A cycloaddition strategy for use toward Berkelic acid, an MMP inhibitor and potent anticancer agent displaying a unique chroman spiroketal motif

Article abstract of DOI:10.1055/s-2008-1072750

A kinetically controlled diastereoselective cycloaddition between a chiral enol ether and an ortho-quinone methide (o-QM) produces a chroman spiroketal motif that is found in the core of berkelic acid, a novel matrix metalloproteinase (MMP) inhibitor and potent anticancer agent. The transformation lays the groundwork for preparation of future inhibitors aimed at distinguishing among the active sites of the twenty-three known MMP. Experimental findings suggest that the stereochemistry that emerges from cycloaddition is opposite that which results from thermodynamic ketalization. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072750

LETTER
1353
A Cycloaddition Strategy for Use toward Berkelic Acid, an MMP Inhibitor
and Potent Anticancer Agent Displaying a Unique Chroman Spiroketal Motif
C
ycloaddition Str
a
a
tegy for
U
s
o
e
toward Ber
d
kelic
A
cid ong Huang, Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, University of California at Santa Barbara, Santa Barbara CA 93106-9510, USA
Fax +1(805)8935690; E-mail: pettus@chem.ucsb.edu
Received 8 February 2008
targets,5 such as MMP (-1, -2, and -7). Diminished zinc
Abstract: A kinetically controlled diastereoselective cycloaddition
chelation might enable better differentiation among the
subtle steric differences found with the side pockets of the
between a chiral enol ether and an ortho-quinone methide (o-QM)
produces a chroman spiroketal motif that is found in the core of ber-
kelic acid, a novel matrix metalloproteinase (MMP) inhibitor and
twenty-three MMP. Compound 1 is enormously different
potent anticancer agent. The transformation lays the groundwork from prior MMP inhibitors,6 and it may possess sufficient
for preparation of future inhibitors aimed at distinguishing among
structural complexity to probe the subtle differences
the active sites of the twenty-three known MMP. Experimental
among the active sites of these related enzymes.
findings suggest that the stereochemistry that emerges from cy-
A first step in improving selectivity among MMP in our
minds was the development of a straightforward synthesis
of this rare chroman spiroketal (Scheme 1). The unas-
signed quaternary center, which is far removed from other
stereocenters, however, complicates planning. This fix-
ture would have to be introduced near the end of the syn-
thesis through enolate addition to the -CH=X residue
masked in earlier intermediates as either a nitrile or an
ether so that both stereochemical possibilities could be ac-
cessed with minimal effort (disconnection 1). Our plan,
therefore, simplified to the diastereoselective synthesis of
the tetracyclic (ABCD) core with the added provision that
the salicylic acid involved with zinc coordination could be
readily modified so that the effects of other residues on
MMP selectivity might be studied (disconnection 2). We
suspected that the chroman spiroketal ABC would be con-
formationally locked and thus would enable the construc-
tion of the isobenzopyran ring D by stereoselective
oxidation and reduction (disconnections 3 and 4). There-
fore, in our mind the entire strategy hinged on whether the
a-methyl residue in the enol ether A would control the ste-
reochemistry accruing in its cycloaddition with C (discon-
nections 5) instead of the b-substituent in A, which we
saw as too distant from the forming spiroketal carbon to
exert much influence.
cloaddition is opposite that which results from thermodynamic ket-
alization.
Key words: o-quinone methide, chroman spiroketal, berkelic acid,
diastereoselective synthesis, MMP, anticancer agent, ketalization
(–)-Berkelic acid (1), a unique chroman spiroketal, was
isolated from green Penicillium slime thriving in the larg-
est superfund clean-up site in America in Butte, Montana
(Scheme 1).1 The organism that produces 1 flourishes in a
witches’ brew of mercury, cadmium, copper, and other
heavy-metal contaminants dissolved in a 1.5 mile long
and 1,800 foot-deep waste pit filled with acidic water
(pH 2.0). (–)-Berkelic acid (1) displays potent anticancer
activity toward OVCAR-3 in the NCI-60 panel screen
(GI50 = 91.0 nM) and it inhibits MMP-3 and caspase-1
(GI50 = 1.87 mM; GI50 = 98.0 mM, respectively). Perhaps
the unusual bioactivity of 1 is related to its ability to pro-
tect its parent organism from the surrounding hostile envi-
ronment, which is as extreme as the nearby volcanic
estuaries of Yellowstone park.
