Exploiting PdII and TiIII chemistry to obtain γ-dioxygenated terpenoids: Synthesis of rostratone and novel approaches to aphidicolin and pyripyropene A

Article abstract of DOI:10.1021/jo0502910

In nature there are several terpenoids with a characteristic γ-dioxygenated system on the A ring, and many of them show interesting pharmacological properties. We have developed a novel strategy for the synthesis of these terpenoids involving three stages: (a) the selective epoxidation of commercial polyenes, (b) titanium(III)-catalyzed cyclization of the epoxypolyprenes thus obtained, and (c) Pd-mediated remote functionalization of the equatorial methyl group attached at C-4 on ring A of the cyclic terpenoid thus formed. This strategy has proved to be useful for the synthesis of the natural labdane rostratone (1) and related terpenoids, as well as for advanced synthetic approaches toward the pharmacologically active products aphidicolin (2) and pyripyropene A (3).

Full text of DOI:10.1021/jo0502910

VOLUME 70, NUMBER 21
OCTOBER 14, 2005
©
Copyright 2005 by the American Chemical Society
Exploiting Pd and TiIII Chemistry To Obtain γ-Dioxygenated
Terpenoids: Synthesis of Rostratone and Novel Approaches to
Aphidicolin and Pyripyropene A
II
Jos e´ Justicia, J. Enrique Oltra,* and Juan M. Cuerva*
Department of Organic Chemistry, Faculty of Sciences, University of Granada, E-18071 Granada, Spain
jmcuerva@platon.ugr.es
Received February 15, 2005
In nature there are several terpenoids with a characteristic γ-dioxygenated system on the A ring,
and many of them show interesting pharmacological properties. We have developed a novel strategy
for the synthesis of these terpenoids involving three stages: (a) the selective epoxidation of
commercial polyenes, (b) titanium(III)-catalyzed cyclization of the epoxypolyprenes thus obtained,
and (c) Pd-mediated remote functionalization of the equatorial methyl group attached at C-4 on
ring A of the cyclic terpenoid thus formed. This strategy has proved to be useful for the synthesis
of the natural labdane rostratone (1) and related terpenoids, as well as for advanced synthetic
approaches toward the pharmacologically active products aphidicolin (2) and pyripyropene A (3).
Introduction
colin, for example, shows marked activity against Herpes
4
simplex, and pyripyropene A has proved to be a powerful
Some organisms belonging to the kingdoms of plants
and fungi are capable of synthesizing small quantities
of highly functionalized terpenoids bearing a character-
istic γ-dioxygenated system on the A ring (Figure 1), as
occurs in the labdane diterpenoid 1 (rostratone) found
5
inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT),
an enzyme related to atherosclerosis. These compounds
have consequently attracted the attention of chemists,
6
who have reported some procedures for synthesizing 2
and 3.7 These syntheses, however, generally require
1
in the plant Nolana rostrata, in the antibiotic aphidicolin
numerous steps, including tedious protection and depro-
tection protocols, and eventually provide only low overall
yields.
2
(
2) excreted by Cephalosporium aphidicola, and in the
meroterpenoid pyripyropene A (3) isolated from the
fungus Aspergillus fumigatus. Many of these terpenoids
3
possess interesting pharmacological properties. Aphidi-
(4) Bucknall, R. A.; Moores, H.; Simms, R.; Hesp, B. Antimicrob.
Agents Chemother. 1973, 4, 294-298.
(
5) (a) Kim, Y. K.; Tomoda, H.; Nishida, H.; Sunazuka, T.; Oba, R.;
*
To whom correspondence should be addressed. Tel: +0034 958
48437. Fax: 0034 958 248090.
1) Garbarino, J. A.; Chamy, M. C.; Gambaro, V. Phytochemistry
986, 25, 2833-2836.
Omura, S. J. Antibiot. 1994, 47, 154-162. (b) Tomoda, H.; Kim, Y. K.;
Nishida, H.; Masuma, R.; Omura, S. J. Antibiot. 1994, 47, 148-153.
(c) Tomoda, H.; Tabata, N.; Yang, D. J.; Takayanagi, H.; Nishida, H.;
Omura, S.; Kaneko, T. J. Antibiot. 1995, 48, 495-503.
2
(
1
(
2) (a) Brundret, K. M.; Dalziel, W.; Hesp, B.; Jarvis, J. A. J.; Neidle,
(6) For a review concerning the total synthesis of aphidicolin, see:
Toyota, M.; Ihara, M. Tetrahedron 1999, 55, 5641-5679.
(7) (a) Nagamitsu, T.; Sunazuka, T.; Obata, R.; Tomoda, H.; Tanaka,
H.; Harigaya, Y.; Omura, S.; Smith, A. B., III. J. Org. Chem. 1995, 60,
8126-8127. (b) Aggarwal, V. K.; Bethel, P. A.; Giles, R. J. Chem Soc.,
Perkin Trans. 1 1999, 3315-3321.
S. J. Chem. Soc., Chem. Commun. 1972, 1027-1028. (b) Dalziel, W.;
Hesp, B.; Stevenson, K. M.; Jarvis, J. A. J. J. Chem. Soc., Perkin Trans.
1
1973, 2841-2851.
(
3) Omura, S.; Tomoda, H.; Kim, Y. K.; Nishida, H. J. Antibiot. 1993,
4
6, 1168-1169.
1
0.1021/jo0502910 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/16/2005
J. Org. Chem. 2005, 70, 8265-8272
8265

Justicia et al.
clopalladation reactions have proved to be capable of
activating primary C-H bonds for the formation of C-I,
C-O, and even C-C bonds.12 Surprisingly, this kind of
chemistry has been largely overlooked in the field of
terpenoids.13 In a preliminary communication we de-
II
scribed how Pd -mediated C-H activation via pallada-
cycles can be used for the remote functionalization of C-4
methyl groups of terpenoids obtained by titanocene(III)-
14
catalyzed radical cyclization of epoxypolyenes. Here we
report on this procedure in full detail and its application
to the synthesis of rostratone (1) and related labdanes
and advanced approaches toward the pharmacologically
active products aphidicolin (2) and pyripyropene A (3).
Results and Discussion
First we explored the efficiency of palladium-mediated
C-H activation reactions over a wide range of terpenoid
skeletons to facilitate the completion of the sequence
depicted in Scheme 1. We began the process by preparing
a set of model ketones (commercial 8b and 9b-14b) with
different cyclic skeletons containing five-, six-, and seven-
membered rings (Figure 2) via the oxidation of alcohols
FIGURE 1. γ-Dioxygenated system of the ring A present in
several bioactive terpenoids.
9
a-14a with Dess-Martin periodinane. These ketones
SCHEME 1. Anticipated Synthesis of Terpenoids
were subsequently treated with hydroxylamine to form
with the γ-Dioxygenated System on the A Ringa
ketoximes 8c-14c at yields ranging from 70% (9c) to 92%
(
13c).
Remote functionalization processes were then carried
out as depicted in Scheme 2.15 Reactions between ke-
toximes 10c-14c and sodium tetrachloropalladate(II)/
NaOAc gave palladacycle dimers 10f-14f (in contrast to
8
c and 9c, which decomposed after treatment with Na
2
-
a
Key: (a) selective epoxidation; (b) titanocene(III)-catalyzed
PdCl ), which were then treated with pyridine and lead
4
cyclization; (c) oxidation and Pd-mediated remote functionaliza-
tion.
tetraacetate to obtain acetoxy oximes 10d-14d in yields
ranging from 72% to 100% (Table 1).
A year ago we developed a novel method for the
To check the possibility of activating C-H bonds of
terpenoid (pseudo)axial methyl groups, we made further
reactions with sodium tetrachloropalladate(II), this time
using acetoxy oximes 10d-14d as substrates. In this way
we obtained moderate yields (42-55%) of acetates 15d
and 16d (Figure 3) deriving from monocyclic oximes 10d
and 11d, although the polycyclic substrates 12d-14d
remained unchanged. Presumably the stereochemical
rigidity of these compounds prevents a suitable confor-
mation to produce the required palladacycles.
Finally, the hydrolysis of oximes 10d-16d with TiCl3/
2
synthesis of complex terpenoids based on the titanocene-
8
(
(
III)-catalyzed radical cyclization of epoxypolyprenes
such as 5) prepared from commercial polyenes.9
This method, which adheres to the principles of selec-
tivity and atom- and step-economy required in contem-
porary chemistry,10 provides 3â-hydroxy terpenoids (such
as 6) with two “unactivated” methyl groups at C-4
9
(
Scheme 1). With such derivatives in our hands we only
needed to oxidize their equatorial methyl group to achieve
the γ-dioxygenated system of compounds such as 7
(including 1-3). The advantage of making this transfor-
H O avoided any undesirable isomerization of the double
mation by remote functionalization at the end of the
synthetic sequence is that protecting groups would not
be required during the building of the carbocyclic frame-
work.
(11) For a recent review into the potentials of organometallic
chemistry for useful C-H bond activation procedures, see: Labinger,
J. A.; Bercaw, J. E. Nature 2002, 417, 507-514.
(
12) (a) Carr, K.; Sutherland, J. K. J. Chem. Soc., Chem. Commun.
Organometallic chemistry affords mild and effective
1984, 1227-1228. (b) Baldwin, J. E.; N a´ jera, C.; Yus, M. J. Chem. Soc.,
Chem. Commun. 1985, 126-127. (c) Dangel, B. D.; Godula, K.; Youn,
S. W.; Sezen, B.; Sames, D. J. Am. Chem. Soc. 2002, 124, 11856-11857.
procedures to activate C-H bonds.11 In particular, cy-
(
d) Sezen, B.; Franz, R.; Sames, D. J. Am. Chem. Soc. 2002, 124,
(
8) For different titanocene(III)-based catalytic systems, see: (a)
Gans a¨ uer, A.; Pierobon, M.; Bluhm, H. Angew. Chem., Int. Ed. 1998,
7, 101-103. (b) Gans a¨ uer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem.
