Stereoselective synthesis of (+)-SCH 351448: A unique ligand system for sodium, calcium, and other cations

Article abstract of DOI:10.1021/jo0507993

(+)-SCH 351448 (Na⁺ salt A) was synthesized employing ring-closing olefin metathesis reaction of an open diene diester intermediate for construction of the 28-membered macrodiolide structure. The open diene diester was prepared from the monomeric hydroxy carboxylic acid and two different olefin fragments. The monomeric hydroxy acid was synthesized via Julia-Julia coupling reaction of intermediates derived from the same olefinic fragments. Oxane units in these fragments were prepared by radical cyclization reactions of β-alkoxyacrylates. Analogous SCH 351448 salts incorporating other mono- and divalent cations may be prepared. Under acidic conditions, SCH 351448 (Na⁺ salt A) was the most stable complex, but SCH 351448 (Ca²⁺ salt) and (Na⁺ salt B) appear to be physiologically important species.

Full text of DOI:10.1021/jo0507993

Stereoselective Synthesis of (+)-SCH 351448: A Unique Ligand
System for Sodium, Calcium, and Other Cations
Eun Joo Kang,† Eun Jin Cho,† Mi Kyung Ji,† Young Eun Lee,† Dong Mok Shin,†
Soo Young Choi,† Young Keun Chung,† Jong-Seo Kim,† Hie-Joon Kim,† Sueg-Geun Lee,‡
Myoung Soo Lah,§ and Eun Lee*,†
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, Korea,
Korea Research Institute of Chemical Technology, Post Office Box 107, Yusong, Daejeon 305-600, Korea,
and Department of Chemistry and Applied Chemistry, Hanyang University, 1271 Sa-1-dong,
Ansan, Kyunggi-do 426-791, Korea
eunlee@snu.ac.kr
Received April 19, 2005
(+)-SCH 351448 (Na+ salt A) was synthesized employing ring-closing olefin metathesis reaction of
an open diene diester intermediate for construction of the 28-membered macrodiolide structure.
The open diene diester was prepared from the monomeric hydroxy carboxylic acid and two different
olefin fragments. The monomeric hydroxy acid was synthesized via Julia-Julia coupling reaction
of intermediates derived from the same olefinic fragments. Oxane units in these fragments were
prepared by radical cyclization reactions of â-alkoxyacrylates. Analogous SCH 351448 salts
incorporating other mono- and divalent cations may be prepared. Under acidic conditions, SCH
351448 (Na+ salt A) was the most stable complex, but SCH 351448 (Ca2+ salt) and (Na+ salt B)
appear to be physiologically important species.
Introduction
an ED50 of 25 µM in the LDL-R promoter transcription
assay using hGH as a reporter gene, but it did not
activate transcription of hGH from the SRR promoter.
Thus, 1 selectively activates transcription from the
LDL-R promoter, and it is the first small molecule
activator of the LDL-R promoter identified to date. The
structure of 1 features a 28-membered macrodiolide
consisting of two identical hydroxy carboxylic acid units
(Figure 1). In the X-ray crystal structure of 1 reported
by the Schering-Plough and Duke researchers, the so-
dium ion appears to be surrounded by seven oxygen
atoms rendering a pseudo-C2 symmetric structure for the
complex. The unique bioactivity and the intriguing
structure of 1 makes it an attractive target for synthetic
chemists,2 and we wish to describe here a full account of
the first total synthesis.3
LDL uptake by the LDL receptor (LDL-R) is an
important mechanism for clearing serum cholesterol.
Selective activators of LDL-R transcription may be able
to decrease serum LDL levels by increasing LDL uptake
by the LDL-R. Screening the ethyl acetate extracts of
several microbial fermentation broths, researchers at
Schering-Plough Research Institute and Duke University
recently found that a microorganism belonging to Mi-
cromonospora sp. yielded an extract that displayed
distinct activity in the LDL-R assay, and identified the
structure of SCH 351448 (1).1 Purified SCH 351448 has
* Corresponding author. Tel: +82-2-880-6646. Fax: +82-2-889-
1568.
† Seoul National University.
‡ Korea Research Institute of Chemical Technology.
§ Hanyang University.
(1) Hegde, V. R.; Puar, M. S.; Dai, P.; Patel, M.; Gullo, V. P.; Das,
P. R.; Bond, R. W.; McPhail, A. T. Tetrahedron Lett. 2000, 41, 1351-
1354.
(2) For previous synthetic efforts, see: Bhattacharjee, A.; Soltani,
O.; De Brabander, J. K. Org. Lett. 2002, 4, 481-484.
10.1021/jo0507993 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/06/2005
J. Org. Chem. 2005, 70, 6321-6329
6321

Kang et al.
SCHEME 1. Retrosynthetic Analysis
FIGURE 1. Structure of SCH 351448.
Total Synthesis
At the outset, ring-closing metathesis reaction of the
diester intermediate A was envisaged for construction
of the 28-membered ring macrodiolide structure. The
diester intermediate A would be prepared from the
monomeric unit B and fragments C and D. Fragments
C and D are the basic modules in the synthetic plan as
they may serve as precursors for the monomer B.
Synthesis of fragments C and D calls for preparation of
the oxane derivatives E and H, which may be formed via
radical cyclization reactions of â-alkoxyacrylates F and
I (Scheme 1).
SCHEME 2. Synthesis of the Fragment Ea
Synthesis of the fragment E started with a 2-step
conversion of 1, 4-butanediol (2) into aldehyde 3.4
Mukaiyama aldol reaction of aldehyde 3 and silyl enol
ether 5 was mediated by a chiral borane reagent5
prepared from N-tosyl-l-valine (4). The secondary alcohol
6 thus obtained (>95% e.e.)6 was converted into â-alkoxy-
acrylate 7 via reaction with methyl propiolate, TBS
deprotection, and iodide substitution. Radical cyclization7
in the presence of 1-ethylpiperidinium hypophosphite and
a Reagents and conditions: (1) 0.7 equiv NaH, 0.7 equiv TBSCl,
THF, 0 °C, 1 h; (2) 3.0 equiv SO3‚Pyr, 5.0 equiv TEA, DMSO-DCM
(1:1), 0 °C, 30 min; (3) 4, 1.0 equiv BH3‚THF, DCM, r.t. 30 min;
1.0 equiv 3, 1.1 equiv 5, -78 °C, 4 h; (4) 1.5 equiv HCCCO2Me,
0.2 equiv NMM, MeCN, r.t. 48 h; (5) concentrated HCl, MeOH,
r.t. 30 min; (6) 1.5 equiv I2, 1.5 equiv Ph3P, 3.0 equiv imidazole,
THF, 0 °C, 2 h; (7) 5.0 equiv H3PO2, 5.0 equiv 1-ethylpiperidine,
1.5 equiv Et3B, EtOH, r.t. 30 min.
