Syntheses of pantolactone and pantothenic acid derivatives as potential lipid regulating agents

Article abstract of DOI:10.1080/00397910500377545

A series of pantolactone and pantothenic acid derivatives (1-10) were synthesized to be tested for their potential as lipid regulating agents that act as Coenzyme-A mimics. The syntheses were performed with moderate to high yields. Copyright Taylor & Fran

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Syntheses of Pantolactone and Pantothenic
Acid Derivatives as Potential Lipid Regulating
Agents
Daniela C. Oniciu a b , Roel P. L. Bell c , Bruce H. McCosar d , Charles L.
Bisgaier a , Jean‐Louis H. Dasseux a , Dennis Verdijk c , Mike Relou c , Dennis
Smith c , Henk Regeling c , Frank M. C. Leemhuis c , Eelco J. Ebbers c , Ralf
Mueller d , Lianhao Zhang d , Emil Pop d , Clay T. Cramer a , Brian Goetz a ,
Andrew McKee a , Michael E. Pape a & Brian R. Krause a
a Esperion Therapeutics , Pfizer Global Research and Development , Ann
Arbor, Michigan, USA
b Department of Chemistry , University of Florida , Gainesville, Florida, USA
c MercaChem BV , Nijmegen, The Netherlands
d Alchem Laboratories Corporation , Alachua, Florida, USA
Published online: 19 Aug 2006.
To cite this article: Daniela C. Oniciu , Roel P. L. Bell , Bruce H. McCosar , Charles L. Bisgaier , Jean‐Louis
H. Dasseux , Dennis Verdijk , Mike Relou , Dennis Smith , Henk Regeling , Frank M. C. Leemhuis , Eelco J.
Ebbers , Ralf Mueller , Lianhao Zhang , Emil Pop , Clay T. Cramer , Brian Goetz , Andrew McKee , Michael E.
Pape & Brian R. Krause (2006) Syntheses of Pantolactone and Pantothenic Acid Derivatives as Potential Lipid
Regulating Agents, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 36:3, 365-391, DOI: 10.1080/00397910500377545
To link to this article: http://dx.doi.org/10.1080/00397910500377545
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Synthetic Communicationsw, 36: 365–391, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500377545
Syntheses of Pantolactone and Pantothenic
Acid Derivatives as Potential Lipid
Regulating Agents
Daniela C. Oniciu
Esperion Therapeutics, Pfizer Global Research and Development,
Ann Arbor, Michigan, USA and Department of Chemistry, University of
Florida, Gainesville, Florida, USA
Roel P. L. Bell
MercaChem BV, Nijmegen, The Netherlands
Bruce H. McCosar
Alchem Laboratories Corporation, Alachua, Florida, USA
Charles L. Bisgaier and Jean-Louis H. Dasseux
Esperion Therapeutics, Pfizer Global Research and Development,
Ann Arbor, Michigan, USA
Dennis Verdijk, Mike Relou, Dennis Smith, Henk Regeling,
Frank M. C. Leemhuis, and Eelco J. Ebbers
MercaChem BV, Nijmegen, The Netherlands
Ralf Mueller, Lianhao Zhang, and Emil Pop
Alchem Laboratories Corporation, Alachua, Florida, USA
Clay T. Cramer, Brian Goetz, Andrew McKee, Michael E. Pape, and
Brian R. Krause
Esperion Therapeutics, Pfizer Global Research and Development,
Ann Arbor, Michigan, USA
Received in the USA July 28, 2005
Address correspondence to Daniela C. Oniciu, Department of Chemistry,
University of Florida, Gainesville, FL 32611-7200, USA. Tel.: 1-(352) 514-1886;
Fax: 1-(352) 371-1886; E-mail: oniciu@yahoo.com
365

366
D. C. Oniciu et al.
Abstract: A series of pantolactone and pantothenic acid derivatives (1–10) were
synthesized to be tested for their potential as lipid regulating agents that act as
Coenzyme-A mimics. The syntheses were performed with moderate to high yields.
Keywords: Pantolactone, pantothenic acid, coenzyme-A, dyslipidemia, metabolic
disorder
INTRODUCTION
Acyl Coenzymes-A (AcCoA) are key metabolic intermediates utilized for
energy storage as well as energy production. For example, naturally
occurring (endogenous) CoAs are utilized in triglyceride storage (such as
the ones stored in adipose tissues) and to produce energy in muscle and
liver via a b-oxidation pathway. Efforts have been made to mimic these
agents to affect lipid metabolism and cardiovascular health.[1a–d] Pantosin,
a dimer of pantothenic acid, has been demonstrated to be a lipid regulator
in humans.[1e] AcCoA mimics that bind to and/or inhibit the activity of
AcCoA-metabolizing or -binding proteins are considered to be essential in
treating or preventing dyslipidemia and other metabolic disorders. The termi-
nology of “AcCoA mimics” includes compounds that are CoA analogs as well
as portions of CoA, such as the pantothenic acid portion, phosphorylated
derivatives of pantothenic acid, and their analogs. Efforts in our groups
have been directed toward obtaining AcCoA mimics that are not only
selective but also nonsubstrate inhibitors of AcCoA ligases and metabolizing
enzymes.[1f–g] Identification of such inhibitors is usually carried out using
computer-assisted methods including docking procedures and pharmacophore
models. We describe syntheses of various substituted pantamide derivatives
that have been designed as pharmacophores to mimic AcCoA.
RESULTS AND DISCUSSION
A series of pantothenic acid mimics (1–10) was synthesized.[1f–g] Target
compounds 1, 2, 3, and 4 (SS and RR) were all prepared by treatment
of pantolactone, either racemic (11), L-(þ) (11S), or D-(2) (11R) with
an appropriately functionalized amine (12, 13, 14, (prepared from the
corresponding bis-HCl salt by in situ treatment with NaHCO3) or 15)
in refluxing EtOH (Schemes 1 and 2). Diamine 14 was prepared from the
corresponding bis-HCI salt by in situ treatment with NaHCO3.
The synthesis of target compound 5 was planned via alkylation of the
known amide 18[2] (18 was crystallized from EtOAc; mp 117.5–119.18C).
with ditosylate 17, which was easily prepared from the known diol 16[3]
(Scheme 3). Treatment of 18 with NaH in THF at reflux and subsequent
addition of 17 at room temperature gave, after stirring for 7 h at reflux, bis-
amide 19 in moderate yield. Deprotection of 19 under acidic conditions

Pantolactone and Pantothenic Acid Derivatives
367
Scheme 1. (a) EtOH, D.
afforded target compound 5 as an inseparable mixture with ethylene glycol. To
circumvent this purification problem, 19 was treated with acetone and TsOH
to give the dioxolane deprotected analogue 20 and the isopropylidene acetal of
ethylene glycol. The latter could easily be removed via evaporation. On acidic
treatment of 20 in the presence of H2O, target compound 5 was isolated in
good yield.
The synthesis of pantothenic acid derivative 6 started with the reduction
of chloro ester 21[4] with LiBH4 in MeOH[5] to chloro alcohol 22 (Scheme 4).
Protection of the hydroxyl group in 22 gave THP ether 23, which was sub-
sequently transformed by Gabriel synthesis via phthalimide 24 to amine 25.
The sodium salt of D-pantothenic acid (26) was then activated with N-hydroxy-
succinimide and N,N0-dicylohexylcarbodiimide (DCC) and coupled with
amine 25 to afford THP ether 27. Removal of the THP protection in 27
with pyridinium p-toluenesulfonate (PPTS) in EtOH at 558C furnished
compound 6.
For the syntheses of target compounds 7 and 8, it was planned to treat the
sterically hindered anilines 31 and 37 with the known pantolactone derivative
32[6] (Schemes 5 and 6). Because it was expected that stronger conditions
were needed than in the syntheses of target compounds 1–4, the rather
acidic a-hydroxyl moiety present in pantolactone (11) was protected with
ethyl vinyl ether. The anilines 31 and 37 were prepared via reductive
Scheme 2. (a) EtOH, D.

368
D. C. Oniciu et al.
Scheme 3. (a) TsCl, Et3N, 0–48C; (b) NaH, THF, 758C; (c) TsOH, acetone;
(d) HOAc, H2O.
cleavage of the corresponding diazo-compounds 30 and 36 prepared respect-
ively from phenolether 29[7] via a diazonium coupling and alkylation of diazo-
compound 34[8] with bromide 35.[9] Deprotonation of anilines 31 and 37 with
NaH in DMF and subsequent treatment with 32 afforded, respectively, the
amides 33 and 38 as mixtures of diastereomers in moderate yields. Acidic
cleavage of the 1-ethoxyethyl-protected hydroxyl group present in 33 and
38 gave target compound 7 and ester 39, respectively. Treatment of 39 with
LiAlH4 yielded target compound 8.
With compound 39 in hand, saponification of the ester moiety was
expected to give target compound 9. However, on treatment of 39 with
LiOH in refluxing EtOH/H2O, the corresponding acid derivative of ester 37
was isolated as the main product, most probably formed via intramolecular
attack of the primary hydroxyl on the amide moiety in 39. To avoid this
lactonization, the primary hydroxyl moiety had to be protected. For that
purpose, it was chosen to prepare benzylidene acetal 40 (Scheme 7).
Treatment of 39 with benzaldehyde dimethylacetal and TsOH in CH2Cl2
gave benzylidene acetal 40 in high yield. Subsequent saponification with
LiOH gave 41 without any noticeable cleavage of the amide moiety.
Reductive debenzylation of 41 provided target compound 9.

Pantolactone and Pantothenic Acid Derivatives
369
Scheme 4. (a) LiBH4, MeOH, CH2Cl2, rt-D; (b) DHP, TsOH, CH2Cl2, 08C;
(c) potassium phthalimide, DMF, 908C; (d) H2NNH2, EtOH, 708C-D; (e) N-hydroxy-
succinimide, DCC, DMF, CH2Cl2; (f) PPTS, EtOH, 558C.
For the introduction of the a-D-xylosyl moiety in target compound 10, a
similar methodology as reported by Schmidt et al. for the synthesis of a-gly-
cosides[10,11] was planned (Scheme 8). For that purpose the diprotected triol
47 and the known trichloroacetimidate 51 (isolation of 51 (ꢀ50 mg) as a
Scheme 5. (a) 1) 28, HCl (concd.), NaNO2, H2O, 0–58C; 2) 29, AcOH, ꢀ108C;
(b) Na2S2O4, H2O/EtOH, D; (c) NaH, DMF; (d) HOAc, H2O.

370
D. C. Oniciu et al.
Scheme 6. (a) K2CO3, DMSO; (b) Na2S2O4, H2O/EtOH, D; (c) NaH, DMF;
(d) HOAc, H2O; (e) LiAlH4, DME, 08C.
by-product, see Ref.[12]; preparation of 51 on a 24-g scale, see Experimental
section) were desired. The synthesis of the aglycon part of target compound
10 was performed via a similar strategy as reported for the preparation of
compounds 7 and 8. Treatment of aniline 44, prepared from the known
diazo compound 34,[8] with NaH and 32 gave amide 45 as a 2:1 mixture of
diastereomers in moderate yield. A one-pot reductive debenzylation and
acidic deprotection of the ethoxyethyl group in 45 provided triol 46. Protec-
tion of the 1,3-diol moiety in 46 by treatment with 2,2-dimethoxypropane
and TsOH gave compound 47. An alternative preparation of 46, via
coupling of aniline 44 with acid chloride 49 and subsequent deprotection of
50, was also developed (Scheme 8). (Starting from the isopropylidene acetal
analogue of benzylidene acetal 48, the desired isopropylidene acetal
analogue of benzylidene acetal 50 could not be isolated). The novel acid

Pantolactone and Pantothenic Acid Derivatives
371
Scheme 7. (a) PhCH(OMe)2, TsOH, CH2Cl2; (b) LiOH, EtOH/H2O, D; (c) Pd/C, H2,
EtOH, 358C.
chloride (49), prepared from pantolactone (11), is a convenient reagent for the
synthesis of pantoic acid (2,4-dihydroxy-3,3-dimethylbutyric acid) or
pantamide (2,4-dihydroxy-3,3-dimethylbutyramide) derivatives. Despite the
vast amount of work published in this field no such reactive diprotected
pantoic acid synthon is described. (For the synthesis of diprotected pantoic
acid derivatives, see Ref.[13]) For the coupling of alcohol 47 with trichloroa-
cetamide 51, a method modified to the one developed by Schmidt
et al.[10,11] was used. (Optimization experiments, performed in our laboratory
for the synthesis of several a-xylopyranosyl alkylethers, revealed that the best
a-selectivity was obtained when the Lewis acid catalyst TMSOTf was used in
Et2O at low temperature (230 2788C). However, at 2788C 51 was not
soluble in Et2O and 1,2-dichloroethane was needed as a cosolvent. As a
result xyloside 52 was isolated as a mixture of anomers (52a:52b ꢀ 2:1) in
good yield. Debenzylation of 52 and subsequent acetylation of 53 provided
compound 54 as a mixture of anomers, which could be partially separated
by column chromatography (54a:54b ꢀ 12:1). The target compound 10
(10a:10b ꢀ 14:1) was obtained after treatment of 54 with acetic acid and
column chromatography.
In conclusion, we have devised straightforward syntheses for ten different
pantamide derivatives that are being evaluated for their lipid-lowering proper-
ties. In addition, the novel protected acid chloride 49 was developed, which
should be of utility for the synthesis of related substituted pantoic esters and
pantamides in the future.