13372-13373. (e) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem.
Soc. 2004, 126, 2300-2301. (f) Desai, L. V.; Hull, K. L.; Sanford, M. S.
J. Am. Chem. Soc. 2004, 126, 9542-9543.
3
Soc. 1998, 120, 12849-12859. (c) Barrero, A. F.; Rosales, A.; Cuerva,
J. M.; Oltra, J. E. Org. Lett. 2003, 5, 1935-1938. For a recent report
about the monomeric/dimeric nature of the titanocene(III) complex in
solution, see: (d) Enemærke, R. J.; Larsen, J.; Skrydstrup, T.;
Daasbjerg, K. J. Am. Chem. Soc. 2004, 126, 7853-7864.
(13) We have only found two reports, both dealing with Pd-mediated
primary C-H activation of pentacyclic triterpenoids; see: (a) Peakman,
T. M.; Lo ten Haven, H.; Rullkotter, J.; Curiale, J. A. Tetrahedron 1991,
47, 3779-3786. (b) Bore, L.; Honda, T.; Gribble, G. W. J. Org. Chem.
2000, 65, 6278-6282.
(
9) (a) Justicia, J.; Rosales, A.; Bu n˜ uel, E.; Oller-L o´ pez, J. L.;
(14) Justicia, J.; Oltra, J. E.; Cuerva, J. M. Tetrahedron Lett. 2004,
45, 4293-4296.
Valdivia M.; Ha ¨ı dour, A.; Oltra, J. E.; Barrero, A. F.; C a´ rdenas, D. J.;
Cuerva, J. M. Chem. Eur. J. 2004, 10, 1778-1788. (b) Justicia, J.;
Oltra, J. E.; Cuerva, J. M. J. Org. Chem. 2004, 69, 5803-5806.
(15) Reactions between ketoximes 10c-14c and sodium tetrachlo-
ropalladate(II)/NaOAc can be carried out either in MeOH or AcOH,
but giving different yields. The best solvent for each substrate is that
indicated in Table 1.
(
10) (a) Trost, B. M. Science 1991, 254, 1471-1477. (b) Trost, B. M.
Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281.
8266 J. Org. Chem., Vol. 70, No. 21, 2005

Exploiting PdII and TiIII Chemistry
FIGURE 3. Chemical structure of products 15 and 16.
SCHEME 3. Formal Synthesis of Rostratone (1)
and Related Labdanes 21b and Methyl
3-Oxoanticopalate (22a)
FIGURE 2. Chemical structure of the alcohols 9a-14a, the
model ketones 8b-14b, the corresponding oximes, and the
products derived from Pd-mediated remote functionalization.
SCHEME 2. Remote Functionalization of
Terpenoids via Dimeric Organopalladium
Complexes
conditions, gave exocyclic alkene 199a (17% yield from
farnesylacetone) with high degrees of regio- and stereo-
3 2
selectivity. Further hydrolysis of ketal 19 with CeCl /H O
TABLE 1. Yields of Products Obtained by Pd-Mediated
Remote Functionalization of Oximes 10c-14c, 10d, and
avoided undesired double-bond isomerization and pro-
1
1d
9a
vided an 85% yield of ketone 20. Horner-Emmons
acetoxy oxime
(yield)
acetoxy ketone
(yield)
olefination of 20 yielded 21a, the methyl ester of the
natural labdane 21b found in both the Brazilian Copaiba
substrate
solvent15
1
7
tree and the Australian plant Olearia teretifolia. The
chemical synthesis of carboxylic acid 21b has been
achieved by Armstrong and Weiler through a 10-step
sequence (4% overall yield) that ends with the saponifica-
tion of ester 21a.18 Therefore, the titanocene(III)-based
preparation of this ester (five steps, 11% overall yield)
achieves a substantially improved formal synthesis of
10c
11c
12c
13c
14c
10d
11d
AcOH
MeOH
MeOH
MeOH
MeOH
AcOH
MeOH
10d (82%)
11d (88%)
12d (100%)
13d (85%)
14d (72%)
15d (55%)
16d (42%)
10e (82%)
11e (85%)
12e (85%)
13e (85%)
14e (85%)
15e (83%)
16e (85%)
2
1b.
Dess-Martin oxidation of 21a led to ketone 22a (80%
bonds, thus providing good yields of acetoxy ketones
10e-16e (Table 1).
yield). Spectroscopic data of this ketone matched those
reported for the methyl ester of 3-oxoanticopalic acid
(22b), found in the needles of Pinus strobus.19 To the best
of our knowledge, this is the first total synthesis reported
for 22a, which confirms the structure proposed by Zinkel
Once we were confident about the possibilities of the
Pd-based method, we went on to try and synthesize the
target molecule 1 (Scheme 3). As starting material we
chose ethylene ketal 17, which was easily prepared from
commercially available farnesylacetone.16 Bromonium-
mediated epoxidation of 17, followed by the titanium(III)-
catalyzed cyclization of epoxypolyene 18 under anhydrous
19
and Magee for the natural product 22b.
(17) (a) Mahajan, J. R.; Ferreira, G. A. L. An. Acad. Bras. Cienc.
1
971, 43, 611-613. (b) Zdero, C.; Bohlmann, F.; King, R. M. Phy-
tochemistry 1992, 31, 1703-1711.
(
16) Gopalan, A. S.; Prieto, R.; Mueller, B.; Peters, D. Tetrahedron
(18) Armstrong, R. J.; Weiler, L. Can. J. Chem. 1986, 64, 584-596.
(19) Zinkel, D. F.; Magee, T. V. Phytochemistry 1987, 26, 769-774.
Lett. 1992, 33, 1679-1682.
J. Org. Chem, Vol. 70, No. 21, 2005 8267

Justicia et al.
keto ester 29 (60% yield), which was easily transformed
into oxime 30. The Pd-mediated remote functionalization
of 30 gave acetate 31, which was hydrolyzed to acetoxy
ketone 32 (50% yield from 29). Finally, the stereoselective
reduction of ketone provided diol 33 (77%). This γ-dihy-
droxylated sesquiterpenoid contains an exocyclic double
bond that might undergo ozonolysis to the corresponding
ketone, which after suitable protection should provide 26.
The transformation of 26 into aphidicolin (2) was solved
by Corey et al. employing the Robinson spiroannulation
process.20
FIGURE 4. Chemical structure of synthons 26 and 27.
SCHEME 4. Advanced Approach toward Synthon
26
In the synthetic branch toward pyripyropene A (Scheme
), the exocyclic double bond was isomerized to a conju-
5
gated position after Dess-Martin oxidation of 28 and
subsequent basic treatment, giving R,â-unsaturated al-
dehyde 34 (65%). Further oxidation of this aldehyde,
followed by esterification of the corresponding acid,
furnished 35. The palladium-mediated remote function-
alization of 35, via oxime 36, furnished acetate 37, which
was hydrolyzed to obtain 38 (32% from 34). Finally,
borohydride reduction of 38 and selective saponification
of the acetate group provided 39 (50%). Dibenzylation of
SCHEME 5. Advanced Approach toward Synthon
27
3
9 would presumably give 27, thus completing the formal
synthesis of pyripyropene A (3).
In summary, the results described here prove that Pd-
mediated C-H activation is a suitable procedure for the
remote functionalization of C-4 methyl groups of different
terpenoid-like skeletons containing six- and seven-
membered A rings. This procedure might facilitate the
chemical preparation of terpenoids with a γ-dioxygenated
system on the A ring, and in fact it has proved itself
useful for the synthesis of the natural terpenoid rostra-
tone (1) and related labdanes (21b, 22a) and for synthetic
approaches to aphidicolin (2) and pyripyropene A (3). At
the moment we are attempting to complete the synthesis
of both 2 and 3 using shorter and more efficient synthetic
sequences than those reported to date.
Treatment of ketone 22a with hydroxylamine led to
the oxime 23 (60% yield from 20) and finally the Pd-
mediated remote functionalization of 23 and hydrolysis
of oxime 24 afforded acetoxy ketone 25 (53% yield from
2
3). The natural metabolite (1) from N. rostrata has been
isolated and characterized by Garbarino et al. as its
Experimental Section
1
acetate (25). Spectroscopic data of synthetic 25 matched
General. For the reactions with titanocene all solvents and
additives were thoroughly deoxygenated prior to use. Although
all structures have been drawn as one enantiomer the syn-
those of the acetate reported by Garbarino and co-
1
workers, supporting the structure proposed for the
9
a,21
16
natural product 1. These authors also describe the
selective saponification of the acetate group of 25 to give
, and therefore the sequence depicted in Scheme 3 may
be regarded as the formal synthesis of 1. To the best of
our knowledge this is the first chemical synthesis of this
ketone, which we have called rostratone.
thesized compounds are racemic. Substances 9a-14a,
17,
9
a
9a
20, and 28 were prepared according to known procedures.
The following known compounds were isolated as pure samples
and showed NMR spectra identical to those of the reported
1
2
2
23
17,18
19
1
compounds: 8c, 11b, 21,
22, and 25.