The MMP are zinc-dependent endopeptidases that cause
degradation of peptide bonds within the extracellular ma-
trix (ECM). These enzymes play a crucial role in angio-
genesis and tumor invasion.2 In the case of ovarian cancer,
tumors originate from the ovarian surface epithelium
(OSE) and require MMP activity for infiltration of the sur-
rounding connective tissues of OSE. Thus, the implica-
tions are that MMP inhibition should correlate with
anticancer activity towards ovarian carcinomas. Of the
twenty-three MMP identified thus far, several (-3, -8, -9,
and -12) are proven antitargets that when inhibited en-
hance angiogenesis and metastasis.3 This paradoxical
property likely led to the clinical failure of the first gener-
ation of broad-spectrum MMP inhibitors. Future genera-
tions must spare antitargets,4 yet inhibit validated cancer
To resolve this question, we chose a short, versatile entry
point, which began by the addition of lithiated acetonitrile
to the unsaturated lactone 2 (Scheme 2). This reaction
avoids the problem of an undesirable proton transfer dur-
ing the course of the 1,4-conjugate addition, enables a
one-pot procedure to secure the two stereocenters, and
provides access to several functional groups which could
serve as a surrogate for -CH=X. The intermediate enolate
expectedly undergoes in situ C-methylation with methyl
iodide and affords the trans-substituted lactone 3 in 73%
yield (>10:1 dr). After chromatographic purification, re-
fluxing lactone 3 (0.1 M 3:2 v/v ratio of toluene–THF)
with Petasis’ reagent (2.5 equiv, 4 h) affords the enol ether
5 in an acceptable 40–50% yield after sequential purifica-
tion by flash chromatography and distillation.7 No isomer-
SYNLETT 2008, No. 9, pp 1353–1356
x
x.
x
x.
2
0
0
8
Advanced online publication: 07.05.2008
DOI: 10.1055/s-2008-1072750; Art ID: S01508ST
© Georg Thieme Verlag Stuttgart · New York

1354
Y. Huang, T. R. R. Pettus
LETTER
OH
RO2C
2
OR'
Table 1 Diastereoselective Cycloadditions
O
O
OH
* unknown
stereochemistry
OR'
R''
O
C
D
O
A
O
C
D
B
OR'
R''
A
B
BocO
1
*
H
4
3
O
X
Et
Me
O
O
7–9
O
1
HO
O
O
t-BuMgCl, toluene, –78 °C
CO2Me
NC
non-racemic
OR'
5
10–12
NC
OR'
R"
R"
O
o-QM
R"'
deprotonation, Boc transfer, β-elimination, cycloaddition
C
O
O
Yield
(%)
A
B
Benzyl alcohol
Chroman spiroketal
dra
O
A
5
O
X
OBn
BocO
OBn
O
O
enol
ether
61
3:1
X
NC
HO
X
O
7
10
offensive
Me
OBoc
R"
BocO
OBoc
O
O
OR'
R"'
77b 3.5:1
O
O
NC
HO
X
8
11
unoffensive
Me
Br
Br
OBoc
Scheme 1 Our retrosynthetic strategy for 1 suggests starting with a
derivative of a chiral enol ether corresponding to ring A of 1
O
BocO
OBoc
O
72
4.5:1
NC
HO
Petasis,
THF–toluene
9
NC
NC
12
LiCH2CN
O
O
O
a The dr is based on 1H NMR analysis of crude product mixtures.
b The combined yield of two isomers.
MeI
73% yield
>10:1 dr
45 °C,
40-50% yield
O
O
2
3
5
AcOH: HClconc
60 °C,
95% yield
chromatography allowed isolation of the major diastere-
omer in 61% yield. Exchange of the benzyl ether for a
more electron-deficient OBoc residue as in 88 led to a
small increase in diastereoselectivity (3.5:1 for 11), but
the diastereomers proved inseparable. On the other hand,
introduction of a bromine atom to the o-QM generated
from 9 resulted in still higher selectivity (4.5:1 for 12).
The bromine atom also facilitates chromatographic sepa-
ration of the diastereomers enabling isolation of the major
spiroketal 12 (72% yield) and minor diastereomer 12¢ (8%
yield).