(3) Kang, E. J.; Cho, E. J.; Lee, Y. E.; Ji, M. K.; Shin, D. M.; Chung,
Y. K.; Lee, E. J. Am. Chem. Soc. 2004, 126, 2680-2681.
(4) Danishefsky, S. J.; Pearson, W. H. J. Org. Chem. 1983, 48, 3865-
3866.
(5) Kiyooka, S.; Kaneko, Y.; Komura, M.; Matsuo, H.; Nakano, M.
J. Org. Chem. 1991, 56, 2276-2278.
(6) Due to interference from other signals around δ 3.40 from the
minor diastereomer 10, the exact enantiomeric excess value was
difficult to determine.
triethylborane in ethanol8 proceeded efficiently to yield
the oxane diester 8 (Scheme 2).
The 3-(R)-configuration of the secondary alcohol 6 was
confirmed by converting it into (O)-acetyl-(S)-mandelate
(7) For recent examples of â-alkoxyacrylate radical cyclization, see:
(a) Song, H. Y.; Joo, J. M.; Kang, J. W.; Kim, D.-S.; Jung, C.-K.; Kwak,
H. S.; Park, J. H.; Lee, E.; Hong, C. Y.; Jeong, S.; Jeon, K.; Park, J. H.
J. Org. Chem. 2003, 68, 8080-8087. (b) Jeong, E. J.; Kang, E. J.; Sung,
L. T.; Hong, S. K.; Lee, E. J. Am. Chem. Soc. 2002, 124, 14655-14662.
(c) Lee, E.; Choi, S. J.; Kim, H.; Han, H. O.; Kim, Y. K.; Min, S. J.;
Son, S. H.; Lim, S. M.; Jang, W. S. Angew. Chem., Int. Ed. Engl. 2002,
41, 176-178.
(8) Lee, E.; Han, H. O. Tetrahedron Lett. 2002, 43, 7295-7296.
6322 J. Org. Chem., Vol. 70, No. 16, 2005

Total Synthesis of SCH 351448
SCHEME 3. Configuration at C-3a
SCHEME 4. Synthesis of the Fragment Ca
a Reagents and conditions: (1) 3.0 equiv (O)-acetyl-(S)-mande-
loyl chloride, 5.0 equiv pyridine, benzene, r.t. 5 h.
1
9. The H NMR signal of the methyl ester moiety of 9
was located at δ 3.61 while the same signal of the 3-(S)-
diastereomer 10 appeared at δ 3.40 (Scheme 3).
Reactivity of the two ester groups in 8 was vastly
different, and basic hydrolysis of 8 provided a monocar-
boxylic acid. The corresponding aldehyde 11 was con-
verted into the correct homoallylic alcohol 12 (dr ) 17.6:
1) via Brown allylation.9 At this point, a crucial decision
was made to proceed further after converting the methyl
ester into the 2-trimethylsilylethyl ester moiety. Hydroly-
sis of the sterically crowded carboxylic ester group was
anticipated to be the last step in the synthesis, and the
2-trimethylsilylethyl ester functionality made much more
sense than the original methyl ester group. In practice,
benzyl protection of 12 and transesterification10 with
2-trimethylsilylethanol in the presence of titanium(IV)
isopropoxide led to a new ester 13. Aldehyde 14 was then
obtained via oxidative cleavage, and it was converted into
the homoallylic alcohol 16 (dr ) 14.1:1) via Brown
crotylation using the (E)-crotylborane reagent 1511 (Scheme
4).
a Reagents and conditions: (1) 0.3 N KOH, THF-H2O-MeOH
(3:1:1), r.t. 3 h; (2) 3.0 equiv BH3‚DMS, 3.0 equiv B(OMe)3, THF,
0 °C, 3 h; (3) 3.0 equiv SO3‚Pyr, 5.0 equiv TEA, DMSO-DCM (1:
1), 0 °C, 1 h; (4) 2.0 equiv (+)-DIPCl, 1.5 equiv CH2CHCH2MgBr,
THF, -78 °C, 1 h; 11, -78 C ∼ r.t. 2 h; NaOH, H2O2, r.t. 1 h; (5)
1.2 equiv NaHMDS, 1.5 equiv BnBr, THF-DMF (4:1), 0 °C ∼ r.t.
12 h; (6) 0.25 equiv Ti(Oi-Pr)4, 10 equiv TMSCH2CH2OH, DME,
120 °C, 48 h; (7) 0.05 equiv OsO4, 3.0 equiv NMO, acetone-H2O
(3:1), r.t. 12 h; 3.0 equiv NaIO4, r.t. 30 min; (8) 1.5 equiv 15, THF,
-78 °C, 4 h; NaOH, H2O2, -78 °C ∼ r.t. 1 h.
SCHEME 5. Configuration at C-9a
The 9-(R)-configuration of 12 was confirmed by com-
paring the 1H NMR data of the corresponding (O)-acetyl-
(S)-mandelate 17 with those of the 9-(S)-epimer 18. In
particular, the vinyl proton signals of 17 appeared at δ
5.40 and 4.77, and those of 18 appeared at δ 5.73 and
5.07 (Scheme 5).
For synthesis of fragment H, D-mannitol (19) was
converted into glyceraldyhyde acetonide, from which
ester 20 was obtained via Horner-Emmons reaction.12
Hydrogenation of 20, LAH reduction, and tosylation led
to the primary tosylate 21.13 Selenide 22 was obtained
from 21 via selenide substitution and acetonide depro-
tection. Regioselective benzylation of 22 and reaction with
methyl propiolate then led to â-alkoxyacrylate 23. Radical
cyclization of 23 proceeded smoothly in the presence of
tributylstannane and AIBN to provide the oxane ester
24 in good yield (Scheme 6). Radical cyclization reaction
of selenides such as 23 was sluggish in the presence of
1-ethylpiperidinium hypophosphite and triethylborane in
ethanol.
a Reagents and conditions: (1) 3.0 equiv (O)-acetyl-(S)-mande-
loyl chloride, 5.0 equiv pyridine, benzene, r.t. 5 h.
