. Synlett 1999, 1663-1666.
(15) Amano, S.; Ogawa, M.; Ohtsuka, M.; Childa, N. Tetrahedron
1999, 55, 2205-2224.
(16) In related side chain-modified fumagillin analogues, epoxidation
always occurs on the re-re face of the 1′,2′ olefinic double bond to afford
the (1′R,2′R) epoxide in large excess. See refs 4, 5a, 5b.
(19) Ben-Bassat, A.; Bauer, K.; Chang, S. Y.; Myambo, K.; Boosman,
A.; Chang, S. J . Bacteriol. 1987, 169, 751-757.
J . Org. Chem, Vol. 69, No. 2, 2004 361

Rodeschini et al.
SCHEME 8
F IGURE 5. Planned modification at C7 and C8 of the
fumagillin skeleton.
SCHEME 7 a
Switching to the Matteson’s method was successful,
giving the desired spiroepoxide 31sresulting from an
expected equatorial attack on the carbonyl groups(see
Figure 6 for structural proof) which was converted to
cinnamate 32.
Although the complete stereoselectivity of the reaction
21 f 30 was welcome from the synthetic standpoint, it
also meant that access to thesfor us equally interestings
(7R) isomer of 30 was not possible by the cuprate method.
Some years ago, Liotta, Maryanoff, et al. had shown that
deprotonated p-quinols undergo specific Michael addition
of Grignard compounds, whereby the newly introduced
alkyl or vinyl group ends up cis to the directing hydroxyl
group.20 Unfortunately, attempted treatment of cyclo-
hexenone 21′ with BuLi (to form the lithium alkoxide)
and then vinylmagnesium bromide failed (no 1,4-addition
was observed and 21′ was left unchanged).
More recently, Carren˜o et al. described a diastereose-
lective, sulfoxide-aided Michael addition of alkyl groups
to (R)-4-hydroxy-4-[(p-tolylsulfinyl)methyl]-2,5-cyclohexa-
dienones using excess trialkylalanes.21 The proposed
mechanism involves the transition state shown in Scheme
8, in which a first equivalent of trialkylalane is consumed
to form an aluminum alcoolate, further chelated by the
sulfoxyl oxygen, a second equivalent coordinates and
activates the carbonyl group toward nucleophilic addition
while a third equivalent forms a complex with the
aluminum alkoxide moiety and transfers an alkyl group
with total facial selectivity. We reasoned that cyclohex-
enone 21′ features a similar pattern of potential com-
plexing groups suggesting that the method could be
applied to our problem.
To our delight, as shown in Scheme 9, this proved to
be the case and treatment of 21′ with excess trimethy-
laluminum cleanly led to the stereoselective formation
of 33, along with carbinol 34, formed by the alternative
1,2-addition on the carbonyl group. Our belief that the
mechanism indicated in Scheme 8 is operative is con-
forted by two observations: no significant reaction was
observed when less than 3 equiv of trimethyl aluminum
were used and there is no conjugate addition when 21 is
used as a substrate. Trimethylsilylation of the free
hydroxyl group in 33 was followed by spiroepoxide
formation which, in this case, proceeded in high yield.22
a
Key: (a) Me2CuLi (1.1 equiv), Et2O, 0 °C, 1 h; (b) CH2I2 (5
equiv), BuLi (5 equiv), THF, -78 °C, 1 h f 20 °C, 1.5 h; (c) DDQ
(1.1 equiv), CH2Cl2/H2O, 20 °C, 1 h; (d) p-methoxycinnamic acid
(10 equiv), DCC (10 equiv), DMAP (10 equiv), CH2Cl2, 20 °C, 24
h.
tion of the side chain within the enzyme’s recognition site.
If this is true, it is easy to see on a simple model that
superimposing the “wrong” (1′S,2′S) and “correct” (1′R,2′R)
epoxides within the recognition site places the lipophilic
side chain in completely different locations. If no epoxide
is present, the side chain is free from constraints due to
hydrogen bonding involving the 1′-2′ epoxide and can
locate itself optimally. Although confirmation of this
proposal will obviously require additional work, the
MetAP-2 inhibition data led us to continue our studies
in the structurally simpler dihydro series i.e., starting
from cyclohexenone 21.
3. Cycloh exa n e Rin g Mod ifica tion . Having suc-
ceeded in identifying a simplified side chain for our
studies, we directed our research efforts to the modifica-
tion of the cyclohexane ring. Our aim at that stage was
not to extensively study structure-activity relationships
in the “western” part of the fumagillin molecule, a region
which we felt could be important for interaction with
MetAP-2, but rather to develop the methodologies needed
for accessing C7 and C8. For this purpose, the introduc-
tion of simple lipophilic (methyl, ethyl) or polar (hydroxyl)
groups was planned (Figure 5).
We first studied the introduction of alkyl groups at C7.
Cuprate chemistry is classically used for this type of
transformation. Accordingly, addition of Me2CuLi to the
cyclohexenone 21 afforded a single (within 1H NMR
detection limits) product 30 to which the structure
indicated in Scheme 7 was attributed on the basis of
1
conclusive H NMR data (see Figure 6). The high stereo-
selectivity of the cuprate conjugate addition was expected
and formation of a major isomer can be simply rational-
ized on the basis of steric effects as shown in Figure 6.
Disappointingly, initial epoxidation attempts using Co-
rey’s dimethylsulfoxonium methylide failed completely,
leading only to the formation of cyclopropane derivatives
resulting from elimination of the â-methoxy group in 30.
(20) (a) Solomon, M.; J amison, W. C. L.; McCormick, M.; Liotta, D.
C.; Cherry, D. A.; Mills, J . E.; Shah, R. D.; Rodgers, J . D.; Maryanoff,
C A. J . Am. Chem. Soc. 1988, 110, 3702-3704. (b) Swiss, K. A.;
Hinkley, W.; Maryanoff, C. A.; Liotta, D. C. Synthesis 1992, 127-131.
(21) (a) Carren˜o, M. C.; Perez-Gonzalez, M.; Ribagorda, M.; Houk,
K. N. J . Org. Chem. 1998, 63, 3687-3693. (b) Carren˜o M. C.; Perez-
Gonzalez, M.; Ribagorda M.; Fisher, J . J . Org. Chem. 1996, 61, 6758-
6759.
362 J . Org. Chem., Vol. 69, No. 2, 2004

MetAP-2 Inhibitors Based on the Fumagillin Structure
F IGURE 6. NOESY data for cyclohexyl part of 31 and rationale for the preferential formation of 30.
SCHEME 9 a
a
Key: (a) DDQ (1.1 equiv), CH2Cl2/H2O, 20 °C, 8 h; (b) AlMe3 (10 equiv), CH2Cl2, 20 °C, 4 h; (c) TMSCl (2.5 equiv), NEt3 (10 equiv),
DMAP (3 molar equiv), CH2Cl2, 20 °C, 1 h; (d) Me3S+OI- (15 equiv), NaH (10 equiv), LiI (12 equiv), DMSO/THF (1:1), 0 f 20 °C, 2 h; (e)
PPTS (0.1 molar equiv), MeOH/H2O (20:1), 20 °C, 24 h; (f) m-CPBA (1.5 equiv), NaHCO3 (6 equiv), CH2Cl2, 0 °C, 1 h; (g) p-methoxycinnamic
acid (10 equiv), DCC (10 equiv), DMAP (10 equiv), CH2Cl2, 20 °C, 16 h.
Removal of the TMS group was sluggish, probably due
to steric hindrance of the trimethylsilyloxy group by the
two neighboring substituents, affording alcohol 37 in
modest (30%) yield. Epoxidation of the 1′,2′-double bond
proceeded exceedingly well leading to a single epoxide
38 which was converted to cinnamyl ester 39 as described
previously.
To obtain some preliminary information about steric
requirements at C7, we also wanted to prepare the
7-ethyl analogue of 3. The synthesis, depicted in Scheme
9, is similar to that of 39 but, following introduction of
the ethyl group, the free hydroxyl was converted to the
corresponding benzoate which had been shown by Taber
to be compatible with the basic conditions of Corey’s
epoxidation.5b This modification was positive, leading to
a higher yield at the deprotection step. The other steps
in the synthetic sequence proceeded particularly well
providing the cinnamate 45 in good overall yield (Scheme
10).
C7-C8 double bond in 21 was best effected using H2O2/
K2CO3 in methanol24 and proceeded with complete ste-
reoselectivity to afford epoxide 46.25 Upon treatment by
the reagent prepared in situ from (PhSe)2 and NaBH4,
46 underwent regioselective opening leading to â-hydrox-
yketone 47. Protection of the hydroxyl group in 47 was
followed by formation of the spiroepoxide. At that point,
1
inspection of the H NMR spectrum confirmed the 7 (S)
3
configuration in 49 (see Figure 7 for relevant J values.
In particular, note the lack of large axial-axial coupling
between H-7 and one of the H-8’s). Finally, treatment
with cinnamic acid in the presence of DCC and DMAP
and removal of the silyl protecting groups yielded the
7-hydroxy analogue 51.
Finally, to complete our synthetic studies, we wanted
to establish methods allowing the preparation of C8-
substituted analogues of 3. Our approach was to intro-
duce an hydroxymethyl group at that positionswhich
seemed to be feasible via a Baylis-Hillman reactionsand
to use the hydroxyl group as a starting point for further
modification. This approach, which proved to be fruitful,
although in an unexpected way, is shown in Scheme 12.
Our method for introducing an hydroxyl group at C7
which is shown in Scheme 11, is based upon previous
Miyashita’s work on the organoselenium-mediated reduc-
tion of R,â-epoxyketones.23 Epoxidation of the conjugated
(23) Miyashita, M.; Suzuki, T.; Hoshino, M.; Yoshikoshi, A. Tetra-
hedron 1997, 53, 12469-12486.
(22) Attempted epoxidation of alcohol 33 led to the exclusive
formation of a cyclopropyl ketone as observed earlier. Facile intramo-
lecular deprotonation by the alcoolate derived from OH-6 followed by
â-elimination of the methoxy group may explain this result. During
this work, this type of â-elimination constantly constituted a potential
problem which required particular attention.
(24) The alternative TBHP/triton B method led to erratic results
(yields ranging from 25% to 75%) the major problem being the oxidation
of the PMB group to the corresponding p-methoxybenzoate.
(25) On the basis of literature precedents, the epoxide function was
expected to be located trans to the OPMB group: Barros, M. T.;
Maycock, C. D.; Ventura, M. R. J . Org. Chem. 1997, 62, 3984-3988.
J . Org. Chem, Vol. 69, No. 2, 2004 363

Rodeschini et al.
SCHEME 10 a
a
Key: (a) AlEt3 (10 equiv), CH2Cl2, 20 °C, 4 h; (b) Benzoic acid (10 equiv), DCC (10 equiv), DMAP (10 equiv), CH2Cl2, 20 °C, 16 h; (c)
Me3S+OI- (15 equiv), NaH (10 equiv), LiI (12 equiv), DMSO/THF (1:1), 0 f 20 °C, 2 h; (d) m-CPBA (1.5 equiv), NaHCO3 (6 equiv),
CH2Cl2, 20 °C, 1 h; (e) K2CO3, MeOH, 20 °C, 16 h; (f) p-methoxycinnamic acid (12 equiv), DCC (12 equiv), DMAP (12 equiv), CH2Cl2, 20
°C, 16 h.
SCHEME 11 a
a
Key: (a) H2O2 (3 equiv), K2CO3, (0.1 equiv), MeOH, 0 °C, 30 min; (b) (PhSe)2 (1.5 equiv), NaBH4 (3 equiv), AcOH (0.5 equiv), 0 °C, 15
i
min; (c) Pr(Me)2SiCl (1.5 equiv), DMAP (2 equiv), DMF/THF (1/1: v/v), 20 °C, 1 h; (d) CH2I2 (5 equiv), BuLi (5 equiv), -78 °C, 1 h f 20
°C, 1.5 h; (e) DDQ (1.2 equiv), CH2Cl2/H2O, 20 °C, 2 h; (f) (i) p-methoxycinnamic acid (10 equiv), DCC (10 equiv), DMAP (10 equiv),
CH2Cl2, 20 °C, 36 h, (ii) TBAF (1 equiv), 20 °C, 30 min.
tion of the conjugated double could be effected, however,
using Et3SiH (TESH) in the presence of Wilkinson’s
catalyst, affording silyl enol ether 54.27 Our plans were
then to remove the TES group, form the spiroepoxide and
introduce further functionality based on the hydroxyl
group modification. In fact, formation of the desired R-hy-
droxymethyl cyclohexanone was never observed. Instead,
cleavage of the TES group by fluoride treatment led to
double elimination of the TBS and (again) the methoxy
group to afford an R,â-R′,â′ doubly unsaturated ketone,
F IGURE 7. Coupling constants in spiroepoxide 49.
while acidic treatment of 54 cleanly afforded the R,â-
unsaturated ketone 55. Although the expected intermedi-
ate was not obtained, 55 fulfils our requirements even
better. For example, RaNi reduction led to a mixture of
the two C8 derivatives 56 and 57. We found that only
ketone 57 underwent epoxidation, using Matteson’s con-
ditions to give a single epoxide 58 in 54% yield probably
reflecting the increased steric hindrance on both faces of
the carbonyl group in 56, relative to 57. The synthesis
The synthesis commences by the treatment of cyclohex-
enone 21 with formaldehyde, in the presence of tribu-
tylphosphine to give the hydroxymethylated derivative
52 in good yield.26 We had initially planned to reduce the
conjugated system in 53 by RaNi, a reaction which had
proved very reliable when applied to 21. Unfortunately,
53 was unreactive under a variety of conditions. Reduc-
(26) (a) Kabat, M. M.; Kiegel, J .; Cohen, N.; Toth, K.; Wovkulich, P.
M.; Uskokov´ıc, M. R. J . Org. Chem. 1996, 61, 118-124. (b) Taylor, R.
J . K.; Thorsten, G. Tetrahedron Lett. 2002, 43, 3573-3576.
(27) Liu, H.-J .; Browne, E. N. C. Can. J . Chem. 1980, 59, 601-607.
364 J . Org. Chem., Vol. 69, No. 2, 2004

MetAP-2 Inhibitors Based on the Fumagillin Structure
F IGURE 8. Structure determination of ketone 57 and epoxide 58: relevant NMR data.
SCHEME 12 a
a
Key: (a) PBu3 (0.85 equiv), HCHO, (40% in water, 2.6 equiv), THF, 20 °C, 16 h; (b) TBSCl (1.1 equiv), DMAP (1.5 equiv), THF, 20 °C,
4 h; (c) Et3SiH (35 equiv), RhCl(PPh3)3 (0.03 molar equiv), toluene, 65 °C, 4 h; (d) TFA (1 M, 1 molar equiv), THF/H2O (1/1 v/v), 20 °C, 1.5
h; (e) RaNi, THF, 0 °C, 2 h; (f) CH2I2 (5 equiv), BuLi (5 equiv), -78 °C, 45 min f 20 °C, 1.5 h; (g) DDQ (1.2 equiv), CH2Cl2/H2O, 20 °C,
1 h; (h) p-methoxycinnamic acid (10 equiv), DCC (10 equiv), DMAP (10 equiv), CH2Cl2, 20 °C, 16 h.
TABLE 3. MetAP -2 In h ibition by F u m a gillin a n d
Rin g-m od ified An a logu es
strategy was 2-fold: in the first part of the work, we
identified a simplified side chain compatible with biologi-
cal activity. In the second part, methods were developed
aimed at modifying a precise, difficult to access, part of
the fumagillin molecule and a series of simple analogues
were prepared.
2
3
32
39
45
51 60
IC50 (nM) 10 ( 2 35 ( 10 250 95 ( 5 >2500 35 70
was completed to give our last target molecule, the
In the course of our synthesis, a new (to the best of
our knowledge), efficient, and stereoselective conjugate
addition of organoaluminum compounds to highly func-
tionalized R,â-unsaturated ketones was discovered. In our
case, the method, whose scope we have not yet examined,
nicely complemented the conjugate addition of cuprates.
We have also developed a mild one-pot reduction/
elimination sequence of R-hydroxymethyl-R,â-unsatur-
ated ketones which may be of general usefulness for the
formation of sensitive R-methylene ketones.
cinnamate 60 (see structure determination in Figure 8).