372
D. C. Oniciu et al.

Pantolactone and Pantothenic Acid Derivatives
EXPERIMENTAL
373
General
All reagents and solvents were purchased from commercial suppliers and
were used without prior treatment unless stated otherwise. All product
solutions were dried over Na2SO4 or MgSO4 prior to evaporation of the
solvent under reduced pressure by using a rotary evaporator. Column
chromatography was performed with silica gel (Fluka silica gel 60 with
particle size 70–230 mesh or Acros silica gel with particle size 0.060–
0.200 mm). Reactions were monitored by GC or TLC on Macherey-Nagel
Polygramw SIL G/UV254 plastic sheets or on Whatman AL SIL G/UV
aluminum sheets. Compounds on TLC were visualized by UV detection
and/or dipping in p-anisaldehyde–H2SO4–EtOH ¼ 1:1:19, basic KMnO4,
or ethanolic phosphomolybdic acid solution and subsequent heating. GC
analysis was performed on a Hewlett Packard 5890A gas chromatograph
with a flame ionization detector and an Alltech EC1 fused silica capillary
column, internal diameter 30 m ꢀ 0.32 mm, film thickness 0.25 mm, and N2
as carrier gas. GC peak areas were integrated electronically with a Hewlett
Packard HP3396 series II integrator. LC/MS analysis was performed
on a Shimadzu QP8000a with DAD (210–370 hm)/MSD (100–600 D)
detection and an Alltech Prefail C18, internal diameter 50 ꢀ 4.6 mm,
film thickness 3 mm column with 10 mM of HCO2H in CH3CN/10 mM
of HCO2H in H2O as elutes or a Agilent 1100-SL with ELSD/DAD (220–
320 hm)/MSD (100–800 D) detection and a Zorbaxw SB-C18, internal
diameter 150 mm ꢀ 4.6 mm, film thickness 3.5 mm column with CH3CN/
10 mM HCO2H in H2O as elutes or a Zorbaxw Extend-C18, internal
diameter 150 mm ꢀ 4.6 mm, film thickness 3.5 mm column with CH3CN/
10 mM NH3 in H2O as elutes, flow ¼ 1 mL/min and column tempe-
rature ¼ 358C. 1H and 13C NMR spectra were recorded on either a
Bruker AC-300 or
a Varian Gemini 300 spectrometer in CDCl3
unless otherwise stated. Chemical shifts are reported in parts per million (d)
relative to Me4Si for 1H and relative to the solvent peak for 13C data.
HRMS data were obtained with a VG Micromass VG7070E, Finnigan
MAT95Q, or Finnigan MAT900S spectrometer. Elemental analyses
were carried out on a Carlo Erba Instruments CHNSO EA 1108
element analyser or were performed by Atlantic Microlab, Inc.,
Norcross, Georgia. Melting points were measured on a Bu¨chi Melting
Point B-540 or a Thomas Hoover capillary melting-point apparatus and are
uncorrected. All prepared compounds were .95% pure unless otherwise
stated.
2,4-Dihydroxy-3,3-dimethyl-N-pyridin-3-ylmethyl-butyramide (1).
solution of 12 (5.00 g, 4.72 mL, 43.7 mmol) and 11 (5.68 g, 43.7 mmol) in
A
absolute EtOH (50 mL) was stirred under reflux for 5 d and then concentrated.

374
D. C. Oniciu et al.
The residue was recrystallized from EtOH/iPr2O to give 1 (9.26 g, 84%) as
colorless crystals. Mp 120–1228C. 1H NMR (DMSO-d6):
8.50
d
(d, J ¼ 2.0 Hz, 1H), 8.43 (dd, J ¼ 4.8, 2.0 Hz, 1H), 8.36 (t, J ¼ 6.2 Hz, 1H),
7.67 (d, J ¼ 7.7 Hz, 1H), 7.32 (dd, J ¼ 7.7, 4.8 Hz, 1H), 5.47
(d, J ¼ 5.5 Hz, 1H), 4.47 (t, J ¼ 5.6 Hz, 1H), 4.30 (m, 2H), 3.78 (d, 5.6 Hz,
1H), 3.31 (dd, J ¼ 10.4, 5.8 Hz, 1H), 3.17 (dd, J ¼ 10.4, 5.8 Hz, 1H), 0.80
(s, 3H), 0.79 (s, 3H). 13C NMR (CD3OD): d 176.4, 149.7, 148.8,
137.8, 137.0, 125.2, 77.5, 70.4, 41.2, 40.6, 21.5, 21.0. Anal. calcd. for
C12H18N2O3: C, 60.49; H, 7.61; N, 11.76; found: C, 60.41; H, 7.57; N, 11.70.
N-[3-(2,4-Dihydroxy-3,3-dimethylbutyrylamino)-2-hydroxypropyl]-2,4-
dihydroxy-3,3-dimethylbutyramide (2). A solution of 11 (5.2 g, 40 mmol)
and 13 (1.8 g, 20 mmol) in absolute EtOH (50 mL) was heated to reflux for
3 d and evaporated. The residue was purified by column chromatography
(silica, EtOAc) to obtain a foamy solid (6.0 g). Recrystallization from
MeOH gave 2 (1.6 g, 23%) as a white solid. The mother liquor was purified
by chromatography (silica, EtOAc) to obtain another portion of 2 (2.6 g,
1
37%). Mp 169–1718C (MeOH). H NMR (CD3OD): d 4.90 (s, 7H), 3.92
(s, 2H), 3.80–3.65 (m, 1H), 3.46 (d, J ¼ 11.0 Hz, 2H), 3.40 (d, J ¼ 11.0 Hz,
2H), 3.30–3.18 (m, 4H), 0.94 (s, 12H). 13C NMR (CD3OD): d 176.5 (2ꢀ),
77.4 (2ꢀ), 70.3 (3ꢀ), 43.3 (2ꢀ), 40.6 (2ꢀ), 21.6 (2ꢀ), 21.2 (2ꢀ). HRMS
calcd. for C15H31N2O7 (MHþ): 351.2131; found: 351.2136.
N-f2-[2-(2,4-Dihydroxy-3,3-dimethylbutyrylamino)-ethoxy]-ethylg-2,4-
dihydroxy-3,3-dimethylbutyramide (3). Under Ar atmosphere, a mixture of
11 (7.25 g, 55.1 mmol), the dihydrochloride of 14 (5.03 g, 27.6 mmol), and
NaHCO3 (4.78 g, 56.9 mmol) in EtOH (100 mL) was heated to reflux for
3 d. After cooling to rt, the solids were filtered and the filtrate was evaporated.
The residue was purified by flash chromatography (silica, CHCl3 to CHCl3–
EtOH ¼ 3:2) to give 3 (7.92 g, 79%) as a clear, colorless oil. 1H NMR
(CD3OD): d 3.91 (s, 2H), 3.6–3.3 (m, 14H), 0.93 (s, 12H). 13C NMR
(CD3OD): d 176.2 (2ꢀ), 77.4 (2ꢀ), 70.5 (2ꢀ), 70.4 (2ꢀ), 40.5 (2ꢀ), 39.8
(2ꢀ), 21.5 (2ꢀ), 21.0 (2ꢀ). HRMS calcd. for C16H33N2O7 (MHþ):
365.2288, found: 365.2284. Anal. calcd. for C16H32N2O7: C, 52.78; H,
8.85; N, 7.69; found: C, 52.42; H, 8.84; N, 7.27.
(S,S)-N-[2-(2,4-Dihydroxy-3,3-dimethylbutyrylamino)-ethyl]-2,4-dihydroxy-
3,3-dimethylbutyramide (4-SS). A solution of 11S (5.0 g, 38 mmol) and 15
(1.1 g, 18 mmol) in EtOH (25 mL) was heated to reflux for 3 d and evaporated.
The residue was recrystallized from hot EtOAc (100 mL) containing just
enough EtOH to fully dissolve the product to give 4-SS (4.25 g, 70%) as
1
sharp, rock-salt-like crystals. Mp 124.8–124.98C. H NMR (DMSO-d6): d
7.84 (s, 2H), 5.35 (d, J ¼ 5.0 Hz, 2H), 4.49 (m, 2H), 3.71 (d, J ¼ 5.0 Hz,
2H), 3.50–3.14 (m, 8H), 0.81 (s, 6H), 0.79 (s, 6H). 13C NMR (DMSO-d6):
d 173.3 (2ꢀ), 75.1 (2ꢀ), 68.0 (2ꢀ), 39.0 (2ꢀ), 38.3 (2ꢀ), 21.1 (2ꢀ), 20.4

Pantolactone and Pantothenic Acid Derivatives
375
(2ꢀ). HRMS calcd. for C14H29N2O6 (MHþ): 321.2026; found: 321.2041.
Anal. calcd. for C14H28N2O6: C, 52.48; H, 8.81; N, 8.74; found: C, 52.29;
H, 8.82; N, 8.85. [a]2D5 ¼ 269.2 (c ¼ 1.09, MeOH).
(R,R)-N-[2-(2,4-Dihydroxy-3,3-dimethylbutyrylamino)-ethyl]-2,4-dihydroxy-
3,3-dimethylbutyramide (4-RR). A solution of 11R (5.0 g, 38 mmol) and 15
(1.1 g, 18 mmol) in EtOH (25 mL) was heated to reflux for 3 d and evaporated.
The residue was recrystallized from hot EtOAc (100 mL) containing just
enough EtOH to fully dissolve the product to give 4-RR (3.4 g, 56%) as
1
sharp, rock-salt-like crystals. Mp 124.8–124.98C. H NMR (DMSO-d6): d
7.84 (s, 2H), 5.35 (d, J ¼ 5.0 Hz, 2H), 4.49 (m, 2H), 3.71 (d, J ¼ 5.0 Hz,
2H), 3.50–3.14 (m, 8H), 0.81 (s, 6H), 0.79 (s, 6H). 13C NMR (DMSO-d6):
d 173.3 (2ꢀ), 75.1 (2ꢀ), 68.0 (2ꢀ), 39.0 (2ꢀ), 38.3 (2ꢀ), 21.1 (2ꢀ), 20.4
(2ꢀ). HRMS calcd. for C14H29N2O6 (MHþ): 321.2026; found: 321.2034.
Anal. calcd. for C14H28N2O6: C, 52.48; H, 8.81; N, 8.74; found: C, 52.05;
H, 8.82; N, 8.79. [a]2D5 ¼ þ 67.6 (c ¼ 1.06, MeOH).
3-[2-(3-f[(4-Methylphenyl)sulfonyl]oxygpropyl)-1,3-dioxolan-2-yl]propyl
4-methyl-1-benzenesulfonate (17). (For another preparation of this comp-
ound, see Ref.[14]) At 08C, TsCl (11.84g, 62.1mmol) was added to a
solution of 16[3] (4.72 g, 24.8mmol) and Et3N (10.5 mL, 74.7mmol) in
CH2Cl2 (100 mL), and the reaction mixture was placed in the refrigerator for
16h. The resulting mixture was diluted with Et2O (300mL) and filtered. The
residue was washed with Et2O (100mL). The combined organic layers were
washed successively with aqueous HCl (1M, 25mL) and brine (3 ꢀ 25mL)
and evaporated. The remaining white solid was crystallized from a mixture of
iPr2O and EtOAc (10:1, ꢀ240 mL) to give 17 (8.92 g, 72%) as white crystals.
Mp 90–918C. 1H NMR: d 7.78 (d, J ¼ 8.2 Hz, 4H), 7.35 (d, J ¼ 8.2 Hz, 4H),
4.02 (t, J ¼ 6.2 Hz, 4H), 3.84 (s, 4H), 2.45 (s, 6H), 1.63–1.73 (m, 4H),
1.53–1.59 (m, 4H). 13C NMR: d 144.5 (2ꢀ), 132.9 (2ꢀ), 129.6 (4ꢀ), 127.6
(4ꢀ), 110.2, 70.5 (2ꢀ), 65.0 (2ꢀ), 33.0 (2ꢀ), 23.6 (2ꢀ), 21.8 (2ꢀ). Anal.
calcd. for C23H30O8S2: C, 55.40; H, 6.06; found: C, 55.63; H, 5.96.
N-4-f3-[2-(3-f[(2,2,5,5-Tetramethyl-1,3-dioxan-4-yl)-carbonyl]-aminog-
propyl)-1,3-dioxolan-2-yl]-propylg-2,2,5,5-tetramethyl-1,3-dioxane-4-
carboxamide (19). To a solution of 18[2] (8.26 g, 44.2 mmol) in dry THF
(200 mL) was added NaH (60 %w/w dispersion in mineral oil, 2.12 g,
53.0 mmol). After 10 min, the reaction mixture was stirred at 758C for
30 min and cooled to rt with an H2O bath. Then, 17 (9.95 g, 19.98 mmol)
was added, and after 5 min, the reaction mixture was stirred at 758C. After
7 h, the reaction mixture was allowed to gradually cool to rt and quenched
with a mixture of brine and H2O (2:1, 100 mL). The layers were separated
and the H2O layer was extracted with Et2O (2 ꢀ 100 mL). The combined
organic layers were washed with brine (3 ꢀ 50 mL) and evaporated. The
residue was purified by column chromatography (silica, EtOAc) to give 19