Aldehyde 25 obtained from ester 24 was converted into
the homologous vinylstannane 26 via a modified Corey-
Fuchs protocol14 and radical-mediated hydrostannylation.
Efficient Stille coupling15 of 26 and the known triflate
2716 led to an olefinic intermediate 28. An alternative
way to 28 involved coupling aldehyde 25 with the
boronate reagent 29 following Takai protocol,17 and
subsequent Suzuki reaction18 of boronate 30 with triflate
27. Hydrogenation/ hydrogenolysis of 28 and oxidation
led to aldehyde 31, and the terminal olefin 32 was
obtained via Wittig reaction (Scheme 7).
With the terminal olefin fragments 16 and 32 at hand,
metathesis reaction appeared as the most attractive route
toward the monomeric unit B. The cross metathesis
reaction of 16 and 32 employing the second-generation
(9) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org.
Chem. 1986, 51, 432-439.
(10) Seebach, D.; Hungerbu¨hler, E.; Naef, R.; Schnurrenburger, P.;
Weidmann, B.; Zu¨ger, M. Synth. 1982, 138-141.
(11) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919-
5923.
(12) Takano, S.; Kurotaki, A.; Takahashi, M.; Ogasawara, K. Synth.
1986, 403-406.
(13) Rodriguez, E. B.; Scally, G. D.; Stick, R. V. Aust. J. Chem. 1990,
43, 1391-1405.
(14) Drouet, K. E.; Theodorakis, E. A. J. Am. Chem. Soc. 1999, 121,
456-457.
(15) Saa´, J. M.; Martorell, G.; Garc´ıa-Raso, A. J. Org. Chem. 1992,
57, 678-685.
(16) Fu¨rstner, A.; Konetzki, I. Tetrahedron 1996, 52, 15071-15078.
(17) Takai, K.; Shinomiya, N.; Kaihara, H.; Yoshida, N.; Moriwake,
T. Synlett 1995, 963-964.
(18) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201-
2208.
J. Org. Chem, Vol. 70, No. 16, 2005 6323

Kang et al.
SCHEME 6. Synthesis of the Fragment Ha
SCHEME 8. Synthesis of the Monomeric
Macrolidea
a Reagents and conditions: (1) 2.0 equiv ZnCl2, acetone, r.t. 22
h; 2.0 equiv K2CO3; (2) 1.2 equiv NaIO4, 5% NaHCO3, H2O, r.t. 1
h; 2.2 equiv (EtO)2POCH2CO2Et, 6 N K2CO3, H2O, r.t. 20 h; (3)
H2, 0.1 equiv Pd(OH)2, MeOH, r.t. 2 h; (4) 1.0 equiv LAH, ether,
0 °C, 1 h; (5) 2.0 equiv p-TsCl, 3.0 equiv TEA, DCM, 0 °C, 12 h;
(6) 0.6 equiv PhSeSePh, 1.3 equiv NaBH4, EtOH, r.t. 1 h; (7)
concentrated HCl, MeOH, r.t. 12 h; (8) 1.1 equiv Bu2SnO, benzene,
reflux (-H2O), 16 h; 2.4 equiv BnBr, 1.1 equiv TBAI, benzene,
reflux, 30 min; (9) 1.5 equiv HCCCO2Me, 0.3 equiv NMM, MeCN,
r.t. 12 h; (10) 1.2 equiv n-Bu3SnH, 0.2 equiv AIBN, benzene (0.01
M), reflux, 5 h.
a Reagents and conditions: (1) 2.5 equiv NaHMDS, THF, 0 °C,
30 min; 1.1 equiv 32, 0 °C, 2 h; (2) 10 mol % (PCy3)2RuCl2(CHPh),
DCM (3 mM), 45 °C, 6 h.
was prepared smoothly from the sodium alkoxide of 16
and 32, and it was converted into macrolide 34 in the
presence of the first-generation Grubbs catalyst (Scheme
8). Unfortunately, it was not possible to obtain the
required hydroxy carboxylic acid from macrolide 34 under
hydrolytic conditions employing various acids and bases.
Alternative ways for joining units 16 and 32 were
investigated, and the Julia-Julia reaction20 appeared
most promising. TBS-protection of 16, oxidative cleavage,
and sodium borohydride reduction led to the primary
alcohol 35. The boron-mediated anti aldol reaction21 of
aldehyde 14, and subsequent 5-step transformations also
produced 35, but the route via 16 was more efficient.
Sulfone 37 was obtained via Mitsunobu-type substitution
of 35 with thiol 36 and selective oxidation. The coupling
of sulfone 37 and aldehyde 31 required intensive tuning-
up, but eventually, efficient synthesis of olefin 38 was
possible using sodium hexamethyldisilazide in ether. The
monomeric unit 39 was obtained from olefin 38 via
diimide reduction (Scheme 9). Wittig reaction did not
work between partners derived from 31 and 35. Myers
reductive coupling between appropriate partners was also
unsuccessful.22
SCHEME 7. Synthesis of the Fragment Da
The final assembly of the fragments was initiated by
reacting the sodium alkoxide derived from 16 with 39.
The coupled ester product 40 was then converted into
another alkoxide after TBS-deprotection, which was used
for the coupling with 32 to produce diester 41. Ring-
closing olefin metathesis of 41 mediated by the second-
generation Grubbs catalyst 42 proceeded smoothly, and
macrodiolide 43 was obtained in good yield (Scheme 10).
Macrodiolide 44 was obtained from 43 after hydroge-
nation/hydrogenolysis. The last step toward 1 was hy-
drolytic removal of the 2-trimethylsilylethyl ester func-
tionalities in 44. The macrodiolide diester 44 was treated
a Reagents and conditions: (1) 1.0 equiv LAH, THF, 0 °C, 2 h;
(2) 4.0 equiv SO3‚Pyr, 8.0 equiv TEA, DMSO-DCM (1:1), 0 °C, 5
h; (3) 5.0 equiv CBr4, 10 equiv HMPT, THF, -30 °C, 1 h; (4) 2.1
equiv n-BuLi, THF, -78 °C, 1 h; (5) 1.1 equiv n-Bu3SnH, 0.05 equiv
AIBN, benzene (0.02 M), reflux, 1 h; (6) 0.1 equiv PdCl2(PPh3)2,
0.83 equiv 27, 7.1 equiv LiCl, 0.5 equiv Ph3P, DMF (0.1 M), 120
°C, 6 h; (7) 2.0 equiv 29, 8.0 equiv CrCl2, 4.0 equiv LiI, THF, r.t.