The results obtained in the inhibition assay are shown
in Table 3. As can be seen, introduction of substituents
at positions 7 or 8 of the fumagillin skeleton is compatible
with biological activity in the MetAP-2 assay. The pos-
sibilities for modification in this area of the molecule,
however, appear to be limited as shown by the sharp
decrease of activity when replacing H by Me, then Et at
position 7 (compare 3, 39, and 45). Introduction of a
hydroxyl group at the same position is also possible, as
well as a methyl group at position 8. None of these
modifications, however, led to an improvement of the
biological activity as compared to the standard com-
pounds 2 and 3.
The results obtained with the side-chain-modified
analogues 24, 28, and 29 show that the side-chain
epoxide is dispensable, in line with Liu’s observations.
However, the striking difference between the two ep-
oxides 28 and 29 suggests that, besides its possible role
as H-bond acceptor, the 1′-2′ epoxide may help correctly
orientating the side chain of fumagillin and analogues
4. Con clu sion . In summary, we have demonstrated
the validity of the RCM-based approach for the synthesis
of new types of modified fumagillin analogues. Our
J . Org. Chem, Vol. 69, No. 2, 2004 365

Rodeschini et al.
extracted with AcOEt. The organic layers were combined,
washed with brine, and dried over Na2SO4, and the solvent
was evaporated in vacuo. The residue was dissolved in ether
(50 mL) and treated with excess CH2N2. Solvent removal and
chromatography (SiO2, cyclohexane f cyclohexane/AcOEt 8/2)
for recognition by MetAP-2. More research to check the
validity of this hypothesis is warranted.
Preliminary results obtained with the C7-C8-modified
compounds suggest that modification in this part of the
fumagillin skeleton is limited to the introduction of small
substituents. This, of course would have to be confirmed
in more detailed studies which should include other type
of small polar, acidic, or basic substituents.
afforded pure 10 (8.42 g, 63%) as a colorless oil. [R]20 ) +7 (c
D
) 1.74, CHCl3). 1H NMR (400 MHz, CDCl3): 7.49 (m, 2 H);
7.26 (m, 3 H); 4.32 (ddd, J ) 8.0, 5.3, 4.0 Hz, 1 H); 3.77 (s, 3
H); 3.01 (dd, J ) 8.0, 7.2 Hz, 2 H); 2.79 (d, J ) 5.3 Hz, 1 H);
2.16 and 2.03 (m, 2 H). 13C NMR (100 MHz, CDCl3): 175.0,
132.4, 129.6, 129.0, 126.8, 69.7, 52.5, 34.5, 22.6.
Exp er im en ta l Section
Meth yl (2R)-2-p-Meth oxyben zyloxy-4-p h en ylsela n ylb-
u ta n oa te (11). Camphorsulfonic acid (3.2 g, 13.7 mmol) was
added to a solution of 10 (18.7 g, 68.5 mmol) and freshly
prepared p-methoxybenzyl trichloroacetimidate (38.7 g, 137
mmol) in dichloromethane (150 mL). The mixture was stirred
at 20 °C for 24 h and quenched with a saturated solution of
NaHCO3. The mixture was partitioned between ethyl acetate
and water, and the organic layer was dried and concentrated
in vacuo. The residue was chromatographed (SiO2, eluent/
Gen er a l Meth od s. All manipulations were carried out in
dry solvents under an atmosphere of dry Ar. Commercially
available reagents were used without further purification.
Et2O and THF were freshly distilled from Na/benzophenone
prior to use. DMF, CH2Cl2, and toluene were distilled from
CaH2. Evaporations of solvents were done with a rotary
evaporator. Flash chromatography was conducted on silica gel
(230-400 mesh). 1H NMR were performed at 250 or 400 MHz
and 13C NMR at 62.9 or 100 MHz and calibrated on residual
solvents signals.
cyclohexane/AcOEt 8/2) to afford pure 11 (18.94 g, 70%). [R]20
D
1
) +67 (c ) 1.0, CHCl3). H NMR (250 MHz, CDCl3): 7.47 (m,
2H); 7.26 (m, 5H); 6.86 (d, J ) 8.5 Hz, 2H); 4.62 and 4.29 (2d,
J ) 11.0 Hz, 2H); 4.10 (dd, J ) 4.5, 8.0 Hz, 1H); 3.80 (s, 3H);
3.75 (s, 3H); 2.97 (m, 2H); 2.10 (m, 2H). 13C NMR (62.9 MHz,
CDCl3): 172.9, 159.4, 132.6, 129.7, 129.3, 129.0, 126.9, 113.7,
76.6, 72.1, 55.2, 51.9, 33.4, 23.3. Anal. Calcd for C19H22O4Se:
C, 58.02; H, 5.64. Found: C, 58.12. H, 5.65.
p-Meth oxycin n a m ic Acid (3R,4S,5S,6R)-5-Meth oxy-4-
[(1R,2R)-1,2-epoxy-1,5-d im eth ylh exyl]-1-oxa spir o[2.5]oct-
6-yl Ester (3). p-Methoxycinnamic acid (70 mg, 396 µmol, 8
equiv), followed by DMAP (48 mg, 396 µmol, 8 equiv) and DCC
(50 mg, 396 µmol, 8 equiv) were added to a solution of
fumagillol (14 mg, 49 µmol) in CH2Cl2 (1 mL). The mixture
was stirred for 5 h at 20 °C, and then the solvent was removed
in vacuo and the residue passed over a short pad of silica gel
(cyclohexane/AcOEt 1/1). Chromatography on preparative TLC
(hexane/ethyl acetate, 8/2) afforded pure 3 (19.7 mg, 88%) as
(2R)-2-p -Met h oxyb en zyloxy-4-p h en ylsela n ylb u t a n a l
(12). A solution of DIBAL-H (1.5 M in toluene, 1 mL, 1.5 mmol,
1.5 equiv) was added at -78 °C to a solution of ester 11 (400
mg, 1.02 mmol, 1 equiv) in 2 mL of toluene. The mixture was
stirred 20 min at -78 °C, anhydrous methanol (1 mL) was
added, and the cold bath was removed, allowing the reaction
to reach room temperature. Cyclohexane (40 mL) followed by
40 mL of brine were added. The two-phase mixture was
separated, and the aqueous phase was extracted six times with
cyclohexane. The combined organic phases were dried over
MgSO4, filtered, and evaporated in vacuo. 12 (250 mg, 68%)
was obtained as a slightly yellow oil, which was used for the
next step without further purification (this unstable material
readily epimerizes when exposed to silica gel chromatography).
a colorless oil. [R]20 ) -45 (c ) 95, CHCl3). 1H NMR (250
D
MHz, CDCl3): 7.62 (d, J ) 16 Hz, 1H); 7.46 and 6.89 (2d, J )
8.8 Hz, 4H); 6.36 (d, J ) 16 Hz, 1H); 5.74 (m, 1H); 5.21 (tm, J
) 7.4 Hz, 1H); 3.83 (s, 3H); 3.70 (dd, J ) 2.8, 11.1 Hz, 1H);
3.45 (s, 3H); 3.00 (d, J ) 4.3 Hz, 1H); 2.62 (t, J ) 6.4 Hz, 1H);
2.54 (d, J ) 4.3 Hz, 1H); 2.37 (m, 1H); 2.23-1.80 (m, 4H); 2.05
(d, J ) 11.1 Hz, 1H); 1.74 (s, 3H); 1.65 (s, 3H); 1.23 (s, 3H);
1.10 (ddd, J ) 2.7, 4.6, 13.4 Hz, 1H). 13C NMR (62.9 MHz,
CDCl3): 166.9, 161.3, 144.5, 134.8, 129.7, 127.2, 118.6, 115.9,
114.3, 79.2, 66.2, 61.0, 59.5, 58.5, 56.6, 55.3, 50.9, 48.3, 29.4,
27.4, 25.7, 25.7, 18.0, 13.9.
[R]20 ) +50 (c ) 1.6, CHCl3). 1H NMR (250 MHz, CDCl3):
D
9.64 (d, 1H, J ) 1.6); 7.48 (d, J ) 8.8 Hz, 2H); 7.25 (m, 5H);
6.88 (d, J ) 8.8 Hz Hz, 2H); 4.48 and 4.44 (2d, J ) 11.3 Hz,
2H); 3.93 (ddd, J ) 7.0, 5.2, 1.6 Hz, 1H); 3.80 (s, 3H); 2.99 (m,
2H); 2.02 (m, 2H). 13C NMR (62.9 MHz, CDCl3): 203.0, 159.5,
132.7, 129.7, 129.1, 129.0, 127.0, 113.9, 82.2, 72.3, 55.2, 30.6,
22.8. Anal. Calcd for C18H20O3Se: C, 59.51; H, 5.55. Found:
C, 58.91. H, 5.55.
p-Meth oxycin n a m ic Acid (1R,4S,5S,6R)-5-Meth oxy-4-
[(1S,2S)-1,2-ep oxy-1,5-d im eth ylh exyl]-1-oxa sp ir o[2.5]oct-
6-yl Ester (4). p-Methoxycinnamic acid (75 mg, 425 µmol, 10
equiv) followed by DMAP (52 mg, 425 µmol, 10 equiv) and DCC
(87 mg, 425 µmol, 10 equiv) were added to a solution of 1′,
2′-epi-fumagillol (12 mg, 42 µmol) in CH2Cl2 (1 mL). The
mixture was stirred for 5 h at 20 °C, and then the solvent was
removed in vacuo and the residue passed over a short pad of
silica gel (cyclohexane/AcOEt 1/1). Chromatography on pre-
parative TLC (hexane/ethyl acetate, 7/3) afforded 4 (16.7 mg,
((3E)-4-Iodo-3-m eth ylbu t-3-en yloxy)tr im eth ylsilan e (13).
Butyn-1-ol (5 mL, 66 mmol) was slowly added (ca. 3 h) to a
cold (0 °C) solution containing Cp2ZrCl2 (7.5 g, 25 mmol, 0.4
equiv) and AlMe3 (2 M in toluene, 100 mL, 200 mmol) in 1,2-
dichloroethane (150 mL). The mixture was stirred at 20 °C
for 24 h, and a solution of iodine (20 g, 78 mmol, 1.2 equiv) in
THF (75 mL) was slowly added while keeping the internal
temperature at -30 °C. The cold bath was removed, allowing
the temperature to reach 0 °C, and the mixture was cannu-
lated to a saturated aqueous NaHCO3 solution. The mixture
was extracted four times with a mixture of cyclohexane and
ether (2/1), the organic layers were combined, washed with
brine, and dried, and the solvent was removed. The residue
was dissolved in THF (100 mL) and treated with imidazole
(20 g, 290 mmol, 4.5 equiv) and TBSCl (9 g, 60 mmol, 0.9
equiv). The mixture was stirred at 20 °C for 1 h, quenched
(NH4Cl), and extracted with ether. The organic layers were
combined, washed with brine, and dried, and the solvent was
removed. The residue was filtered through silica gel with ether
as eluent. 13 (16.7 g, 78%) was obtained as a slightly yellow
91%), which contains 10% of the Z-isomer. [R]20 ) -184 (c )
D
0.825, CHCl3). 1H NMR (250 MHz, CDCl3): 7.63 (d, J ) 16
Hz, 1H); 7.48 and 6.90 (2d, J ) 8.8 Hz, 4H); 6.32 (d, J ) 16
Hz, 1H); 5.70 (m, 1H); 5.17 (tm, J ) 7.0 Hz, 1H); 3.84 (s, 3H);
3.54 (dd, J ) 2.8, 11.5 Hz, 1H); 3.37 (s, 3H); 3.33 (d, J ) 4.5
Hz, 1H); 2.70 (t, J ) 6.5 Hz, 1H); 2.66 (d, J ) 4.5 Hz, 1H);
2.34-1.81 (m, 5H); 2.02 (d, J ) 11.5 Hz, 1H); 1.69 (s, 3H);
1.60 (s, 3H); 1.24 (s, 3H); 1.08 (ddd, J ) 2.7, 4.0, 13.3 Hz, 1H).
13C NMR (62.9 MHz, CDCl3): 166.6, 161.4, 144.6, 133.6, 129.8,
127.0, 118.9, 115.7, 114.3, 79.6, 66.2, 64.3, 59.8, 59.3, 56.8, 55.4,
51.9, 48.0, 29.4, 27.4, 25.9, 25.8, 18.0, 13.3.
Meth yl (2R)-2-Hydr oxy-4-ph en ylselan ylbu tan oate (10).
To a solution of diphenyl diselenide (13.7 g, 44 mmol, 0.9 equiv)
in THF (60 mL) was added NaH (60% in oil, 3.49 g, 87.3 mmol,
1.8 equiv). The mixture was stirred for 1 h at 60 °C, then cooled
to 0 °C. 18-C-6 crown ether (650 mg, 2.5 mmol, 0.05 equiv)
was added, followed by a solution of (R)-(+)-R-hydroxybuty-
rolactone (5.00 g, 49 mmol) in THF (10 mL). The mixture was
stirred for 2 h at 20 °C, quenched at 0 °C with 1 M HCl, and
1
oil. H NMR (250 MHz, CDCl3): 5.92 (m, 1H); 3.68 (t, J ) 6.6
Hz, 2H); 2.41 (td, J ) 6.6, 1.1 Hz, 2H); 1.85 (s, 3H); 0.89 (s,
366 J . Org. Chem., Vol. 69, No. 2, 2004

MetAP-2 Inhibitors Based on the Fumagillin Structure
9H); 0.04 (s, 6H). 13C NMR (62.9 MHz, CDCl3): 145.0, 76.4,
61.3, 42.6, 25.9, 24.3, 18.2, -5.2.
(1.6 M in hexanes, 12.85 mL, 20.56 mmol). The mixture was
stirred for 15 min at 0 °C and then cooled to -78 °C, and a
solution of 16 (6.76 g, 20.56 mmol) in THF (10 mL) was added.
The mixture was stirred for 30 min, and aldehyde 12 (8.28 g,
22.62 mmol) in THF (10 mL) was added. The mixture was
stirred for 1 h at -78 °C, quenched with ammonium chloride,
allowed to reach 20 °C, and extracted with ether. The combined
organic layers were dried and the solvent was removed in
vacuo. The residue was dissolved in CHCl3 (60 mL) and treated
with tetrabutylammonium periodate (19.6 g, 45.2 mmol, 2
equiv) for 2 h at 60 °C. Solvent removal and chromatography
(SiO2, cyclohexane/AcOEt 9/1 f 8/2) afforded diastereomeri-
(3E)-3,7-Dim eth yloct-3-en ol (14). To a suspension of
magnesium (965 mg, 39.7 mmol, 2.4 equiv) in THF (20 mL)
was slowly added a solution of 1-bromo-3-methylbutane (3.96
mL, 33.0 mmol, 2 equiv) in THF (15 mL). After nearly all the
magnesium has been consumed, the mixture was heated for 1
h at 70 °C. The mixture was then cooled to 0 °C, and a THF
solution of ZnCl2 (1 M, 35 mL, 35 mmol, 2.1 equiv) was added.
The mixture was stirred for 1 h at 20 °C, cooled to 0 °C, and
treated with Pd(PPh3)4 (350 mg, 0.34 mmol, 0.02 equiv), and
then a solution of compound 13 (5 g, 15.3 mmol) in THF (25
mL) was added. The mixture was stirred overnight at 20 °C,
quenched (NH4Cl), and extracted with cyclohexane. The
combined organic layers were dried, solvent was removed, and
the residue was filtered through cotton wool. This oil was then
dissolved in THF (50 mL) and treated with TBAF (1 M in THF,
16 mL, 16 mmol, 1.1 equiv) for 2 h at 20 °C. The reaction was
stopped (NH4Cl solution) and extracted with ether. The
combined organic layers were dried over Na2SO4, and the
solvent was removed in vacuo. Chromatography (SiO2, cyclo-
hexane/AcOEt 98/2 f 75/25) finally yielded pure 14 (1.84 g,
cally pure 17 (5.83 g, 55%). [R]20 ) -129 (c ) 1.45, CHCl3).