OBn
O
O
1) BH3•THF
HO
2) BnBr, Ag2O,
3) Petasis, THF
42% overall yield
O
O
4
6
Scheme 2 Synthesis of some enol ethers with -CH=X equivalency
ization was evident after purification. Another derivative
of A can be alternatively accessed by exposure of the ni-
trile 3 to a solution of acetic acid and concentrated HCl
(1:10 ratio); these conditions produce the carboxylic acid
4 in 95% yield. Subsequent reduction of the acid 5 (0.06
M in THF, 2.0 equiv BH3·THF), protection of the result-
ing alcohol (0.1 M in Et2O, 1 equiv BnBr, 1 equiv Ag2O),
and methylenation of the lactone (0.5 M in toluene, 2.5
equiv Petasis, 75 °C, 4 h) affords after distillation the enol
ether 6 as an alternative entry point. We were now ready
to examine the role of 5 and, if needed, 6, in determining
the diastereoselectivity of cycloaddition reactions with
various o-quinone methides.
In order to confirm the relative stereochemistry of the pre-
dominant chroman spiroketal produced in these studies,
we had attempted to crystallize compounds 10–12, but
were unsuccessful. Therefore, we decided to cleave the
Boc group from compound 12 so that the phenol function-
al group might allow for more straightforward crystalliza-
tion. This task was accomplished under mild conditions
by treatment of 12 (0.1 M in THF) with 5% LiOH (10
equiv) to furnish the phenol 13, which gratifyingly crys-
tallizes from dichloromethane and methanol (1:1) to pro-
vide X-ray quality crystals (Figure 1). The relative
configuration of the major product suggests that the reac-
tion proceeds through an endo orientation on the face of
the enol ether opposite the a-methyl residue and on the
same side as the b-methylenenitrile. This outcome was
what we had expected from our earlier investigation of
We found that treatment of the benzyl alcohol 7 (0.1 M in
toluene at –78 °C with 2–4 equiv of the enol ether 5) with
tert-butylmagnesium chloride followed by slow warming
to room temperature over eight hours resulted in the for-
mation of the chroman spiroketal 10 (Table 1). Flash
Synlett 2008, No. 9, 1353–1356 © Thieme Stuttgart · New York

LETTER
Cycloaddition Strategy for Use toward Berkelic Acid
1355
Br
Br
OBoc
OBoc
O
O
O
O
NC
NC
12'
exo product
12
endo product
0.2% TFA
THF
0.2% TFA
THF
Figure 1 X-ray crystal structure of 13
1:2 mixture of 12:12'
no destruction
OR'
OR'
R"'
exo
product
R"
Scheme 3 Equilibration of 12 or 12¢ into a 1:2 mixture
O
H
R"
Me
O
O
R"'
R
H
actions with a range of chiral furanoid enol ethers where-
by the stereocenter closest to the site of bond formation
determines the diastereoselective outcome of the reaction.
The stereochemistry that resides within the major product
proves the reaction proceeds through a kinetically favored
endo-boat transition state. This core strategy could prove
useful in the eventual diastereoselective synthesis of 1 by
enabling formation of the unknown quaternary center near
the end of its total synthesis. Most significantly, however,
the equilibration study raises the question as to whether a
recently proposed strategy for 1 can reach the fully elabo-
rated natural product since the effect of stereochemistry
within the furan component was not examined in the ear-
lier thermodynamic ketalization strategy.10
Me
R
12'
O
12
20.07 kJ/mol
25.07 kJ/mol,
R = R' = R" = R"' = H
endo
product
R"
OR'
O
R"'
O
R
Me
Figure 2 Relative stabilities of two diastereomers; endo is 5 KJ/mol
less stable than exo
diastereoselective cycloadditions of o-quinone methides
generated at low temperature by this pKa-driven cascade.9
Compound 3
Next, we performed Macromodel calculations with MM3
and Monte Carlo to determine the relative energies of the
simplified analogues (R1 = R2 = R4 = H) corresponding to
diastereomers 12 and 12¢, which emerge from the corre-
sponding endo and exo transition states (Figure 2). We
find that the lowest energy for each conformer is obtained
by formation of a half-chair spiroketal, whereby the furan
oxygen atom is oriented in axial fashion to benefit from
anomeric stabilization. Remarkably, the endo product is
calculated to be 5 kJ/mol less stable than the exo product.
The cause is quite clear; the methyl group adjacent to the
spiroketal carbon atom prefers to reside in proximity to
the chroman oxygen atom (exo product) as opposed to the
methylene (endo product).