16 h; 8) 0.1 equiv PdCl2(dppf), 0.91 equiv 27, 1.5 equiv K3PO4,
THF, 65 °C, 6 h; (9) H2, 0.1 equiv Pd/C, MeOH, r.t. 2 h; (10) 4.0
equiv SO3‚Pyr, 8.0 equiv TEA, DMSO-DCM (1:1), 0 °C, 5 h; (11)
2.0 equiv Ph3PCH3+Br-, 1.9 equiv n-BuLi, THF, 0 °C, 1 h; 1.0 equiv
31, THF, -78 °C ∼ r.t. 6 h.
(19) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 6543-6554.
(20) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron
Lett. 1991, 32, 1175-1178.
Grubbs catalyst19 did not proceed efficiently, and the
cross metathesis product was isolated in low yield (<7%)
accompanied by the homo dimer of 16. For the ring-
closing metathesis reaction, the diene ester precursor 33
(21) Patterson, I.; Wallace, D. J.; Cowden, C. J. Synth. 1998, 639-
652.
(22) Myers, A. G.; Movassaghi, M. J. Am. Chem. Soc. 1998, 120,
8891-8892.
6324 J. Org. Chem., Vol. 70, No. 16, 2005

Total Synthesis of SCH 351448
SCHEME 9. Synthesis of the Monomeric Unit Ba
SCHEME 10. Synthesis of the Macrodiolide
Intermediatea
a Reagents and conditions: (1) 3.0 equiv TBSOTf, 4.0 equiv 2,6-
lutidine, DCM, 0 °C, 3 h; (2) 0.05 equiv OsO4, 3.0 equiv NMO,
acetone-H2O (3:1), r.t. 12 h; 3.0 equiv NaIO4, r.t. 30 min; (3) 3.0
equiv NaBH4, EtOH, r.t. 30 min; (4) 1.5 equiv 36, 1.5 equiv DIAD,
1.5 equiv Ph3P, THF, 0 °C, 1 h; (5) 2.0 equiv (NH4)6Mo7O24‚4H2O,
10 equiv H2O2, EtOH, 0 °C ∼ r.t. 12 h; (6) 1.1 equiv NaHMDS,
ether, -78 °C, 15 min; 1.5 equiv 31 (syringe pump, 30 min), -78
°C ∼ r.t. 15 h; (7) 10 equiv TsNHNH2, 16 equiv NaOAc, DME-
H2O (1:1), reflux, 4 h.
with tetrabutylammonium fluoride in THF, and a major
product was produced after the usual workup. Unexpect-
edly, TLC analysis showed that the product was much
more nonpolar than the starting material, and the NMR
data of the product did not match those of the natural
product provided by the Schering-Plough workers. Many
different workup conditions were examined, and the
sample of 1 (Na+ salt) with the correct NMR (1H and 13C)
and mass (MALDI m/z 1143.7) data was obtained when
the reaction mixture was extracted with dichloromethane
after equilibration with 4 N HCl saturated with sodium
chloride (Scheme 11). This synthetic sample was desig-
nated as 1 (Na+ salt A), which was found to be the (+)-
a Reagents and conditions: (1) 3.0 equiv NaHMDS, THF, 0 °C,
30 min; 1.2 equiv 39, r.t. 1 h; (2) concentrated HCl, MeOH, r.t. 1
h; (3) 4.0 equiv NaHMDS, THF, 0 °C, 30 min; 1.5 equiv 32, 0 °C,
1 h; (4) 10 mol % 42, DCM (0.003 M), 80 °C, 12 h.
SCHEME 11. Synthesis of SCH 351448a
enantiomer: [R]13 +31.2 (c 0.73, CHCl3).23
D
Sodium (23Na) NMR spectra of this sample were
obtained (at 185.24 MHz) in CDCl3 solution at an
ambient probe temperature of ca. 22-23 °C relative to
external 0.1 M NaCl in D2O. The observed chemical shift
(δ, -8 ppm) and the line width (∼590 Hz) suggest that
the compound 1 (Na+ salt A) wraps itself around the
sodium cation to form strong coordination complex. The
shielding effects on sodium ion were already observed and
used in previous studies.24 The line width (∼590 Hz),
however, suggests that the complex in solution has a
dissymmetric environment around the sodium cation.25
a Reagents and conditions: (1) H2, 0.1 equiv Pd/C, MeOH-
EtOAc (3:1), r.t. 6 h; (2) 6.0 equiv TBAF, THF, r.t. 2 h; 4 N HCl
(sat. with NaCl).
A different sample of 1 was obtained after equilibration
of the reaction mixture with 2 N HCl saturated with
sodium chloride: 1H NMR analysis revealed that the
sample was a mixture (1:1.6) of 1 (Na+ salt A) and a
different species. The new species was the sole product
after equilibration with NaH2PO4/Na2HPO4 (pH 6.8) and
AcOH/NaOAc (pH 5.0) buffer, and it was assigned as 1
(Na+ salt B).26 Sodium (23Na) NMR spectra of 1 (Na+ salt
B) exhibited the same chemical shift and line width as
those recorded for 1 (Na+ salt A).
(23) The specific rotation of the natural sample is unknown.
(24) (a) Schmidt, E.; Hourdakis, A.; Popov, A. I. Inorg. Chim. Acta
1981, 52, 91-95. (b) Gupta, R. K.; Gupta, P. J. Magn. Reson. 1982,
47, 344-350.
(25) (a) Grandjean, J.; Laszlo, P.; Vo¨gtle, F.; Sieger, H. Angew.
Chem., Int. Ed. Engl. 1978, 17, 856-857. (b) Grandjean, J.; Laszlo,
P.; Offermann, W.; Rinaldi, P. L. J. Am. Chem. Soc. 1981, 103, 1380-
1383.
J. Org. Chem, Vol. 70, No. 16, 2005 6325

Kang et al.