D
1H NMR (250 MHz, CDCl3): 7.37-7.20 (m, 5H); 7.11 (m, 2H);
6.83 (d, J ) 8.6 Hz, 2H); 5.92 (ddd, J ) 8.0, 10.3, 17.2 Hz,
1H); 5.56 (tm, J ) 7.0 Hz, 1H); 5.43 and 5.34 (2dd, J ) 1.8,
10.3 Hz and J ) 1.8, 17.2 Hz, 2H); 4.77 (d, J ) 8.7 Hz, 1H);
4.54 (d, J ) 10.8 Hz, 1H); 4.43 (m, 1H); 4.31 (ddd, J ) 3.6,
6.3, 8.7 Hz, 1H); 4.26 (d, J ) 10.8 Hz, 1H); 4.01 (m, 2H); 3.75
(m, 1H); 3.69 (s, 3H); 3.08 (dd, J ) 3.1, 13.2 Hz, 1H); 2.19 (d,
J ) 3.6 Hz, 1H); 2.05 (br q, J ) 7.3 Hz, 2H); 1.86 (dd, J )
10.9, 13.2 Hz, 1H); 1.73 (s, 3H); 1.50 (m, 1H); 1.21 (m, 2H);
0.85 (d, J ) 6.6 Hz, 6H). 13C NMR (62.9 MHz, CDCl3): 171.8,
159.2, 152.7, 135.8, 135.7, 133.7, 130.1, 130.0, 129.4, 128.8,
127.1, 120.3, 113.7, 83.3, 72.0, 70.4, 65.6, 55.9, 55.1, 53.8, 38.4,
37.0, 27.7, 26.1, 22.5, 22.4, 14.6.
1
77%) as a colorless oil. H NMR (250 MHz, CDCl3): 5.22 (br t,
J ) 7 Hz, 1H); 3.63 (t, J ) 6.2 Hz, 2H); 2.22 (t, J ) 6.2 Hz,
2H); 1.99 (br q, J ) 7.5 Hz, 2H); 1.61 (s, 3H); 1.53 (m, 1H);
1.22 (m, 2H); 0.86 (d, J ) 6.6 Hz, 6H). 13C NMR (62.9 MHz,
CDCl3): 130.7, 128.2, 60.1, 42.6, 38.9, 27.6, 25.6, 22.4, 15.6.
Anal. Calcd for C10H20O: C, 76.86; H, 12.90. Found: C, 76.68.
H, 12.89.
(2S)-2-[(1S,2R)-1-Hyd r oxy-2-p-m eth oxyben zyloxybu t-
3-en yl]-3,7-d im eth ylocta -3-en oic Acid Meth oxym eth yla -
m id e (18). A solution of trimethylaluminum in toluene (2 M,
19 mL, 37.9 mmol, 3.5 equiv) was added to a cold (0 °C)
suspension of N,O-dimethylhydroxylamine hydrochloride (3.70
g, 37.9 mmol, 3.5 equiv) in THF (20 mL). The mixture was
stirred at 20 °C for 30 min and then cooled to 0 °C. A solution
of aldol 17 (5.79 g, 10.8 mmol) in THF (10 mL) was added.
The mixture was stirred overnight at 20 °C and then poured
slowly onto a cold aqueous solution of tartaric acid (25%).
Extraction with AcOEt and chromatography (SiO2, cyclohex-
ane/AcOEt 85/15 f 8/2) afforded 18 (3.41 g, 75%) as a colorless
(3E)-3,7-Dim eth yloct-3-en oic Acid (15). A cold (0 °C)
solution of CrO3 (8.84 g, 88.4 mmol, 3 equiv) in water (25 mL)
and 95% H2SO4 (8.2 mL) was added to a solution of alcohol 14
(4.6 g, 29.5 mmol) in acetone (250 mL) while keeping the
temperature at 0 °C. The mixture was stirred a further 15
min at 0 °C, quenched with water (250 mL), and extracted
with ether. The combined organic layers were washed with
brine and dried over Na2SO4, and the solvent was removed in
vacuo. Chromatography (SiO2, cyclohexane/AcOEt 95/5 f 75/
25) finally gave pure 15 (3.26 g, 65%) as a colorless oil. 1H
NMR (250 MHz, CDCl3): 7.5 (br s, 1H); 5.30 (br t, J ) 6.6 Hz,
1H); 3.01 (s, 2H); 2.03 (br q, J ) 7.5 Hz, 2H); 1.70 (s, 3H); 1.55
(m, 1H); 1.22 (m, 2H); 0.88 (d, J ) 6.6 Hz, 6H). 13C NMR (62.9
MHz, CDCl3): 177.9, 130.5, 127.3, 44.7, 38.5, 27.6, 25.9, 22.5,
16.2.
oil. [R]20 ) -125 (c ) 0.975, CHCl3). 1H NMR (250 MHz,
D
CDCl3): 7.25 and 6.87 (2d, J ) 8.6 Hz, 4H); 5.89 (ddd, J )
8.1, 10.3, 17.2 Hz, 1H); 5.39 (dd, J ) 2.0, 10.3 Hz, 1H); 5.36
(m, 1H); 5.30 (dd, J ) 2.0, 17.2 Hz, 1H); 4.52 and 4.26 (2d, J
) 11.0 Hz, 2H); 4.18 (dt, J ) 2.1, 6.2 Hz, 1H); 3.80 (s, 3H);
3.79 (m, 1H); 3.70 (br m, 1H); 3.61 (s, 3H); 3.31 (br s, 1H);
3.12 (s, 3H); 2.06 (br q, J ) 7.1 Hz, 2H); 1.73 (s, 3H); 1.54 (m,
1H); 1.22 (m, 2H); 0.87 (d, J ) 6.6 Hz, 6H). 13C NMR (62.9
MHz, CDCl3): 159.0, 135.5, 131.8, 130.5, 129.6, 129.3, 119.7,
113.7, 81.2, 72.9, 69.7, 61.0, 55.2, 51.3, 38.6, 32.0, 27.7, 26.0,
22.5, 22.4, 15.2.
(4R)-4-Ben zyl-3-[3(E)-(3,7-d im et h yloct a -3-en oyl)]-ox-
a zolid in -2-on e (16). Acid 15 (5.72 g, 33.6 mmol) was dissolved
in CH2Cl2 (60 mL) and treated with oxalyl chloride (3.12 mL,
37.0 mmol, 1.1 equiv) and a few drops DMF at 0 °C. Stirring
was continued for 1 h at 0 °C and for another 3 h at 20 °C,
after which the solvent was evaporated in vacuo. Meanwhile,
(R)-(-)-4-benzyl-2-oxazolidinone (6.85 g, 38.6 mmol, 1.15 equiv)
was dissolved in THF (80 mL) and treated at -78 °C with BuLi
(1.6 M in hexanes, 25.2 mL, 40.2 mmol, 1.2 equiv) for 30 min.
The crude acid chloride was dissolved in THF (100 mL) and
added to the lithio oxazolidinone at -78 °C. Stirring was
continued for 2 h at -78 °C and overnight at 0 °C. The solution
was poured into aqueous NH4Cl solution and extracted with
ether. The combined organic layers were dried over MgSO4,
filtered, and evaporated. Chromatography (SiO2, cyclohexane/
(2S)-2-[1S,2R)-1-Meth oxy-2-p-m eth oxyben zyloxybu t-3-
en yl]-3,7-d im eth ylocta -3-en oic Acid Meth oxym eth yla -
m id e (19). To a suspension of Ag2O (8 g, 35 mmol, 5 equiv)
and activated 4 Å molecular sieves (2 g) in Et2O (10 mL) were
added alcohol 18 (2.96 g, 7 mmol) and MeI (8 mL). The
suspension was stirred overnight at 45 °C and then filtered
through Celite. The residue was chromatographed (SiO2,
cyclohexane/AcOEt 9/1) to afford pure 19 (2.8 g, 93%) as a
colorless oil. [R]20 ) -121 (c ) 1.0, CHCl3). 1H NMR (250
D
MHz, CDCl3): 7.26 and 6.85 (2d, J ) 8.6 Hz, 4H); 5.92 (ddd, J
) 8.1, 10.3, 17.3 Hz, 1H); 5.36 (br t, J ) 7.1 Hz, 1H); 5.31 (dd,
J ) 2.1, 10.3 Hz, 1H); 5.20 (dd, J ) 2.0, 17.3 Hz, 1H); 4.51
and 4.34 (2d, J ) 11.4 Hz, 2H); 3.98 (dd, J ) 3, 9.9 Hz, 1H);
3.80 (m, 1H); 3.79 (s, 3H); 3.58 (s, 3H); 3.49 (br m, 1H); 3.46
(s, 3H); 3.07 (s, 3H); 2.00 (br q, J ) 7.4 Hz, 2H); 1.72 (s, 3H);
1.53 (m, 1H); 1.23 (m, 2H); 0.86 (d, J ) 6.6 Hz, 6H). 13C NMR
(62.9 MHz, CDCl3): 158.8, 135.4, 130.9, 130.7, 129.9, 129.0,
119.2, 113.5, 82.9, 82.8, 69.9, 61.0, 60.9, 55.2, 52.0, 38.5, 32.3,
27.6, 25.9, 22.5, 22.5, 15.3. Anal. Calcd for C25H39NO5: C,
69.25; H, 9.07; N, 3.23. Found: C, 68.99. H, 9.24. N, 3.15.
AcOEt 95/5 f 8/2) gave 16 (9.16 g, 83%) as a colorless oil. [R]20
D
1
) -53 (c ) 1.02, CHCl3). H NMR (250 MHz, CDCl3): 7.37-
7.20 (m, 5H); 5.30 (tm, J ) 6.7 Hz, 1H); 4.67 (dddd, J ) 3.0,
3.5, 7.0, 10.0 Hz, 1H); 4.18 (ABX, 2H); 3.62 (AB, 2H); 3.32 (dd,
J ) 3.3, 13.3 Hz, 1H); 2.75 (dd, J ) 9.8, 13.3 Hz, 1H); 2.06 (br
q, J ) 7.4 Hz, 2H); 1.72 (s, 3H); 1.55 (m, 1H); 1.24 (m, 2H);
0.88 (d, J ) 6.5 Hz, 6H). 13C NMR (62.9 MHz, CDCl3): 171.6,
153.3, 135.3, 130.2, 129.4, 128.9, 127.6, 127.3, 66.1, 55.2, 45.4,
38.6, 37.8, 27.6, 25.9, 22.5, 16.6.
(4R)-4-Ben zyl-3-[(2S)-2-[(1S,2R)-1-h yd r oxy-2-p -m et h -
oxyb en zyloxyb u t -3-en yl]-3,7-d im et h yloct a -3-en oyl]ox-
a zolid in -2-on e (17). To a cold (0 °C) solution of diisopropy-
lamine (2.88 mL, 20.56 mmol) in THF (10 mL) was added BuLi
(4S)-4-((1S,2R)-1-Meth oxy-2-p-m eth oxyben zyloxybu t-
3-en yl)-5,9-d im eth yld eca -1,5-d ien -3-on e (20). To a cold (0
°C) solution of amide 19 (877 mg, 2.02 mmol) in THF (5 mL)
J . Org. Chem, Vol. 69, No. 2, 2004 367

Rodeschini et al.
was added vinylmagnesium bromide (1 M in THF, 10 mL, 10
mmol, 5 equiv). After being stirred for 12 h at 20 °C, the
mixture was cannulated onto 20 mL of a 2:1 (v/v) mixture of
saturated ammonium chloride and THF. After extraction
(ether) and chromatography (SiO2, cyclohexane/AcOEt 95/5),
81.9, 71.1, 70.3, 61.9, 57.4, 55.3, 38.6, 35.8, 27.6, 25.9, 24.5,
22.5, 22.5, 14.1.
(3R,4S,5S,6R)-4-[-(E)-1,5-Dim eth ylh ex-1-en yl]-5-m eth -
oxy-6-p-m eth oxyben zyloxy-1-oxa sp ir o[2.5]octa n e (23). To
a suspension of NaH (40 mg, 1.01 mmol, 10 equiv) in DMSO
(1 mL) was added trimethylsulfoxonium iodide (334 mg, 1.52
mmol, 15 equiv). The mixture was stirred at 20 °C for 1 h.
THF (1 mL) and lithium iodide (163 mg, 1.21 mmol, 12 equiv)
were added to the mixture, and stirring was continued for
further 40 min. A solution of 22 (38 mg, 101 µmol) in DMSO/
THF (1/1, 1 mL) was added at 0 °C. The mixture was stirred
for 30 min at 20 °C and quenched with ether (5 mL) and pH
7 buffer (5 mL). Extraction with ether and chromatography
(SiO2, cyclohexane/AcOEt 9/1) afforded pure 23 (colorless oil,
pure 20 was obtained (689 mg, 86%). [R]20 ) -293 (c ) 1.07,
D
CHCl3). 1H NMR (250 MHz, CDCl3): 7.24 and 6.86 (2d, J )
8.6 Hz, 4H); 6.35 (dd, J ) 10.1, 17.4 Hz, 1H); 6.18 (dd, J )
1.8, 17.4 Hz, 1H); 5.88 (ddd, J ) 8.2, 10.3, 17.3 Hz, 1H); 5.64
(dd, J ) 1.8, 10.1 Hz, 1H); 5.36 (tm, J ) 7.0 Hz, 1H); 5.31
(dm, J ) 10.3 Hz, 1H); 5.15 (dm, J ) 17.4 Hz, 1H); 4.49 and
4.28 (2d, J ) 11.4 Hz, 2H); 4.01 (dd, J ) 3.8, 9.1 Hz, 1H); 3.80
(s, 3H); 3.70 (dd, J ) 3.8, 9.1 Hz, 1H); 3.47 (s, 3H); 3.46 (d, J
) 9.1 Hz, 1H); 2.03 (br q, J ) 7.6 Hz, 2H); 1.60 (s, 3H); 1.51
(m, 1H); 1.21 (m, 2H); 0.86 (2d, J ) 6.6 Hz, 6H). 13C NMR
(62.9 MHz, CDCl3): 198.0, 158.9, 135.5, 135.5, 132.7, 130.7,
129.3, 129.1, 127.8, 119.5, 113.6, 82.5, 81.4, 69.9, 61.4, 60.7,
55.2, 38.4, 27.6, 26.2, 22.5, 22.5, 14.4. HRMS (FAB): m/z found
407.2794, calcd for C25H36O4Li m/z 407.2774.
30 mg, 77%). [R]20 ) -68 (c ) 0.85, CHCl3). 1H NMR (250
D
MHz, CDCl3): 7.32 and 6.87 (2d, J ) 8.6 Hz, 4H); 5.21 (tm, J
) 7.4 Hz, 1H); 4.62 (s, 2H); 4.07 (dt, J ) 2.3, 4.5 Hz, 1H); 3.80
(s, 3H); 3.49 (dd, J ) 2.6, 11.2 Hz, 1H); 3.30 (s, 3H); 2.99 (d, J
) 11.2 Hz, 1H); 2.65 and 2.42 (2d, J ) 5.0 Hz, 2H); 2.23 (dt,
J ) 4.3, 13.5, 13.5 Hz, 1H); 2.11-1.94 (m, 3H); 1.69-1.47 (m,
2H); 1.54 (s, 3H); 1.29-1.15 (m, 2H); 1.06 (ddd, J ) 2.8, 4.0,
13.5 Hz, 1H); 0.87 and 0.86 (2d, J ) 6.6 Hz, 6H). 13C NMR
(62.9 MHz, CDCl3): 159.0, 131.7, 131.0, 130.7, 129.2, 113.6,
81.0, 70.7, 70.4, 60.9, 56.6, 55.2, 51.4, 48.6, 38.8, 28.5, 27.7,
25.7, 25.0, 22.6, 22.5, 14.1.