General Procedure for the Synthesis of Ketones (9b-
4b) by Dess-Martin Oxidation. A solution of alcohol (9a-
4a) (1.0 mmol) and Dess-Martin periodinane (2.0 mmol) in
1
1
The synthesis of aphidicolin (2), reported by Corey et
2
0
al., goes through an intermediate (26) closely related
to the bicyclic synthon 27 employed by Nagamitsu et al.7a
for the synthesis of pyripyropene A (3). This observation
prompted us to develop a novel, divergent strategy for
the chemical preparation of both intermediates 26 and
wet CH Cl (30 mL) was stirred at room temperature for 2 h.
2
2
The mixture was diluted with tBuOMe, washed with 10%
aqueous Na and brine, and dried (Na SO ), and the
2 2
S O
3
2
4
solvent was removed. The products were isolated by column
chromatography of the residue on silica gel (hexane/tBuOMe)
and characterized by spectroscopic techniques. The ketones
obtained were isolated in the following yields: 9b (70%), 10b
2
7 (Figure 4) starting from isodrimenediol (28), which is
readily prepared by titanocene(III)-catalyzed cyclization
of 10,11-epoxyfarnesyl acetate.9a From this diol the
synthesis split into two branches, one directed toward
(
88%), 11b (76%), 12b (94%), 13b (72%), 14b (91%).
1
Ketone 9b. Hexane/tBuOMe, 4:1; vitreous solid; H NMR
(300 MHz, CDCl ) δ 5.01 (br s, 1H), 4.87 (br s, 1H), 4.15-4.05
3
2
6 (Scheme 4) and the other toward 27 (Scheme 5). In
the former, the exocyclic double bond of 28 remained after
(21) Barrero, A. F.; Cuerva, J. M.; Herrador, M. M.; Valdivia, M. V.
J. Org. Chem. 2001, 66, 4074-4080.
Jones oxidation and treatment with diazomethane, giving
(
22) Conley, R. T.; Nowak, B. E. J. Org. Chem. 1962, 27, 3196-
3
201.
(23) For previous synthesis of karahanaenone (11b) see: Uneyama,
K.; Date, T.; Torii, S. J. Org. Chem. 1985, 50, 3160-3163.
(20) Corey, E. J.; Tius, M. A.; Das, J. J. Am. Chem. Soc. 1980, 102,
1
742-1744.
8268 J. Org. Chem., Vol. 70, No. 21, 2005

Exploiting PdII and TiIII Chemistry
+
(
m, 2H), 2.85-2.20 (m, 4H), 1.97 (s, 3H), 1.90-1.55 (m, 1H),
.19 (s, 3H), 1.05 (s, 3H); 13C NMR (75 MHz, CDCl
) δ 213.7
), 54.5 (CH),
2 3
(CH ), 9.1 (CH ); EIMS m/z 227 (1, M ), 212 (1), 167 (100),
1
3
21 3
153 (75), 111 (40); HRFABMS calcd for C12H O NNa m/z
(
C), 170.6 (C), 143.9 (C), 113.8 (CH
2
), 63.6 (CH
2
250.1419, found m/z 250.1424.
3
7.7 (CH
2
), 35.6 (C), 31.6 (CH
2
), 27.1 (CH
3
), 21.1 (CH
3
), 20.8
Oxime 11c. Hexane/tBuOMe, 4:1; white solid, mp 109-111
2
4
1
(
CH
3
).
°C; H NMR (300 MHz, CDCl ) δ 5.35 (t, J ) 6.6 Hz, 1H), 2.73
3
1
Ketone 10b. Hexane/tBuOMe, 4:1; vitreous solid; H NMR
300 MHz, CDCl
(t, J ) 6.6 Hz, 2H), 2.29 (t, J ) 6.6 Hz, 2H), 2.10 (d, J ) 6.9
1
3
(
3
) δ 3.05 (dt, J ) 14.6, 3.5 Hz, 1H), 2.59 (td,
3
Hz, 2H), 1.62 (s, 3H), 1.13 (s, 6H); C NMR (75 MHz, CDCl )
J ) 14.5, 5.4 Hz, 1H), 2.49 (td, J ) 14.5, 5.4 Hz, 1H), 2.03 (s,
δ 167.5 (C), 137.6 (C), 120.7 (CH), 43.3 (C), 38.6 (CH
(CH ), 27.1 (CH ), 25.5 (CH ), 21.4 (CH ); EIMS m/z 167 (1,
M ), 152 (40), 126 (25), 108 (100), 76 (55); HREIMS calcd for
17ON m/z 167.1310, found m/z 167.1314.
Oxime 12c. Hexane/tBuOMe, 4:1; white solid, mp 125-127
2
), 31.9
3
H), 1.66 (td, J ) 14.6, 4.3 Hz, 1H), 1.52 (s, 3H), 1.49-1.44
2
3
3
2
1
3
+
(
m, 1H), 1.10 (s, 3H), 1.08 (s, 3H), 1.05 (d, J ) 3 Hz, 3H);
C
NMR (75 MHz, CDCl
3
) δ 214.9 (C), 170.1 (C), 82.5 (C), 50.9
), 34.2 (CH ), 26.9 (CH ), 24.6 (CH ),
10
C H
(
2
CH), 48.1 (C), 34.3 (CH
2
2
3
3
2
4
4.4 (CH
3
), 21.6 (CH
3
), 9.1 (CH
3
).
1
°
3
C; H NMR (300 MHz, CDCl ) δ 4.87 (br s, 1H), 4.54 (br s,
Ketone 12b. Hexane/tBuOMe, 7:3; white solid, mp 150-
1H), 4.27 (dd, J ) 11.4, 4.5 Hz, 1H), 4.20 (dd, J ) 11.4, 7.8
Hz, 1H), 3.25 (dt, J ) 18.3, 3.3 Hz, 2H), 2.44-2.38 (m, 1H),
1.99 (s, 3H), 1.92-1.16 (m, 7H), 1.14 (s, 3H), 1.03 (s, 3H), 0.87
1
1
3
52 °C; H NMR (400 MHz, CDCl ) δ 4.95 (br s, 1H), 4.63 (br
s, 1H), 4.34 (dd, J ) 11.4, 4.1 Hz, 1H), 4.26 (dd, J ) 11.4, 8.5
Hz, 1H), 2.66 (td, J ) 12.9, 6.4 Hz, 1H), 2.50-2.38 (m, 2H),
13
(s, 3H); C NMR (75 MHz, CDCl ) δ 171.0 (C), 166.2 (C), 146.0
3
2
3
2
.15-2.05 (m, 3H), 2.04 (s, 3H), 1.88-1.48 (m, 4H), 1.12 (s,
(C), 108.0 (CH ), 61.5 (CH ), 55.2 (CH), 54.1 (CH), 40.8 (C),
2
2
H), 1.05 (s, 3H), 0.96 (s, 3H); 13C NMR (100 MHz, CDCl
16.1 (C), 171.3 (C), 145.5 (C), 108.4 (CH ), 61.4 (CH ), 55.1
), 37.1 (CH ), 34.6
), 21.1 (CH ), 14.6
); EIMS m/z 278 (3, M ), 263 (1), 218 (100), 203 (30), 175
Na m/z
) δ
3
2 3 2
38.9 (C), 37.2 (CH , two carbons), 26.9 (CH ), 24.1 (CH ), 23.3
2
2
3 3 2 3
(CH ), 21.1 (CH ), 17.6 (CH ), 14.8 (CH ); EIMS m/z 293 (8,
+
(
(
(
(
CH), 53.8 (CH), 47.9 (C), 38.6 (C), 37.5 (CH
2
2
M ), 276 (25), 234 (97), 216 (100), 166 (55), 124 (65), 91 (80),
CH
CH
2
), 25.9 (CH
3
3
), 24.6 (CH
2
), 21.9 (CH
3
3
79 (75); HRFABMS calcd for C H O NNa m/z 316.1888, found
17
27
3
+
m/z 316.1889.
50), 133 (65), 93 (55); HRFABMS calcd for C17
01.1779, found m/z 301.1778.
Ketone 13b. (Hexane/tBuOMe, 4:1); vitreous solid; H NMR
300 MHz, CDCl ) δ 5.35 (t, J ) 6.3 Hz, 1H), 2.68 (m, 1H),
.27 (dt, J ) 15.3, 4 Hz, 1H), 2.15-1.77 (m, 3H), 1.73 (s, 3H),
.69-1.10 (m, 6H), 1.07 (s, 3H), 0.99 (s, 3H), 0.96 (s, 3H); 13
) δ 216.7 (C), 141.4 (C), 121.9 (CH), 59.5
CH), 48.7 (C), 44.7 (CH ), 40.9 (CH ), 35.6 (C), 35.2 (CH ),
4.3 (CH ), 25.5 (CH ), 25.4 (CH ), 22.7 (CH ), 21.7 (CH ), 18.8
26 3
H O
Oxime 13c. Hexane/tBuOMe, 4:1; white solid, mp 144-146
3
1
°
3
C; H NMR (300 MHz, CDCl ) δ 9.53 (br s, 1H), 5.35 (t, J )
1
6.6 Hz, 1H), 3.20 (dt, J ) 14.7, 3.9 Hz, 2H), 2.16-1.83 (m,
(
2
1
3
3H), 1.73 (s, 3H), 1.69-1.25 (m, 6H), 1.16 (s, 3H), 0.99 (s, 3H),
0.95 (s, 3H); 13C NMR (75 MHz, CDCl ) δ 167.2 (C), 141.2 (C),
3
C
122.3 (CH), 59.9 (CH), 45.3 (CH ), 41.7 (C), 40.9 (CH ), 35.8
2
2
NMR (75 MHz, CDCl
3
2 3 3 3 2
(C), 34.6 (CH ), 26.4 (CH ), 25.5 (CH ), 23.2 (CH ), 22.1 (CH ),
(
2
2
2
19.0 (CH ), 17.9 (CH ); EIMS m/z 235 (40, M ), 218 (75), 192
+
3
2
3
2
3
3
2
3
(20), 152 (60), 134 (70), 99 (85), 67 (100); HRFABMS calcd for
+
(
CH
3
); EIMS m/z 220 (25, M ), 205 (20), 152 (100), 137 (90),
C H ONNa m/z 258.1833, found m/z 258.1831.