FIGURE 2. Crystal structure of 1 (Ca2+ salt): hydrogen bonds (green) are shown in (b).
Structural and Cation Exchange Studies
workers concerning RK-682.29 Silica gel supplied by
Merck contained a large amount of calcium ion.30
Crystallization of the crude product was difficult, and
column chromatographic purification of the synthetic
sample of 1 (Na+ salt A, obtained after equilibration with
4 N HCl saturated with sodium chloride) was carried out
using Merck silica gel 60 yielding crystals from the
methanol solution of the purified sample. The crystal-
lographic data reveals a C2-symmetric structure in which
the metal cation is surrounded by eight oxygen atoms
(Figure 2a,b). Four different bond lengths (Å) are noted:
2.327 (M-Ocarboxylate), 2.446 (M-Oester carbonyl), 2.576
(M-Ohydroxy), and 2.657 (M-Ophenolic).27 In the crystal
structure, two sets of bifurcated hydrogen bonds between
the hydroxyl protons and the (M+-coordinating) carboxy-
late and oxane oxygens are prominent: the hydrogen
bonds between the phenolic hydrogens and the (free)
carboxylate oxygens are also present (Figure 2b). It was
initially assigned as 1 (Na+ salt A),3 but curiously,
different mass (MALDI m/z 1159.6) and NMR data were
obtained for this crystalline sample. After much thought,
it was realized that the crystal structure represented 1
(Ca2+ salt). The sodium salt was mysteriously trans-
formed into the calcium salt upon chromatographic
separation. The mystery was solved as it was discovered28
that similar incidence was reported by Sodeoka and co-
Crystals of 1 (Na+ salt B) were later obtained as bis-
(dichloromethane) solvate from dichloromethane-meth-
anol solution of the crude sample without chromato-
graphic purification (Figure 3a,b). The crystal structure
reveals that the sodium cation is surrounded by seven
oxygen atoms as reported in the original report by
Schering researchers.1 One M-Ophenolic bond is missing
(4.037 Å), and the opposite M-Ohydroxy bond is the
shortest (2.407 Å) of the M-O bonds. Two sets of
bifurcated hydrogen bonds between the hydroxyl protons
and the (Na+-coordinating) carboxylate and oxane oxy-
gens are present: one hydrogen bond between a phenolic
hydrogen and a (free) carboxylate oxygen is found, but
the second phenolic hydrogen is bonded to the adjacent
ester carbonyl oxygen forming a six-membered ring
structure. (Figure 3b).
Crystals were also obtained from the dichloromethane-
methanol solution of 1 (Na+ salt A), but they were
identical with the crystals of 1 (Na+ salt B) as verified
by NMR analysis of the redissolved samples of the
crystals. It may be concluded that 1 (Na+ salt A) was
converted slowly to 1 (Na+ salt B) in solution, and crystals
were obtained as 1 (Na+ salt B).
Realizing that cation exchange occurred on silica gel,
it was decided to investigate systematically cation-
binding selectivities of 1 guided by NMR and mass
spectral analysis, and prepare salts containing other
cations. As we were not able to prepare the free carboxylic
(26) Samples of 1 (Na+ salt A) and 1 (Na+ salt B) exhibited different
1H NMR data. As for mass spectroscopic data, both samples gave
similar ESI data (m/z 1143.7), but in the MALDI analysis, the strongest
peak for 1 (Na+ salt B) was at m/z 1165.6, as opposed to the normal
m/z 1143.7 peak for 1 (Na+ salt A). For this reason, 1 (Na+ salt B) was
initially thought to be a disodium salt. In solution (for example, hexane-
DCM), 1 (Na+ salt A) was slowly converted to 1 (Na+ salt B).
(27) Slightly different values were found when the crystal structure
was initially solved as a Na+ salt. For simplicity, the values obtained
as the Ca2+ salt are presented here.
(29) Sodeoka, M.; Sampe, R.; Kojima, S.; Baba, Y.; Morisaki, N.;
Hashimoto, Y. Chem. Phar. Bull. 2001, 49, 206-212.
(30) Kanto silica gel 60 (spherical) had different characteristics and
the sample of 1 (Na+ salt A) survived column chromatographic
separation.
(28) The authors thank Prof. Hyeongjin Cho of Inha University for
the information on the Sodeoka paper.
6326 J. Org. Chem., Vol. 70, No. 16, 2005

Total Synthesis of SCH 351448
FIGURE 3. Crystal structure of 1 (Na+ salt B, CH2Cl2 omitted): hydrogen bonds (green) are shown in (b).
TABLE 1. Exchange Reactions of 1 (Na+ Salt A)
additive (saturation)
analysis (1H NMR)
analysis (MALDI & FAB)
4 N HCl solution
aqueous solution
LiCl
(broad signals)
(m/z 1127.7)a
KCl
(K+ salt) & (Na+ salt A) (3.8:1)
(Rb+ salt) & (Na+ salt A) (2.9:1)
(Na+ salt A)
(m/z 1159.6 & 1143.7)a
(m/z 1205.6 & 1143.7)a
(m/z 1143.7)a
RbCl
CaCl2
MgCl2
CaCl2
(Mg2+ salt)
(m/z 1143.6)a
(Ca2+ salt)
(m/z 1159.6)a
b
Cu(OAc)2
(Cu2+ salt)
(m/z 1181.6)c
b
Mn(OAc)2
(no spectrum)
(m/z 1227.5)d
Co(OAc)2
(no spectrum)
(m/z 1235.5)d
a MALDI data for protonated metal salts. b Metal ion exchange did not occur when equilibrated with relatively acidic sat. CuCl2 solution
and sat. MnSO4 solution. c MALDI data for metal salts. d MALDI data for doubly metalated salts.