(4R,5S,6S)-5-Met h oxy-4-p -m et h oxyb en zyloxy-6-[(E)-
1,5-d im eth ylh ex-1-en yl]cycloh ex-2-en on e (21). To a solu-
tion of 20 (38 mg, 95 µmol) in toluene (3 mL) was added
dropwise a solution of Grubbs type II catalyst (8 mg, 9.5 µmol,
0.1 equiv) in toluene (0.5 mL). The mixture was stirred for 45
min at 70 °C and quenched with pH 7 buffer. Extraction with
ether and chromatography (SiO2, cyclohexane/AcOEt 6/4)
p-Meth oxycin n a m ic Acid (3R,4S,5S,6R)-5-Meth oxy-4-
[(E)-1,5-d im eth ylh ex-1-en yl]-1-oxa sp ir o[2.5]oct-6-yl Ester
(24). A solution of spiroepoxide 23 (17 mg, 43.8 µmol) in CH2-
Cl2 (2 mL) containing water (65 µL) was treated with DDQ
(11 mg, 48 µmol, 1.1 equiv) for 1.5 h at 20 °C. The reaction
was stopped with saturated NaHCO3 solution (0.5 mL) and
extracted with ethyl acetate. The combined organic phases
were dried over MgSO4, filtered, and concentrated in vacuo.
The residue was filtered through a short pad of silica gel
(cyclohexane/AcOEt 6/4) to afford 23′ (10.5 mg, 90%), which
was used without further purification for the next step. 1H
NMR (250 MHz, CDCl3) (23′): 5.22 (tm, J ) 7.6 Hz, 1H); 4.34
(dt, J ) 6.0, 3.0 Hz, 1H); 3.51 (dd, J ) 3.0, 11.2 Hz, 1H); 3.38
(s, 3H); 2.80 (d, J ) 11.2 Hz, 1H); 2.62 and 2.44 (2d, J ) 5.0
Hz, 2H); 2.33 (br s, 1H); 2.26 (td, J ) 13.6, 4.5 Hz, 1H); 2.10-
1.96 (m, 3H); 1.76 (tm, J ) 13.9 Hz, 1H); 1.56 (s, 3H); 1.53 (m,
1H); 1.19 (m, 2H); 1.03 (ddd, J ) 2.5, 4.5, 13.6 Hz, 1H); 0.87
(2d, J ) 6.6 Hz, 6H).
A solution of alcohol 23′ (10.5 mg) in CH2Cl2 (2 mL) was
treated with p-methoxycinnamic acid (61 mg, 390 µmol, 10
equiv), followed by DMAP (48 mg, 390 µmol, 10 equiv) and
DCC (80 mg, 390 µmol, 10 equiv). The mixture was stirred for
48 h at 20 °C, and then the solvent was removed in vacuo and
the residue purified on preparative TLC (SiO2 hexane/AcOEt
8/2). Pure 24 (13.5 mg, 80%) was obtained, which contains 10%
of the Z-isomer. [R]20D ) -118 (c ) 0.67, CHCl3). 1H NMR (250
MHz, CDCl3) (24): 7.66 (d, J ) 16 Hz, 1H); 7.48 and 6.90 (2d,
J ) 8.8 Hz, 4H); 6.38 (d, J ) 16 Hz, 1H); 5.72 (dt, J ) 2.6, 3.9
Hz, 1H); 5.26 (tm, J ) 7.2 Hz, 1H); 3.84 (s, 3H); 3.63 (dd, J )
2.8, 11.2 Hz, 1H); 3.37 (s, 3H); 2.93 (d, J ) 11.2 Hz, 1H); 2.70
and 2.49 (2d, J ) 5 Hz, 2H); 2.22 (dt, J ) 4.5, 13.6 Hz, 1H);
2.12-1.99 (m, 3H); 1.89 (tdd, J ) 13.6, 2.4, 4.2 Hz, 1H); 1.58
(s, 3H); 1.54 (m, 1H); 1.26-1.17 (m, 2H); 1.18 (ddd, J ) 2.5,
4.1, 13.8 Hz, 1H); 0.87 and 0.86 (2d, J ) 6.6 Hz, 6H). 13C NMR
(62.9 MHz, CDCl3) (24): 166.9, 161.3, 144.5, 131.0, 130.8,
129.7, 127.2, 115.9, 114.3, 79.2, 66.7, 60.6, 57.0, 55.3, 51.4, 49.4,
38.8, 28.8, 27.7, 25.8, 25.7, 22.6, 22.4, 14.1. HRMS (FAB): m/z
found 435.2710, calcd for C26H36O5Li m/z 435.2723.
afforded 21 (27.1 mg, 78%) as a colorless oil. [R]20 ) -86
D
1
(CHCl3, C ) 1.8). H NMR (250 MHz, CDCl3): 7.30 and 6.89
(2d, J ) 8.7 Hz, 4H); 6.78 (ddd, J ) 10.1, 3.7, 1.0 Hz, 1H);
6.06 (dd, J ) 10.1, 1.5 Hz, 1H); 5.13 (tm, J ) 7.0 Hz, 1H); 4.65
(AB, 2H); 4.31 (dt, J ) 3.4, 1.5 Hz, 1H); 3.81 (s, 3H); 3.75 (ddd,
J ) 6.8, 3.2, 1.1 Hz, 1H); 3.42 (d, J ) 6.8, 1H); 3.41 (s, 3H);
2.00 (br q, J ) 7.2 Hz, 2H); 1.58 (s, 3H); 1.50 (m, 1H); 1.19 (m,
2H); 0.86 (d, J ) 6.6 Hz, 6H). 13C NMR (62.9 MHz, CDCl3):
199.0, 159.4, 145.5, 130.8, 130.2, 129.9, 129.6, 128.9, 113.9,
80.0, 71.6, 70.6, 58.6, 57.7, 55.3, 38.4, 27.6, 25.9, 22.5, 22.5,
15.3. HRMS (FAB): m/z found 379.2462, calcd for C23H32O4Li
m/z 379.2461.
(4R ,5S ,6S )-6-(1,5-Dim e t h ylh e x-1-e n yl)-4-h yd r oxy-5-
m eth oxycycloh ex-2-en on e (21′). A solution of 21 (20 mg,
53 µmol) in CH2Cl2 (2 mL) containing water (65 µL) was
treated with DDQ (13 mg, 59 µmol, 1.1 equiv) for 7 h at 20 °C.
The reaction was stopped with saturated NaHCO3 solution (0.5
mL) and extracted with ethyl acetate. The combined organic
phases were dried over MgSO4, filtered, and concentrated in
vacuo. The residue was filtered through a short pad of silica
gel (eluent: cyclohexane/AcOEt 6/4) to afford 21′ (white solid,
10.5 mg, 78%). Mp ) 46-47 °C. [R]20D ) -43 (c ) 1.02, CHCl3).
1H NMR (250 MHz, CDCl3): 6.78 (ddd, J ) 1.3, 3.1, 10.1 Hz,
1H); 6.07 (dd, J ) 1.7, 10.1 Hz, 1H); 5.15 (tm, J ) 7.0 Hz,
1H); 4.51 (m, 1H); 3.77 (ddd, J ) 1.3, 3.7, 5.1 Hz, 1H); 3.44 (s,
3H); 3.39 (d, J ) 5.2 Hz, 1H); 3.84 (s, 1H); 2.02 (br q, J ) 7.1
Hz, 2H); 1.68 (s, 3H); 1.52 (m, 1H); 1.19 (m, 2H); 0.86 (2d, J )
6.6 Hz, 6H). 13C NMR (62.9 MHz, CDCl3): 198.4, 147.3, 130.4,
130.0, 128.7, 81.2, 64.8, 57.4, 57.3, 38.5, 27.6, 26.0, 22.5, 22.4,
15.8.
(2S,3S,4R)-3-Met h oxy-4-p -m et h oxyb en zyloxy-2-[(E)-
1,5-d im eth ylh ex-1-en yl]cycloh exa n on e (22). Under vigor-
ous stirring, 15 drops of a 50% suspension of RaNi in water
were added to a cold (0 °C) solution of 21 (45 mg, 0.121 mmol)
in THF (1.5 mL). The mixture was stirred for 20 min at 0 °C.
Ether (2 mL) was added and the mixture was extracted with
ethyl acetate. Chromatography (SiO2, cyclohexane/AcOEt 8/2)
(3R,4S,5S,6R)-4-[(1R,2R)-1,2-Ep oxy-1,5-d im eth ylh exyl]-
5-m e t h o x y -6-p -m e t h o x y b e n z y lo x y -1-o x a s p ir o [2.5]-
oct a n e (25) a n d (3R,4S,5S,6R)-4-[(1S,2S)-1,2-E p oxy-1,5-
d im e t h ylh e xyl]-5-m e t h oxy-6-p -m e t h oxyb e n zyloxy-1-
oxa sp ir o[2.5]octa n e (26). To a cold (0 °C) mixture of 23 (40
mg, 103 µmol) and NaHCO3 (52 mg, 618 µmol, 6 equiv) in CH2-
Cl2 (2 mL) was added m-CPBA (70%, 37 mg, 154 µmol, 1.5
equiv). The mixture was stirred for 1 h at 0 °C and then 1 h
at 20 °C. The mixture was quenched with a saturated aqueous
afforded pure 22 (colorless oil, 37 mg, 82%). [R]20 ) -10
D
1
(CHCl3, C ) 1.0). H NMR (250 MHz, CDCl3): 7.33 and 6.88
(2d, J ) 8.6 Hz, 4H); 5.16 (tm, J ) 7.0 Hz, 1H); 4.67 (AB, 2H);
4.11 (dt, J ) 2.2, 4.6 Hz, 1H); 3.80 (s, 3H); 3.49 (d, J ) 10.7
Hz, 1H); 3.43 (dd, J ) 2.2, 10.7 Hz, 1H); 3.33 (s, 3H); 2.60 (m,
1H); 2.26-2.14 (m, 2H); 2.06 (m, 2H); 1.65-1.46 (m, 2H); 1.57
(s, 3H); 1.19 (m, 2H); 0.87 (d, J ) 6.6 Hz, 6H). 13C NMR (62.9
MHz, CDCl3): 209.1, 159.2, 130.8, 130.5, 129.2, 129.0, 113.7,
368 J . Org. Chem., Vol. 69, No. 2, 2004

MetAP-2 Inhibitors Based on the Fumagillin Structure
NaHCO3 solution (5 mL) and extracted with ethyl acetate. The
combined organic layers were dried over Na2SO4 and evapo-
rated in vacuo. Chromatography (SiO2, cyclohexane/AcOEt 8/2)
°C, and then the solvent was removed in vacuo and the residue
filtered through a short pad of silica (eluent: cyclohexane/
AcOEt 1/1). Preparative TLC (SiO2 hexane/AcOEt 8/2) afforded
29 (6.8 mg, 80%), containing 10% of the Z-isomer. 1H NMR
(250 MHz, CDCl3): 7.63 (d, J ) 16 Hz, 1H); 7.48 and 6.90 (2d,
J ) 8.7 Hz, 4H); 6.33 (d, J ) 16 Hz, 1H); 5.71 (m, 1H); 3.84 (s,
3H); 3.55 (dd, J ) 2.7, 11.3 Hz, 1H); 3.38 (s, 3H); 3.34 and
2.66 (2d, J ) 4.5 Hz, 2H); 2.62 (m, 1H); 2.14 (dt, J ) 4.4, 13.3
Hz, 1H); 2.02 (d, J ) 11.4 Hz, 1H); 2.06-1.83 (m, 2H); 1.63-
1.23 (m, 5H); 1.23 (s, 3H); 1.13 (ddd, J ) 2.4, 4.0, 13.5 Hz,
1H); 0.86 (2d, J ) 6.6 Hz, 6H). 13C NMR (62.9 MHz, CDCl3):
166.6, 161.4, 144.6, 129.7, 127.0, 115.7, 114.3, 79.7, 66.2, 65.2,
59.8, 59.2, 56.8, 55.4, 51.9, 48.1, 35.0, 29.4, 27.9, 26.0, 25.9,
22.6, 22.3, 13.2.
afforded 26 (5.7 mg, 13%) followed by 25 (32.5 mg). 25. [R]20
D
) - 54 (c ) 0.95, CHCl3). 1H NMR (250 MHz, CDCl3): 7.31
and 6.86 (2d, J ) 8.6 Hz, 4H); 4.61 (AB, 2H); 4.07 (dt, J ) 2.2,
2.2, 4.4 Hz, 1H); 3.80 (s, 3H); 3.55 (dd, J ) 2.5, 10.9 Hz, 1H);
3.37 (s, 3H); 2.85 and 2.55 (2d, J ) 4.4 Hz, 2H); 2.52 (dd, J )
4.6, 7.4 Hz, 1H); 2.14 (dt, J ) 4.4, 13.4, 13.4 Hz, 1H); 2.12 (d,
J ) 10.9 Hz, 1H); 1.95 (dq, J ) 4.3, 13.8 Hz, 1H); 1.68-1.17
(m, 6H); 1.17 (s, 3H); 1.01 (dt, J ) 4.0, 13.5 Hz, 1H); 0.89 (2d,
J ) 6.6 Hz, 6H). 13C NMR (62.9 MHz, CDCl3): 159.0, 131.0,
129.2, 113.6, 81.3, 70.9, 70.1, 61.5, 60.0, 58.5, 56.4, 55.2, 51.1,
47.7, 35.6, 29.1, 27.9, 26.0, 25.3, 22.6, 22.4, 14.1. HRMS
(FAB): m/z found 411.2722, calcd for C24H36O5Li m/z 411.2723.
26. 1H NMR (250 MHz, CDCl3): 7.29 and 6.87 (2d, J ) 8.6
Hz, 4H); 4.60 (s, 2H); 4.05 (m, 1H); 3.80 (s, 3H); 3.43 (dd, J )
2.5, 11.2 Hz, 1H); 3.32 (s, 3H); 3.28 (d, J ) 4.5 Hz, 1H); 2.68
(t, J ) 6.0 Hz, 1H); 2.60 (d, J ) 4.5 Hz, 1H); 2.12-2.04 (m,
3H); 1.69-1.18 (m, 6H); 1.18 (s, 3H); 0.98 (m, 1H); 0.88 (2d, J
) 6.6 Hz, 6H).
(2S,3S,4R,5S)-2-(1,5-Dim eth ylh ex-1-en yl)-3-m eth oxy-4-
p-m eth oxyben zyloxy-5-m eth ylcycloh exa n on e (30). A sus-
pension of CuI (56 mg, 290 µmol, 1.1 equiv) in Et2O (1 mL)
was treated with MeLi (1.4 M in Et2O, 422 µL, 590 µmol, 2.2
equiv) at 0 °C. After 1 h, a solution of enone 21 (100 mg, 270
µmol, 1 equiv) in Et2O (0.5 mL) was added. The mixture was
stirred at 0 °C for 1 h, quenched with saturated NH4Cl (2 mL),
and extracted with Et2O. The combined organic phases were
dried over MgSO4, filtered, and concentrated in vacuo. Puri-
fication on preparative TLC (hexane/ethyl acetate, 4/1) pro-
(-)-Dih yd r ofu m a gillol (27). A solution of spiroepoxide 25
(38 mg, 94 µmol) in CH2Cl2 (2 mL) containing water (65 µL)
was treated with DDQ (24 mg, 103 µmol, 1.1 equiv) for 1.5 h
at 20 °C. The reaction was stopped with a saturated NaHCO3
solution (0.5 mL) and extracted with ethyl acetate. The
combined organic phases were dried over Na2SO4, filtered, and
concentrated in vacuo. Preparative TLC (SiO2, cyclohexane/
AcOEt 1/1) afforded (-)-dihydrofumagillol 27 (23 mg, 86%).
vided 30 as a colorless oil (80 mg, 77%). [R]20 ) +43 (c ) 1.1,
D
CHCl3). 1H NMR (400 MHz, CDCl3): 6.81 and 7.24 (2d, J )
8.4 Hz, 4H), 5.03 (t, J ) 7.0 Hz, 1H), 4.56 and 4.63 (2d, AB, J
) 11.8 Hz, 2H), 3.73 (s, 3H)), 3.65 (dd, J ) 6.0, 2.0 Hz, 1H),
3.60 (dd, J ) 8.5, 2.0 Hz, 1H), 3.31 (m, 1H), 3.28 (s, 3H), 2.57
(dd, J ) 14.5, 6.0 Hz, 1H), 2.36 (m, 1H), 2.05 (m, 3H), 1.50 (s,
3H), 1.46 (m, 1H), 1.15 (m, 2H), 0.92 (d, J ) 7.2 Hz, 3H), 0.81
(d, J ) 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3): 15.11, 18.8,
22.9, 26.3, 28.1, 31.8, 39.0, 44.2, 55.7, 58.0, 62.3, 72.1, 77.4,
79.4, 114.1, 129.7, 130.4, 131, 159.6, 210.0. HRMS (FAB): m/z
found 395.2790, calcd for C24H36O4Li m/z 395.2774.