1
5
25
2
4
9
7 (95), 67 (80).
Oxime 14c. Hexane/tBuOMe, 4:1; white solid, mp 166-168
1
Ketone 14b. Hexane/tBuOMe, 4:1; vitreous solid; H NMR
300 MHz, CDCl ) δ 4.86 (br s, 1H), 4.53 (br s, 1H), 4.33 (dd,
1
°
1
C; H NMR (300 MHz, CDCl
H), 4.31 (dd, J ) 11.1, 3.3 Hz, 1H), 4.17 (dd, J ) 11.1, 9.3
Hz, 1H), 2.98 (dt, J ) 15.3, 4.6 Hz, 2H), 2.41-2.21 (m, 4H),
.00 (s, 3H), 1.90-1.17 (m, 9H), 1.14 (s, 3H), 1.04 (s, 3H), 0.90
3
) δ 4.84 (br s, 1H), 4.51 (br s,
(
3
J ) 11.1, 3.6 Hz, 1H), 4.18 (dd, J ) 11.1, 9 Hz, 1H), 2.56-2.39
(
(
m, 4H), 2.01 (s, 3H), 2.00-1.09 (m, 11H), 1.08 (s, 3H), 1.02
2
13
s, 3H), 0.90 (s, 3H), 0.78 (s, 3H); C NMR (75 MHz, CDCl
), 61.4 (CH ), 58.9
CH), 54.9 (CH), 54.9 (CH), 47.3 (C), 39.9 (CH ), 39.4 (CH ),
3
)
13
(
s, 3H), 0.76 (s, 3H); C NMR (75 MHz, CDCl
66.9 (C), 146.4 (C), 107.4 (CH ), 61.5 (CH ), 59.2 (CH), 55.4
CH), 55.0 (CH), 40.3 (C), 40.2 (CH ), 39.4 (CH ), 39.2 (C), 38.5
CH ), 37.6 (C), 37.5 (CH ), 27.5 (CH ), 23.1 (CH ), 23.0 (CH ),
1.2 (CH ), 19.4 (CH ), 16.1 (CH ), 15.9 (CH ); EIMS m/z 361
1, M ), 331 (7), 286 (90), 271 (15), 243 (10), 205 (100), 187
3
) δ 171.5 (C),
δ 217.6 (C), 171.4 (C), 146.2 (C), 107.6 (CH
2
2
1
2
2
(
3
2
2
(
(
2
2
9.1 (C), 37.5 (CH
2
), 37.3 (C), 34.1 (CH
), 21.0 (CH ), 20.0 (CH
); EIMS m/z 346 (5, M ), 331 (3), 303 (3), 286 (90), 218
2
), 26.8 (CH
), 16.2 (CH
3
), 23.3
), 15.8
2
2
3
2
3
(
(
(
CH
2
), 21.2 (CH
3
3
2
3
2
3
2
3
3
+
CH
3
+
(
(
+
45), 205 (100), 163 (45), 121 (55), 93 (60); HREIMS [M
30O m/z 286.2296, found m/z 286.2304.
General Procedure for Oxime Synthesis: A mixture of
ketone (8b-14b, 1 mmol), NH OH‚HCl (2 mmol), and NaOAc
1 mmol) in MeOH (20 mL) was stirred at room temperature
-
17), 163 (35), 121 (55), 93 (65); HREIMS calcd for C22
35 3
H O N
AcOH] calcd for C20
H
m/z 361.2617, found m/z 361.2620.
II
General Procedure for Pd -Mediated Remote Func-
2
tionalization. A mixture of oxime (10c-14c, 10d and 11d; 1
(
2 4
mmol), NaOAc (1.2 mmol), and Na PdCl (1.2 mmol) in AcOH
until the starting ketone was consumed. The solvent was then
removed, and the residue was submitted to flash chromatog-
raphy (hexane/tBuOMe), giving the corresponding oximes in
the following yields: 8c (75%), 9c (70%), 10c (89%), 11c (80%),
or MeOH (2-5 mL) (see Table 1) was stirred at room
temperature for 48 h. The solvent was removed, and the
2 2
residue diluted with CH Cl , filtered through a Celite pad, and
concentrated. The residue obtained and Py (3.2 mmol) in THF
10 mL) were stirred at room temperature for 15 min. The
reaction was then cooled to -78 °C, AcOH (66 mmol) and Pb-
1
2c (88%), 13c (92%), 14c (91%).
(
Oxime 9c. Hexane.tBuOMe, 4:1; white solid, mp 142-144
1
°
1
C; H NMR (300 MHz, CDCl
3
) δ 4.92 (br s, 1H), 4.77 (br s,
(
4
OAc) (1.1 mmol) were added, and the resulting mixture
H), 4.19 (dd, J ) 11.4, 5.1 Hz, 1H), 4.03 (dd, J ) 16.2, 6.3
allowed to warm to room temperature and stirred for 24 h.
Hz, 1H), 3.25 (dt, J ) 14.4, 4.5 Hz, 2H), 2.50-2.00 (m, 3H),
Subsequently, tBuOMe was added, and the mixture was
1
.97 (s, 3H), 1.15 (s, 3H), 1.14 (s, 3H); 13C NMR (75 MHz,
CDCl ) δ 171.0 (C), 163.2 (C), 144.5 (C), 113.1 (CH ), 62.9
CH ), 54.4 (CH), 40.5 (C), 29.9 (CH ), 28.3 (CH ), 22.9 (CH ),
0.9 (CH ), 20.8 (CH ); HRFABMS calcd for C12 NNa m/z
48.1263, found m/z 248.1261.
Oxime 10c. Hexane/tBuOMe, 4:1; white solid, mp 114-116
washed with saturated NaHCO
SO
3 2
and dried (anhydroud Na -
3
2
), and the solvent was removed. The residue was submitted
4
(
2
2
2
2
3
3
to flash chromatography (hexane/tBuOMe) giving the corre-
sponding acetoxy oximes in the following yields: 10d (82%),
3
2
19 3
H O
1
1d (88%), 12d (100%), 13d (85%), 14d (72%), 15d (55%) and
16d (42%). Oximes 14d-16d were isolated contaminated with
minor amounts of their hydrolysis products (14e-16e), so we
decided to describe these products directly below.
1
°
3
C; H NMR (300 MHz, CDCl ) δ 9.50 (br s, 1H), 3.21 (dt, 1H),
2
1
.93 (dt, 1H), 2.01 (s, 3H), 1.49 (s, 3H), 1.48-1.13 (m, 6H),
.12 (s, 3H), 1.05 (d, J ) 6.8 Hz, 3H); 13C NMR (75 MHz,
Acetoxy Oxime 10d. Hexane/tBuOMe, 4:1; vitreous solid;
CDCl
3
3
) δ 170.2 (C), 165.9 (C), 83.3 (C), 51.0 (CH), 40.9 (C),
), 25.6 (CH ), 25.1 (CH ), 22.5 (CH ), 22.4 (CH ), 17.0
1
3
H NMR (300 MHz, CDCl ) δ 4.27 (d, J ) 11.4 Hz, 1H), 4.00
3.8 (CH
2
3
3
3
3
(
d, J ) 11.4 Hz, 1H), 3.17 (dt, J ) 15, 3.7 Hz, 1H), 2.89 (dt, J
)
14.5, 4 Hz, 1H), 2.02 (s, 3H), 2.01 (s, 3H), 1.98-1.75 (m,
13
(24) We could not achieve good quality HRMS for ketones 9b, 10b,
3H), 1.53 (s, 3H), 1.09 (s, 3H), 1.01 (d, J ) 6.9 Hz, 3H);
C
and 13b.
3
NMR (75 MHz, CDCl ) δ 169.2 (C), 168.2 (C), 159.6 (C), 81.4
J. Org. Chem, Vol. 70, No. 21, 2005 8269

Justicia et al.
), 20.6 (CH );35EIMS
(
C), 64.0 (CH
0.9 (CH ), 19.1 (CH
m/z 285 (1, M ) 225 (35), 152 (100), 135 (55), 108 (30);
2
), 42.2 (CH), 41.7 (C), 31.0 (CH
2
), 23.1 (CH
3
),
(CH
2
), 31.8 (CH
2
), 25.3 (CH
3
), 20.9 (CH
3
3
+
2
3
3
), 17.0 (CH ), 15.3 (CH ), 6.6 (CH
3
2
3
); EIMS
m/z 210 (10, M ), 150 (50), 122 (52), 93 (100), 79 (35).
Acetoxy Ketone 12e. Hexane/tBuOMe, 4:1; vitreous solid;
+
1
HRFABMS calcd for C14
3
H
23
O
5
NNa m/z 308.1473, found m/z
H NMR (300 MHz, CDCl ) δ 4.95 (br s, 1H), 4.64 (br s, 1H),
3
08.1480.