TABLE 2. Exchange Reactions of 1 (Ca2+ Salt)
additive (saturation)
analysis (1H NMR)
analysis (MALDI & FAB)
4 N HCl solution
aqueous solution
LiCl
NaCl
KCl
RbCl
LiCl
NaCl
MgCl2
(broad signals)
(m/z 1127.7)a
(Na+ salt A)
(m/z 1143.7)a
(K+ salt) & (Na+ salt A) (3.6:1)
(Rb+ salt) & (Na+ salt A) (2.1:1)
(Ca2+ salt)
(m/z 1159.6 & 1143.7)a
(m/z 1205.6 & 1143.7)a
(m/z 1159.6)a
(Na+ salt B) & (Ca2+ salt) (3.7:1)
(Mg2+ salt) & (Ca2+ salt) (1:1.6)
(m/z 1143.7 & 1159.6)a
(m/z 1143.6 & 1159.6)a
a MALDI data for protonated metal salts.
acid of 1 from the synthetic scheme31 or from any of the
salts, studies were limited on the relative stabilities of
various salts under defined conditions. The results of the
exchange experiments (NMR and mass data) using 1
(Na+ salt A) in dichloromethane equilibrated with dif-
ferent metal salt solutions in 4 N HCl or water are
presented in Table 1. The results of the exchange
experiments using 1 (Ca2+ salt) are presented in Table
2. From the results, it was obvious that (Na+ salt A) was
the most stable form in 4 N HCl solutions. Alkali metal
salts (Li+, K+, and Rb+) may be prepared under highly
acidic conditions, and alkaline earth metal salts (Mg2+
and Ca2+) and others (Cu2+, Mn2+, and Co2+) may be
prepared under (near) neutral conditions. It is to be noted
that 1 (Na+ salt A) was stable under equilibrating
conditions with 4 N HCl saturated with calcium chloride,
but it was converted into 1 (Ca2+ salt) when equilibrated
(31) A variety of different deprotection procedures starting from 44
yielded 1 (Na+ salt A) as the sole product. Treatment of 43 with
tetrabutylammonium fluoride in THF produced a dicarboxylic acid,
and hydrogenolysis (H2, Pd/C, ethyl acetate, polypropylene vessel)
yielded 1 (Na+ salt A) and a polar product, which stayed unchanged
upon treatment with sodium chloride.
J. Org. Chem, Vol. 70, No. 16, 2005 6327

Kang et al.
TABLE 3. Studies on the Relative Stability of 1 (Na+
Salt A) and 1 (K+ Salt)a
Regulation of calcium signals in the nucleus is an
important area of research.35 The known bioactivity of 1
as a small molecule activator of the LDL-R promoter may
then be related to the structural characteristics of 1 (Ca2+
salt) and 1 (Na+ salt B) and also to their interconversion
leading to calcium transport.
KCl:NaCl
500:5
250:5
100:5
50:5
5:5
(K+ salt):(Na+ salt A) 1.53: 1 0.57: 1 0.35: 1 0.23: 1 ∼0: 1
a In each experiment, a DCM solution (5 mL) containing 1 (Na+
salt A) (5 mg) was treated with 4 N HCl solution (5 mL) containing
the given amounts (equiv.) of KCl and NaCl, and the mixture was
stirred vigorously for 1 h. The ratios were determined by compar-
ing the signals at δ 5.83 (K+ salt) and δ 5.63 (Na+ salt A) in the
1H NMR spectra (300 MHz, CDCl3). Mass spectral analyses were
also carried out. ESI data gave similar results as the 1H NMR
data. MALDI data confirmed the relative stability of the (Na+ salt
A), but the exact ratios were not reliable because of the problems
associated with extraneous cations.
Conclusion
In the present studies, the two oxane fragments of SCH
351448 (Na+ salt) were prepared stereoselectively via
radical cyclization reactions of â-alkoxyacrylates. The
monomeric unit was obtained via Julia-Julia coupling
reaction, and the ring-closing olefin metathesis reaction
was employed for the 28-membered macrodiolide ring
formation. SCH 351448 analogues containing other cat-
ions were prepared, but SCH 351448 (Na+ salt A)
appeared to be the most stable complex under acidic
conditions. SCH 351448 (Ca2+ salt), which is relatively
stable under neutral conditions, may be a physiologically
important species.
TABLE 4. Studies on the Solvent Effectsa
solvents
(dielectric constants)
Hexane
(1.9)
Et2O
(4.3)
DCM
(9.1)
MeCN
(38)
(K+ salt):(Na+ salt A)
∼0: 1
∼0: 1
3.8: 1
4.2: 1
a In each experiment, a solution (5 mL) containing 1 (Na+ salt
A) (5 mg) was treated with 4 N HCl solution (5 mL) saturated
with KCl.
with saturated aqueous solution of calcium chloride.32
A
Experimental Section
mixture of 1 (Na+ salt B) and 1 (Ca2+ salt) resulted when
1 (Ca2+ salt) was equilibrated with saturated aqueous
solution of sodium chloride. Higher stability of 1 (Ca2+
salt) over 1 (Mg2+ salt) under neutral conditions was also
obvious from the equilibration experiment.
Preparation of SCH 351448 1 (Na+ Salt A). TBAF (1.0
M in THF, 0.1 mL, 0.1 mmol) was added to a solution of
macrodiolide 44 (17 mg, 0.013 mmol) in THF (3 mL). After
being stirred for 2 h at room temperature, the reaction mixture
was diluted with hexane (10 mL) and washed with 4 N HCl
solution (saturated with NaCl, 12 mL). The aqueous layer was
extracted with hexane (3 × 8 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated to afford a
monosodium salt as a white solid without further purification
(13.5 mg, 91%). Rf 0.62 (Hex-EtOAc, 2:1). 1H NMR (500 MHz,
CDCl3): δ 7.23 (t, 2H, J ) 7.8 Hz), 6.84 (d, 2H, J ) 8.2 Hz),
6.69 (d, 2H, J ) 7.3 Hz), 5.63-5.61 (m, 2H), 3.77-3.73 (m,
2H), 3.63-3.59 (m, 2H), 3.50 (d, 2H, J ) 11.0 Hz), 3.17-3.09
(m, 6H), 2.53-2.59 (m, 2H), 2.03-1.97 (m, 2H), 1.85-1.76 (m,
8H), 1.73-1.57 (m, 8H), 1.51-1.35 (m, 20H), 1.28-1.15 (m,
12H), 1.15 (s, 6H), 1.12 (s, 6H), 1.00 (d, 6H, J ) 6.2 Hz). 13C
NMR (75 MHz, CD2Cl2): δ 178.8, 171.2, 160.2, 145.2, 133.6,
122.4, 116.0, 115.7, 83.3, 79.3, 78.4, 78.2, 77.8, 67.6, 46.6, 43.7,
37.8, 37.6, 37.0, 36.8, 35.3, 33.1, 32.7, 32.0, 30.2, 29.7, 25.3,
24.4, 23.6, 23.4, 19.4, 15.2. MS m/z (FAB, relative intensity):
1143 (M+ + 1, 47), 1121 (13), 1098 (6), 561 (31), 245 (39), 154
(65), 81 (100), 55 (82), 23 (71). HRMS (FAB): calcd for
Relative stability of 1 (Na+ salt A) and 1 (K+ salt) in
dichloromethane was investigated by equilibration ex-
periments with 4 N HCl solutions containing different
amounts of sodium and potassium chloride starting from
1 (Na+ salt A) (Table 3). From the experiments, it is
clearly shown that 1 (Na+ salt A) is much more stable in
dichloromethane than 1 (K+ salt) under acidic conditions.