[R]20 ) -44 (c ) 1.15, CHCl3). 1H NMR (250 MHz, CDCl3):
D
4.35 (br m, 1H); 3.61 (dd, J ) 2.7, 11.1 Hz, 1H); 3.48 (s, 3H);
2.83 and 2.57 (2d, J ) 4.3 Hz, 2H); 2.54 (dd, J ) 4.4, 7.4 Hz,
1H); 2.37 (d, J ) 2.0 Hz, 1H); 2.20 (dt, J ) 4.5, 13.5, 13.5 Hz,
1H); 2.00 (ddt, J ) 2.5, 2.5, 4.1, 14.2 Hz, 1H); 1.92 (d, J ) 11.1
Hz, 1H); 1.82-1.22 (m, 6H); 1.18 (s, 3H); 0.98 (ddd, J ) 2.5,
4.5, 13.5 Hz, 1H); 0.88 (2d, J ) 6.5 Hz, 6H). 13C NMR (62.9
MHz, CDCl3): 80.9, 64.1, 62.0, 59.9, 58.5, 56.5, 50.9, 47.2, 35.6,
28.4, 27.9, 26.5, 26.0, 22.6, 22.3, 13.9.
(3R,4S,5S,6R,7S)-4-[(E)-1,5-Dim eth yl-h ex-1-en yl]-5-m eth -
oxy-6-p -m e t h oxyb e n zyloxy-7-m e t h yl-1-oxa sp ir o[2.5]-
octa n e (31). A solution of ketone 30 (65 mg, 167 µmol, 1.0
equiv) and CH2I2 (68 µmol, 835 µmol, 5 equiv) in THF (1 mL)
was treated with BuLi (1.6 M in hexanes, 520 µL, 835 µmol,
5.0 equiv) at -78 °C. The mixture was stirred for 1 h at -78
°C and then for 1.5 h at 20 °C. The reaction was quenched
with saturated NH4Cl and extracted with ethyl acetate. The
combined organic phases were dried over MgSO4, filtered, and
concentrated in vacuo. Purification on preparative TLC (hex-
ane/ethyl acetate, 4/1) afforded pure 31 as a colorless oil (35
p-Meth oxycin n a m ic Acid (3R,4S,5S,6R)-5-Meth oxy-4-
[(1R,2R)-1,2-epoxy-1,5-d im eth ylh exyl]-1-oxa spir o[2.5]oct-
6-yl Ester (28). A solution of alcohol 27 (20 mg, 70 µmol) in
CH2Cl2 (2 mL) was treated with p-methoxycinnamic acid (215
mg, 704 µmol, 10 equiv), followed by DMAP (85 mg, 704 µmol,
10 equiv) and DCC (145 mg, 704 µmol, 10 equiv). The mixture
was stirred overnight at 20 °C, and then the solvent was
removed in vacuo and the residue passed through a pad of
silica gel (eluent: cyclohexane/AcOEt 1/1). Preparative TLC
(SiO2, hexane/AcOEt 8/2) afforded 28 (30 mg, 95%), containing
10% of the Z-isomer. [R]20D ) -56.5 (CHCl3, C ) 0.92). 1H NMR
(250 MHz, CDCl3): 7.63 (d, J ) 16 Hz, 1H); 7.46 and 6.89 (2d,
J ) 8.7 Hz, 4H); 6.36 (d, J ) 16 Hz, 1H); 5.73 (m, 1H); 3.83 (s,
3H); 3.71 (dd, J ) 2.8, 11.0 Hz, 1H); 3.45 (s, 3H); 2.0.91 and
2.61 (2d, J ) 4.3 Hz, 2H); 2.59 (dd, J ) 4.4, 8.0 Hz, 1H); 2.13
(dt, J ) 4.3, 13.3, 13.3 Hz, 1H); 2.05 (d, J ) 11.0 Hz, 1H);
2.07-1.82 (m, 2H); 1.68-1.20 (m, 5H); 1.20 (s, 3H); 1.13 (dt, J
) 3.0, 3.0, 13.2 Hz, 1H); 0.90 (2d, J ) 6.5 Hz, 6H). 13C NMR
(62.9 MHz, CDCl3): 166.9, 161.3, 144.5, 129.7, 127.2, 115.9,
114.3, 79.1, 66.3, 61.7, 59.6, 58.5, 56.6, 55.3, 51.1, 48.4, 35.6,
29.3, 27.8, 26.0, 25.7, 22.6, 22.3, 13.9. HRMS (FAB): m/z found
451.2663, calcd for C26H36O6Li m/z 451.2672.
p-Meth oxycin n a m ic Acid (3R,4S,5S,6R)-5-Meth oxy-4-
[(1S,2S)-1,2-ep oxy-1,5-d im eth ylh exyl]-1-oxa sp ir o[2.5]oct-
6-yl Ester (29). A solution of spiroepoxide 26 (7.7 mg, 19 µmol)
in CH2Cl2 (0.5 mL) containing water (30 µL) was treated with
DDQ (5 mg, 21 µmol, 1.1 equiv) for 1.5 h at 20 °C. The reaction
was stopped with saturated NaHCO3 solution (0.5 mL) and
extracted with ethyl acetate. The combined organic phases
were dried over MgSO4, filtered, and concentrated in vacuo.
The residue was dissolved in CH2Cl2 (0.5 mL) and successively
treated with p-methoxycinnamic acid (34 mg, 190 µmol, 10
equiv), DMAP (24 mg, 190 µmol, 10 equiv), and DCC (40 mg,
190 µmol, 10 equiv). The mixture was stirred overnight at 20
mg, 52%). [R]20 ) -12 (c ) 1.75, CHCl3). 1H NMR (400 MHz,
D
CDCl3): 6.87 and 7.29 (2d, J ) 8.3 Hz, 4H), 5.29 (m, 1H), 4.58
(2d, AB, J ) 11.8 Hz, 2H), 3.80 (s, 3H), 3.70 (dd, J ) 8.3, 2.0
Hz, 1H), 3.54 (br d, J ) 4.3 Hz, 1H), 3.34 (s, 3H), 2.71 (d, J )
8.0 Hz, 1H), 2.38 and 2.54 (2d, J ) 5.0 Hz), 2.26 (m, 1H), 2.02
(m, 2H), 1.93 (dd, J ) 13.7, 5.0 Hz, 1H), 1.57 (s, 3H), 1.54 (m,
1H), 1.32 (dd, J ) 13.7, 5.8 Hz, 1H), 1.22 (m, 2H), 1.04 (d, J )
7.0 Hz, 3H), 0.88 and 0.89 (2d, J ) 6.6 Hz, 6H). 13C NMR (100
MHz, CDCl3): 159.1, 131, 130.0, 129.2, 113.7, 78.0, 77.7, 71.4,
58.8, 57.0, 55.3, 51.0, 49.5, 38.8, 35.6, 31.7, 27.8, 25.9, 22.5
and 22.6, 18.1, 14.9).
(3R,4S,5S,6R,7S)-4-[(E)-1,5-Dim eth yl-h ex-1-en yl]-5-m eth -
oxy-7-m eth yl-1-oxa sp ir o[2.5]octa n -6-ol (31′). A solution of
spiroepoxide 31 (35 mg, 87 µmol) in CH2Cl2 (3 mL) was treated
with DDQ (22 mg, 96 µmol, 1.1 equiv) in the presence of H2O
(85 µL) for 1.5 h at 20 °C. The reaction was stopped with
saturated NaHCO3 solution (0.5 mL) and extracted with ethyl
acetate. The combined organic phases were dried over MgSO4,
filtered and concentrated in vacuo. Purification on preparative
TLC (hexane/ethyl acetate, 4/1) afforded pure 31′ as colorless
1
oil (20 mg, 80%). H NMR (400 MHz, CDCl3): 5.28 (t, J ) 7.0
Hz, 1H), 3.89 (m, 1H), 3.68 (dd, J ) 9.0, 2.5 Hz, 1H), 3.39 (s,
3H), 2.66 (d, J ) 9.0 Hz, 1H), 2.36 and 2.51 (2d, J ) 5.2 Hz,
2H), 2.34 (br s, 1H), 2.18 (m, 1H), 1.95-2.10 (m, 3H), 1.60 (s,
3H), 1.53 (m, 1H), 1.22 (m, 3H), 1.10 (d, J ) 7.6 Hz, 3H), 0.88
(d, J ) 6.4 Hz, 6H). 13C NMR (100 MHz, CDCl3): 130.7, 130.4,
J . Org. Chem, Vol. 69, No. 2, 2004 369

Rodeschini et al.
79.3, 70.7, 58.9, 57.1, 50.0, 48.5, 38.8, 33.6, 33.4, 27.7, 25.9,
22.6, 22.5, 17.8, 15.11.
(SiO2, cyclohexane/AcOEt 9/1) afforded pure 36 (colorless oil,
1
21.6 mg, 83%). [R]20 ) -55 (c ) 1.52, CHCl3). H NMR (250
D
MHz, CDCl3): 5.16 (tm, J ) 6.7 Hz, 1H); 4.07 (br s, 1H); 3.34
(dd, J ) 2.1, 11.6 Hz, 1H); 3.33 (s, 3H); 2.85 (d, J ) 11.5 Hz,
1H); 2.62 and 2.38 (2d, J ) 5.1 Hz, 2H); 2.11-1.79 (m, 3H);
2.05 (t, J ) 12.9 Hz, 1H); 1.54 (s, 3H); 1.53 (m, 1H); 1.20 (m,
2H); 0.92 (d, J ) 6.6 Hz, 3H); 0.87 and 0.86 (2d, J ) 6.6 Hz,
6H); 0.85 (m, 1H); 0.16 (s, 9H). 13C NMR (62.9 MHz, CDCl3):
131.2, 130.6, 82.4, 70.6, 60.6, 57.1, 51.0, 47.1, 38.9, 36.1, 32.8,
27.7, 25.8, 22.6, 22.5, 18.2, 14.6, 0.6. HRMS (FAB): m/z found
361.2755, calcd for C20H38O3SiLi m/z 361.2750.
(3R,4S,5S,6R,7R)-6-Hydr oxy-5-m eth oxy-7-m eth yl-4-[(E)-
1,5-d im eth ylh ex-1-en yl]-1-oxa sp ir o[2.5]octa n e (37). A so-
lution of epoxide 36 (28 mg, 79 µmol, 1.0 equiv) in THF (2 mL)
containing water (0.1 mL) was treated with PPTS (2 mg, 7.9
µmol, 10 mol %) for 24 h at 20 °C. The reaction was stopped
with saturated aqueous NaHCO3 and extracted with ether.
Solvent removal and preparative TLC (SiO2, cyclohexane/
AcOEt 7/3) afforded 37 (6.6 mg, 30%) as a colorless oil. 1H NMR
(250 MHz, CDCl3): 5.21 (tm, J ) 7.6 Hz, 1H); 4.13 (br s, 1H);
3.50 (dd, J ) 2.7, 11.4 Hz, 1H); 3.39 (s, 3H); 2.77 (d, J ) 11.4
Hz, 1H); 2.62 and 2.43 (2d, J ) 5.0 Hz, 2H); 2.16 (br s, 1H);
2.09 (t, J ) 13.0 Hz, 1H); 2.08-1.93 (m, 3H); 1.56 (s, 3H); 1.53
(m, 1H); 1.19 (m, 2H); 1.08 (d, J ) 6.6 Hz, 3H); 0.94 (dd, J )
3.6, 13.1 Hz, 1H); 0.88 and 0.87 (2d, J ) 6.6 Hz, 6H). 13C NMR
(62.9 MHz, CDCl3): 130.9, 81.4, 68.5, 60.4, 56.8, 50.9, 47.3,
38.8, 35.6, 31.7, 27.7, 25.7, 22.6, 22.5, 17.7, 14.5.
5-(R)-5-Meth yld ih yd r ofu m a gillol (38). To a cold (0 °C)
solution of 37 (6.6 mg, 21 µmol) and NaHCO3 (10 mg, 126 µmol,
6 equiv) in CH2Cl2 (2 mL) was added m-CPBA (70%, 8 mg, 31
µmol, 1.5 equiv). The mixture was stirred for 1 h at 0 °C and
then 1 h at 20 °C. The mixture was quenched with a saturated
aqueous NaHCO3 solution (5 mL) and extracted with ethyl
acetate. The combined organic layers were dried over Na2SO4
and evaporated in vacuo. Preparative TLC (SiO2, cyclohexane/
AcOEt 7/3) afforded 38 (6.0 mg, 94%) as a colorless oil. 1H NMR
(250 MHz, CDCl3): 4.16 (br s, 1H); 3.62 (dd, J ) 2.5, 11.3 Hz,
1H); 3.50 (s, 3H); 2.85 and 2.57 (2d, J ) 4.9 Hz, 2H); 2.54 (dd,
J ) 4.5, 7.4 Hz, 1H); 2.04 (t, J ) 13.5 Hz, 1H); 1.92 (m, 1H);
1.90 (d, J ) 11.4 Hz, 1H); 1.66-1.20 (m, 6H); 1.18 (s, 3H);
1.08 (d, J ) 6.6, 3H); 0.90 (2d, J ) 6.6 Hz, 6H); 0.89 (m, 1H).
13C NMR (62.9 MHz, CDCl3): 81.5, 68.1, 62.0, 59.5, 58.4, 56.4,
50.6, 46.5, 36.1, 35.6, 31.7, 27.9, 26.0, 22.6, 22.3, 17.5, 13.9.
p-Meth oxycin n a m ic Acid (3R,4S,5S,6R,7S)-4-[(E)-1,5-
Dim et h yl-h ex-1-en yl]-5-m et h oxy-7-m et h yl-1-oxa sp ir o-
[2.5]oct-6-yl Ester (32). p-Methoxycinnamic acid (185 mg, 1.04
mmol, 12 equiv) followed by DMAP (127 mg, 1.04 mmol, 12
equiv) and DCC (215 mg, 1.04 mmol, 12 equiv) were added to
a solution of alcohol 31′ (25 mg, 87 µmol) in CH2Cl2 (2 mL).
The mixture was stirred overnight at 20 °C, and then the
solvent was removed in vacuo and the residue passed over a
short pad of silica gel (cyclohexane/AcOEt 1/1). Chromatog-
raphy on preparative TLC (hexane/ethyl acetate, 85/15) af-
forded pure 32 containing ca. 10% of the Z-isomer as a colorless
1
oil (18 mg, 49%). [R]20 ) -49 (c ) 0.9, CHCl3). H NMR (400
D
MHz, CDCl3): 7.66 (d, J ) 16.0 Hz, 1H), 6.91 and 7.48 (2d, J
) 8.8 Hz, 4H), 6.38 (d, J ) 16.0 Hz, 1H), 5.40 (t, J ) 6.8 Hz,
1H), 5.25 (m, 1H), 3.87 (m, 1H), 3.83 (s, 3H), 3.36 (s, 3H), 2.70
(d, J ) 8.3 Hz, 1H), 2.44 and 2.60 (2d, J ) 5.0 Hz, 2H), 2.32
(m, 1H), 2.05 (m, 2H), 1.98 (dd, J ) 13.5, 4.5 Hz, 1H), 1.65 (s,
3H), 1.55 (m, 1H), 1.45 (dd, J ) 13.5, 5.6 Hz, 1H), 1.26 (m,
2H), 1.13 (d, J ) 7.2 Hz, 3H), 0.89 (d, 6H, J ) 6.4 Hz). 13C
NMR (100 MHz, CDCl3): 166.9, 161.4, 144.6, 129.8, 130.5,
130.3, 127.2, 115.8, 114.3, 77.3, 73.0, 58.6, 57.5, 55.3, 50.7, 50.0,
38.8, 35.5), 32.0, 27.8, 25.9, 22.5, 17.9, 14.8. HRMS (FAB): m/z
found 443.2793, calcd for C27H39O5 m/z 443.2797.