376
D. C. Oniciu et al.
(6.35 g containing ꢀ7% w/w) EtOAc, 56%) as a colorless oil, which slowly
crystallized on standing. An analytical sample of 19 for melting-point deter-
mination, 1H NMR (containing ꢀ1% w/w iPr2O), 13C NMR, elemental
analysis, and LCMS was obtained via crystallization from iPr2O as a white
solid. Mp 109–1258C. 1H NMR: d 6.58 (br s, 2H), 4.07 (s, 2H), 3.93
(s, 4H), 3.68 (d, J ¼ 11.7 Hz, 2H), 3.27 (d, J ¼ 11.4 Hz, 2H), 3.16–3.35
(m, 4H), 1.56–1.67 (m, 8H), 1.46 (s, 6H), 1.43 (s, 6H), 1.05 (s, 6H), 0.99
(s, 6H). 13C NMR: d 169.2 (2ꢀ), 110.9, 98.9 (2ꢀ), 77.2 (2ꢀ), 71.5 (2ꢀ),
65.0 (2ꢀ), 38.7 (2ꢀ), 34.4 (2ꢀ), 33.1 (2ꢀ), 29.7 (2ꢀ), 24.2 (2ꢀ), 22.3
(2ꢀ), 19.1 (2ꢀ), 18.9 (2ꢀ). Anal. calcd. for C27H48N2O8: C, 61.34; H,
9.15; N, 5.30; found: C, 61.63; H, 9.43; N, 5.21.
N-1-f7-[(2,4-Dihydroxy-3,3-dimethylbutanoyl)-amino]-4-oxoheptylg-2,4-
dihydroxy-3,3-dimethylbutanamide (5). To a solution of 19 (5.93 g, ꢀ93%
pure; containing ꢀ7% EtOAc; 10.44 mmol) in acetone (250 mL) was added
.
TsOH H2O (0.249 g, 1.31 mmol). After 18 h, the reaction mixture was con-
centrated at 308C to ꢀ50 mL, diluted with EtOAc (250 mL), washed with
saturated aqueous NaHCO3 (50 mL) and brine (3 ꢀ 50 mL), and evaporated.
According to NMR analysis the residue still contained starting material.
.
Therefore, this residue was taken up in acetone (100 mL), and TsOH H2O
(0.250 g, 1.31 mmol) was added. After 19.5 h, the reaction mixture was con-
centrated at 308C to ꢀ50 mL, diluted with EtOAc (250 mL), washed with
saturated aqueous NaHCO3 (50 mL) and brine (3 ꢀ 50 mL), and evaporated.
According to NMR analysis the residue still contained starting material.
.
Therefore, this residue was taken up in acetone (100 mL), and TsOH H2O
(0.253 g, 1.33 mmol) was added. After 3 d, the reaction mixture was concen-
trated at 308C to ꢀ50 mL, diluted with EtOAc (250 mL), washed with
saturated aqueous NaHCO3 (50 mL) and brine (3 ꢀ 50 mL), and evaporated
to give crude 20 (5.26 g, containing ꢀ7% w/w EtOAc) as a yellow oil.
According to NMR analysis almost all starting material was converted.
Compound 20 (4.97 g, ꢀ 9.86 mmol) was dissolved in HOAc (10 mL),
and H2O (20 mL) was added. After 22 h, the reaction mixture was evaporated
and concentrated twice from toluene. The residue was purified by column
chromatography (silica, CH2Cl2–MeOH ¼ 4:1) to give 5 (2.94 g, 72%,
containing ꢀ3% w/w MeOH and ꢀ0.5% w/w ethylene glycol) as a
1
colorless oil. H NMR (CD3OD): d 3.93 (s, 2H), 3.52 (d, J ¼ 11.1 Hz, 2H),
3.43 (d, J ¼ 11.1 Hz, 2H), 3.25 (t, J ¼ 6.9 Hz, 2H), 3.25 (t, J ¼ 6.8 Hz, 2H),
2.55 (t, J ¼ 7.2 Hz, 4H), 1.81 (quintet, J ¼ 6.9 Hz, 4H), 0.98 (s, 12H).
13C NMR (CD3OD): d 212.0, 176.1 (2ꢀ), 77.8 (2ꢀ), 70.8 (2ꢀ), 41.0 (2ꢀ),
40.8 (2ꢀ), 39.7 (2ꢀ), 25.2 (2ꢀ), 22.0 (2ꢀ), 21.6 (2ꢀ). HRMS calcd. for
C19H36NaN2O7 (MNaþ): 427.2420; found: 427.2384.
4-Chloro-2,2-dimethylbutan-1-ol (22). Under Ar atmosphere, CH2Cl2
(150 mL) was added to LiBH4 (9.2 g, 0.42 mmol) followed by dropwise
addition of anhydrous MeOH (17.2 mL, 0.42 mmol) over 1 h. After the H2

Pantolactone and Pantothenic Acid Derivatives
377
effervescence had ceased, 21[4] (50.5 g, 0.28 mmol) was added dropwise over
1 h. The reaction mixture was heated to reflux for 16 h, cooled to rt, and
carefully hydrolyzed with saturated NH4Cl solution (250 mL). The formed
suspension was extracted with CH2Cl2 (3 ꢀ 100 mL). The combined
organic layers were washed with HCl (1M, 200 mL) and brine (100 mL), evap-
orated, and dried in high vacuo to furnish 22 (36.6 g, 96%) as a clear, colorless
oil. 1H NMR: d 3.57 (m, 2H), 3.54–3.38 (m, 1H), 3.34 (s, 2H), 1.80 (m, 2H),
0.92 (s, 6H). 13C NMR: d 71.4, 42.0, 41.8, 35.7, 24.0 (2ꢀ).
2-(4-Chloro-2,2-dimethylbutyloxy)-tetrahydropyran (23). Under Ar atmos-
phere at 08C, 3,4-dihydro-2H-pyran (DHP, 29.5 mL, 0.32 mmol) was added
.
dropwise to a solution of 22 (35.3 g, 0.26 mmol) and TsOH H2O (260 mg,
1.4 mmol) in CH2Cl2 (200 mL) in 15 min. After 1 h, the reaction mixture
was filtered through a bed of Al2O3 (activated, basic), concentrated, and
dried in high vacuo to afford 23 (56.3 g, 98%) as a clear, colorless oil. A
sample of 16.5 g was further purified by fractional distillation under reduced
pressure to give 23 (13.6 g) as a clear, colorless oil. Bp 75–848C
(0.5 mmHg). 1H NMR: d 4.55 (t, J ¼ 2.9 Hz, 1H), 3.81 (m, 1H), 3.57
(m, 2H), 3.50 (m, 1H), 3.48 (d, J ¼ 9.3 Hz, 1H), 3.00 (d, J ¼ 9.3 Hz, 1H),
1.84 (m, 2H), 1.80–1.46 (m, 6H), 0.95 (s, 3H), 0.94 (s, 3H). 13C NMR: d
98.1, 76.3, 62.0, 43.0, 41.6, 34.8, 30.7, 25.6, 24.7 (2ꢀ), 19.5. HRMS calcd.
for C11H22ClO2 (MHþ): 221.1308; found: 221.1346.
2-[3,3-Dimethyl-4-(tetrahydropyran-2-yloxy)-butyl]-isoindole-1,3-dione (24).
To solution of 23 (13.5 g, 61.2 mmol) in anhydrous DMF (120 mL) was added
potassium phthalimide (11.3 g, 61.2 mmol). The reaction mixture was heated
to 908C for 24 h and poured into ice-H2O (200 mL). The resulting mixture was
extracted with EtOAc (4 ꢀ 50 mL), and the combined organic layers were
evaporated. The residue was purified by column chromatography (silica,
hexane–EtOAc ¼ 4:1) to furnish 24 (14.0 g, 69%) as a colorless oil.
1H NMR: d 7.90–7.80 (m, 2H), 7.80–7.60 (m, 2H), 4.59 (t, J ¼ 3.2 Hz,
1H), 3.85 (m, 1H), 3.75 (t, J ¼ 8.3 Hz, 2H), 3.53 (d, J ¼ 9.1 Hz, 1H), 3.50
(m, 1H), 3.07 (d, J ¼ 9.1 Hz, 1H), 1.90–1.40 (m, 8H), 1.03 (s, 3H), 1.01
(s, 3H). 13C NMR: d 168.2 (2ꢀ), 133.7 (2ꢀ), 132.2 (2ꢀ), 123.0 (2ꢀ), 99.0,
76.3, 61.8, 37.6, 34.4, 33.8, 30.5, 25.5, 24.6, 24.4, 19.3. HRMS calcd. for
C19H26NO4 (MHþ): 332.1861; found: 332.1860.
3,3-Dimethyl-4-(tetrahydropyran-2-yloxy)-butylamine (25). A mixture of
24 (14.0 g, 42.2 mmol) and absolute EtOH (85 mL) was heated to 708C for
10 min until the starting material was completely dissolved. Hydrazine mono-
hydrate (85%, 3.6 g, 71.9 mmol) was added and the reaction mixture was
heated to reflux for 1 h. The formed solid was removed by filtration and the
filtrate was concentrated. The residue was dissolved in CHCl3 (100 mL) and
washed with aqueous NaHCO3 solution (10%, 100 mL). The aqueous layer
was extracted with CHCl3 (2 ꢀ 60 mL). The combined organic layers were