To a stirring solution of n-BuLi (4.45 mL, 7.125 mmol) in THF
(12.5 mL) at –78 °C was added MeCN (1.50 mL, 4.0 equiv) over 2
min. The reaction was stirred for an additional 2 min at –78 °C, and
then lactone 2 (500 mL, 7.125 mmol) dissolved in THF (3 mL) was
added dropwise. After 2 h stirring, a solution of MeI (440 mL, 7.125
mmol) and HMPA (1.25 mL, 7.125 mmol) in THF (6 mL) was add-
ed slowly via cannula. The reaction was allowed to warm up to r.t.
over 6 h and quenched with 0.5 M HCl. The mixture was extracted
with EtOAc (3×). The combined organics were then washed with
sat. NaHSO3, brine, H2O, dried (MgSO4), filtered, and concentrated
to give crude product 3 (720 mg) in 73% yield. No further purifica-
tion was required.
1H NMR (400 MHz, CDCl3): d = 4.50 (dd, J1 = 9.3 Hz, J2 = 7.3 Hz,
1 H), 3.97 (t, J = 9.2 Hz, 1 H), 2.62 (t, J = 5.7 Hz, 2 H), 2.58–2.40
(m, 2 H), 1.35 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): d = 177.8, 116.5, 69.0, 39.8, 39.6, 19.5, 13.8 ppm.
To experimentally confirm the meaning of this calcula-
tion, the major diastereomer 12 and the minor diastere-
omer 12¢ that had emerged from the earlier Diels–Alder
reaction were separated and independently subjected to
acidic THF (0.2% TFA). Over time (48 h), the major iso-
mer 12 equilibrates to a 1:2 mixture of 12:12¢ (Scheme 3).
Similarly, the minor diastereomer 12¢ equilibrates to a 1:2
mixture of 12:12¢. This result indicates that the endo prod-
uct 12 is the kinetic product, whereas the minor diastereo-
mer 12¢ is the thermodynamic product. Moreover the ratio
(1:2, 12/12¢) reflects the energy difference of the previous
calculation.
Compound 5
To a stirring solution of compound 3 (100 mg, 0.7168 mmol) in
THF (2.7 mL) was added the Petasis reagent (3.5 mL, 0.5 M in tol-
uene). The reaction was warmed up to 75 °C and stirred for 4.5 h.
The reaction was then cooled down to r.t. and treated with NaHCO3
(100 mg), MeOH (1.63 mL), and H2O (60 mL), followed by warm-
ing to 45 °C and stirred overnight. The reaction mixture was diluted
with hexane (40 mL), filtered through Celite (washing with hex-
ane), and concentrated to give the crude product. Purification by
column chromatography [i-PrOH–hexanes (1:10) with trace Et3N
and using KMnO4 stain) followed by bulb-to-bulb distillation (0.16
torr, 80 °C) provided enol ether 5 (40 mg) in 40% yield.
1H NMR (400 MHz, CDCl3): d = 4.29 (t, J = 2.0 Hz, 1 H), 4.29 (t,
In conclusion, we have shown that several b-unsubstituted
o-QM undergo diastereoselective [4+2] cycloaddition re- J = 8.0 Hz, 1 H), 3.87 (t, J = 2.0 Hz, 1 H), 3.81 (t, J = 8.0 Hz, 1 H),
Synlett 2008, No. 9, 1353–1356 © Thieme Stuttgart · New York

1356
Y. Huang, T. R. R. Pettus
LETTER
2.57–2.43 (m, 3 H), 2.26–2.18 (m, 1 H), 1.24 (d, J = 6.8 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): d = 166.3, 117.7, 80.5, 72.0,
42.0, 41.0, 19.0, 16.9 ppm.
H), 2.94 (m, 1 H), 2.80–2.78 (m, 1 H), 2.69–2.57 (m, 1 H), 2.33–
2.27 (m, 2 H), 2.02–1.98 (m, 1 H), 1.88–1.83 (m, 1 H), 1.55 (s, 9 H),
1.13 (d, J = 7.2 Hz, 3 H).
Compound 7
Compound 12
To a stirring solution of 4-benzyl-2-hydroxy benzaldehyde (300
mg, 1.316 mmol) in DMF (20 mL) at r.t. was added NaH (58 mg,
60% in mineral oil), followed by Boc anhydride (315 mg). The re-
action was allowed to stir overnight and quenched with cold H2O.
The reaction mixture was extracted with Et2O (3×). The combined
Et2O extracts were washed with brine, dried over MgSO4, filtered,
and concentrated to give the crude product. Flash chromatography
on silica gel afforded tert-butyl 5-(benzyloxy)-2-formyl phenyl car-
bonate (400 mg) in 93% yield.