Higher relative stability of 1 (Na+ salt A) is obtained in
nonpolar solvents, and remarkably, 1 (Na+ salt A) was
stable when equilibrated in hexane or ether with 4 N HCl
solution saturated with potassium chloride.
More comments on 1 (Ca2+ salt) are deemed necessary
aside from the story on its “surprise” formation on
(Merck) silica gel columns. Octacoordination by oxygen
is the most common chelate scheme for Ca2+ for small
molecules and is also the most common in proteins.33 The
relative stability of 1 (Ca2+ salt) attests to the maximum
stabilization of the calcium ion complex via intramolecu-
lar octacoordination:34 intramolecular hydrogen bonds
discussed above should also help stabilizing the complex.
From the cation exchange studies, 1 (Ca2+ salt) appears
to be the most stable species under (near) neutral
conditions, and equilibrium between 1 (Ca2+ salt) and 1
(Na+ salt B) is a distinct possibility under physiological
conditions. Calcium is a second messenger in virtually
all cells. In particular, calcium signals in the nucleus
have effects on gene transcription and cell growth that
are distinct from those of cytosolic calcium signals.
C64H96O16Na (M+ + 1) 1143.6596, found 1143.6598. [R]13
+31.2 (c 0.73, CHCl3).
D
Preparation of SCH 351448 1 (Na+ Salt B). When the
TBAF reaction mixture of 44 (as described above) was washed
with NaH2PO4/Na2HPO4 (pH 6.8) or AcOH/NaOAc (pH 5.0)
buffer, 1 (Na+ salt B) was obtained as the sole product. It was
also obtained when 1 (Na+ salt A) was equilibrated with
aqueous NaCl solution. 1H NMR (500 MHz, CDCl3): δ 7.16 (t,
2H, J ) 7.9 Hz), 6.96 (d, 2H, J ) 8.2 Hz), 6.63 (d, 2H, J ) 7.4
Hz), 5.87-5.84 (m, 2H), 4.89 (s, 2H), 3.75 (d, 2H, J ) 10.7
Hz), 3.73-3.67 (m, 2H), 3.59 (t, 2H, J ) 10.6 Hz), 3.35 (td,
2H, J ) 12.9, 4.4 Hz), 3.08-3.03 (m, 4H), 2.30 (td, 2H, J )
13.4, 3.9 Hz), 2.12-2.06 (m, 2H), 2.02-1.95 (m, 2H), 1.92-
1.87 (m, 2H), 1.80-1.75 (m, 4H), 1.63-1.55 (m, 2H), 1.53-
1.43 (m, 14H), 1.38-1.33 (m, 4H), 1.31-1.22 (m, 12H), 1.20-
1.11 (m, 8H), 1.17 (s, 6H), 1.10 (s, 6H), 1.00 (d, 6H, J ) 6.1
Hz). 13C NMR (75 MHz, CD2Cl2): δ 185.2, 170.7, 159.4, 143.9,
(32) It was important to check the ratio with the crude equilibrium
mixture. The usual drying over anhydrous MgSO4 some times resulted
in the formation of 1 (Na+ salt A) regardless the original composition.
(33) Katz, A. K.; Glusker, J. P.; Beebe, S. A.; Bock, C. W. J. Am.
Chem. Soc. 1996, 118, 5752-5763.
(34) For examples of intramolecular calcium ion octacoordination,
read the following articles. (a) Adams, S. R.; Kao, J. P. Y.; Grynkiewicz,
G.; Minta, A.; Tsien, R. Y. J. Am. Chem. Soc. 1988, 110, 3212-3220.
(b) Ellis-Davies, G. C. R. Tetrahedron Lett. 1998, 39, 953-956.
(35) For introduction to this area of research, read the following
articles. (a) Deisseroth, K.; Heist, E. K.; Tsien, R. W. Nature 1998,
392, 198-202. (b) Dolmetsch, R. E.; Pajvani, U.; Fife, K.; Spotts, J.
M.; Greenberg, M. E. Science 2001, 294, 333-339. (c) Echevarria, W.;
Leite, M. F.; Guerra, M. T.; Zipfel, W. R.; Nathanson, M. H. Nature
Cell Biol. 2003, 5, 440-446.
6328 J. Org. Chem., Vol. 70, No. 16, 2005

Total Synthesis of SCH 351448
132.8, 121.5, 117.9, 116.4, 82.7, 80.2, 78.4, 78.1, 76.0, 68.9, 46.9,
43.2, 38.2, 36.9, 36.3, 35.7, 33.5, 33.2, 32.5, 31.0, 30.5, 24.8,
24.5, 23.8, 23.7, 18.3, 14.4. MS m/z (FAB, relative intensity):
1187 (M+ - 1 + 2Na, 28), 1165 (M+ + Na, 100), 1143 (M+ + 1,
90), 1098 (16), 1001 (11), 957 (4), 583 (3), 23 (71). HRMS
(FAB): calcd for C64H95O16Na2 (M+ + Na) 1165.6416, found
1165.6431. Crystals of 1 (Na+ salt B) were obtained from
DCM-MeOH (1:5) at 3 °C.
599 (27), 23 (100). HRMS (FAB): calcd for C64H95O16Ca (M+
+ 1) 1159.6246, found 1159.6266. Crystals of 1 (Ca2+ salt) were
obtained from MeOH at room temperature.