378
D. C. Oniciu et al.
washed with NaHCO3 solution (10%, 100 mL), dried over MgSO4, and con-
1
centrated to give 25 (6.7 g, 79%) as a light yellow oil. H NMR: d 4.55
(t, J ¼ 3.0 Hz, 1H), 3.90–3.70 (m, 1H), 3.50 (m, 1H), 3.47 (d, J ¼ 9.0 Hz,
1H), 2.98 (d, J ¼ 9.0 Hz, 1H), 2.72 (m, 2H), 1.95–1.35 (m, 8H), 1.23
(m, 2H), 0.92 (s, 3H), 0.91 (s, 3H). 13C NMR: d 99.0, 76.6, 61.9, 43.7,
37.8, 33.8, 30.6, 25.5, 24.7 (2ꢀ), 19.4. HRMS calcd. for C11H24NO2
(MHþ): 202.1807; found: 202.1806.
(2R)-N-f2-[3,3-Dimethyl-4-(tetrahydropyran-2-yloxy)-butylcarbamoyl]-
ethylg-2,4-dihydroxy-3,3-dimethyl-butyramide (27). To a solution of 26
(9.1 g, 37.6 mmol) in a mixture of DMF/CH2Cl2 (200 mL/135 mL) were
added N-hydroxysuccinimide (4.4 g, 37.9 mmol) and N, N0-dicyclohexyl-
carbodiimide (DCC, 8.4 g, 40.7 mmol). After stirring for 3 h at room tempera-
ture, 25 (6.7 g, 33.3 mmol) was added, and stirring was continued overnight.
The reaction mixture was concentrated. The residue was dissolved in
EtOAc (300 mL), and the solution was washed with water (3 ꢀ 100 mL).
The combined organic layers were dried over MgSO4 and concentrated. The
residue was purified by column chromatography (silica, EtOAc) to give 27
1
(7.5 g, 56%) as a colorless oil. H NMR (acetone-d6): d 7.65 (br s, 1H),
7.28 (br s, 1H), 4.98 (d, J ¼ 5.2 Hz, 1H), 4.53 (s, 1H), 4.32 (m, 1H), 3.92
(d, J ¼ 4.9 Hz, 1H), 3.84–3.70 (m, 1H), 3.50–3.28 (m, 6H), 3.28–3.12
(m, 2H), 2.99 (d, J ¼ 9.0 Hz, 1H), 2.38 (t, J ¼ 6.3 Hz, 2H), 1.86–1.70
(m, 1H), 1.70–1.36 (m, 7H), 0.93 (s, 3H), 0.91 (s, 6H), 0.86 (s, 3H).
13C NMR (acetone-d6): d 174.6, 171.9, 100.0, 77.8, 77.1, 71.1, 62.6, 40.5,
39.9, 36.7, 36.4 (2ꢀ), 34.7, 31.8, 26.7, 25.4 (2ꢀ), 22.3, 21.1, 20.6. HRMS
calcd. for C20H38N2O6Na (MNaþ): 425.2622; found: 425.2652.
(2R)-2,4-Dihydroxy-N-[2-(4-hydroxy-3,3-dimethyl-butylcarbamoyl)-ethyl]-
3,3-dimethylbutyramide (6). A solution of 27 (7.3 g, 18.2 mmol) and
pyridinium p-toluenesulfonate (PPTS, 0.91 g, 3.63 mmol) in absolute EtOH
(166 mL) was stirred at 558C for 6 h and then evaporated. The residue was
dissolved in water (20 mL), and solid Na2CO3 (1.0 g, 9.43 mmol) was added.
The mixture was extracted with EtOAc (3 ꢀ 150 mL). The combined organic
layers were dried over MgSO4 and concentrated. The residue was purified by
column chromatography (silica, CHCl3–EtOH ¼ 4:1) to give 6 (2.5 g, 43%) as
1
a foam. H NMR (CD3OD): d 3.88 (s, 1H), 3.52–3.30 (m, 4H), 3.25 (s, 2H),
3.45–3.18 (m, 2H), 2.40 (t, J ¼ 6.5 Hz, 2H), 1.45 (t, J ¼ 8.5 Hz, 2H), 0.91
(s, 6H), 0.89 (s, 6H). 13C NMR (CD3OD): d 176.1, 173.5, 77.3, 71.8, 70.4, 40.5,
39.0, 36.7 (2ꢀ), 36.5, 35.6, 24.5 (2ꢀ), 21.5, 21.0. HRMS calcd. for
C15H31N2O5 (MHþ): 319.2232, found: 319.2217. [a]2D2 ¼ þ24.5 (c ¼ 0.96,
MeOH). Anal. calcd. for C15H30N2O5: C, 56.58; H, 9.50; N, 8.80, found: C,
56.16; H, 9.58; N, 8.58. (AccordingtoHPLC analysisthis sample was 96.3% pure.)
(2,6-Dimethyl-4-pentyloxyphenyl)-(4-nitrophenyl)-diazene (30). A mixture
of 28 (19.4 g, 0.141 mol), H2O (50.5 mL), and concd. HCl (50.5 mL) was

Pantolactone and Pantothenic Acid Derivatives
379
heated until a clear solution was obtained. The mixture was cooled to 08C
using an ice-salt bath, and a solution of NaNO2 (14.4 g, 0.209 mol) in H2O
(31 mL) was added dropwise at such a rate that the temperature remained
below 58C. The addition of the NaNO2 solution was stopped when a
positive reaction on KI/starch paper was observed. The obtained solution
was kept cold (08C) and added dropwise in 0.5 h to a solution of 29[7] (27 g,
0.141 mol) in AcOH (500 mL). At the beginning of the addition, the
solution of 29 was cooled to 158C with an ice bath. During the addition the
temperature dropped to 88C. Then, AcOH (500 mL) was added to the
reaction mixture under cooling in an ice bath (reaction mixture temperature
was 108C), until an almost homogeneous solution was obtained. H2O
(20 mL) was added, and the reaction mixture was set aside in the refrigerator.
After 3 d, the mixture was filtered and the obtained crystalline material was
washed with aqueous AcOH (50%, 3 ꢀ 130 mL). The filtrate and washings
were combined and set aside in the refrigerator. The residue was washed
with H2O (3 ꢀ 100 mL) and air dried to give 30 (22.0 g, 46%) as a red-
brown crystalline material. After 3 d, a second crop (6.1 g, 13%) was
obtained, using the same procedure. A third crop (2.0 g, 4 %) was isolated
after 3 d, and a fourth crop (2.1 g, 4 %) was isolated after standing for 5 d
at rt. The third and fourth crops (sticky material) were combined and recrys-
tallized from 2-propanol to give pure 30 (3.1 g, 6%). The combined yield of 30
amounted to 31.1 g (65%). Mp 98–998C. 1H NMR: d 8.32 (d, J ¼ 9.0 Hz, 2H),
7.89 (d, J ¼ 9.0 Hz, 2H), 6.67 (s, 2H), 4.01 (t, J ¼ 6.6 Hz, 2H), 2.55 (s, 6H),
1.81 (quintet, J ¼ 6.9 Hz, 2H), 1.51–1.34 (m, 4H), 0.95 (t, J ¼ 7.1 Hz, 3H).
13C NMR: d 160.8, 156.5, 147.9, 143.6, 137.2 (2ꢀ), 124.6 (2ꢀ), 122.6
(2ꢀ), 115.3 (2ꢀ), 68.1, 28.9, 28.1, 22.4, 21.1, 14.0. Anal. calcd. for
C19H23N3O3: C, 66.84; H, 6.79; N, 12.31; found: C, 67.06; H, 6.56; N, 12.23.
2,6-Dimethyl-4-pentyloxyphenylamine (31). To a mixture of sodium dithio-
nite (112 g, 0.644 mol) in EtOH (660 mL) and H2O (660 mL) was added 30
(22.0 g, 0.0644 mol) portionwise in 10 min. The reaction mixture was stirred
under reflux for 1 h, and then allowed to reach rt. The reaction mixture was
concentrated to half its volume and extracted with Et2O (1 ꢀ 600 mL,
2 ꢀ 100 mL). The combined organic layers were washed with brine
(300 mL) and evaporated. The residue was purified by column chromatography
(silica, heptane–EtOAc ¼ 4:1) to give 31 (10.7 g, 80%) as a purple, thin oil.
1H NMR: d 6.55 (s, 2H), 3.86 (t, J ¼ 6.6 Hz, 2H), 3.32 (br s, 2H) 2.15 (s, 6H),
1.73 (quintet, J ¼ 7.0 Hz, 2H), 1.47-1.35 (m, 4H), 0.92 (t, J ¼ 7.1 Hz, 3H).
13C NMR: d 151.5, 136.2 (2ꢀ), 123.1, 114.7 (2ꢀ), 68.5, 29.1, 28.2, 22.4, 17.9
(2ꢀ), 14.0. HRMS calcd. for C13H21NO (Mþ): 207.1623; found: 207.1623.
N-(2,6-Dimethyl-4-pentyloxyphenyl)-2-(1-ethoxy-ethoxy)-4-hydroxy-3,3-
dimethylbutyramide (33). A solution of 31 (4.44 g, 21.4 mmol) in dry DMF
(22 mL) was treated with NaH (60% w/w dispersion in mineral oil, 0.856 g,
21.4 mmol) and stirred for 5 min under an Ar atmosphere. Then, 32[6]

380
D. C. Oniciu et al.
(4.32 g, 21.4 mmol) was added to the mixture. The resultant mixture was
stirred overnight, poured into a mixture of H2O, ice (200 mL), and brine
(50 mL), and extracted with Et2O (2 ꢀ 100 mL). The combined organic
layers were washed with brine (3 ꢀ 100 mL) and evaporated. The residue
was purified by column chromatography (silica, heptane–EtOAc ¼ 4:1 to
2:1) to give recovered 31 (1.88 g, 42%) and 33 (two partly separated diaster-
eomers, which were combined, 5.06 g, 58%). 1H NMR (mixture of diastereo-
mers), major diastereomer: d ¼ 7.68 (s, 1H), 6.63 (s, 2H), 4.74 (q, J ¼ 5.1 Hz,
1H), 4.19 (s, 1H), 3.91 (t, J ¼ 6.5 Hz, 2H), 3.65–3.54 (m, 4H), 3.31 (dd,
J ¼ 13.7, 10.4 Hz, 1H), 2.20 (s, 6H), 1.76 (quintet, J ¼ 6.9 Hz, 2H), 1.44–
1.38 (m, 7H), 1.25 (t, J ¼ 7.1, 3H), 1.09 (s, 3H), 1.06 (s, 3H), 0.93
(t, J ¼ 7.1 Hz, 3H), peaks not covered by major diastereomer: d ¼ 7.99 (s),
6.59 (s), 4.63 (q, J ¼ 5.1 Hz), 3.98 (s), 3.77 (m), 3.50–3.37 (m), 2.21 (s),
1.16 (t, J ¼ 7.1 Hz), 0.97 (s). 13C NMR (mixture of diastereomers), major dia-
stereomer: d ¼ 170.7, 157.9, 136.2 (2ꢀ), 125.7, 114.1 (2ꢀ), 100.6, 81.1, 70.1,
67.9, 62.5, 39.9, 28.8, 28.1, 22.3, 21.6, 20.7, 20.4, 19.3 (2ꢀ), 15.0, 13.9, peaks
not covered by major diastereomer: d ¼ 171.5, 157.7, 136.3, 125.9, 113.9,
103.8, 83.5, 70.3, 63.7, 40.8, 23.4, 20.6, 19.2, 19.1, 15.3. HRMS calcd. for
C23H40NO5 (MHþ): 410.2906; found: 410.2919.
N-(2,6-Dimethyl-4-pentyloxyphenyl)-2,4-dihydroxy-3,3-dimethylbutyra-
mide (7). Compound 33 (5.00 g, 12.2 mmol) was dissolved in a mixture of
AcOH (40 mL) and H2O (10 mL), set aside for 2 h and concentrated (10 Torr,
378C). The resultant oil was concentrated from toluene (2 ꢀ 30mL) and then
crystallized from iPr2O (30 mL) to give 7 (3.56 g, 86%) as beige crystals. Mp
1
101–1038C. H NMR: d 7.99 (s, 1H), 6.62 (s, 2H), 4.23 (d, J ¼ 4.8 Hz, 1H),
3.90 (t, J ¼ 6.6 Hz, 2H), 3.70 (br s, 1H), 3.65 (dd, J ¼ 11.1, 5.7 Hz, 1H), 3.56
(dd, J ¼ 11.1, 5.7 Hz, 1H), 3.08 (br s, 1H), 2.20 (s, 1H), 1.75 (quintet,
J ¼ 6.9 Hz, 2H), 1.47–1.31 (m, 4H), 1.14 (3H), 1.04 (3H), 0.92
(t, J ¼ 7.2 Hz, 3H). 13C NMR: d 172.2, 157.9, 136.4 (2ꢀ), 125.8, 114.0 (2ꢀ),
78.2, 71.6, 68.0, 39.5, 28.9, 28.1, 22.4, 21.5, 20.3, 18.9 (2ꢀ), 14.0. HRMS
calcd. for C19H32NO4 (MHþ): 338.2331; found: 338.2337.
6-[3,5-Dimethyl-4-(4-nitrophenylazo)-phenoxy]-2,2-dimethylhexanoic
acid ethyl ester (36). A solution of 34[8] (10 g, 36.9 mmol) and 35[9]
(9.26 g, 36.9 mmol) in DMSO (50 mL) was treated with K2CO3 (5.09 g,
36.9 mmol). After 3 d, the reaction mixture was poured into a mixture of
H2O/ice (300 mL), and the resulting mixture was filtered, washed with H2O
(300 mL), and air dried. The residue was recrystallized from EtOH
(100 mL) to give 36 (11.5 g, 71%) as dark red-brown needles. Mp 89–908C.
1H NMR: d 8.34 (d, J ¼ 9.0 Hz, 2H), 7.92 (d, J ¼ 9.0 Hz, 2H), 6.67 (s, 2H),
4.13 (q, J ¼ 7.2 Hz, 2H), 4.01 (t, J ¼ 6.5 Hz, 2H), 2.56 (s, 6H), 1.79
(q, J ¼ 7.0 Hz, 2H), 1.63–1.58 (m, 2H), 1.47–1.37 (m, 2H), 1.25
(t, J ¼ 7.2 Hz, 3H), 1.20 (s, 6H). 13C NMR: d 177.8, 160.7, 156.5, 147.9,
143.7, 137.2 (2ꢀ), 124.7 (2ꢀ), 122.6 (2ꢀ), 115.3 (2ꢀ), 67.8, 60.2, 42.1,