(2S,3S,4R,5R)-4-H yd r oxy-3-m et h oxy-5-m et h yl-2-[(E)-
1,5-d im eth yl-h ex-1-en yl]cycloh exa n on e (33). To a cold (0
°C) solution of 21′ (42 mg, 166 µmol) in CH2Cl2 (0.8 mL) was
added AlMe3 (2 M in toluene, 800 µL, 1.6 mmol, 10 equiv).
The mixture was stirred for 4 h at 20 °C and then slowly
transferred onto a 20% aqueous tartaric acid solution. The
mixture was extracted with ethyl acetate. The combined
organic layers were dried over Na2SO4 and evaporated in
vacuo. The residue was purified by preparative TLC (SiO2,
cyclohexane/AcOEt 7/3) to afford 33 (26.5 mg, 58%) as a white
solid. Mp ) 33-34 °C. [R]20D ) +22 (c ) 0.95, CHCl3). 1H NMR
(250 MHz, CDCl3): 5.18 (tm, J ) 6.9 Hz, 1H); 4.14 (br s, 1H);
3.41 (s, 3H); 3.39 (dd, J ) 2.6, 11.2 Hz, 1H); 3.26 (d, J ) 11.2
Hz, 1H); 2.55 (t, J ) 13.9 Hz, 1H); 2.37 (s, 1H,); 2.15-2.04 (m,
3H); 1.83 (m, 1H); 1.61 (s, 3H); 1.57 (m, 1H); 1.26 (m, 2H);
1.17 (d, J ) 6.7 Hz, 3H); 0.86 (2d, J ) 6.6 Hz, 6H). 13C NMR
(62.9 MHz, CDCl3): 208.3, 131.4, 128.7, 82.2, 68.4, 60.5, 57.6,
42.8, 38.6, 32.0, 27.6, 25.9, 22.6, 22.5, 17.7, 14.2. HRMS
(FAB): m/z found 275.2200, calcd for C16H28O3Li m/z 275.2198.
p-Meth oxycin n a m ic a cid (3R,4S,5S,6R,7R)-5-Meth oxy-
7-m e t h yl-4-[(1R ,2R )-1,2-e p oxy-1,5-d im e t h ylh e xyl]-1-
oxa sp ir o[2.5]oct-6-yl Ester (39). A solution of alcohol 38 (6
mg, 20 µmol) in CH2Cl2 (2 mL) was successively treated with
p-methoxycinnamic acid (35 mg, 200 µmol, 10 equiv), DMAP
(25 mg, 200 µmol, 10 equiv), and DCC (41 mg, 200 µmol, 10
equiv). The mixture was stirred overnight at 20 °C, and then
the solvent was removed in vacuo and the residue filtered
through a short pad of silica gel (eluent: cyclohexane/AcOEt
1/1). Preparative TLC (SiO2, n-hexane/AcOEt 8/2) afforded 39
(2S,3S,4R,5R)-4-Tr im eth ylsilyloxy-3-m eth oxy-5-m eth -
yl-2-[(E)-1,5-dim eth yl-h ex-1-en yl]cycloh exan on e (35). TM-
SCl (29 µL, 233 µmol, 2.5 equiv) was added to a solution of
alcohol 33 (25 mg, 93 µmol), DMAP (34 mg, 279 µmol, 3.0
equiv), and triethylamine (130 µL, 0.93 mmol, 10 equiv) in CH2-
Cl2 (2 mL). The mixture was stirred for 1 h at 20 °C and then
quenched with a saturated aqueous NH4Cl solution. Extraction
with ether, solvent removal, and preparative TLC (SiO2,
cyclohexane/AcOEt 9/1) afforded 35 (29.8 mg, 94%) as a
colorless oil. [R]20 ) -4.3 (c ) 1.40, CHCl3). 1H NMR (250
(7.9 mg, 95%), containing 15% of the Z-isomer. [R]20 ) -43
D
D
MHz, CDCl3): 5.12 (tm, J ) 6.9 Hz, 1H); 4.10 (br s, 1H); 3.33
(s, 3H); 3.32 (d, J ) 11.4 Hz, 1H); 3.22 (dd, J ) 1.9, 11.4 Hz,
1H); 2.44 (t, J ) 13.9 Hz, 1H); 2.13-2.02 (m, 3H,); 1.76 (m,
1H); 1.58 (s, 3H); 1.57 (m, 1H); 1.25 (m, 2H); 1.01 (d, J ) 6.6
Hz, 3H); 0.87 (2d, J ) 6.9 Hz, 6H); 0.16 (s, 9H). 13C NMR (62.9
MHz, CDCl3): 209.3, 131.0, 129.0, 82.8, 70.5, 60.6, 57.7, 43.4,
38.7, 32.6, 27.7, 25.9, 22.6, 22.6, 18.1, 14.3, 0.6.
(3R,4S,5S,6R,7R)-4-[(E)-1,5-Dim eth ylh ex-1-en yl]-5-m eth -
o x y -7-m e t h y l-6-t r i m e t h y ls i ly lo x y -1-o x a s p i r o [2.5]-
octa n e (36). To a suspension of NaH (31 mg, 790 µmol, 10
equiv) in DMSO (1 mL) was added trimethylsulfoxonium
iodide (261 mg, 1.19 mmol, 15 equiv). The mixture was stirred
at 20 °C for 1 h. THF (1 mL) and lithium iodide (127 mg, 0.95
mmol, 12 equiv) were added to the mixture, and stirring was
continued for 40 min. A solution of 35 (25 mg, 73 µmol) in
DMSO/THF (1/1, 1 mL) was added at 0 °C. The mixture was
stirred for 2 h at 20 °C and quenched with ether (5 mL) and
pH 7 buffer (5 mL). Extraction with ether and chromatography
(c ) 0.39, CHCl3). 1H NMR (250 MHz, CDCl3): 7.62 (d, J )
15.9 Hz, 1H); 7.47 and 6.90 (2d, J ) 8.7 Hz, 4H); 6.36 (d, J )
15.9 Hz, 1H); 5.90 (br s, 1H); 3.83 (s, 3H); 3.70 (dd, J ) 2.7,
11.5 Hz, 1H); 3.48 (s, 3H); 2.92 and 2.60 (2d, J ) 4.4 Hz, 2H);
2.57 (m, 1H); 2.10 (m, 1H); 1.99 (t, J ) 13.0 Hz, 1H); 1.97 (d,
J ) 11.4 Hz, 1H); 1.67-1.16 (m, 5H); 1.18 (s, 3H); 1.00 (m,
1H); 0.94 (d, J ) 6.6 Hz, 3H); 0.89 (2d, J ) 6.6 Hz, 6H). 13C
NMR (62.9 MHz, CDCl3): 167.1, 161.3, 144.6, 129.8, 127.3,
115.9, 114.3, 79.7, 69.3, 61.7, 59.3, 58.4, 56.8, 55.4, 50.7, 47.7,
37.5, 35.7, 31.4, 27.9, 26.0, 22.6, 22.3, 17.2, 13.9. HRMS
(FAB): m/z found 465.2823, calcd for C27H38O6Li m/z 465.2828.
(2S,3S,4R,5R)-4-Hyd r oxy-3-m eth oxy-5-eth yl-2-[(E)-1,5-
d im eth yl-h ex-1-en yl]cycloh exa n on e (40). To a cold (0 °C)
solution of 21′ (14 mg, 55.5 µmol) in CH2Cl2 (0.8 mL) was added
AlEt3 (1 M in hexane, 550 µL, 550 µmol, 10 equiv). The mixture
was stirred for 2 h at 20 °C, then slowly transferred onto a
20% aqueous tartaric acid solution. The mixture was extracted
with ethyl acetate. The combined organic layers were dried
370 J . Org. Chem., Vol. 69, No. 2, 2004

MetAP-2 Inhibitors Based on the Fumagillin Structure
over Na2SO4 and evaporated in vacuo. The residue was
purified on preparative TLC (SiO2, cyclohexane/AcOEt 7/3) to
5-(R)-5-Eth yld ih yd r ofu m a gillol (44). To a solution of 43
(16 mg, 37 µmol) in MeOH (1 mL) was added potassium
carbonate (50 mg). The mixture was stirred for 24 h at 20 °C,
quenched with a saturated aqueous NH4Cl solution, and
extracted with ethyl acetate. The combined organic layers were
dried (Na2SO4) and evaporated in vacuo. The residue was
chromatographed (SiO2, cyclohexane/AcOEt 6/4) to afford 44
(7 mg) as a colorless oil which was directly used for the next
afford 40 (8.0 mg, 51%) as a colorless oil. [R]20 ) +20 (c )
D
1.05, CHCl3). 1H NMR (250 MHz, CDCl3): 5.18 (tm, J ) 7.0
Hz, 1H); 4.25 (br s, 1H); 3.41 (s, 3H); 3.38 (dd, J ) 2.4, 11.2
Hz, 1H); 3.29 (d, J ) 11.3 Hz, 1H); 2.49 (t, J ) 13.4 Hz, 1H);
2.35 (br s, 1H); 2.20 (dd, J ) 3.8, 13.8 Hz, 1H); 2.09 (br q, J )
7.3 Hz, 2H); 1.71-1.45 (m, 4H); 1.61 (s, 3H); 1.24 (m, 2H); 0.96
(t, J ) 7.0 Hz, 3H); 0.88 (2d, J ) 6.6 Hz, 6H). 13C NMR (62.9
MHz, CDCl3): 208.3, 131.3, 128.8, 82.3, 66.4, 61.0, 57.7, 41.2,
38.7, 38.6, 27.6, 25.9, 25.0, 22.6, 22.5, 14.2, 11.6. HRMS
(FAB): m/z found 289.2354, calcd for C17H30O3Li m/z 289.2355.
1
step. H NMR (250 MHz, CDCl3): 4.27 (br s, 1H); 3.60 (dd, J
) 2.6, 11.3 Hz, 1H); 3.50 (s, 3H); 2.86 and 2.58 (2d, J ) 4.3
Hz, 2H); 2.54 (dd, J ) 4.4, 7.5 Hz, 1H); 2.19 (br s, 1H); 1.98 (t,
J ) 12.9 Hz, 1H); 1.92 (d, J ) 11.3 Hz, 1H); 1.68-1.20 (m,
8H); 1.18 (s, 3H); 0.97 (t, J ) 7.4 Hz, 3H); 0.96 (m, 1H); 0.89
(2d, J ) 6.6 Hz, 6H).
p-Meth oxycin n a m ic Acid (3R,4S,5S,6R,7R)-5-Meth oxy-
7-e t h y l-4-[(1R ,2R )-1,2-e p o x y -1,5-d i m e t h y lh e x y l]-1-
oxa sp ir o[2.5]oct-6-yl Ester (45). A solution of alcohol 44 (9
mg, 28.8 µmol) in CH2Cl2 (2 mL) was successively treated with
p-methoxycinnamic acid (62 mg, 350 µmol, 12 equiv), DMAP
(43 mg, 350 µmol, 12 equiv), and DCC (72 mg, 350 µmol, 12
equiv). The mixture was stirred overnight at 20 °C, and then
the solvent was removed in vacuo and the residue filtered
through a short pad of silica gel (eluent: cyclohexane/AcOEt
1/1). Preparative TLC (SiO2, n-hexane/AcOEt 8/2) afforded 45
(2S,3S,4R,5R)-4-Ben zoyloxy-3-m eth oxy-[(E)-1,5-d im e-
th yl-h ex-1-en yl]cycloh exa n on e (41). A solution of alcohol
40 (20 mg, 71 µmol) in CH2Cl2 (2 mL) was successively treated
with benzoic acid (86 mg, 0.71 mmol, 10 equiv), DMAP (86
mg, 0.71 mmol, 10 equiv), and DCC (146 mg, 0.71 mmol, 10
equiv). The mixture was stirred overnight at 20 °C. The solvent
were removed in vacuo and the residue filtered through a short
pad of silica gel (eluent: cyclohexane/AcOEt 1/1). Preparative
TLC (SiO2, n-hexane/AcOEt 8/2) finally gave pure 41 (26 mg,
92%) as a colorless oil. [R]20D ) -45 (c ) 1.25, CHCl3). 1H NMR
(250 MHz, CDCl3): 8.05 (d, J ) 7.0 Hz, 2H); 7.58 and 7.46 (2m,
3H); 5.99 (br s, 1H); 5.18 (tm, J ) 6.9 Hz, 1H); 3.54 (dd, J )
2.6, 11.6 Hz, 1H); 3.43 (s, 3H); 3.39 (d, J ) 11.6 Hz, 1H); 2.53
(t, J ) 14.6 Hz, 1H); 2.43 (dd, J ) 4.7, 14.6 Hz, 1H); 2.07 (m,
2H); 1.83 (m, 1H); 1.60 (s, 3H); 1.60-1.20 (m, 5H); 0.97 (t, J )
7.4 Hz, 3H); 0.86 (2d, J ) 6.6 Hz, 6H). 13C NMR (62.9 MHz,
CDCl3): 207.5, 165.8, 133.2, 132.8, 131.6, 130.0, 129.7, 128.5,
80.6, 68.0, 62.2, 57.7, 42.5, 38.6, 38.1, 27.6, 25.9, 25.0, 22.5,
22.5, 13.9, 11.5.
(12.3 mg, 52% for two steps), which contained 10% of the
1
Z-isomer. [R]20 ) -43 (CHCl3, C ) 0.6). H NMR (250 MHz,
D
CDCl3): 7.61 (d, J ) 16.0 Hz, 1H); 7.46 and 6.89 (2d, J ) 8.7
Hz, 4H); 6.32 (d, J ) 16.0 Hz, 1H); 5.85 (br s, 1H); 3.83 (s,
3H); 3.68 (dd, J ) 2.7, 11.5 Hz, 1H); 3.49 (s, 3H); 2.93 and
2.61 (2d, J ) 4.4 Hz, 2H); 2.56 (dd, J ) 4.2, 7.5 Hz, 1H); 1.99
(d, J ) 11.3 Hz, 1H); 1.98 (t, J ) 12.7 Hz, 1H); 1.86 (m, 1H);
1.67-1.18 (m, 7H); 1.20 (s, 3H); 1.08 (dd, J ) 3.0, 12.9 Hz,
1H); 0.92 (t, J ) 7.3 Hz, 3H); 0.89 (2d, J ) 6.6 Hz, 6H). 13C
NMR (62.9 MHz, CDCl3): 166.9, 161.3, 144.5, 129.7, 127.3,
115.9, 114.3, 80.0, 67.5, 61.7, 59.3, 58.4, 56.9, 55.4, 50.8, 48.0,
38.3, 35.8, 35.7, 27.9, 26.0, 24.6, 22.6, 22.3, 13.8, 11.5. HRMS
(FAB): m/z found 479.2981, calcd for C28H40O6Li m/z 479.2985
(3R,4S,5S,6R,7R)-6-Ben zoyloxy-4-[(E)-1,5-d im eth ylh ex-
1-en yl]-5-m et h oxy-7-m et h yl-1-oxa sp ir o[2.5]oct a n e (42).
To a suspension of NaH (60% in oil, 25 mg, 620 µmol, 10 equiv)
in DMSO (1 mL) was added trimethylsulfoxonium iodide (204
mg, 0.93 mmol, 15 equiv). The mixture was stirred at 20 °C
for 1 h. THF (1 mL) and lithium iodide (99 mg, 0.74 mmol, 12
equiv) were added to the mixture, and stirring was continued
for further 40 min. A solution of 41 (25 mg, 62 µmol) in DMSO/
THF 1/1 (1 mL) was added at 0 °C. The mixture was stirred
for 2 h at 20 °C and quenched with ether (5 mL) and pH 7
buffer (5 mL). Extraction with ether and chromatography
(SiO2, cyclohexane/AcOEt 8/2) afforded pure 42 (colorless oil,
(1R,3S,4S,5R,6S)-3-[(E)-1,5-Dim eth yl-h ex-1-en yl]-4-m eth -
oxy-5-p-m eth oxyben zyloxy-7-oxa bicyclo[4.1.0]h ep ta n -2-
on e (46). To a solution of enone 21 (32 mg, 86 µmol) in MeOH
(1 mL) at 0 °C was added K2CO3 (20% solution in H2O (w/w),
5 µL, 8 µmol, 0.1 equiv) followed by H2O2 (30% solution, 30
µL, 260 µmol, 3 equiv). The mixture was stirred for 2 h at 0
°C, stopped with a NH4Cl solution, and extracted with AcOEt.