4.37 (dd, J ) 11.5, 4.0 Hz, 1H), 4.24 (dd, J ) 11.5, 8.5 Hz,
1H), 4.16 (d, J ) 10.9 Hz, 1H), 3.95 (d, J ) 10.9 Hz, 1H), 2.64-
2.43 (m, 3H), 2.03 (s, 6H), 1.85-1.15 (m, 7H), 0.98 (s, 3H), 0.95
Acetoxy Oxime 11d. Hexane/tBuOMe, 4:1; vitreous solid;
H NMR (300 MHz, CDCl ) δ 5.31 (t, J ) 6.3 Hz, 1H), 4.11 (d,
3
1
13
J ) 11 Hz, 1H), 3.96 (d, J ) 11 Hz, 1H), 2.87-2.62 (m, 3H),
(s, 3H); C NMR (75 MHz, CDCl
(C), 145.1 (C), 108.8 (CH ), 66.9 (CH
3
) δ 212.7 (C), 171.2 (C), 170.7
), 61.3 (CH ), 53.6 (CH),
2
.38 (dd, J ) 15, 6 Hz, 1H), 2.29 (br t, 2H), 2.04 (s, 3H), 1.62
2
2
2
(
s, 3H), 1.15 (s, 3H); 13C NMR (75 MHz, CDCl
3
) δ 171.1 (C),
), 46.7 (C), 33.1
), 21.8 (CH ), 20.1 (CH );
50.6 (C), 47.6 (CH), 38.3 (C), 37.0 (CH ), 35.8 (CH ), 35.1 (CH ),
2
2
2
1
64.5 (C), 138.2 (C), 119.3 (CH), 69.8 (CH
2
24.4 (CH
2
), 21.1 (CH
3
), 20.9 (CH
3
3 3
), 18.0 (CH ), 15.0 (CH );
+
EIMS m/z 336 (3, M ), 276 (100), 234 (20), 216 (65), 201 (60),
(
CH
2
), 322 (CH ), 25.5 (CH ), 22.3 (CH
2
3
3
2
3
+
19 28 5
161 (63), 133 (75), 91 (73); HRFABMS calcd for C H O Na
EIMS m/z 225 (1, M ), 208 (1), 165 (50), 148 (100), 94 (35);
m/z 359.1834, found m/z 359.1834.
Acetoxy Ketone 13e. Hexane/tBuOMe, 4:1; white solid; mp
HRFABMS calcd for C12
2
19 3
H O NNa m/z 248.1262, found m/z
48.1266.
1
1
3
23-125 °C; H NMR (300 MHz, CDCl ) δ 5.38 (br t, J ) 6.8
Acetoxy Oxime 12d. Hexane/tBuOMe, 4:1; vitreous solid;
1
Hz, 1H), 4.16 (d, J ) 10.9 Hz, 1H), 4.03 (d, J ) 10.9 Hz, 1H),
H NMR (300 MHz, CDCl
.35-4.08 (m, 2H), 4.19 (d, J ) 11.1 Hz, 1H), 4.03 (d, J ) 11.1
Hz, 1H), 3.09 (dt, J ) 16.3, 3.1 Hz, 1H), 2.44-2.35 (m, 1H),
3
) δ 4.90 (br s, 1H), 4.58 (br s, 1H),
2
.65 (ddd, J ) 16.6, 7.1, 4.0 Hz, 1H), 2.36 (ddd, J ) 16.6, 3.0,
.5 Hz, 1H), 2.02 (s, 3H), 2.10-1.25 (m, 9H), 1.74 (s, 3H), 1.02
4
2
1
3
(
s, 3H), 0.96 (s, 3H); C NMR (75 MHz, CDCl
170.8 (C), 141.5 (C), 121.8 (CH), 66.4 (CH
CH ), 39.6 (CH ), 35.6 (CH ), 35.1 (C), 34.0 (CH
2.4 (CH ), 21.0 (CH ), 18.8 (CH ), 17.8 (CH ), (one quaternary-
3
) δ 213.6 (C),
), 51.6 (CH), 44.7
), 25.4 (CH ),
2
7
1
.25-2.05 (m, 1H), 2.04 (s, 3H), 2.01 (s, 3H), 2.00-1.10 (m,
H), 1.02 (s, 3H), 0.85 (s, 3H); 1 C NMR (75 MHz, CDCl
72.1 (C), 171.0 (C), 162.0 (C), 145.5 (C), 108.2 (CH ), 67.4
), 53.8 (CH), 47.9 (CH), 43.2 (C), 38.5 (C), 37.1
), 35.5 (CH ), 24.3 (CH ), 21.1 (CH ), 21.0 (CH ), 19.7
), 18.1 (CH ), 14.7 (CH ); EIMS m/z 351 (1, M ), 336 (1),
3
2
3
) δ
(
2
2
2
2
2
3
2
2
3
3
3
(
(
(
CH
2
2
3
), 61.4 (CH
2
+
carbon signal was not observed); EIMS m/z 278 (40, M ), 263
CH
CH
2
2
3
3
+
(1), 218 (20), 205 (25), 150 (55), 132 (70), 93 (100), 67 (97);
2
3
HRFABMS calcd for C17
26 3
H O Na m/z 301.1779, found m/z
3
17 (5), 276 (100), 264 (25), 216 (65), 201 (63), 173 (75), 133
301.1777.
29 5
(95), 91 (75); HRFABMS calcd for C19H O NNa m/z 374.1943,
Acetoxy Ketone 14e. Hexane/tBuOMe, 4:1; colorless oil;
found m/z 374.1941.
1
H NMR (300 MHz, CDCl
3
) δ 4.85 (br s, 1H), 4.52 (br s, 1H),
.31 (dd, J ) 11.1, 3.3 Hz, 1H), 4.17 (dd, J ) 11.1, 9.3 Hz,
H), 4.08-4.02 (m, 2H), 2.50-2.28 (m, 2H), 2.03 (s, 3H), 2.02
Acetoxy Oxime 13d. Hexane/MeOtBu, 4:1; vitreous solid;
4
1
(
1
H NMR (300 MHz, CDCl
3
) δ 8.21 (br s, 1H), 5.35 (t, J ) 6.4
Hz, 1H), 4.17 (d, J ) 11.1 Hz, 1H), 4.10 (d, J ) 11.1 Hz, 1H),
3
1
s, 3H), 1.90-1.10 (m, 13H), 0.99 (s, 3H), 0.93 (s, 3H), 0.80 (s,
.06 (dt, J ) 16, 3 Hz, 2H), 2.26-2.14 (m, 2H), 2.05 (s, 3H),
.72 (s, 3H), 1.70-1.10 (m, 7H), 0.97 (s, 3H), 0.93 (s, 3H); 13
) δ 171.2 (C), 163.2 (C), 141.4 (C), 122.1
), 51.9 (CH), 45.0 (CH ), 44.2 (C), 39.4 (CH ),
5.3 (C), 34.1 (CH ), 25.4 (CH ), 22.1 (CH ), 21.1 (CH ), 19.5
CH ), 19.0 (CH ), 18.4 (CH ); EIMS m/z 293 (10, M ), 276 (5),
34 (15), 220 (65), 178 (18), 152 (98), 134 (60), 93 (55), 67 (70);
NNa m/z 316.1888, found m/z
1
3
3
H); C NMR (75 MHz, CDCl
), 67.7 (CH
4.8 (CH), 50.1 (C), 47.9 (CH), 39.6 (CH
7.4 (C), 36.9 (CH ), 35.1 (CH ), 23.2 (CH
), 19.9 (CH ), 17.3 (CH ), 15.9 (CH ), 15.8 (CH
3
3
) δ 213.1 (C), 171.5 (C), 170.8
), 61.4 (CH ), 58.5 (CH),
), 39.1 (C), 37.9 (CH ),
), 21.2 (CH ), 21.0
); EIMS
C
(
C), 146.0 (C), 107.7 (CH
2
2
2
NMR (75 MHz, CDCl
CH), 66.7 (CH
3
5
3
2
2
(
2
2
2
2
2
2
3
3
2
3
2
3
(
CH
3
2
3
3
+
(
3
3
2
+
m/z 404 (8, M ), 344 (30), 302 (15), 284 (27), 217 (40), 203 (100),
2
1
4
36 5
61 (55), 133 (85), 93 (97); HREIMS calcd for C24H O m/z
HRFABMS calcd for C17
27 3
H O
04.2563, found m/z 404.2568.
3
16.1882.
General Procedure for Oxime Hydrolysis. A mixture
of NH OAc (28 mmol), 20% HCl (0.5 mL), H O (15 mL), and
TiCl (5 mmol) was added to a solution of acetoxy oxime (10d-
Diacetoxy Ketone 15e. Hexane/tBuOMe, 4:1; colorless oil;
1
3
H NMR (300 MHz, CDCl ) δ 5.09 (d, J ) 11.4 Hz, 1H), 4.67
4
2
(
d, J ) 11.4 Hz, 1H), 4.06 (d, J ) 11.4 Hz, 1H), 3.96 (d, J )
3
1
1
1
1.4 Hz, 1H), 3.14 (dt, J ) 14.6, 5.0 Hz, 1H), 2.76 (td, J )
5.0, 5.6, 1H), 2.25 (dt, J ) 15.0, 4.0, 1H), 2.12 (s, 3H), 2.10-
1
6d, 1 mmol) in THF (20 mL), and the resulting mixture was
stirred at room temperature until the starting oxime was
.90 (m, 1H), 2.02 (s, 3H), 1.98 (s, 3H), 1.74 (dt, J ) 14.3, 4.6
consumed. The reaction was then diluted with tBuOMe,
13
Hz, 1H), 1.61 (s, 3H), 1.12 (d, J ) 7.1 Hz, 3H); C NMR (75
washed with saturated NaHCO
3
, and dried over anhydroud
MHz, CDCl
C), 62.9 (CH
3.8 (CH ), 24.5 (CH
CH ); EIMS m/z 328 (1, M ), 268 (4), 208 (6), 195 (5), 166
15), 148 (20), 99 (100); HRFABMS calcd for C16 Na m/z
3
) δ 207.4 (C), 170.7 (C), 170.6 (C), 169.9 (C), 82.4
), 62.7 (CH ), 54.8 (C), 44.8 (CH), 34.9 (CH ),
), 22.4 (CH ), 21.0 (CH ), 20.8 (CH ), 8.9
Na SO , and the solvent was removed. The residue was
2
4
(
3
(
(
3
2
2
2
submitted to flash chromatography (hexane/tBuOMe, 4:1)
giving the corresponding acetoxy ketones in the following
yields: 10e (82%), 11e (85%), 12e (85%), 13e (85%), 14e (85%),
2
3
3
3
3
+
3
24 7
H O
1
5e (83%), 16e (85%).