Pantolactone and Pantothenic Acid Derivatives
381
40.3, 29.6, 25.1 (2ꢀ), 21.5, 21.1 (2ꢀ), 14.2. Anal. calcd. for C24H31N3O5: C,
65.29; H, 7.08; N, 9.52; found: C, 65.62; H, 7.01; N, 9.71.
6-(4-Amino-3,5-dimethylphenoxy)-2,2-dimethyl-hexanoic acid ethyl ester
(37). A mixture of 36 (10.75 g, 24.4 mmol) and sodium dithionite (44.9 g,
0.244 mol) in EtOH (250 mL) and H2O (250 mL) was stirred under reflux
for 1 h and concentrated to 200 mL. The mixture was extracted with Et2O
(1 ꢀ 300 mL, 2 ꢀ 100 mL), and the combined organic layers were washed
with brine (150 mL) and evaporated. The residue was purified by column
chromatography (silica, heptane–EtOAc ¼ 2:1) to give 37 (6.74 g, 90%) as
a brownish, thin oil, which solidified when kept at 2208C. A sample
(0.727 g) was further purified by recrystallization from a mixture of EtOH
and H2O (1:1) to give 37 (0.583 g) as light red-brown crystals. Mp 32–
348C. 1H NMR: d 6.54 (s, 2H), 4.11 (q, J ¼ 7.2 Hz, 2H), 3.85 (t, J ¼ 6.5 Hz,
2H), 3.23 (br s, 2H), 2.15 (s, 6H), 1.70 (quintet, J ¼ 6.9 Hz, 2H), 1.60–1.54
(m, 2H), 1.43–1.32 (m, 2H), 1.23 (t, J ¼ 7.2 Hz, 3H), 1.67 (s, 6H).
13C NMR: d 177.8, 151.3, 136.3, 123.0 (2ꢀ), 114.7 (2ꢀ), 68.2, 60.1, 42.1,
40.3, 29.8, 25.0 (2ꢀ), 21.4, 17.8 (2ꢀ), 14.1. Anal. calcd. for C18H29NO3: C,
70.32; H, 9.51; N, 4.56; found: C, 70.50; H, 9.59; N, 4.31.
6-f4-[2-(1-Ethoxyethoxy)-4-hydroxy-3,3-dimethyl-butyrylamino]-3,5-
dimethylphenoxyg-2,2-dimethyl-hexanoic acid ethyl ester (38). A solution
of 37 (5.42 g, 17.7 mmol) in dry DMF (30 mL) was treated with NaH (60% w/w
dispersion in mineral oil, 0.76 g, 19 mmol) and stirred for 30 min under N2
atmosphere. Then, 32[6] (3.57 g, 17.7 mmol) was added to the reaction
mixture, and stirring was continued for another 6 h. The resultant mixture
was poured into a mixture of ice (100 mL), H2O (100 mL), and saturated
aqueous NaHCO3 (100 mL). After 1 h, the mixture was extracted with Et2O
(3 ꢀ 100 mL). The combined organic layers were washed with brine
(3 ꢀ 75 mL) and evaporated. The residue was purified by column chromato-
graphy (silica, heptane–EtOAc ¼ 2:1) to give recovered 37 (1.59 g) and 38
(3.47 g, 39%) as a brown oil. 1H NMR (CDCl3 þ D2O) (mixture of
diastereomers ꢀ 2.5:1), major diastereomer: d ¼ 7.67 (s, 1H), 6.62 (s, 2H),
4.74 (q, J ¼ 5.1 Hz, 1H), 4.19 (s, 1H), 4.11 (q, J ¼ 7.1 Hz, 2H), 3.91
(t, J ¼ 6.5 Hz, 2H), 3.62 (q, J ¼ 7.0 Hz, 2H), 3.57 (d, J ¼ 11.4 Hz, 1H),
3.31 (d, J ¼ 11.4 Hz, 1H), 2.20 (s, 6H), 1.73 (quintet, J ¼ 6.9 Hz, 2H),
1.60–1.54 (m, 2H), 1.44 (d, J ¼ 5.1 Hz, 3H), 1.42–1.37 (m, 2H), 1.25
(t, J ¼ 7.0 Hz, 3H), 1.24 (t, J ¼ 7.0 Hz, 3H), 1.17 (s, 6H), 1.09 (s, 3H), 1.07
(s, 3H), peaks not covered by major diastereomer: d ¼ 8.02 (s), 6.60 (s),
4.65 (q, J ¼ 5.1 Hz), 2.32 (s). 13C NMR (mixture of diastereomers), major
diastereomer: d ¼ 177.8, 170.7, 157.8, 136.2 (2ꢀ), 125.8, 114.2 (2ꢀ),
100.6, 81.1, 70.1, 67.6, 62.6, 60.1, 42.0, 40.2, 39.9, 29.6, 25.0 (2ꢀ),
21.6, 21.4, 20.7, 20.4, 19.3 (2ꢀ), 15.0, 14.1, peaks not covered by major dia-
stereomer: d ¼ 171.5, 157.6, 136.4, 126.0, 114.0, 103.8, 83.6, 70.3, 63.7, 40.8,
23.5, 20.6, 19.1, 17.8, 15.3.

382
D. C. Oniciu et al.
6-[4-(2,4-Dihydroxy-3,3-dimethylbutyrylamino)-3,5-dimethylphenoxy]-
2,2-dimethylhexanoic acid ethyl ester (39). A solution of 38 (2.98 g,
5.86 mmol) in HOAc (28 mL) and H2O (7 mL) was stirred for 4 h and then
concentrated. The resultant oil was concentrated from toluene (2 ꢀ 20 mL)
and purified by column chromatography (silica, heptane–EtOAc ¼ 1:2) to
1
give 39 (1.94 g, 76%) as a light brown oil. H NMR (CDCl3 þ D2O): d 8.12
(s, 1H), 6.59 (s, 2H), 4.12 (s, 1H), 4.11 (q, J ¼ 7.1 Hz, 2H), 3.88
(t, J ¼ 6.3 Hz, 2H), 3.50 (d, J ¼ 11.4 Hz, 1H), 3.47 (d, J ¼ 11.4 Hz, 1H),
2.17 (s, 6H), 1.72 (quintet, J ¼ 7.0 Hz, 2H), 1.60–1.54 (m, 2H), 1.42–1.34
(m, 2H), 1.24 (t, J ¼ 7.1 Hz, 3H), 1.17 (s, 6H), 1.07 (s, 3H), 1.00 (s, 3H).
13C NMR: d 178.1, 172.3, 157.8, 136.4 (2ꢀ), 125.9, 114.0 (2ꢀ), 78.1, 71.6,
67.6, 60.3, 42.1, 40.3, 39.5, 29.7, 25.1 (2ꢀ), 21.5, 21.4, 20.2, 18.9 (2ꢀ),
14.2. HRMS calcd. for C24H40NO6 (MHþ): 438.2856; found: 438.2833.
2,4-Dihydroxy-N-[4-(6-hydroxy-5,5-dimethylhexyloxy)-2,6-dimethylphenyl]-
3,3-dimethylbutyramide (8). Under N2 atmosphere at 08 C, a solution of 39
(4.48 g, 10.25 mmol) in 1,2-dimethoxyethane (DME, 90 mL) was added
dropwise to a suspension of LiAlH4 (1.67 g, 43.8mmol) in DME (450mL)
over a period of 30min. After 1 h, H2O (7 mL) was added dropwise in
30min. The resultant mixture was treated with Na2SO4 (ꢀ40g) and then
filtered through a layer of Na2SO4 (1cm) in a glass filter. The residue was
washed with DME (5 ꢀ 100 mL), and the combined filtrates were concentrated.
The residue was purified by column chromatography (silica, heptane–
1
EtOAc ¼ 3:1) to give 8 as an almost colorless foam (2.67 g, 67%). H NMR
(CDCl3 þ D2O): d 8.20 (s, 1H), 6.59 (s, 2H), 4.05 (s, 1H), 3.89 (t, J ¼ 6.5 Hz,
2H), 3.44 (s, 2H), 3.25 (s, 2H), 2.14 (s, 6H), 1.71 (quintet, J ¼ 6.8 Hz, 2H),
1.43–1.33 (m, 2H), 1.30–1.23 (m, 2H), 1.02 (s, 3H), 0.97 (s, 3H), 0.85
(s, 6H). 13C NMR: d 172.8, 157.7, 136.4 (2ꢀ), 125.9, 113.9 (2ꢀ), 77.7, 71.6,
71.3, 67.8, 39.4, 38.2, 35.0, 30.0, 23.8 (2ꢀ), 21.3, 20.3 (2ꢀ), 18.8 (2ꢀ).
HRMS calcd. for C22H37NO5 (Mþ): 395.2664; found: 395.2671.
Ethyl 6-(4-[(5,5-dimethyl-2-phenyl-1,3-dioxan-4-yl)-carbonyl]-amino-3,5-
dimethylphenoxy)-2,2-dimethylhexanoate (40). To a solution of 39 (1.29 g,
2.95 mmol) and benzaldehyde dimethylacetal (0.54 mL, 3.59 mmol) in
.
CH2Cl2 (13 mL) was added TsOH H2O (10 mg, 0.053 mmol) under Ar atmos-
phere. The reaction mixture was stirred for 20 h, treated with NaHCO3 (1 g),
stirred for another 1 h, and filtered. The residue was washed with CH2Cl2
(5 ꢀ 5 mL), and the combined filtrate and washings were evaporated.
The residue was purified by column chromatography (silica, heptane–
EtOAc ¼ 4:1) and concentrated from Et2O (2 ꢀ 15 mL) to give 40 (1.47 g,
1
95%) as a slightly yellow oil. H NMR: d 7.71 (s, 1H), 7.53–7.50 (m, 2H),
7.42–7.37 (m, 3H), 6.56 (s, 2H), 5.59 (s, 1H), 4.30 (s, 1H), 4.09
(q, J ¼ 7.0 Hz, 2H), 3.87 (t, J ¼ 6.5 Hz, 2H), 3.78 (d, J ¼ 11.4 Hz, 1H),
3.72 (d, J ¼ 11.4 Hz, 1H), 2.18 (s, 6H), 1.72 (quintet, J ¼ 6.8 Hz, 2H),
1.59–1.54 (m, 2H), 1.42–1.34 (m, 2H), 1.32 (s, 3H), 1.23 (t, J ¼ 7.0 Hz,