The combined organic phases were dried over MgSO4, filtered,
and concentrated in vacuo. Purification on preparative TLC
21 mg, 82%). [R]20 ) -72 (c ) 1.05, CHCl3). 1H NMR (250
D
MHz, CDCl3): 8.04 (m, 2H); 7.55 (m, 1H); 7.41 (m, 2H); 5.95
(br s, 1H); 5.22 (tm, J ) 6.6 Hz, 1H); 3.65 (dd, J ) 2.7, 11.6
Hz, 1H); 3.42 (s, 3H); 2.93 (d, J ) 11.6 Hz, 1H); 2.73 and 2.51
(2d, J ) 5.0 Hz, 2H); 2.14 (t, J ) 13.2 Hz, 1H); 2.11-1.86 (m,
3H); 1.56 (s, 3H); 1.55-1.15 (m, 6H); 0.94 (t, J ) 7.4 Hz, 3H);
0.86 (2d, J ) 6.6 Hz, 6H). 13C NMR (62.9 MHz, CDCl3): 166.0,
132.9, 131.2, 130.8, 130.5, 129.7, 128.3, 80.1, 68.8, 60.2, 57.2,
51.2, 49.2, 38.8, 38.3, 35.4, 27.7, 25.7, 24.8, 22.6, 22.4, 14.0,
11.6.
(hexane/ethyl acetate, 85/15) provided pure 46 as a colorless
1
oil (27 mg, 82%). [R]20 ) -46 (c ) 1.0, CHCl3). H NMR (400
D
MHz, CDCl3): 6.89 and 7.28 (2d, J ) 8.5 Hz, 4H), 5.37 (t, 1H,
J ) 7.2 Hz), 4.59 and 4.87 (2d, AB, J ) 11.8 Hz, 2H), 4.45 (dd,
J ) 3.6, 2.7 Hz, 1H), 3.81 (s, 3H), 3.78 (dd, J ) 10.1, 2.5 Hz,
1H), 3.47 (t, J ) 3.8 Hz, 1H), 3.37 (s, 3H), 3.27 (d, J ) 3.8 Hz,
1H), 3.10 (d, J ) 10.1 Hz, 1H), 2.06 (m, 2H), 1.43 (s, 3H), 1.20-
1.29 (m, 3H), 0.89 (d, J ) 6.4 Hz, 6H). 13C NMR (100 MHz,
CDCl3): 204.6, 159.5, 132.4, 130.3, 129.5, 129.3, 114.0, 73.5,
70.4, 59.9, 58.4, 55.3, 54.6, 54.5, 38.5, 27.6, 26.0, 22.6, 22.5,
14.4.
(3R,4S,5S,6R,7R)-6-Ben zyloxy-4-[(1R,2R)-1,2-ep oxy-1,5-
d im e t h y l-h e x y l]-7-e t h y l-5-m e t h o x y -1-o x a s p ir o [2.5]-
octa n e (43). To a cold (0 °C) solution of 42 (19 mg, 45 µmol)
and NaHCO3 (50 mg) in CH2Cl2 (2 mL) was added m-CPBA
(70%, 16 mg, 68 µmol, 1.5 equiv). The mixture was stirred for
1 h at 0 °C and then 1 h at 20 °C. The mixture was quenched
with a saturated aqueous NaHCO3 solution (5 mL) and
extracted with ethyl acetate. The combined organic layers were
dried over Na2SO4 and evaporated in vacuo. Preparative TLC
(SiO2, cyclohexane/AcOEt 7/3) afforded 43 (16.6 mg, 84%) as
a colorless oil. 1H NMR (250 MHz, CDCl3): 7.98 (m, 2H); 7.54
(m, 1H); 7.41 (m, 2H); 5.97 (br s, 1H); 3.73 (dd, J ) 2.7, 11.5
Hz, 1H); 3.52 (s, 3H); 2.96 and 2.64 (2d, J ) 4.5 Hz, 2H); 2.56
(dd, J ) 4.0, 7.0 Hz, 1H); 2.07 (t, J ) 13.0 Hz, 1H); 2.01 (d, J
) 11.5 Hz, 1H); 1.91 (m, 1H); 1.68-1.18 (m, 7H); 1.19 (s, 3H);
1.13 (dd, J ) 3.5, 13.0 Hz); 0.93 (t, J ) 7.3 Hz, 3H); 0.89 (2d,
J ) 6.6 Hz, 6H). 13C NMR (62.9 MHz, CDCl3): 166.0, 132.8,
130.4, 129.7, 128.3, 80.1, 68.3, 61.7, 59.2, 58.2, 57.0, 50.8, 48.3,
38.4, 36.0, 35.7, 27.8, 26.0, 24.6, 22.6, 22.3, 13.9, 11.5.
(2S,3S,4R,5S)-2-[(E)-1,5-Dim eth yl-h ex-1-en yl]-5-h ydr oxy-
3-m eth oxy-4-p-m eth oxyben zyloxycycloh exa n on e (47). To
a solution of PhSeSePh (109 mg, 350 µmol, 1.5 equiv) in
ethanol (4 mL) was added NaBH4 (26.2 mg, 700 µmol, 3 equiv)
at 20 °C. After 15 min, this solution was cooled to 0 °C, and
AcOH (6 µl, 0.5 equiv) was added, followed by a solution of
epoxide 46 (90 mg, 231 µmol) in ethanol (3 mL). After 15 min,
the reaction was diluted with AcOEt and washed with brine.
The aqueous phase was further extracted with AcOEt, and the
combined organic phases were dried over MgSO4, filtered, and
concentrated in vacuo. The residue was passed over a short
pad of silica gel (cyclohexane/AcOEt 1/1). After purification on
preparative TLC (SiO2, n-hexane/ethyl acetate, 75/25), pure
47 was obtained as a yellow oil (74 mg, 82%). [R]20 ) +34 (c
D
) 1.48, CHCl3). 1H NMR (400 MHz, CDCl3): 6.89 and 7.30
J . Org. Chem, Vol. 69, No. 2, 2004 371

Rodeschini et al.
(2d, J ) 8.3 Hz, 4H), 5.13 (t, J ) 6.6 Hz, 1H), 4.63 and 4.80
(2d, AB, J ) 11.6 Hz, 2H), 4.22 (m, 1H), 3.96 (dd, J ) 5.8, 2.5
Hz, 1H), 3.85 (dd, J ) 8.8, 2.5 Hz, 1H), 3.81 (s, 3H), 3.40 (m,
1H), 3.37 (s, 3H), 2.82 (dd, J ) 14.8, 3.8 Hz, 1H), 2.37 (dd, J
) 14.8, 5.3 Hz, 1H), 2.05 (m, 2H), 1.58 (s, 3H), 1.53 (m, 1H),
1.22 (m, 2H), 0.88 (d, J ) 6.4 Hz, 6H). 13C NMR (100 MHz,
CDCl3): 208.0, 159.4, 131.9, 131.0, 130.0, 129.5, 113.8, 78.5,
75.7, 72.8, 67.9, 61.9, 57.9, 55.3, 45.0, 38.6, 27.7, 26.0, 22.5,
14.6.
removed in vacuo and the residue passed over a short pad of
silica gel (cyclohexane/AcOEt 1/1). The residue obtained was
dissolved in THF (1 mL) and treated with TBAF (1 M in THF,
20 µL, 20 µmol) for 0.5 h. The reaction was stopped with
saturated NH4
Cl and extracted with AcOEt. Combined organic
phases were dried over MgSO4, filtered, and concentrated in
vacuo. Two successive purifications by preparative TLC on
silica gel ((1) hexane/ethyl acetate, 3/2; (2) CH2Cl2/ethyl
acetate, 9/1) afforded 51 as a 7:3 mixture of E/ Z cinnamates
(2 mg, 7% from 48). 1H NMR (400 MHz, CDCl3): E-Isomer:
7.67 (d, J ) 16.0, 1H), 7.48 and 6.91 (2d, J ) 8.8 Hz, 4H), 6.35
(d, J ) 16.0 Hz, 1H), 5.62 (m, 1H), 5.33 (t, J ) 7.2 Hz, 1H),
4.20 (m, 1H), 4.02 (dd, J ) 10.0, 2.8 Hz, 1H), 3.85 (s, 3H), 3.39
(s, 3H), 2.84 (d, J ) 10.4 Hz, 1H), 2.57 (d, J ) 6.4 Hz, 1H),
2.66 and 2.47 (2d, AB, J ) 4.8 Hz, 2H), 2.37 (dd, J ) 14.6, 3.3
Hz, 1H), 2.05 (m, 2H), 1.61 (s, 3H), 1.61-1.48 (m, 2H), 1.23
(m, 2H), 0.89 and 0.88 (d, J ) 6.4 Hz, 6H). Z-Isomer: 6.90 (d,
J ) 12.4 Hz, 1H), 7.68 and 6.88 (2d, J ) 8.8 Hz, 4H), 5.88 (d,
J ) 12.4 Hz, 1H), 5.59 (m, 1H), 5.28 (t, J ) 7.2 Hz, 1H), 4.00
(m, 1H), 3.98 (dd, J ) 10.0, 2.8 Hz, 1H), 3.83 (s, 3H), 3.38 (s,
3H), 2.75 (d, J ) 10.4 Hz, 1H), 2.55 (d, J ) 6.4 Hz, 1H), 2.62
and 2.42 (2d, AB, J ) 4.8 Hz, 2H), 2.22 (dd, J ) 14.6, 3.3 Hz,
1H), 2.05 (m, 2H), 1.59 (s, 3H), 1.61-1.48 (m, 2H), 1.23 (m,
2H), 0.89 and 0.88 (d, J ) 6.4 Hz, 6H). HRMS (FAB): m/z
found 451.2704, calcd for C26H36O6Li m/z 451.2672.
(4R,5S,6S)-6-[(E)-1,5-Dim eth yl-h ex-1-en yl]-2-h ydr oxym -
e t h y l-5-m e t h o x y -4-p -m e t h o x y b e n zy lo x y c y c lo h e x -2-
en on e (52). To a solution of enone 21 (230 mg, 618 µmol) in
THF (5 mL) at 20 °C was added tri-n-butylphosphine (130 µl,
530 µmol, 0.85 equiv) followed by formaldehyde (40% aqueous
solution, 130 µL, 1.62 mmol, 2.6 equiv). The mixture was
stirred overnight, diluted with H2O, and extracted with AcOEt.
The combined organic phases were dried over MgSO4, filtered,
and concentrated in vacuo. The residue was chromatographed
(2S,3S,4R,5S)-2-[(E)-1,5-Dim et h yl-h ex-1-en yl]-5-(iso-
p r op yld im eth ylsila n yloxy)-3-m eth oxy-4-p-m eth oxyben -
zyloxycycloh exa n on e (48). Isopropyldimethylsilyl chloride
(37 µL, 237 µmol, 1.5 equiv) was added to a solution of alcohol
47 (62 mg, 158 µmol) and DMAP (38 mg, 316 µmol, 2 equiv)
in THF/DMF 1:1 (1 mL). The mixture was stirred for 1 h at
20 °C. After quenching (ammonium chloride), extraction
(cyclohexane), and preparative TLC (hexane/AcOEt 9/1), pure
48 (59 mg, 76%) was obtained as a colorless oil. [R]20 ) +19
D
1
(c ) 0.65, CHCl3). H NMR (400 MHz, CDCl3): 6.90 and 7.30
(2d, J ) 8.8 Hz, 4H), 5.19 (t, J ) 6.9 Hz, 1H), 4.60 and 4.84
(2d, AB, J ) 11.8 Hz, 2H), 4.08 (dt, J ) 4.5, 3.3 Hz, 1H), 3.88
(m, 1H), 3.81 (s, 3H), 3.80 (dd, J ) 10.7, 2.8 Hz, 1H), 3.36 (d,
J ) 10.7 Hz, 1H), 3.35 (s, 3H), 2.76 (dd, J ) 14.7, 3.4 Hz, 1H),
2.24 (ddd, J ) 14.7, 3.3, 0.9 Hz, 1H), 2.08 (m, 2H), 1.56 (m,
4H), 1.24 (m, 2H), 0.88 (m, 12H), 0.70 (m, 1H), -0.02 and
-0.01 (s, 6H). Anal. Calcd for C28H46O5Si: C, 68.53; H, 9.45.
Found: C, 68.29. H, 9.11.
(3R,5S,6R,7S,8S)-8-[(E)-1,5-Dim eth yl-h ex-1-en yl]-7-m eth -
oxy-6-p -m et h oxyb en zyloxy-1-oxa sp ir o[2.5]oct -5-yloxy]-
isop r op yld im eth ylsila n e (49). A solution of ketone 48 (59
mg, 120 µmol, 1.0 equiv) and CH2I2 (49 µL, 600 µmol, 5 equiv)
in THF (1 mL) was treated with BuLi (1.6 M in hexanes, 375
µL, 600 µmol, 5.0 equiv) at -78 °C. The mixture was stirred
for 1 h at -78 °C and then for 1.5 h at 20 °C. The reaction
was quenched with saturated NH4Cl and extracted with ethyl
acetate. The combined organic phases were dried over MgSO4,
filtered, and concentrated in vacuo. Purification by preparative
TLC (hexane/ethyl acetate, 9/1) provided 49 as a colorless oil
(22 mg) which was directly used for the next step. 1H NMR
(400 MHz, CDCl3): 6.87 and 7.29 (2d, J ) 8.8 Hz, 4H), 5.21
(t, J ) 6.9 Hz, 1H), 4.57 and 4.70 (2d, AB, J ) 12.1 Hz, 2H),
4.01 (m, 1H), 3.84 (dd, J ) 9.8, 2.5 Hz, 1H), 3.81 (s, 3H), 3.74
(dd, J ) 5.0, 2.3 Hz, 1H), 3.34 (s, 3H), 2.79 (d, J ) 9.8 Hz,
1H), 2.24 and 2.49 (2d, AB, J ) 5.3 Hz, 2H), 2.15 (dd, J )
13.8, 2.5 Hz, 1H), 1.96 (m, 2H), 1.54 (s, 3H), 1.35 (dd, J ) 13.8,
4.7 Hz, 1H), 1.20 (m, 2H), 0.93 and 0.94 (2d, 6H), 0.86 and
0.88 (2d, J ) 6.6 Hz Hz, 6H), 0.76 (m, 1H), 0.00 and 0.01 (s,
6H).
(3R,4S,5S,6R,7S)-4-[(E)-1,5-Dim eth yl-h ex-1-en yl]-7-(iso-
p r op yld im et h ylsila n yloxy)-5-m et h oxy-1-oxa sp ir o[2.5]-
octa n -6-ol (50). DDQ (7 mg, 31 µmol, 1.2 equiv) was added
to a solution of epoxide 49 (13 mg, 26 µmol) in CH2Cl2 (1 mL)
containing water (25 µL). The mixture was stirred for 2 h at
20 °C and then stopped by addition of saturated NaHCO3 and
extracted with ethyl acetate. The combined organic phases
were dried over MgSO4, filtered and concentrated in vacuo.
Purification on preparative TLC (SiO2, CH2Cl2) provided 50
(8 mg) as a colorless oil which was directly used for the next
step. 1H NMR (400 MHz, CDCl3): 5.27 (t, J ) 7.8 Hz, 1H),
4.09 (m, 1H), 3.97 (m, 1H), 3.86 (dd, J ) 9.0, 2.8 Hz, 1H), 3.39
(s, 3H), 2.62 (d, J ) 9.0 Hz, 1H), 2.32 (d, J ) 2.0, 1H), 2.30
and 2.49 (2d, AB, J ) 4.5 Hz, 2H), 2.00 (m, 2H), 1.62 (s, 3H),
1.53 (m, 1H), 1.46 (dd, J ) 14.1, 5.0 Hz, 1H), 1.23 (m, 2H),
0.97 (d, J ) 6.8 Hz, 6H), 0.88 and 0.87 (d, J ) 6.4 Hz, 6H),
0.82 (m, 1H), 0.08 and 0.07 (2 s, 6H).