51.1419, found m/z 351.1427. The acidic hydrolysis of the
Acetoxy Ketone 10e. Hexane/tBuOMe, 4:1; white solid; mp
oxime precursor produced minor amounts of a C-3 epimer.
1
1
55-159 °C; H NMR (300 MHz, CDCl
3
) δ 4.27 (d, J ) 11.1
Diacetoxy Ketone 16e. Hexane/tBuOMe, 4:1; colorless oil;
Hz, 1H), 3.87 (d, J ) 11.1 Hz, 1H), 3.02 (ddd, J ) 14.4, 5.5,
1
3
H NMR (300 MHz, CDCl ) δ 5.41 (br t, 1H), 4.32 (d, J ) 11.3
3
4
1
1
.4 Hz, 1H), 2.49 (td, J ) 15.0, 5.6 Hz, 1H), 2.27 (dt, J ) 15.8,
.0 Hz, 1H), 2.03 (s, 3H), 1.99 (s, 3H), 1.89 (q, J ) 7.0 Hz,
H), 1.74 (td, J ) 14.3, 4.6 Hz, 1H), 1.58 (s, 3H), 1.07 (s, 3H),
Hz, 2H), 4.10 (d, J ) 11.3 Hz, 2H), 2.77 (t, J ) 6.6 Hz, 2H),
13
2
.37-2.30 (m, 4H), 2.03 (s, 6H), 1.69 (s, 3H); C NMR (75
MHz, CDCl ) δ 211.4 (C), 170.7 (C), 138.8 (C), 119.3 (CH), 64.8
CH ), 56.6 (C), 38.6 (CH ), 31.6 (CH ), 27.3 (CH ), 25.4 (CH ),
20.9 (CH ); EIMS m/z 268 (2, M ), 208 (25), 166 (8), 148 (65),
120 (25), 106 (100), 79 (40); HREIMS [M - AcOH] calcd for
C H O m/z 208.1099, found m/z 208.1104.
3
.04 (d, J ) 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl
) δ 211.4
), 50.9 (C), 43.7
), 22.3 (CH ), 20.1 (CH ),
3
); EIMS m/z 270 (1, M ), 255 (1), 210 (5),
3
(
2
2
2
2
3
(
C), 170.6 (C), 170.0 (C), 82.7 (C), 65.9 (CH
CH), 34.5 (CH ), 33.2 (CH ), 24.6 (CH
), 8.9 (CH
2
+
3
(
2
2
3
3
3
+
+
1
1
2
7.5 (CH
3
1
2
16
3
50 (15), 99 (100); HRFABMS calcd for C14
22 5
H O Na m/z
Synthesis of 21a. A mixture of NaH (61 mg, 2.6 mmol)
93.1364, found m/z 293.1359.
and methyl diethylphosphonoacetate in THF (15 mL) was
stirred at room temperature for 30 min. A solution of ketone
20 (74 mg, 0.25 mmol) in THF (5 mL) was added, and the
mixture was stirred at 50 °C for 48 h. The mixture was then
diluted with tBuOMe, washed with water, and dried over
Acetoxy Ketone 11e. Hexane/tBuOMe, 4:1; colorless oil;
H NMR (300 MHz, CDCl ) δ 5.43 (br t, 1H), 4.11 (d, J ) 10.8
3
1
Hz, 1H), 4.05 (d, J ) 10.8 Hz, 1H), 2.80-2.75 (m, 1H), 2.75-
2
2
1
1
.65 (m, 1H), 2.53 (dd, J ) 15.8, 5.7 Hz, 1H), 2.30-2.25 (m,
H), 2.10 (dd, J ) 15.9, 7.3 Hz, 1H), 2.02 (s, 3H), 1.67 (s, 3H),
2 4
anhydrous Na SO , and the solvent was removed. The residue
was submitted to flash chromatography (hexane/tBuOMe, 65:
35) giving methyl esther 21a (65 mg, 75%) as 9:1 mixture of
1
3
.09 (s, 3H); C NMR (75 MHz, CDCl
3
) δ 214.5 (C), 170.8 (C),
), 32.2
37.4 (C), 120.6 (CH), 69.5 (CH ), 53.5 (C), 38.5 (CH
2
2
8270 J. Org. Chem., Vol. 70, No. 21, 2005

Exploiting PdII and TiIII Chemistry
1
E/Z stereoisomers: vitreous solid; H NMR (300 MHz, CDCl
3
)
(dq, J ) 13.5, 2 Hz, 1H), 2.04 (td, J ) 14.4, 4.8 Hz, 2H), 1.80-
1.65 (m, 3H), 1.65-1.22 (m, 3H), 1.18 (s, 3H), 1.15 (s, 3H), 1.05
(
major isomer) δ 5.62 (br s, 1H), 4.84 (br s, 1H), 4.49 (br s,
H), 3.66 (s, 3H), 3.22 (dd, J ) 11.5, 4.2 Hz, 1H), 2.40-2.20
m, 3H), 2.13 (s, 3H), 2.00-1.80 (m, 4H), 1.75-1.05 (m, 7H),
.97 (s, 3H), 0.75 (s, 3H), 0.66 (s, 3H); 13C NMR (75 MHz,
) (major isomer) δ 160.9 (C), 147.7 (C), 122.7 (C), 115.1
CH), 106.8 (CH ), 78.8 (CH), 55.9 (CH), 54.7 (CH ), 50.8 (CH),
13
1
(s, 3H); C NMR (75 MHz, CDCl
(C), 109.2 (CH ), 62.2 (CH), 54.8 (CH), 51.1 (CH
38.9 (C), 37.1 (CH ), 35.7 (CH ), 26.8 (CH ), 23.5 (CH
(CH ), 17.6 (CH ), 13.9 (CH ); EIMS m/z 279 (10), 262 (15),
220 (15), 166 (30), 119 (40), 91 (100); HREIMS calcd for C16
NO m/z 279.1912, found m/z 279.1912.
3
) δ 171.8 (C), 166.1 (C), 142.9
), 40.8 (C),
), 23.4
(
2
3
0
2
2
3
2
CDCl
3
3
2
3
(
2
3
25
H -
4
3.3 (C), 39.8 (CH
2
), 39.8 (C), 38.2 (CH
), 24.1 (CH ), 21.7 (CH
); EIMS m/z 334 (1), 319 (10), 301 (15), 260
2
), 37.1 (CH
), 18.9 (CH
2
), 28.4
), 15.5
3
(
(
(
CH
3
), 28.0 (CH
), 14.5 (CH
2
2
2
3
Synthesis of Acetoxy Oxime 31. The palladium-mediated
remote functionalization of oxime 30 (see general procedure)
gave acetoxy oxime 31 (90%) as a vitreous solid: hexane/
CH
3
3
15), 203 (18), 175 (20), 135 (100), 114 (90), 82 (50); HRFABMS
Na m/z 357.2405, found m/z 357.2402.
calcd for C21
H
34
O
3
1
3
tBuOMe, 7:3; H NMR (300 MHz, CDCl ) δ 4.86 (br s, 1H),
Synthesis of 22a. Oxidation of alcohol 21a with Dess-
4.67 (br s, 1H), 4.12 (d, J ) 11.2 Hz, 1H), 4.02 (d, J ) 11.2 Hz,
1H), 3.64 (s, 3H), 3.09 (ddd, J ) 16.5, 5.1, 2.6 Hz, 2H), 2.82 (s,
1H), 2.44-2.40 (m, 2H), 2.03 (s, 3H), 1.72-1.32 (m, 6H), 1.14
Martin periodinane (see general procedure described above)
yielded ketone 22a (80%) as a vitreous solid: hexane/tBuOMe,
1
13
4
1
3
:1; H NMR (300 MHz, CDCl
3
) δ 5.63 (br s, 1H), 4.91 (br s,
(s, 3H), 1.03 (s, 3H); C NMR (75 MHz, CDCl ) δ 171.6 (C),
3
H), 4.56 (br s, 1H), 3.67 (s, 3H), 2.70-2.26 (m, 5H), 2.14 (s,
H), 2.05-1.05 (m, 9H), 1.07 (s, 3H), 1.00 (s, 3H), 0.85 (s, 3H);
171.0 (C), 166.8 (C), 142.5 (C), 109.4 (CH ), 67.4 (CH ), 62.1
2
2
(CH), 51.1 (CH ), 47.6 (CH), 43.1 (C), 38.6 (C), 35.7 (CH ), 35.6
3
2
1
3
C NMR (75 MHz, CDCl
22.5 (C), 115.2 (CH), 107.7 (CH
), 39.6 (CH
), 25.2 (CH ), 22.1 (CH
3
) δ 216.6 (C), 160.5 (C), 147.0 (C),
), 55.2 (CH), 55.2 (CH ), 50.9
), 39.4 (C), 37.9 (CH ),
), 21.8 (CH ), 19.0
2 2 3 3 2
(CH ), 23.6 (CH ), 21.0 (CH ), 19.8 (CH ), 18.1 (CH ), 13.9
1
2
3
(CH ); EIMS m/z 337 (70), 321 (10), 277 (85), 260 (88), 218
3
(
CH), 47.8 (C), 39.7 (CH
2
2
2
(55), 186 (75), 134 (77), 91 (100), 79 (65); HRFABMS calcd for
C H O NNa m/z 360.1786, found m/z 360.1787.