Pantolactone and Pantothenic Acid Derivatives
383
3H), 1.17 (s, 3H), 1.16 (s, 6H). 13C NMR: d 177.5, 167.3, 157.4, 137.5, 136.1
(2ꢀ), 129.0, 128.2 (2ꢀ), 125.8 (2ꢀ), 125.6, 113.8 (2ꢀ), 101.4, 84.1, 78.7,
67.6, 60.2, 42.2, 40.4, 33.6, 29.8, 25.3 (2ꢀ), 22.1, 21.6, 19.8, 19.1 (2ꢀ),
14.4. HRMS calcd. for C31H43NO6 (Mþ): 525.3032; found: 525.3044.
6-(4-[(5,5-Dimethyl-2-phenyl-1,3-dioxan-4-yl)-carbonyl]-amino-3,5-
dimethylphenoxy)-2,2-dimethylhexanoic acid (41). Compound 40 (11.05 g,
95% pure, 20.0 mmol) was dissolved in EtOH (300 mL) by heating and H2O
.
(100 mL) followed by LiOH H2O (3.716 g, 89 mmol) were added. The
reaction mixture was refluxed for 38 h, allowed to cool to rt, and evaporated.
The residue was dissolved in H2O (200 mL) and CH2Cl2 (200 mL) and
aqueous HCl (2M, 200 mL) were added. The layers were separated and the
aqueous layer was extracted with CH2Cl2 (1 ꢀ 200 mL, 1 ꢀ 100 mL). The
combined organic layers were washed with H2O (200 mL) and saturated
aqueous NaHCO3 (200 mL), dried (Na2SO4, minimal amount), and concen-
1
trated, to give 41 (9.66 g, 97%) as a white foam. H NMR: d 7.72 (s, 1H),
7.53–7.49 (m, 2H), 7.42–7.35 (m, 3H), 6.57 (s, 2H), 5.60 (s, 1H), 4.31
(s, 1H), 3.89 (t, J ¼ 6.5 Hz, 2H), 3.78 (d, J ¼ 11.1 Hz, 1H), 3.72
(d, J ¼ 11.4 Hz, 1H), 2.17 (s, 6H), 1.73 (quintet, J ¼ 6.8 Hz, 2H), 1.61–
1.36 (m, 4H), 1.32 (s, 3H), 1.19 (s, 6H), 1.17 (s, 3H). 13C NMR: d 183.4,
167.5, 157.5, 137.5, 136.2 (2ꢀ), 129.0, 128.2 (2ꢀ), 125.9 (2ꢀ), 125.6,
114.0 (2ꢀ), 101.4, 84.1, 78.7, 67.7, 42.2, 40.2, 33.7, 29.9, 25.1 (2ꢀ), 22.1,
21.6, 19.8, 19.1 (2ꢀ). HRMS calcd. for C29H29NO6Na (MNaþ): 520.2660;
found: 520.2661.
6-f4-[(2,4-Dihydroxy-3,3-dimethylbutanoyl)-amino]-3,5-dimethylphenoxyg-
2,2-dimethylhexanoic acid (9). Under N2 atmosphere at 358C, Pd on C
(5% w/w, ꢀ0.4 g) was added to a solution of 41 (8.96 g, 18.0 mmol) in
EtOH (200 mL). The reaction mixture was stirred for 2 d under hydrogen
atmosphere and filtered. The filtrate was concentrated to give 9 (7.14 g,
96%) as hard, white foam. An analytical sample was obtained by crystalliza-
1
tion from iPr2O (0.11 g from 0.21 g). Mp 130–1328C. H NMR (CD3OD): d
6.63 (s, 2H), 4.09 (s, 1H), 3.92 (t, J ¼ 6.3 Hz, 2H), 3.56 (d, J ¼ 11.0 Hz, 1H),
3.47 (d, J ¼ 11.0 Hz, 1H), 2.18 (s, 6H), 1.72 (quintet, J ¼ 6.8 Hz, 2H), 1.61–
1.38 (m, 4H), 1.17 (s, 6H), 1.06 (s, 3H), 1.05 (s, 3H). 13C NMR (CD3OD): d
182.0, 175.6, 159.4, 138.1 (2ꢀ), 128.1, 115.1 (2ꢀ), 77.9, 70.7, 68.9, 43.2,
41.7, 40.8, 31.0, 25.8 (2ꢀ), 22.9, 21.6, 21.3, 19.2 (2ꢀ). Anal. calcd. for
C22H35NO6: C, 64.52; H, 8.61; N, 3.42; found: C, 64.25; H, 8.99; N, 3.47.
HRMS calcd. for C22H36NO6 (MHþ): 410.2543; found: 410.2514.
[4-(4-Benzyloxybutoxy)-2,6-dimethylphenyl]-(4-nitrophenyl)-diazene (43).
To a solution of 42 (18.3 g, 75.2 mmol) and 34[8] (19.59 g, 72.3 mmol) in
DMSO (100 mL) was added K2CO3 (10.4 g, 75.2 mmol). The mixture was
stirred overnight and then poured into a mixture of ice and H2O (300 mL).
The amorphous solid material was filtered, washed with H2O (4 ꢀ 75 mL),

384
D. C. Oniciu et al.
and air dried (30.3 g). The residue (28.3 g) was purified by column chromato-
graphy (silica, heptane–EtOAc ¼ 12:1) to give 43 (18.4 g, 63%) as a crystal-
line solid. An analytical sample of 43 (0.682 g, red-brown needles) was
obtained after recrystallization of 0.757 g from iPrOH (50 mL). Mp 68–
1
69.58C. H NMR: d 8.34 (d with fine splitting, J ¼ 9 Hz, 2H), 7.91 (d with
fine splitting, J ¼ 9 Hz, 2H), 7.36–7.25 (m, 5H), 6.67 (s, 2H), 4.53 (s, 2H),
4.05 (t, J ¼ 6.2 Hz, 2H), 3.56 (t, J ¼ 6.0 Hz, 2H), 2.56 (s, 6H), 1.97–1.88
(m, 2H), 1.86-1.76 (m, 2H). 13C NMR: d 160.7, 156.6, 148,0, 143.7, 138.5,
137.2 (2ꢀ), 128.4 (2ꢀ), 127.62 (2ꢀ), 127.56, 124.7 (2ꢀ), 122.7 (2ꢀ),
115.3 (2ꢀ), 72.9, 69.8, 67.8, 26.3, 26.1, 21.1 (2ꢀ). Anal. calcd. for
C25H27N3O4: C, 69.27; H, 6.28; N, 9.69; found: C, 69.29; H, 6.17; N, 9.59.
4-(4-Benzyloxybutoxy)-2,6-dimethylphenylamine (44). A mixture of 43
(18.35 g, 42.4 mmol) and sodium dithionite (73.7 g, 0.424 mol) in EtOH
(460 mL) and H2O (460 mL) was stirred under reflux for 1.5 h. An almost
colorless mixture was obtained, which was allowed to cool to rt, concentrated
to approximately 450-mL volume, and then extracted with Et2O (1 ꢀ 300 mL,
2 ꢀ 100 mL). The combined organic layers were washed with brine (100 mL),
and evaporated. The residue was purified by column chromatography (silica,
1
heptane–EtOAc ¼ 4:1) to give 44 (10.6 g, 84%) as a brown oil. H NMR: d
7.33–7.26 (m, 5H), 6.54 (s, 2H), 4.50 (s, 2H), 3.88 (t, J ¼ 5.9 Hz, 2H), 3.52
(t, J ¼ 5.9 Hz, 2H), 3.17 (br s, 2H), 2.15 (s, 6H), 1.84–1.77 (m, 4H).
13C NMR: d 151.4, 138.6, 136.3, 128.3 (2ꢀ), 127.6 (2ꢀ), 127.4, 123.1
(2ꢀ), 114.7 (2ꢀ), 72.8, 70.0, 68.2, 26.35, 26.27, 17.9 (2ꢀ). HRMS calcd.
for C19H25NO2 (Mþ): 299.1885; found: 299.1881.
N-[4-(4-Benzyloxy-butoxy)-2,6-dimethyl-phenyl]-2-(1-ethoxy-ethoxy)-4-
hydroxy-3,3-dimethyl-butyramide (45).
A solution of 44 (1.00 g,
3.34 mmol) in dry DMF (4 mL) was treated with NaH (60% w/w dispersion
in mineral oil, 0.134 g, 3.35 mmol) under Ar atmosphere. Then, 32[6]
(0.676 g, 3.34 mmol) was added to the reaction mixture and stirring was
continued for 16 h. The resultant mixture was poured into a mixture of H2O
and ice (50 mL) and extracted with Et2O (3 ꢀ 20mL). The combined organic
layers were washed with brine (3 ꢀ 20mL) and evaporated. The residue was
purified by column chromatography (silica, heptane–EtOAc ¼ 2:1 to 1:1) to
give recovered 44 (0.51 g) and 45 (0.742 g, 44%) as a light brown oil.
1H NMR (CDCl3 þ D2O) (mixture of diastereomers ꢀ 2:1), major diastereomer:
d ¼ 7.66 (br s, 1H), 7.30–7.20 (m, 5H), 6.59 (s, 2H), 4.71 (q, J ¼ 5.1 Hz, 1H),
4.49 (s, 2H), 4.17 (s, 1H), 3.92 (t, J ¼ 6.2 Hz, 2H), 3.60 (q, J ¼ 6.9 Hz, 2H),
3.55 (d, J ¼ 11.4Hz, 1H), 3.51 (t, J ¼ 6.0Hz, 2H), 3.29 (d, J ¼ 11.4Hz, 1H),
2.18 (s, 6H), 1.90–1.71 (m, 4H), 1.42 (d, J ¼ 5.1 Hz, 3H), 1.24 (t, J ¼ 7.1 Hz,
3H), 1.08 (s, 3H), 1.06 (s, 3H), peaks not covered by major diastereomer:
d ¼ 7.98 (br s), 6.57 (s), 4.62 (q, J ¼ 5.0 Hz), 3.98 (s), 3.40 (d, J ¼ 11.7Hz),
2.21 (s), 1.40 (d, J ¼ 4.8 Hz), 1.17 (t, J ¼ 7.1 Hz), 0.98 (s). 13C NMR (mixture
of diastereomers ꢀ 2:1), major diastereomer: d 170.4, 157.6, 138.3, 136.1

Pantolactone and Pantothenic Acid Derivatives
385
(2ꢀ), 128.2 (2ꢀ), 127.4 (2ꢀ), 127.3, 125.7, 114.1 (2ꢀ), 100.7, 81.3, 72.9, 70.3,
69.9, 67.71, 62.8, 40.2, 26.5, 26.3, 21.9, 21.0, 20.7, 19.6 (2ꢀ), 15.3, peaks not
covered by major diastereomer: d ¼ 171.2, 157.4, 136.3, 125.9, 113.9, 103.9,
83.7, 70.5, 67.67, 63.9, 41.1, 23.9, 19.4, 15.6.
2,4-Dihydroxy-N-[4-(4-hydroxybutoxy)-2,6-dimethyl-phenyl]-3,3-dime-
thylbutyramide (46). Under N2 atmosphere, Pd on C (10% w/w, 0.070 g) was
added to a solution of 45 (0.732 g, 1.46 mmol) in AcOH (8 mL) and H2O
(2 mL). The reaction mixture was stirred for 16 h under an H2 atmosphere
and filtered. The residue was washed with a mixture of HOAc and H2O
(1:1, 4 ꢀ 5 mL), and the combined filtrate and washings were evaporated.
The residue was purified by column chromatography (silica, CH2Cl2–
MeOH ¼ 9:1) to give 46 (0.350 g, 71%) as a colorless oil. Crystallization
from EtOAc/iPr2O afforded 46 (0.312 g, 63%) as colorless crystals. Mp
101–102.58C. 1H NMR (DMSO-d6): d 8.89 (s, 1H), 6.62 (s, 2H), 5.60
(d, J ¼ 5.9 Hz, 1H), 4.52 (t, J ¼ 5.5 Hz, 1H), 4.43 (t, J ¼ 5.2 Hz, 1H), 3.93
(s, 1H), 3.93 (t, J ¼ 5.7 Hz, 2H), 3.48–3.37 (m, 3H), 3.26 (dd, J ¼ 10.4,
5.2 Hz, 1H), 2.11 (s, 6H), 1.76–1.67 (m, 2H). 1.59–1.50 (m, 2H), 0.94
(s, 3H), 0.93 (s, 3H). 13C NMR (DMSO-d6): d 171.5, 156.2, 136.0 (2ꢀ),
127.6, 113.0 (2ꢀ), 75.4, 68.0, 67.2, 60.3, 39.2, 29.0, 25.5, 21.3, 20.5, 18.8
(2ꢀ). Anal. calcd. for C18H29NO5: C, 63.69; H, 8.61; N, 4.13; found: C,
63.96; H, 8.68; N, 3.85.
5,5-Dimethyl-2-phenyl-[1,3]-dioxane-4-carboxylic acid methyl ester (48).
To a solution of 11 (20.4 g, 156 mmol) and benzaldehyde dimethylacetal
.
(40 mL, 265 mmol) in 1,4-dioxane (100 mL) was added TsOH H2O (0.606 g,
3.2 mmol). The reaction mixture was stirred for 2 d, treated with NaHCO3
(5.1 g), and stirred for another 3 h. Et2O (250 mL) was added, and the
resulting mixture was washed successively with a mixture of saturated
aquous NaHCO3 solution (100 mL), H2O (200 mL), and brine (100 mL).
The organic layer was evaporated, and the residue was purified by column
chromatography (silica, heptane–EtOAc ¼ 7:1) to give a white solid
(15.5 g). This solid was recrystallized from heptane (30 mL) to give 48
1
(14.0 g, 36%) as colorless crystals. Mp 86.5–888C. H NMR: d 7.54–7.50
(m, 2H), 7.38–7.29 (m, 3H), 5.46 (s, 1H), 4.23 (s, 1H), 3.73 (s, 3H), 3.72
(d, J ¼ 11.4 Hz, 1H), 3.64 (d, J ¼ 11.4 Hz, 1H), 1.18 (s, 3H), 0.96 (s, 3H).
13C NMR: d 168.9, 137.5, 128.9, 128.1 (2ꢀ), 126.1 (2ꢀ), 101.4, 83.7, 78.1,
51.5, 32.7, 21.5, 19.4. Anal. calcd. for C14H18O4: C, 67.18; H, 7.25; found:
C, 67.18; H, 7.23.
5,5-Dimethyl-2-phenyl-[1,3]dioxane-4-carboxylic acid [4-(4-benzyloxy-
butoxy)-2,6-dimethylphenyl]-amide (50). A mixture of 48 (9.87 g, 39.5 mmol),
.
LiOH H2O (1.99 g, 47.4 mmol), H2O (6 mL), and MeOH (200 mL) was
stirred at 408C for 2 d. The reaction mixture was evaporated, and the
residue was evaporated from toluene (2 ꢀ 100 mL). Toluene (300 mL) was