(SiO2, cyclohexane/ethyl acetate, 7/3) to afford pure 52 (200
1
mg, 80%) as a colorless oil. [R]20 ) -116 (c ) 1.4, CHCl3). H
D
NMR (400 MHz, CDCl3): 7.28 and 6.88 (2d, J ) 8.8 Hz, 4H),
6.75 (m, 1H), 5.12 (t, J ) 7.0 Hz, 1H), 4.68 and 4.64 (2d, AB,
J ) 11.6 Hz, 2H), 4.36 (m, 2H), 4.18 (d, J ) 14.4 Hz, 1H), 3.80
(s, 3H), 3.74 (m, 1H), 3.45 (d, J ) 6.4 Hz, 1H), 3.40 (s, 3H),
2.00 (m, 2H), 1.56 (s, 3H), 1.50 (m, 1H), 1.15 (m, 2H), 0.85 (d,
J ) 6.4 Hz, 6H). RMN 13C (100 MHz, CDCl3): 199.5, 159.5,
140.6, 139.6, 130.4, 129.9, 129.5, 128.9, 113.9, 80.1, 71.6, 69.7,
61.1, 58.8, 57.7, 55.3, 38.4, 27.7, 26.0, 22.5, 15.2.
(4R,5S,6S)-2-(ter t-Bu tyld im eth ylsila n yloxym eth yl)-6-
[(E)-1,5-d im et h yl-h ex-1-en yl]-5-m et h oxy-4-p -m et h oxy-
ben zyloxycycloh ex-2-en on e (53). TBSCl (80 mg, 530 µmol,
1.5 equiv) was added to a solution of alcohol 52 (195 mg, 485
µmol) and DMAP (89 mg, 728 µmol, 2 equiv) in THF (3 mL).
The mixture was stirred for 4 h at 20 °C. After quenching
(ammonium chloride), extraction (cyclohexane), and chroma-
tography (SiO2, cyclohexane/AcOEt 9/1), pure 53 (170 mg, 68%)
was obtained as a colorless oil. [R]20 ) -74 (c ) 0.9, CHCl3).
D
1H NMR (400 MHz, CDCl3): 7.30 and 6.88 (2d, J ) 8.0 Hz,
4H), 6.84 (br s, 1H), 5.13 (t, J ) 7.0 Hz, 1H), 4.66 (s, 2H), 4.34
(m, 3H), 3.81 (s, 3H), 3.71 (m, 1H), 3.46 (d, J ) 6.4 Hz, 1H),
3.40 (s, 3H), 2.03 (m, 2H), 1.56 (s, 3H), 1.52 (m, 1H), 1.19 (q,
J ) 7.6 Hz, 2H), 0.92 (s, 9H), 0.86 (d, J ) 6.8 Hz, 6H), 0.08
and 0.06 (2s, 6H). 13C NMR (100 MHz, CDCl3): 198.2, 159.4,
140.2, 138.5, 130.5, 130.3, 129.5, 129.0, 113.9, 80.1, 71.5, 70.2,
59.8, 58.9, 57.5, 55.2, 38.4, 27.6, 25.9, 22.5, 18.3, 15.0, -4.6.
HRMS (FAB): m/z found 523.3429, calcd for C30H48O5LiSi m/z
523.3431.
(2S,3S,4R)-2-[(E)-1,5-Dim eth yl-h ex-1-en yl]-3-m eth oxy-
4-p-m eth oxyben zyloxy-6-m eth ylen ecycloh exa n on e (55).
To a solution of 53 (135 mg, 261 µmol) in toluene (1.5 mL)
was added Et3SiH (1.5 mL) followed by Wilkinson’s catalyst
RhCl(PPh3)3 (6 mg, 7 µmol, 0.03 equiv). The mixture was
heated to 65 °C for 4 h, and then the solvent was removed in
vacuo and the residue filtered through a short pad of silica
(cyclohexane f cyclohexane/AcOEt 9/1) to yield 176 mg of
crude 54, which were dissolved in THF/H2O (1/1), and treated
p-Meth oxycin n a m ic Acid (3R,4S,5S,6R,7S)-4-[(E)-1,5-
Dim eth yl-h ex-1-en yl]-7-h yd r oxy-5-m eth oxy-1-oxa sp ir o-
[2.5]oct-6-yl Ester (51). p-Methoxycinnamic acid (35 mg, 200
µmol, 10 equiv) followed by DMAP (24 mg, 200 µmol, 10 equiv)
and DCC (41 mg, 200 µmol, 10 equiv) were added to a solution
of alcohol 50 (8 mg, 20 µmol) in CH2Cl2 (2 mL). The mixture
was stirred overnight at 20 °C, and then the solvent was
372 J . Org. Chem., Vol. 69, No. 2, 2004

MetAP-2 Inhibitors Based on the Fumagillin Structure
with TFA (1M in THF, 260 µl, 260 µmol, 1 equiv). The reaction
was stirred for 1.5 h, quenched with H2O, and extracted with
CH2Cl2. The combined organic phases were dried over MgSO4,
filtered and concentrated in vacuo. The residue was chromato-
graphed (SiO2, cyclohexane/ethyl acetate, 9/1) to afford pure
3H), 3.01 (d, J ) 11.6 Hz, 1H), 2.61 and 2.47 (2d, AB, J ) 4.8
Hz, 2H), 2.34 (dtd, J ) 13.0, 6.8, 3.8 Hz, 1H), 2.01 (m, 2H),
1.89 (dt, J ) 14.0, 3.8 Hz, 1H), 1.54 (s, 3H), 1.52 (m, 1H), 1.37
(td, J ) 13.0, 2.0 Hz, 1H), 1.22 (m, 3H), 0.88 and 0.87 (2d, J
) 6.4 Hz, 6H), 0.67 (d, J ) 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3): 159.1, 131.3, 130.6, 129.2, 114.8, 81.1, 70.0, 56.6, 55.3,
49.8, 47.9, 38.9, 34.4, 28.4, 27.7, 25.8, 22.6 and 22.5, 13.8.
(3R,4S,5S,6R,8R)-4-[(E-1,5-Dim eth yl-h ex-1-en yl]-5-m eth -
oxy-8-m eth yl-1-oxa sp ir o[2.5]octa n -6-ol (59). DDQ (8 mg,
33 µmol, 1.2 equiv) was added to a solution of epoxide 58 (11
mg, 27 µmol) in CH2Cl2 (0.5 mL) containing water (30 µL).
The mixture was stirred for 1 h at 20 °C and then stopped by
addition of saturated NaHCO3 and extracted with ethyl
acetate. The combined organic phases were dried over MgSO4,
filtered, and concentrated in vacuo. Purification on preparative
TLC (SiO2, n-hexane/AcOEt 9/1) afforded 59 (6 mg) as a
colorless oil which was directly used for the next step. 1H NMR
(400 MHz, CDCl3): 5.22 (t, J ) 6.9 Hz, 1H), 4.33 (m, 1H), 3.49
(dd, J ) 11.3, 2.8 Hz, 1H), 3.38 (s, 3H), 2.80 (d, J ) 11.3 Hz,
1H), 2.51 and 2.64 (2d, AB, J ) 4.5 Hz, 2H), 2.37 (m, 2H),
2.04 (m, 2H), 1.93 (dt, J ) 14.1, 3.7 Hz, 1H), 1.57 (s, 3H), 1.52
(m, 1H), 1.22 (m, 2H), 0.87 and 0.89 (d, J ) 6.4 Hz, 6H), 0.69
(d, J ) 6.8 Hz, 3H).
55 (70 mg, 70%) as a colorless oil. [R]20 ) -5.6 (c ) 1.8,
D
CHCl3). 1H NMR (400 MHz, CDCl3): 7.27 and 6.87 (2d, J )
8.8 Hz, 4H), 5.98 (s, 1H), 5.21 (d, J ) 1.5 Hz, 1H), 5.17 (t, J )
7.0 Hz, 1H), 4.60 (s, 2H), 4.08 (m, 1H), 3.81 (s, 3H), 3.60 (dd,
J ) 8.6, 1.5 Hz, 1H), 3.42 (d, J ) 8.6 Hz, 1H), 3.38 (s, 3H),
2.92 (dd, J ) 16.0, 6.4 Hz, 1H), 2.53 (dd, J ) 16.0, 2.8 Hz,
1H), 2.03 (m, 2H), 1.57 (s, 3H), 1.55 (m, 1H), 1.23 (m, 2H),
0.87 (d, J ) 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3): 200.0,
159.2, 141.2, 131.2, 130.5, 130.0, 129.2, 123.2, 113.9, 113.8,
80.7, 71.1, 70.7, 60.9, 57.6, 55.3, 32.5, 27.6, 26.0, 22.5, 14.8.
(2S,3S,4R,6S)-2-[(E)-1,5-Dim eth yl-h ex-1-en yl]-3-m eth -
oxy-4-p-m eth oxyben zyloxy-6-m eth yl-cycloh exa n on e (56)
a n d (2S,3S,4R,6R)-2-[(E-1,5-Dim eth yl-h ex-1-en yl]-3-m eth -
oxy-4-p-m eth oxyben zyloxy-6-m eth ylcycloh exa n on e (57).
Under vigorous stirring, 10 drops of a 50% suspension of Raney
Nickel in water were added to a cold (0 °C) solution of enone
55 (70 mg, 106 µmol) in THF (1 mL). After 2 h, the mixture
was diluted with ether and filtered through Celite. The residue
was chromatographed on preparative TLC (SiO2, n-hexane/
p-Meth oxycin n a m ic Acid (1R,4S,5S,6R,8R)-4-[(E)-(1,5-
Dim et h yl-h ex-1-en yl]-5-m et h oxy-8-m et h yl-1-oxa sp ir o-
[2.5]oct-6-yl Ester (60). p-Methoxycinnamic acid (44 mg, 250
µmol, 10 equiv) followed by DMAP (30 mg, 250 µmol, 10 equiv)
and DCC (51 mg, 250 µmol, 10 equiv) were added to a solution
of alcohol 59 (6 mg, 87 µmol) in CH2Cl2 (1 mL). The mixture
was stirred overnight at 20 °C, and then the solvent was
removed in vacuo and the residue passed over a short pad of
silica gel (cyclohexane/AcOEt 7/3). Chromatography on pre-
parative TLC (SiO2, n-hexane/AcOEt 9/1) afforded pure 60 (8
mg, 69% from 58) containing ca.0.13% of the Z-cinnamate.
AcOEt 9/1) to afford pure 56 (25 mg, 36%) alongside with pure
1
57 (11 mg, 16%). 56. [R]20 ) +50 (c ) 1.2, CHCl3). H NMR
D
(400 MHz, CDCl3): 7.30 and 6.89 (2 d, J ) 8.4 Hz, 4 H), 4.98
(t, J ) 7.0 Hz, 1 H), 4.61 and 4.54 (2 d, AB, J ) 12.0 Hz, 2 H),
4.03 (ddd, J ) 10.1, 4.3, 2.0 Hz, 1 H), 3.90 (br s, 1 H), 3.81 (s,
3 H), 3.42 (s, 3 H), 3.30 (m, 1 H), 2.39 (m, 1 H), 1.99-1.92 (m,
4 H), 1.53 (s, 3 H), 1.49 (m, 1 H), 1.13 (m, 2 H), 1.06 (d, J )
6.4 Hz, 3 H), 0.86 (d, J ) 6.8 Hz, 6 H). 13C NMR (100 MHz,
CDCl3): 211.9, 159.3, 130.6, 130.0, 129.3, 128.0, 113.8, 80.8,
73.4, 70.5, 60.6, 57.9, 55.3, 40.2, 38.5, 33.5, 27.8, 25.9, 22.5,
15.6, 15.1. 57. [R]20 ) -16 (c ) 0.5, CHCl3). 1H NMR (400
[R]20 ) -90 (c ) 0.4, CHCl3). 1H NMR (400 MHz, CDCl3):
D
D
MHz, CDCl3): 7.34 and 6.88 (2d, J ) 8.4 Hz, 4H), 5.18 (t, J )
6.8 Hz, 1H), 4.63 (2d, AB, J ) 11.6 Hz, 2H), 4.11 (m, 1H), 3.82
(s, 3H), 3.57 (d, J ) 11.9 Hz, 1H), 3.35 (dd, J ) 11.9, 2.5 Hz,
1H), 3.30 (s, 3H), 2.75 (d quint, J ) 13.0, 6.6 Hz, 1H), 2.20
(ddd, J ) 14.4, 5.8, 4.0 Hz, 1H), 2.08 (m, 2H), 1.59 (s, 3H),
1.55 (m, 1H), 1.28-1.17 (m, 3H), 0.98 (d, J ) 6.8 Hz, 3H), 0.88
(d, J ) 6.4 Hz, 6H). 13C NMR (100 MHz, CDCl3): 209.7, 159.2,
130.8, 130.7, 129.4, 129.3, 117.1, 82.7, 71.4, 70.4, 61.8, 57.2,
55.3, 38.7, 38.5, 33.9, 29.7, 27.7, 25.9, 22.6, 13.9. HRMS
(FAB): m/z found 395.2768, calcd for C24H36O4Li m/z 395.2774.
(3R,4S,5S,6R,8R)-4-[(E)-1,5-Dim eth yl-h ex-1-en yl]-5-m eth -
oxy-6-p -m e t h oxyb e n zyloxy-8-m e t h yl-1-oxa sp ir o[2.5]-
octa n e (58). A solution of ketone 57 (20 mg, 51 µmol) and
CH2I2 (20 µL, 250 µmol, 5 equiv) in THF (0.3 mL) was treated
with BuLi (1.6 M in hexanes, 160 µL, 250 µmol, 5 equiv) at
-78 °C. The mixture was stirred for 45 min at -78 °C and
then for 1.5 h at 20 °C. The reaction was quenched with
saturated NH4Cl and extracted with ethyl acetate. The com-
bined organic phases were dried over MgSO4, filtered, and
concentrated in vacuo. Purification on preparative TLC (SiO2,
7.66 (d, J ) 16 Hz, 1H), 6.91 and 7.48 (2d, J ) 8.8 Hz, 4H),
6.38 (d, J ) 16 Hz, 1H), 5.40 (t, J ) 6.8 Hz, 1H), 5.25 (m, 1H),
3.87 (m, 1H), 3.83 (s, 3H), 3.36 (s, 3H), 2.70 (d, J ) 8.3 Hz,
1H), 2.44 and 2.60 (2d, J ) 5.0 Hz, 2H), 2.32 (m, 1H), 2.05 (m,
2H), 1.95 (dt, J ) 14.6, 3.8 Hz, 1H), 1.64 (td, J ) 13.7, 2.0 Hz,
1H), 1.53 (m, 1H), 1.26 (m, 2H), 0.89 and 0.88 (d, J ) 6.6 Hz,
6H), 0.71 (d, J ) 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
166.9, 161.4, 144.5, 132.1, 130.8, 129.8, 127.3, 116.1, 114.4,
79.1, 66.9, 62.7, 57.0, 55.3, 50.5, 47.9, 38.8, 34.6, 28.9, 27.7,
25.7, 22.5, 22.6, 13.6. HRMS (FAB): m/z found 443.2790, calcd
for C27H39O5 m/z 443.2797.
Ack n ow led gm en t. We thank Drs. Didier Le Nouen
and Ste´phane Bourg for help with NMR recording and
interpretation. We thank the CNRS and Galderma R&D
for a fellowship to J .-G.B. and V.R. Financial support
of this project by the CNRS and Galderma R&D is
gratefully aknowledged.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra of
compounds 4, 10-12, 14-21, 21′, 22-25, 27-31, 31′, 32, 33,
35-43, 45-47, 52, 53, 55-58, and 60. This material is
available free of charge via the Internet at http://pubs.acs.org.
n-hexane/ethyl acetate, 9/1) provided pure 58 (11 mg, 54%) as
1
a colorless oil. [R]20 ) -53 (c ) 0.55, CHCl3). H NMR (400
D
MHz, CDCl3): 7.32 and 6.87 (2d, J ) 8.8 Hz, 4H), 5.21 (t, J )
6.6 Hz, 1H), 4.67 and 4.61 (2d, AB, J ) 12.0 Hz, 2H), 4.06 (br
s, 1H), 3.81 (s, 3H), 3.46 (dd, J ) 11.6, 2.4 Hz, 1H), 3.29 (s,
J O035065+
J . Org. Chem, Vol. 69, No. 2, 2004 373