1H NMR (400 MHz, CDCl3): d = 10.0 (s, 1 H), 7.82 (d, J = 8.8 Hz,
1 H), 7.43–7.37 (m, 5 H), 6.96 (dd, J1 = 8.6 Hz, J2 = 2.4 Hz, 1 H),
6.85 (d, J = 2.4 Hz, 1 H), 5.13 (s, 2 H), 1.59 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): d = 187.6, 164.4, 153.7, 151.3, 135.6, 133.0,
128.9, 128.6, 127.8, 122.2, 113.1, 109.5, 84.7, 70.8, 27.8 ppm.
1H NMR (500 MHz, CDCl3): d = 7.03 (d, J = 8.5 Hz, 1 H), 6.76 (d,
J = 8.5 Hz, 1 H), 4.24 (dd, J1 = J2 = 8.7 Hz, 1 H), 3.71 (dd, J1 = 8.8
Hz, J2 = 7.7 Hz, 1 H), 3.08 (ddd, J1 = 16.0, J2 = 13.0 Hz, J3 = 6.0
Hz, 1 H), 2.80–2.71 (m, 2 H), 2.62 (dd, J1 = 17.0, J2 = 5.0 Hz, 1 H),
2.55 (dd, J1 = 17.0, J2 = 6.5 Hz, 1 H), 2.03–1.90 (m, 3 H), 1.57 (s, 9
H), 1.22 (d, J = 6.8 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3):
d = 151.3, 150.2, 147.8, 128.1, 121.2, 117.8, 115.1, 107.6, 106.5,
84.2, 70.5, 48.0, 40.6, 27.86, 27.42, 22.0, 19.7, 12.1 ppm. IR
(CH2Cl2 solution): nmax = 2977, 2933, 1760, 1477, 1423, 1286,
1236, 1151, 1062, 1010, 989, 894, 879 cm–1. HRMS (ESI+/TOF):
m/z calcd for C20H24NO5NaBr [M + Na]+ = 460.0730; found:
460.0737.
Compound 13
To a stirring solution of 12 (20 mg) in THF (3 mL) and MeOH (3
mL), LiOH (5%, 3 mL) was added at r.t. The reaction mixture was
stirred at r.t. for 12 h. The reaction mixture was diluted with EtOAc
and neutralized with HCl (0.1 M) until the pH of the solution
changed to 7. The reaction mixture was extracted with EtOAc. The
combined EtOAc extracts was washed with brine, dried over
MgSO4, filtered, and concentrated to give the crude product 13
(15.5 mg, 99%) without further purification. The product 13 can be
recrystallized from a mixture of MeOH and CH2Cl2 (1:1); mp 124–
126 °C.
1H NMR (400 MHz, CDCl3): d = 6.94 (d, J = 8.3 Hz, 1 H), 6.77 (d,
J = 8.4 Hz, 1 H), 5.31 (br s, 1 H), 4.28 (dd, J1 = 9.1 Hz, J2 = 8.3 Hz,
1 H), 3.72 (dd, J1 = 9.2 Hz, J2 = 5.7 Hz, 1 H), 3.06 (dd, J1 = 16.7 Hz,
J2 = 8.3 Hz, 1 H), 2.96 (ddd, J1 = 16.8 Hz, J2 = 13.8 Hz, J3 = 6.0 Hz,
1 H), 2.87 (dd, J1 = 16.7 Hz, J2 = 7.5 Hz, 1 H), 2.74 (ddd, J1 = 15.8
Hz, J2 = 5.7 Hz, J3 = 2.3 Hz, 1 H), 2.44 (qd, J1 = 7.4 Hz, J2 = 2.6 Hz,
1 H), 2.40–2.32 (m, 1 H), 2.05 (ddd, J1 = 13.5 Hz, J2 = 6.1 Hz,
J3 = 2.6 Hz, 1 H), 1.88 (ddd, J1 = J2 = 13.0 Hz, J3 = 6.0 Hz, 1 H),
1.15 (d, J = 7.3 Hz, 2 H).
To a stirring solution of tert-butyl 5-(benzyloxy)-2-formyl phenyl
carbonate (400 mg, 1.219 mmol) in THF at 0 °C was added
BH3·SMe2 (640 mL, 2 M in THF, 1.05 equiv). The reaction was al-
lowed to warm up to r.t. over 3 h and quenched by 0.1 M HCl. The
mixture was extracted with EtOAc (3×), and the combined extracts
were then washed with brine, H2O, dried (MgSO4), filtered, and
concentrated to give product 7 (382 mg) in 95% yield. No further
purification was required.