386
D. C. Oniciu et al.
added, and the mixture was concentrated to ꢀ200-mL volume. The resultant
solution was treated with SOCl2 (4.0 mL, 54 mmol) and stirred at rt for 1 h.
Then, the mixture containing 49 was cooled to 2408C and treated with
pyridine (40 mL). The cooling bath was removed, and immediately a
solution of 44 (10.62 g, 35.5 mmol) in pyridine (40 ml) was added. The
reaction mixture was stirred for 45 min and then poured into a H2O/ice
mixture (1 L). After 1 h, the obtained mixture was separated, and the H2O
layer was extracted with toluene (2 ꢀ 200 mL). The combined organic
layers were washed with a mixture of aqueous HCl (4M, 350 mL) and ice
(150 mL), brine (150 mL), and saturated aqueous NaHCO3 solution
(150 mL) and evaporated. The remaining oil (19.6 g) was purified by
column chromatography (silica, heptane–EtOAc ¼ 3:2) to give, after evapor-
ation from Et2O (100 mL), 50 (13.9 g, 76%) as a dark yellow oil. 1H NMR: d
7.70 (br s, 1H), 7.53–7.50 (m, 2H), 7.41–7.36 (m, 3H), 7.31–7.22 (m, 5H),
6.56 (s, 2H), 5.59 (s, 1H), 4.49 (s, 2H), 4.30 (s, 1H), 3.91 (t, J ¼ 6.0 Hz,
2H), 3.79 (d, J ¼ 11.3 Hz, 1H), 3.72 (d, J ¼ 11.3 Hz, 1H), 3.51
(t, J ¼ 6.0 Hz, 2H), 2.17 (s, 6H), 1.89–1.71 (m, 4H). 1.31 (s, 3H), 1.17
(s, 3H). 13C NMR: d 167.3, 157.4, 138.3, 137.6, 136.2 (2ꢀ), 129.0, 128.2
(2ꢀ), 128.1 (2ꢀ), 127.4 (2ꢀ), 127.3, 125.9 (2ꢀ), 125.7, 113.9 (2ꢀ), 101.4,
84.1 78.7, 72.9, 69.9, 67.7, 33.7, 26.5, 26.3, 22.1, 19.8, 19.1 (2ꢀ). HRMS
calcd. for C32H39NO5 (Mþ): 517.2828; found: 517.2829.
2,4-Dihydroxy-N-[4-(4-hydroxybutoxy)-2,6-dimethyl-phenyl]-3,3-dimethyl-
butyramide (46). Under N2 atmosphere, Pd on C (10% w/w, 1.0 g) was added
to a solution of 50 (13.5 g, 26.2 mmol) in EtOH (300 mL). (In some instances
the reaction ceased. Most likely the catalyst became inactive because of the
presence of small amounts of impurities. In those cases, the reaction
mixture was filtered and treated again with fresh catalyst). The reaction
mixture was stirred for 3 d under 5 bar H2 atmosphere and filtered. The
residue was washed with EtOH (4 ꢀ 50 mL), and the combined filtrate and
washings were concentrated and concentrated from toluene (2 ꢀ 100 mL).
The remaining oil was crystallized from a mixture of EtOAc and iPr2O to
give 46 (10.8 g, 84%) as yellowish crystals. Mp 101–1038C.
2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [4-(4-hydroxybutoxy)-
2,6-dimethylphenyl]-amide (47). A mixture of 46 (7.31 g, 21.6 mmol) in
2,2-dimethoxypropane (10 mL, 81 mmol) and 1,4-dioxane (100 mL) was
.
treated with TsOH H2O (0.200 g, 1.05 mmol). After 1.5 h, NaHCO3 (2.5 g)
was added, and the resultant mixture was set aside over the weekend. The
mixture was filtered and the filtrate was concentrated. The residue was
dissolved in EtOAc (100 mL) and filtered through a layer of silica in a glass
filter. The residue was eluted with EtOAc (5 ꢀ 10 mL), and the filtrate and
eluates were combined and concentrated to ꢀ 30 mL. Heptane was added to
the resultant solution until spontaneous crystallization started. The obtained
crystalline mass was filtered, washed with a mixture of heptane and EtOAc

Pantolactone and Pantothenic Acid Derivatives
387
(10:1, 3 ꢀ 20 mL), and air dried to give 47 (5.45 g, 67%) as colorless crystals.
The mother liquor, which mainly consisted of less polar products, was concen-
trated and dissolved in a mixture of HOAc and H2O (4:1, 10 mL). After
15 min, NaOAc (2.5 g) and H2O (20 mL) were added, and after another
15 min, the formed crystalline material was filtered, washed with H2O
(3 ꢀ 10 mL), and air dried. The remaining solid was recrystallized from a
mixture of iPrOH and H2O to give another crop of 47 (2.09 g, 26%) as
1
colorless crystals. Mp 127–1288C. H NMR: d 7.77 (s, 1H), 6.62 (s, 2H),
4.29 (s, 1H), 3.97 (t, J ¼ 6.0 Hz, 2H), 3.76 (d, J ¼ 11.7 Hz, 1H), 3.70
(t, J ¼ 6.1 Hz, 2H), 3.35 (d, J ¼ 11.7 Hz, 1H), 2.20 (s, 6H), 1.90–1.82
(m, 2H), 1.78–1.69 (m, 2H), 1.52 (s, 3H), 1.50 (s, 3H), 1.19 (s, 3H), 1.11
(s, 3H). 13C NMR: d 168.3, 157.5, 136.4 (2ꢀ), 126.2, 114.0 (2ꢀ), 99.3,
77.6, 71.7, 67.8, 62.4, 33.3, 29.51, 29.46, 25.8, 22.1, 19.4, 18.9 (2ꢀ), 18.8.
Anal. calcd. for C21H33NO5: C, 66.46; H, 8.76; N, 3.69; found: C, 66.42; H,
8.92; N, 3.65.
O-(2,3,4-Tri-O-benzyl-b-D-xylopyranosyl)-trichloroacetimidate (51).[12]
A mixture of 2,3,4-tri-O-benzyl-a-D-xylopyranose[15] (32.8 g, 78.1 mmol),
trichloroacetonitrile (30 mL, 299 mmol), and powdered K2CO3 (32.8 g,
238 mmol) in CH2Cl2 (160 mL) was stirred for 6 h and then filtered through
a layer of kieselguhr. The residue was washed with CH2Cl2 and the
combined filtrate and washings were evaporated. The remaining oil was
crystallized from iPr2O to give 51 (24.1 g, 55%) as colorless needles. Mp
1
81.5–838C. H NMR: d 8.69 (s, 1H), 7.30 (m, 15H), 5.81 (m, 1H), 4.89
(d, J ¼ 11.0 Hz, 1H), 4.85 (s, 2H), 4.75 (d, J ¼ 11.0 Hz, 1H), 4.72
(d, J ¼ 11.7 Hz, 1H), 4.43 (d, J ¼ 11.7 Hz, 1H), 4.02 (m, 1H), 3.69 (m, 3H),
3.45 (m, 1H). 13C NMR: d 160.6, 138.0, 137.48, 137.45, 128.0 (2ꢀ), 127.92
(2ꢀ), 127.91 (2ꢀ), 127.49 (2ꢀ), 127.48, 127.43 (2ꢀ), 127.42 (2ꢀ), 127.3,
127.2, 98.5, 90.6, 82.7, 79.8, 76.4, 75.1, 74.6, 72.9, 64.3. Anal. calcd. for
C28H38Cl3NO5: C, 59.54; H, 5.00; N, 2.48; found: C, 59.54; H, 5.00; N,
2.24. [a]2D0: þ22.5 (c ¼ 1.02, CHCl3), [a] : þ23.0 (c ¼ 1.02, CHCl3).
20
578
2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid f4-[4-(2,3,4-tri-O-
benzyl-D-xylopyranosyl)-butoxy]-2,6-dimethyl-phenylg-amide (52). To a
mixture of 51 (13.6 g, 24.0 mmol), and 47 (7.00 g, 18.5 mmol) in Et2O
(140 mL) and 1,2-dichloroethane (70 mL) was added TMSOTf (0.30 mL,
1.17 mmol) under N2 atmosphere at 2788C. After 45 min, NaHCO3 (5 g)
was added, and the reaction mixture was allowed to reach rt. The reaction
mixture was diluted with Et2O (100 mL), washed with a mixture of brine
(100 mL) and water (75 mL), and concentrated. The residue was purified by
column chromatography (silica, heptane–EtOAc ¼ 3:1) to give 52 (8.20 g,
57%, a:b ꢀ 2:1) as a colorless oil. Continued elution gave another batch of
52 (7.26 g) contaminated with 2,2,2-trichloroacetamide, which was partly
removed via crystallization from a mixture of CH2Cl2 and heptane. The
mother liquor was evaporated and the residue was purified by column

388
D. C. Oniciu et al.
chromatography (silica, heptane–EtOAc ¼ 3:1) to give another crop of 52
1
(3.90 g, 27%, 52a:52b ꢀ 2:1) as a colorless oil. 52a: H NMR: d 7.76 (br
s, 1H), 7.40–7.25 (m, 15H), 6.63 (s, 2H), 4.91 (d, J ¼ 10.8 Hz, 1H), 4.84
(d, J ¼ 10.8 Hz, 1H), 4.76 (d, J ¼ 10.8 Hz, 1H), 4.72–4.57 (m, 4H), 4.27
(s, 1H), 3.94–3.86 (m, 3H), 3.73 (d, J ¼ 11.7 Hz, 1H), 3.77–3.64 (m, 1H),
3.62–3.52 (m, 3H), 3.47–3.41 (m, 2H), 3.33 (d, J ¼ 11.7 Hz, 1H) 2.18
(s, 6H), 1.89-1.76 (m, 4H) 1.51 (s, 3H), 1.49 (s, 3H), 1.18 (s, 3H), 1.10
(s, 3H). 13C NMR: d 167.9, 157.3, 138.7, 138.1, 138.0, 136.1 (2ꢀ), 128.16
(2ꢀ), 128.14 (2ꢀ), 128.07 (2ꢀ), 127.74 (2ꢀ), 127.69 (2ꢀ), 127.56 (2ꢀ),
125.86, 113.8 (2ꢀ), 99.1, 96.9, 81.3, 79.8, 78.1, 77.5, 75.7, 73.5, 73.2, 71.7,
67.7, 67.6, 60.0, 33.5, 29.7, 26.32, 26.28, 22.3, 19.6, 19.1 (2ꢀ), 19.0.
(Three tertiary aromatic signals of the a-anomer fell in the region d 128.2–
127.2. They could not be assigned because of the presence of aromatic
signals of the b-isomer). 52b: 1H NMR: (visible signals) d 6.60, 4.32
(d, J ¼ 7.5 Hz), 3.22–3.15 (m). 13C NMR: (visible signals) d 157.25, 138.4,
138.2, 137.9, 104.0, 83.7, 81.9, 77.8, 75.5, 74.9, 73.3, 69.4, 67.4, 63.9, 26.6,
26.1. 52a:52b ꢀ 2:1: HRMS calcd. for C47H59NO9 (MNaþ): 804.4088;
found 804.4084. [a]2D0: þ26.9 (c ¼ 0.88, CH2Cl2).
2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid f4-[4-(D-xylopyrano-
syl)-butoxy]-2,6-dimethylphenylg-amide (53). Under N2 atmosphere, Pd
on C (10% w/w, 0.50 g, 0.47 mmol) and CaCO3 (1.70 g, 17.0 mmol) were
added to a solution of 52 (7.85 g, 10.1 mmol, 52a:52b ꢀ 2:1) in EtOH
(140 mL). The reaction flask was flushed with H2, and the reaction mixture
was stirred under a H2 atmosphere for 4 h. (In some instances the reaction
ceased. Most likely the catalyst became inactive because of the presence of
small amounts of impurities. In those cases, the reaction mixture was
filtered and treated again with fresh catalyst). The reaction mixture was
treated with NaHCO3 (1.00 g, 11.9 mmol), stirred for 0.5 h, and filtered. The
residue was washed with EtOH (4 ꢀ 20 mL), and the combined filtrate and
washings were evaporated. The residue was purified by column chro-
matography (silica, CH2Cl2–MeOH ¼ 9:1) to give 53 (4.49 g, 87%,
1
53a:53b ꢀ 2:1) as a foam. 53a: H NMR (DMSO-d6 þ D2O): d 8.66 (br s,
1H), 6.60 (s, 2H), 4.58 (d, J ¼ 3.6 Hz, 1H), 4.18 (s, 1H), 3.92 (br q,
J ¼ 5.6 Hz, 2H), 3.80–3.44 (m, 3H), 3.41–3.15 (m, 6H), 2.05 (s, 6H),
1.84–1.61 (m, 4H), 1.41 (s, 3H), 1.40 (s, 3H), 1.06 (s, 3H), 0.94 (s, 3H).
13C NMR: d 168.5, 157.2, 136.3 (2ꢀ), 125.7, 113.9 (2ꢀ), 99.2, 98.4, 77.4,
74.5, 72.0, 71.6, 69.9, 68.0, 67.4, 61.7, 33.4, 29.6, 26.28, 26.0, 22.3, 19.5,
19.0 (2ꢀ), 18.9. (The presence of 53a as a mixture of two diastereomers
resulted in slightly different chemical shifts for the resonances of correspond-
1
ing carbon atoms in the separate diastereomers). 53b: H NMR (DMSO-
d6 þ D2O): (visible signals) d 4.08 (d, J ¼ 7.5 Hz), 3.09 (t, J ¼ 8.7 Hz),
3.02 (t, J ¼ 10.8 Hz), 2.93 (dd, J ¼ 8.2, 7.5 Hz). 13C NMR: (visible signals)
d 168.2, 157.3, 136.1, 125.6, 102.8, 75.7, 72.7, 69.5, 69.2, 65.0, 26.33, 25.9.