34.8 (CH
2
), 26.2 (CH
).
3
2
2
3
1
8
27
5
(
CH
3
), 14.1 (CH
3
Synthesis of Acetoxy Ketone 32. Standard hydrolysis of
oxime 31 gave acetoxy ketone 32 (65%) as a vitreous solid:
hexane/tBuOMe, 7:3; H NMR (300 MHz, CDCl ) δ 4.91 (br s,
Preparation of Oxime 23. Starting from ketone 22a and
following the general procedure described above for oxime
1
3
synthesis, we obtained 23 (100%) as a vitreous solid: hexane/
1H), 4.71 (br s, 1H), 4.11 (d, J ) 10.8 Hz, 1H), 3.94 (d, J )
10.8 Hz, 1H), 3.67 (s, 3H), 2.88 (br s, 1H), 2.65-2.53 (m, 1H),
2.48-2.34 (m, 2H), 2.01 (s, 3H), 1.90-1.73 (m, 2H), 1.69-1.40
1
MeOtBu, 85:15; H NMR (300 MHz, CDCl
3
) δ 5.62 (br s, 1H),
4
3
1
.90 (br s, 1H), 4.53 (br s, 1H), 3.67 (s, 3H), 3.21 (dt, J ) 14.7,
.6 Hz, 2H), 2.43-2.20 (m, 2H), 2.13 (s, 3H), 2.08-1.17 (m,
(m, 4H), 1.24 (s, 3H), 0.99 (s, 3H); 13C NMR (75 MHz, CDCl )
3
1
3
0H), 1.14 (s, 3H), 1.02 (s, 3H), 0.79 (s, 3H); C NMR (75 MHz,
) δ 166.7 (C), 160.8 (C), 147.4 (C), 122.5 (C), 115.2 (CH),
07.3 (CH ), 55.5 (CH), 55.5 (CH ), 50.9 (CH), 40.8 (C), 39.7
CH ), 39.6 (C), 37.9 (CH ), 37.4 (CH
3.2 (CH ), 21.9 (CH ), 19.0 (CH ), 17.7 (CH
δ 212.4 (C), 171.5 (C), 170.0 (C), 142.2 (C), 109.9 (CH ), 69.9
2
CDCl
3
(CH ), 61.9 (CH), 51.2 (CH ), 50.5 (C), 47.1 (CH), 38.3 (C), 35.7
2
3
1
2
3
2 2 2 2 3
(CH ), 35.4 (CH ), 35.0 (CH ), 23.9 (CH ), 20.9 (CH ), 18.1
(
2
2
2
), 27.1 (CH
3
), 24.6 (CH
2
),
);
(CH ), 13.8 (CH ); EIMS m/z 322 (15, M ), 290 (10), 250 (45),
+
3
3
2
3
2
3
2
), 14.2 (CH
3
230 (80), 203 (55), 161 (65), 133 (100), 91 (98), 55 (70);
HRFABMS calcd for C H O Na m/z 345.1677, found m/z
EIMS m/z 347 (2), 332 (5), 317 (8), 281 (20), 258 (40), 207 (100),
1
8
26
5
1
74 (35), 159 (42), 121 (55), 95 (70), 55 (90); HRFABMS calcd
345.1674.
for C21 NNa m/z 370.2358, found m/z 370.2360.
33 3
H O
Obtention of γ-Dihydroxylated Synthon 33. L-Selec-
tride (0.32 mL, 0.32 mmol) was added to a solution of ketone
Synthesis of Acetoxy Oxime 24. Palladium-mediated
remote functionalization of oxime 23 (see general procedure)
gave acetoxy oxime 24 (76%) as a vitreous solid. NMR spectra
indicated that, after flash chromatography, oxime 24 was
contaminated by some proportion of its hydrolysis product (25).
Therefore, this contaminated oxime was used in the next
hydrolysis step without further purification.
Synthesis of Ketone 25. Standard oxime hydrolysis of
compound 24 gave acetoxy ketone 25 (70%) as a vitreous solid.
Spectroscopic data matched those reported in ref 1.
3
2 (9 mg, 0.032 mmol) in THF (3 mL) at -78 °C; the resulting
mixture was stirred for 22 h, extracted with tBuOMe, washed
2 4
with 2 N HCl, and dried over anhydrous Na SO ; and the
solvent was removed. The residue was submitted to flash
chromatography (hexane/tBuOMe, 1:1) giving diol 33 (7 mg,
1
7
7%) as a white solid: mp 203-205 °C; H NMR (300 MHz,
CDCl ) δ 4.84 (s, 1H), 4.66 (s, 1H), 3.70 (br t, J ) 2.0 Hz, 1H),
3
3.65 (s, 3H), 3.48 (d, J ) 11.4 Hz, 1H), 3.39 (d, J ) 11.4 Hz,
1H), 2.96 (br s, 1H), 2.41 (ddd, J ) 15.0, 3.5, 2.1 Hz, 1H), 2.22-
1
3
Preparation of Keto Ester 29. A sample of Jones’ reagent
1.80 (m, 8H), 1.10 (s, 3H), 0.70 (s, 3H); C NMR (75 MHz,
(
1 mL) was added to a solution of diol 28 (275 mg, 1.15 mmol)
CDCl
3
) δ 177.1 (C), 143.6 (C), 108.7 (CH
), 62.8 (CH), 51.1 (CH ), 41.4 (CH), 40.6 (C), 38.8 (C), 36.0
), 31.3 (CH ), 26.8 (CH ), 22.7 (CH ), 18.0 (CH ), 14.5
2
), 76.8 (CH), 71.2
in acetone (35 mL) and stirred at room temperature for 1 h.
The solvent was then removed, and the residue was dissolved
(CH
(CH
(CH
2
2
3
3
2
2
+
2
3
in tBuOMe, washed with brine, dried over anhydrous Na
2
SO
4
,
); EIMS m/z 282 (10, M ), 251 (35), 235 (100), 191 (45),
and concentrated. The residue was stirred with a saturated
173 (40), 147 (42), 91 (55); HRFABMS calcd for C16
m/z 305.1728, found m/z 305.1725.
26 4
H O Na
solution of CH
N
2 2
in Et
2
O (5 mL) for 30 min. The solvent was
removed, and the residue was submitted to flash chro-
Synthesis of Keto Aldehyde 34. Dess-Martin periodi-
nane (1.20 g, 3.0 mmol) was added to a solution of diol 28 (237
mg, 0.99 mmol) in CH Cl (25 mL), and the mixture was stirred
matograpy (hexane/tBuOMe, 7:3) giving 29 (187 mg, 62%) as
1
a white solid: mp 119-121 °C; H NMR (300 MHz, CDCl
3
) δ
2
2
4
1
.87 (s, 1H), 4.67 (s, 1H), 3.62 (s, 3H), 2.68 (s, 1H), 2.66 (m,
H), 2.43 (dt, J ) 15, 3.3 Hz, 1H), 2.27 (ddq, J ) 15, 3.3, 1.5
at room temperature for 4 h. Then tBuOMe was added, and
the solution was washed with a 1:1 mixture of aqueous 10%
Na S O and saturated NaHCO , and brine. The organic layer
Hz, 1H), 2.04 (m, 1H), 1.77 (m, 1H), 1.65-1.44 (m, 4H), 1.22
2
2
3
3
1
3
(
s, 3H), 1.05 (s, 3H), 1.02 (s, 3H); C NMR (75 MHz, CDCl
δ 215.5 (C), 171.6 (C), 142.6 (C), 109.6 (CH ), 61.9 (CH), 54.6
CH), 51.3 (CH ), 47.8 (C), 38.7 (C), 37.3 (CH
4.6 (CH ), 25.7 (CH ), 23.9 (CH ), 22.0 (CH
3
)
2 4
was dried (anhydrous Na SO ), and the solvent was removed.
The residue was dissolved in 0.5 M methanolic K CO (20 mL)
2 3
2
(
3
3
2
), 35.5 (CH
3
), 13.7 (CH
2
),
);
at 0 °C and stirred for 3 h. The mixture was then diluted with
tBuOMe and washed with 2 N HCl and brine. The organic
layer was dried (anhyd. Na SO ), and the solvent was removed.
2
3
2
3
EIMS m/z 264 (80), 232 (40), 189 (30), 147 (70), 123 (85), 91
100); HRFABMS calcd for C16 Na m/z 287.1623, found
m/z 287.1623.
2
4
(
H
24
O
3
Flash chromatography (hexane/tBuOMe, 7:3) of the residue
provided keto aldehyde 34 (148 mg, 64%) as a vitreous solid:
1
Preparation of Oxime 30. This oxime was obtained from
3
H NMR (300 MHz, CDCl ) δ 9.99 (s, 1H), 2.73 (q, J ) 6.4 Hz,
ketone 29 following the general procedure for oxime synthesis
1H), 2.43 (dd, J ) 8, 7 Hz, 2H), 2.27 (dd, J ) 8, 4.2 Hz, 2H),
(
85% yield): white solid (hexane/tBuOMe, 1:1) mp 179-181
2.04 (s, 3H), 1.68-1.40 (m, 3H), 1.32-1.20 (m, 1H), 1.12 (s,
1
13
°
C; H NMR (300 MHz, CDCl
3
) δ 4.86 (s, 1H), 4.66 (s, 1H),
3H), 1.03 (s, 3H), 0.99 (s, 3H); C NMR (75 MHz, CDCl
3
) δ
3
.62 (s, 3H), 3.26 (dt, J ) 15, 3.6 Hz, 1H), 2.75 (s, 1H), 2.43
217.3 (C), 191.6 (CH), 156.1 (C), 141.7 (C), 51.2 (CH), 47.0 (C),
J. Org. Chem, Vol. 70, No. 21, 2005 8271

Justicia et al.