1H NMR (400 MHz, CDCl3): d = 7.44–7.34 (m, 6 H), 6.89 (dd,
J1 = 8.5 Hz, J2 = 2.6 Hz, 1 H), 6.80 (d, J = 2.6 Hz, 1 H), 5.05 (s, 2
H), 4.56 (s, 2 H), 2.05 (br s, 1 H), 1.57 (s, 9 H) ppm. 13C NMR (100
MHz, CDCl3): d = 159.6, 152.6, 149.9, 136.6, 131.0, 128.8, 128.3,
127.7, 125.5, 113.2, 109.0, 84.3, 70.5, 60.4, 27.8 ppm.
General Procedure for Compounds 10–12
Enol ether (2.0 equiv) was dissolved in anhyd toluene (0.1 M) and
added to a stirring solution of the benzyl alcohol (1.0 equiv) in an-
hyd toluene (0.1 M) at –78 °C. Next, t-BuMgCl (1.1 equiv 1 M in
toluene) was added slowly, and the reaction was allowed to warm
up to r.t. over 3 h. Upon completion by TLC, the reaction was then
quenched by 0.1 M HCl, extracted with EtOAc, washed with brine,
H2O, dried (Mg2SO4), and concentrated.
Acknowledgment
A research grant from the University of California, Cancer Rese-
arch Coordinating Committee [http://crcc.ucdavis.edu/] for the in-
vestigations leading to the synthesis of 1 is greatly appreciated.
Compound 10
1H NMR (500 MHz, CDCl3): d = 7.43–7.31 (m, 5 H), 6.97 (d,
J = 8.4 Hz, 1 H), 6.54 (dd, J1 = 8.4 Hz, J2 = 2.6 Hz, 1 H), 6.45 (d,
J = 2.5 Hz, 1 H), 5.04 (s, 2 H), 4.23 (dd, J1 = J2 = 8.6 Hz, 1 H), 3.68
(dd, J1 = 8.7 Hz, J2 = 7.6 Hz, 1 H), 3.00 (ddd, J1 = 15.0 Hz,
J2 = 14.0 Hz, J3 = 6.0 Hz, 1 H), 2.71–2.61 (m, 2 H), 2.59 (dd,
J1 = 17.0 Hz, J2 = 5.5 Hz, 1 H), 2.51 (dd, J1 = 17.0 Hz, J2 = 7.0 Hz,
1 H), 2.01 (ddd, J1 = J2 = 13.0 Hz, J3 = 6.0 Hz, 1 H), 1.92 (ddd,
J1 = 13.0 Hz, J2 = 6.0 Hz, J3 = 3.0 Hz, 1 H), 1.17 (d, J = 6.8 Hz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): d = 158.5, 153.3, 137.3,
129.7, 128.7, 128.1, 127.6, 117.9, 114.4, 108.3, 106.8, 103.2, 70.4,
70.2, 48.1, 40.7, 28.2, 21.3, 19.8, 12.0 ppm. IR (CH2Cl2 solution):
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n
max = 2958, 2929, 2885, 2360, 2341, 1622, 1583, 1506, 1458, 1380,
1267, 1150, 1114, 1014, 987, 906, 877, 738, 696 cm–1. HRMS
(ESI+/TOF): m/z calcd for C22H23NO3Na [M + Na]+: 372.1570;
found: 372.1573.
Compound 11
(9) (a) Selenski, C.; Pettus, T. R. R. J. Org. Chem. 2004, 69,
9196. (b) Selenski, C.; Mejorado, L. H.; Pettus, T. R. R.
Synlett 2004, 1101.
1H NMR (500 MHz, CDCl3): d = 7.05 (d, J = 3.0 Hz, 1 H), 6.70 (dd,
J1 = 6.0 Hz, J2 = 3.0 Hz, 1 H), 6.62 (d, J = 3.0 Hz, 1 H), 4.22 (dd,
J1 = 8.0 Hz, J2 = 1.5 Hz, 1 H), 3.72 (dd, J1 = 8.0 Hz, J2 = 1.5 Hz, 1
(10) Zhou, J.; Snider, B. B. Org. Lett. 2007, 9, 2071.
Synlett 2008, No. 9, 1353–1356 © Thieme Stuttgart · New York

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