Pantolactone and Pantothenic Acid Derivatives
389
53a:53b ꢀ 2:1: HRMS calcd. for C26H42NO9 (MHþ): 512.2859; found
512.2842. [a]2D0: þ33.7 (c ¼ 0.73, EtOAc).
2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid f4-[4-(2,3,4-tri-O-acetyl-
D-xylopyranosyl)-butoxy]-2,6-dimethylphenylg-amide (54). To a solution
of 53 (5.74 g, 11.2 mmol, 53a:53b ꢀ 2:1) in pyridine (15 mL) was added
Ac2O (10 mL) at 08C. After 30 min, the reaction mixture was allowed to
warm to rt, and stirring was continued for 16 h. The reaction mixture was
poured into a mixture of H2O and ice (200 mL), and, after 2 h, extracted
with CH2Cl2 (2 ꢀ 100 mL). The combined organic layers were washed with
aqueous HCl (2M, 200 mL) and saturated aqueous NaHCO3 (100 mL), and
evaporated. The residue was purified by repeated column chromatography
(silica, heptane–EtOAc ¼ 1:1) to give 54 (4.10 g, 57%, 54a:54b ꢀ 12:1),
54 (1.39 g, 20%, 54a:54b ꢀ 1:1), and 54 (1.25 g, 17%, 54a:54b ꢀ 1:8).
1
54a: H NMR: d 7.74 (br s, 1H), 6.59 (s, 2H), 5.47 (t, J ¼ 9.8 Hz, 1H),
4.99 (d, J ¼ 3.6 Hz, 1H), 4.94 (ddd, J ¼ 10.5, 9.5, 5.9 Hz, 1H), 4.79 (dd,
J ¼ 10.2, 3.6 Hz, 1H), 4.27 (s, 1H), 3.93 (t, J ¼ 6.0 Hz, 2H), 3.80–3.72
(m, 3H), 3.61 (t, J ¼ 10.7 Hz, 1H), 3.45 (dt, J ¼ 9.9, 6.0 Hz, 1H), 3.33
(d, J ¼ 11.4 Hz, 1H), 2.19 (s, 6H), 2.04 (s, 3H), 2.02 (s, 6H), 1.87–1.72
(m, 4H), 1.51 (s, 3H), 1.50 (s, 3H), 1.19 (s, 3H), 1.10 (s, 3H). 13C NMR: d
169.9, 169.64, 169.59, 167.9, 157.2, 136.2 (2ꢀ), 126.0, 113.8 (2ꢀ), 99.2,
95.6, 77.6, 71.7, 71.1, 69.7, 69.4, 68.1, 67.5, 58.4, 33.5, 29.7, 26.26, 26.21,
22.3, 20.94, 20.89, 20.85, 19.6, 19.1 (2ꢀ), 19.0. 54a:54b ꢀ 12:1: Anal.
calcd. for C32H47NO12: C, 60.27; H, 7.43; N, 2.20; found: C, 60.21; H,
1
7.57; N, 2.14. [a]2D0: þ65 (c ¼ 0.73, EtOAc). 54b: H NMR: d 7.74 (br s,
1H), 6.58 (s, 2H), 5.14 (t, J ¼ 9.8 Hz, 1H), 4.97–4.88 (m, 2H), 4.46
(d, J ¼ 6.6 Hz, 1H), 4.27 (s, 1H), 4.10 (dd, J ¼ 11.7, 5.1 Hz, 1H), 3.93–
3.83 (m, 3H), 3.74 (d, J ¼ 11.7 Hz, 1H), 3.56–3.46 (m, 1H), 3.35 (dd,
J ¼ 11.7, 9.2 Hz, 1H), 3.33 (d, J ¼ 11.4 Hz, 1H) 2.19 (s, 6H), 2.04 (s, 6H),
2.03 (s, 3H), 1.84–1.70 (m, 4H), 1.51 (s, 3H), 1.50 (s, 3H), 1.19 (s, 3H),
1.10 (s, 3H). 13C NMR: d 169.7, 169.4, 169.0, 167.9, 157.2, 136.1 (2ꢀ),
125.9, 113.8 (2ꢀ), 100.5, 99.1, 77.5, 71.7, 71.4, 70.8, 69.1, 68.9, 67.4, 62.0,
33.4, 29.7, 26.3, 25.9, 22.3, 20.88, 20.85 (2ꢀ), 19.6, 19.1 (2ꢀ), 19.0.
54a:54b ꢀ 1:8: Anal. calcd. for C32H47NO12: C, 60.27; H, 7.43; N, 2.20;
found: C, 60.25; H, 7.59; N, 2.13. [a]2D0: 221 (c ¼ 1.10, EtOAc).
2,4-Dihydroxy-N-f4-[4-(2,3,4-tri-O-acetyl-a-D-xylopyranosyl)-butoxy]-2,6-
dimethylphenylg-3,3-dimethylbutyramide (10). A mixture of AcOH (32 mL)
and H2O (8 mL) was added to 54 (3.70 g, 5.76 mmol, 54a:54b ꢀ 12:1). After
24 h, the reaction mixture was concentrated, and the resultant foam was
concentrated from toluene (3 ꢀ 20 mL). The residue was purified by column
chromatography (silica, CH2Cl2–MeOH ¼ 19:1) to give 10 (3.26 g, 95%,
10a:10b ꢀ14:1) as a foam. 10a: 1H NMR (CDCl3 þ D2O): d 8.06 (br s, 1H),
6.60 (s, 2H), 5.46 (t, J ¼ 9.8 Hz, 1H), 4.99 (d, J ¼ 3.6 Hz, 1H),
4.94 (dt, J ¼ 9.9, 5.9 Hz, 1H), 4.79 (dd, J ¼ 9.9, 3.6 Hz, 1H), 4.15 (s, 1H),

390
D. C. Oniciu et al.
3.93 (t, J ¼ 6.0 Hz, 2H), 3.80–3.71 (m, 2H), 3.61 (t, J ¼ 10.4 Hz, 1H), 3.56
(d, J ¼ 10.5 Hz, 1H), 3.50 (d, J ¼ 10.5 Hz, 1H), 3.44–341 (m, 1H), 2.18
(s, 6H), 2.04 (s, 3H), 2.03 (s, 6H), 1.86–1.75 (m, 4H), 1.10 (s, 3H), 1.02
(s, 3H). 13C NMR: d 171.6, 169.9, 169.7, 169.6, 157.4, 136.2 (2ꢀ), 125.9,
113.9 (2ꢀ), 95.6, 78.2, 71.6, 71.1, 69.7, 69.5, 68.1, 67.5, 58.3, 39.6, 26.3,
26.2, 21.8, 20.95, 20.90, 20.86, 20.4, 19.1 (2ꢀ). 10a:10b ꢀ14:1: Anal.
calcd. for C29H43NO12: C, 58.28; H, 7.25; N, 2.34; found: C, 58.22; H, 7.23;
N, 2.40. [a]2D0: þ64.9 (c ¼ 0.69, EtOAc).
ACKNOWLEDGMENTS
The authors thank Helene I. V. Amatdjais-Groenen and Peter M. van Galen
from the Catholic University of Nijmegen for performing the HRMS and
CHN measurements. The authors also acknowledge Janell Lutostanski,
Michelle Washburn, Martha Humes, Terri Bancero, and LeighAnn
Jankowski for collection and analysis of biological samples.
REFERENCES
1. (a) Sirtori, C. R.; Galli, C.; Franeschini, G. Eur. J. Clin. Inv. 2003, 23, 686–689;
(b) Russell, J. C.; Amy, R. M.; Graham, S. E.; Dolphin, P. J.; Wood, G. O.;
Bar-Tana, J. Arterioscler. Thromb. Vasc. Biol. 1995, 15, 918–923;
(c) Cramer, C. T.; Goetz, B.; Hopson, K. L.; Fici, G. J.; Ackermann, R. M.;
Brown, S. C.; Bisgaier, C. L.; Rajeswaran, W. G.; Oniciu, D. C.; Pape, M. E.
J. Lipid Res. 2004, 45, 1289–1301; (d) Bisgaier, C. L.; Pape, M. E. Curr.
Pharm. Des. 1998, 4, 53–70; (e) Sirtori, C. R.; Donati, C. Pantethine: A Review
of Experimental and Clinical Studies on Its Mode of Action and Efficacy in the
Treatment of Hyperlipidemia. In: Pharmacology Control of Hyperlipidemia;
Sirtori, C. R., Donati, C., Eds; J.R. Prous Publ.: Madrid, 1986, pp. 401–407;
(f) Dasseux, J.-L. H.; Oniciu, D. C U.S. Pat. Appl. 20030236213, December 25,
2003. U.S. Pat. Appl. 10/410,444, filed April 10, 2003.; (g) Dasseux, J.-L. H.;
Oniciu, D. C U.S. Pat. Appl. 20030236212, December 25, 2003. U.S. Pat. Appl.
10/410,262, filed April 10, 2003.
2. Aquino, F.; Pauling, H.; Walther, W.; Plattner, D. A.; Bonrath, W. Synthesis 2000,
5, 731–737.
3. Drouin, J.; Leyendecker, F.; Conia, J. M. Tetrahedron 1980, 36, 1195–1201.
4. Kuwahara, M.; Kawano, Y.; Kajino, M.; Ashida, Y.; Miyake, A. Chem. Pharm.
Bull. 1997, 45, 1447–1457.
5. Yang, J.; Mueller, R.; Pop, E.; Dasseux, J.-L. H.; Oniciu, D. Org. Prep. Proced.
Int. 2004, 36, 587–596.
6. Dujardin, G.; Rossignol, S.; Brown, E. Synthesis 1998, 5, 763–770.
7. de Benneville, P. L.; Bock, L. H. U.S. patent 2499214, 1947.
8. Smith, L. I.; Irwin, W. B. J. Am. Chem. Soc. 1941, 63, 1036–1043.
9. Ackerley, N.; Brewster, A. G.; Brown, G. R.; Clarke, D. S.; Foubister, A. J.;
Griffin, S. J.; Hudson, J. A.; Smithers, M. J.; Whittamore, P. R. O. J. Med.
Chem. 1995, 38, 1608–1628.
10. Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem. BioChem. 1994, 50, 21–123.

Pantolactone and Pantothenic Acid Derivatives
391
11. Wegmann, B.; Schmidt, R. R. J. Carbohydr. Chem. 1987, 357–375.
12. Schmidt, R. R.; Michel, J.; Roos, M. Liebigs Ann. Chem. 1984, 1343–1357.
13. (a) Harris, S. A.; Boyack, G. A.; Folkers, K. J. Am. Chem. Soc. 1941, 63,
2662–2667; (b) Sakuragi, T.; Kummerov, F. A. J. Am. Chem. Soc. 1956, 78,
838–839; (c) Rama Rao, A. V.; Mahender Rao, S.; Sharma, G. V. M. Tetrahedron
Lett. 1994, 35, 5735–5738; (d) Rychlik, M. J. Mass Spectrom. 2001, 36, 555–562.
14. Dittmer, D. C.; Blidner, B. B. J. Org. Chem. 1973, 38, 2873–2882.
15. Tejima, S.; Ness, R. K.; Kaufman, H. G.; Fletcher, H. G., Jr. Carbohydr. Res. 1968,
7, 485–490.