3
8.1 (C), 36.4 (CH
CH ), 19.3 (CH ), 19.2 (CH
06 (40), 149 (50), 123 (80), 91 (85); HRFABMS calcd for
Na m/z 257.1517, found m/z 257.1521.
Synthesis of Keto Ester 35. A mixture of NaClO
mg, 4.72 mmol) and NaH PO ‚H O (305 mg, 3.54 mmol) was
added to a solution of 34 (138 mg, 0.59 mmol) in a mixture of
2
), 34.5 (CH
2
), 34.1 (CH
2
), 27.3 (CH
3
), 20.8
Synthesis of Acetoxy Ketone 38. Standard hydrolysis of
(
3
3
2
), 18.9 (CH
3
); EIMS m/z 234 (100),
oxime 37 gave acetoxy ketone 38 (71%) as a vitreous solid:
1
2
C
hexane/tBuOMe, 7:3; H NMR (300 MHz, CDCl
3
) δ 4.06-4.02
15
H
22
O
2
(m, 2H), 3.74 (s, 3H), 2.61-2.40 (m, 2H), 2.18-2.00 (m, 3H),
1.99 (s, 3H), 1.85-1.75 (m, 4H), 1.65 (s, 3H), 1.28 (s, 3H), 1.01
2
(422
1
3
2
4
2
(s, 3H); C NMR (75 MHz, CDCl ) δ 213.5 (C), 170.7 (C), 170.3
3
(C), 136.1 (C), 134.5 (C), 67.7 (CH ), 51.3 (CH ), 50.1 (C), 43.3
2
3
tBuOH/H
2
O/2-methyl-2-butene (4.5:1.6:1 ratio, 20 mL). The
2 2 2 3
(CH), 36.1 (C), 35.2 (CH ), 33.9 (CH ), 31.8 (CH ), 21.0 (CH ),
solution was stirred at room temperature for 20 h before being
3 3 2 3
20.9 (CH ), 19.7 (CH ), 19.3 (CH ), 17.4 (CH ); EIMS m/z 322
extracted with tBuOMe, washed with brine, dried over anhy-
(50, M
75), 91 (83); HRFABMS calcd for C18
found m/z 345.1674.
Obtention of γ-Dihydroxylated Synthon 39. A sample
of NaBH (26 mg, 0.81 mmol) was added to a solution of 38
26 mg, 0.081 mmol) in DME (5 mL) and stirred at 0 °C for 1
h. The mixture was then diluted with tBuOMe, washed with
N HCl, and dried (anhydrous Na SO ), and the solvent was
removed. The residue was dissolved in 0.5 M methanolic K
CO (20 mL) at 0 °C and stirred for 2 h. The mixture was then
diluted with tBuOMe and washed with 2 N HCl and brine.
The organic layer was dried (anhydrous Na SO ), and the
solvent was removed. Flash chromatography (hexane/tBuOMe,
:4) of the residue provided diol 39 (11 mg, 50%) as a colorless
+
), 291 (50), 262 (35), 215 (100), 187 (45), 175 (80), 147
drous Na
a saturated solution of CH
2 4
SO , and concentrated. The residue was stirred with
(
26 5
H O Na m/z 345.1677,
2 2 2
N in Et O (5 mL) for 30 min. The
solvent was removed and the residue submitted to flash
chromatograpy (hexane/MeOtBu, 3:1) giving 35 (90 mg, 60%)
4
1
as a vitreous solid: H NMR (300 MHz, CDCl
3
) δ 3.68 (s, 3H),
(
2
.59-2.47 (m, 2H), 2.41 (t, J ) 5.3 Hz, 1H), 2.09 (t, J ) 6.8
Hz, 4H), 1.77-1.60 (m, 2H), 1.61 (s, 3H), 1.24 (s, 3H), 1.06 (s,
2
2
4
13
3
(
(
2
(
H), 1.02 (s, 3H); C NMR (75 MHz, CDCl
C), 136.2 (C), 134.0 (C), 51.2 (CH ), 50.1 (CH), 47.2 (C), 38.2
C), 34.9 (CH ), 34.2 (CH ), 32.0 (CH ), 26.5 (CH ), 22.2 (CH ),
1.9 (CH ), 19.5 (CH ), 18.2 (CH ); EIMS m/z 264 (45), 217
55), 182 (70), 147 (75), 91 (100), 79 (70); HRFABMS calcd for
Na m/z 287.1623, found m/z 287.1626.
3
) δ 216.4 (C), 170.3
2
-
3
3
2
2
2
3
3
3
3
2
2
4
16 24 3
C H O
1
Preparation of Oxime 36. Starting from ketone 35 and
1
oil: H NMR (300 MHz, CDCl
.71 (s, 3H), 3.68 (dd, J ) 11.4, 4.6 Hz, 1H), 3.42 (d, J ) 10.3
Hz, 1H), 2.11-2.04 (m, 2H), 1.75-1.10 (m, 7H), 1.59 (s, 3H),
3
) δ 3.73 (d, J ) 10.3 Hz, 1H),
following the general procedure described above, we obtained
3
oxime 36 (85% yield) as a white solid: hexane/tBuOMe, 1:1;
1
mp 151-153 °C; H NMR (300 MHz, CDCl
3
) δ 3.69 (s, 3H),
1
3
1
(
.23 (s, 3H), 0.92 (s, 3H); C NMR (75 MHz, CDCl
3
) δ 170.58
), 51.1 (CH ), 44.5
), 31.9 (CH ), 27.1 (CH ),
), 11.1 (CH ); EIMS m/z 282
3
.10 (ddd, J ) 16.0, 5.3, 3.3 Hz, 1H), 2.27-2.05 (m, 4H), 1.60
s, 3H), 1.55-1.30 (m, 4H), 1.26 (s, 3H), 1.15 (s, 3H), 1.07 (s,
C), 137.9 (C), 132.9 (C), 76.6 (CH), 71.8 (CH
2
3
(
1
3
(CH), 41.8 (C), 36.4 (C), 34.6 (CH
2
2
2
3
H); C NMR (75 MHz, CDCl
), 50.4 (CH), 40.1 (C), 36.6 (C), 34.6
), 27.49 (CH ), 23.27 (CH ), 20.93 (CH ), 19.97
), 19.06 (CH ), 17.52 (CH ); EIMS m/z 279 (1), 262 (35),
3
) δ 170.5 (C), 165.9 (C), 137.1
2
0.9 (CH
3
), 20.8 (CH
3
), 18.4 (CH
2
3
(
(
(
C), 133.5 (C), 51.2 (CH
3
+
(
(
10, M ), 251 (35), 235 (100), 191 (45), 173 (40), 147 (42), 91
55); HRFABMS calcd for C16 Na m/z 305.1728, found m/z
05.1725.
CH
CH
2
), 32.2 (CH
2
3
3
3
26 4
H O
3
2
2
3
2
25
22 (15), 158 (50), 119 (60), 91 (100); HREIMS calcd for C16H -
NO
3
m/z 279.1912, found m/z 279.1912.
Synthesis of Acetoxy Oxime 37. The palladium-mediated
remote functionalization of oxime 36 (see general procedure)
Acknowledgment. The authors acknowledge the
Spanish “Junta de Andaluc ´ı a” for financial support
research group FQM339), Dr. A. F. Barrero for his
collaboration in the early stage of the work, and our
English colleague Dr. J. Trout for revising our text. J.J.
thanks the Spanish Ministry of Science and Technology
for a grant enabling him to pursue these studies.
gave acetoxy oxime 37 (83%) as a vitreous solid: hexane/
(
1
tBuOMe, 7:3; H NMR (300 MHz, CDCl
3
) δ 8.50 (br s, 1H),
4
.07 (br s, 2H), 3.72 (s, 3H), 2.90 (dq, J ) 17.5, 2.7 Hz, 2H),
.47-2.35 (m, 1H), 2.12-2.02 (m, 2H), 2.01 (s, 3H), 1.80-1.67
m, 2H), 1.66 (s, 3H), 1.22 (s, 3H), 1.08 (s, 3H); C NMR (75
MHz, CDCl ) δ 171.1 (C), 170.5 (C), 161.9 (C), 136.6 (C), 133.9
C), 68.6 (CH ), 51.2 (CH ), 43.6 (CH), 42.7 (C), 36.3 (C), 33.3
), 32.0 (CH ), 21.0 (CH ), 20.8 (CH ), 19.7 (CH ), 19.5
), 19.1 (CH ), 18.6 (CH ); EIMS m/z 337 (35), 306 (20),
2
(
1
3
3
(
(
(
2
3
CH
CH
2
2
3
3
3
Supporting Information Available: 1H or 13C NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
3
2
2
2
78 (18), 260 (40), 215 (20), 189 (25), 153 (100), 121 (30), 91
55); HRFABMS calcd for C18 NNa m/z 360.1786, found
m/z 360.1785.
(
27 5
H O
JO0502910
8272 J. Org. Chem., Vol. 70, No. 21, 2005