SCH 351448 1 (Cu2+ Salt). 1H NMR (500 MHz, CDCl3): δ
7.12 (t, 2H, J ) 7.8 Hz), 6.84 (d, 2H, J ) 8.1 Hz), 6.63 (d, 2H,
J ) 7.4 Hz), 5.75-5.72 (m, 2H), 4.58 (s, 2H), 3.87 (d, 2H, J )
10.8 Hz), 3.85-3.82 (m, 2H), 3.61 (t, 2H, J ) 10.5 Hz), 3.08-
3.00 (m, 6H), 2.35-2.29 (m, 2H), 2.07-1.98 (m, 6H), 1.81-
1.74 (m, 4H), 1.67-1.35 (m, 22H), 1.33-1.05 (m, 18H), 1.13
(s, 6H), 1.09 (s, 6H), 0.97 (d, 6H, J ) 6.7 Hz). 13C NMR (125
MHz, CDCl3): δ 184.0, 169.9, 156.4, 141.6, 131.0, 120.6, 115.3,
82.4, 80.6, 78.0, 77.9, 75.5, 68.7, 46.9, 42.7, 38.0, 37.0, 35.8,
35.7, 35.6, 33.3, 33.0, 32.3, 30.2, 29.9, 24.6, 24.2, 23.9, 23.5,
18.0, 13.9. MS m/z (FAB, relative intensity): 1181 (M+, 4), 1159
(8), 1143 (3), 1114 (2), 1098 (1), 599 (1), 39 (100). HRMS
(FAB): calcdforC64H94O1663Cu(M+)1181.5838,found1181.5811.
SCH 351448 1 (Mn2+ Salt). MS m/z (FAB, relative inten-
sity): 1228 (M+ - 1 + Mn, 20), 1144 (3), 1143 (2), 1098 (1),
1041 (2), 685 (13), 667 (30), 649 (8), 55 (100). HRMS (FAB):
calcd for C64H93O16Mn2 (M+ - 1 + Mn) 1227.5225, found
1227.5256.
General Procedure for Exchange Reactions of 1 (Na+
Salt A) or 1 (Ca2+ Salt). A sample (5 mg) of 1 (Na+ salt A) or
1 (Ca2+ salt) in DCM (5 mL) was equilibrated with different
saturated metal salt solutions in 4 N HCl or water (5 mL).
After vigorous stirring for 1 h, the organic layer was separated
and concentrated. The composition of the crude equilibrium
mixture was checked by 1H NMR and mass (MALDI and FAB)
spectral analysis (Tables 1 and 2).
SCH 351448 1 (K+ Salt). Ms m/z (FAB, relative intensity):
1197 (M+ + K, 2), 1159 (M+ + 1, 10), 1143 (2), 1114 (2), 973
(1), 599 (10), 555 (6), 55 (100). HRMS (FAB): calcd for
C64H96O16K (M+ + 1) 1159.6335, found 1159.6366.
SCH 351448 1 (Rb+ Salt). MS m/z (FAB, relative inten-
sity): 1290 (M+ + Rb, 4), 1205 (M+ + 1, 19), 1159 (6), 1143
(11), 1098 (2), 525 (2), 245 (3), 85 (100). HRMS (FAB): calcd
for C64H96O1685Rb (M+ + 1) 1205.5816, found 1205.5844.
SCH 351448 1 (Mg2+ Salt). Ms m/z (FAB, relative inten-
sity): 1166 (M+ - 1 + Mg, 20), 1143 (M+ + 1, 18), 1098 (4),
1001 (3), 623 (6), 605 (10), 583 (8), 23 (100). HRMS (FAB):
calcd for C64H95O1624Mg (M+ + 1) 1143.6471, found 1143.6460.
SCH 351448 1 (Ca2+ Salt). 1H NMR (500 MHz, CDCl3): δ
7.17 (t, 2H, J ) 7.9 Hz), 7.01 (d, 2H, J ) 8.3 Hz), 6.60 (d, 2H,
J ) 7.4 Hz), 6.20-6.16 (m, 2H), 5.92 (s, 2H), 3.79-3.73 (m,
2H), 3.72 (d, 2H, J ) 11.2 Hz), 3.46 (t, 2H, J ) 10.3 Hz), 3.27
(td, 2H, J ) 12.4, 4.2 Hz), 3.10 (t, 2H, J ) 9.5 Hz), 3.03 (t, 2H,
J ) 10.7 Hz), 2.36-2.30 (m, 2H), 2.07-2.02 (m, 2H), 2.00-
1.93 (m, 2H), 1.89 (t, 2H, J ) 13.0 Hz), 1.80-1.74 (m, 4H),
1.63-1.41 (m, 22H), 1.38-1.30 (m, 10H), 1.25-1.12 (m, 8H),
1.11 (s, 6H), 1.03 (s, 6H), 0.98 (d, 6H, J ) 6.6 Hz). 13C NMR
(75 MHz, CD2Cl2): δ 185.4, 173.5, 160.4, 142.7, 132.6, 120.2,
119.1, 116.9, 82.9, 81.6, 78.0, 77.8, 76.8, 71.5, 46.5, 41.5, 38.6,
36.8, 36.5, 36.1, 34.6, 33.3, 33.2, 32.1, 30.5, 30.2, 25.0, 24.4,
24.2, 24.1, 19.1, 13.7. MS m/z (FAB, relative intensity): 1159
(M+ + 1, 65), 1143 (20), 1114 (13), 1098 (5), 1017 (4), 973 (4),
SCH 351448 1 (Co2+ Salt). MS m/z (FAB, relative inten-
sity): 1235 (M+ - 1 + Co, 18), 1143 (4), 1049 (1), 693 (9), 675
(16), 618 (4), 305 (7), 55 (100). HRMS (FAB): calcd for
C64H93O16Co2 (M+ - 1 + Co) 1235.5128, found 1235.5151.
Acknowledgment. Authors thank the Ministry of
Science and Technology, Republic of Korea, and KISTEP
for a NRL grant (1999) and Center for Bioactive Mo-
lecular Hybrids (Yonsei University and KOSEF) for a
research grant. BK21 graduate fellowship grants to E.
J. Kang, E. J. Cho, and Y. E. Lee are gratefully
acknowledged. Authors also thank Dr. V. R. Hegde
(Schering Plough Research Institute) for providing
spectroscopic data of the natural sample.
Supporting Information Available: Experimental pro-
cedures and a collection of 1H- and 13C NMR spectra of
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0507993
J. Org. Chem, Vol. 70, No. 16, 2005 6329