Phenylglycine methyl ester, a useful tool for absolute configuration determination of various chiral carboxylic acids

Article abstract of DOI:10.1021/jo991218a

A new chiral anisotropic reagent, phenylglycine methyl ester (PGME), developed for the elucidation of the absolute configuration of chiral α,α- disubstituted acetic acids, has turned out to be applicable to other substituted carboxylic acids, such as chiral α-hydroxy-, α-alkoxy-, and α- acyloxy-α,α-disubstituted acetic acids, as well as to chiral β,β- disubstituted propionic acids. Because a carboxylic moiety is convertible from other functional groups, e.g., ozonolysis of an olefin and oxidative cleavage of a glycol, the present findings can expand the utility of the PGME method to the absolute configuration determination of various types of organic compounds, even those which initially lack oxygen functions. Several examples of the combination of chemical reactions and the PGME method are described.

Full text of DOI:10.1021/jo991218a

J . Org. Chem. 2000, 65, 397-404
397
P h en ylglycin e Meth yl Ester , a Usefu l Tool for Absolu te
Con figu r a tion Deter m in a tion of Va r iou s Ch ir a l Ca r boxylic Acid s
Tetsuya Yabuuchi and Takenori Kusumi*
Faculty of Pharmaceutical Sciences, Tokushima University, Tokushima 770-8505, J apan
Received August 3, 1999
A new chiral anisotropic reagent, phenylglycine methyl ester (PGME), developed for the elucidation
of the absolute configuration of chiral R,R-disubstituted acetic acids, has turned out to be applicable
to other substituted carboxylic acids, such as chiral R-hydroxy-, R-alkoxy-, and R-acyloxy-R,R-
disubstituted acetic acids, as well as to chiral â,â-disubstituted propionic acids. Because a carboxylic
moiety is convertible from other functional groups, e.g., ozonolysis of an olefin and oxidative cleavage
of a glycol, the present findings can expand the utility of the PGME method to the absolute
configuration determination of various types of organic compounds, even those which initially lack
oxygen functions. Several examples of the combination of chemical reactions and the PGME method
are described.
Sch em e 1
In tr od u ction
Since the modified Mosher method for determining the
absolute configuration of secondary alcohols,1 which was
principally based on Mosher’s method using MTPA
esters,2 was reported, an increasing number of unique
NMR methods have appeared in various journals.3 While
most of them are for application to secondary alcohols,
like the modified Mosher method, we developed another
new NMR methodology using (R)- and (S)-phenylglycine
methyl ester (PGME method), which enabled the deter-
mination of the absolute configurations of carboxylic
acids.4
The principle of the PGME method is summarized in
Scheme 1: a chiral R,R-disubstituted acetic acid [A] is
condensed with (R)- and (S)-PGME [B], now commercially
available, giving the amide [C]. Coplanarity of the atoms
from position 1 to position 4 is guaranteed owing to the
s-trans amide linkage, which is well established in
peptide chemistry. The planarity can be extended to the
methoxycarbonyl group at the 5-position, because a polar
ester group will prefer the conformation anti (with
respect to the C3-C4 bond) to the polar carbonyl group
at the 2-position. This assumption was verified by X-ray
crystallography and NOE studies.4
same will stand for HA to HC. Therefore, model B,5 in
which ∆δ ) δ(S) - δ(R), illustrates the correct absolute
configuration of the carboxylic acid.
In the diastereomeric pair of PGME amide [D], the
protons, X-Z, of the (S)-isomer will have the more upfield
chemical shifts than those of the (R)-isomer owing to the
diamagnetic anisotropic effect of the benzene ring. The
Resu lts a n d Discu ssion 6
Ap p lica tion to Ch ir a l â,â-Disu bstitu ted P r op ion ic
Acid s. As discussed above, in the most stable conforma-
tion of the PGME amide of an R,R-disubstituted acetic
acid, the planarity of C1 to C5 is well interpreted by the
presence of an amide linkage and dipole-dipole interac-
tion between the methoxycarbonyl group and the amide
carbonyl. Here, the rotation around the C1-C2 bond is
* To whom correspondence should be addressed. Phone and Fax:
81-88-633-7288. E-mail: tkusumi@ph2.tokushima-u.ac.jp.
(1) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am. Chem.
Soc. 1991, 113, 4092.
(2) (a) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.
(b) Sullivan, G. R.; Dale, J . A.; Mosher, H. S. J . Org. Chem. 1973, 38,
2143.
(3) (a) Seco, J . M.; Latypov, S. K.; Quin˜oa´, E.; Riguera, R. Tetrahe-
dron Lett. 1997, 53, 8541. (b) Seco, J . M.; Latypov, S. K.; Quin˜oa´, E.;
Riguera, R. J . Org. Chem. 1997, 62, 5769. (c) Latypov, S. K.; Ferreiro,
M. J .; Quin˜oa´, E.; Riguera, R. J . Am. Chem. Soc. 1998, 120, 4741. (d)
Fukusi, Y.; Shigematsu, K.; Mizutani, J .; Tahara, S. Tetrahedron Lett.
1996, 37, 5737. (e) Latypov, S. K.; Seco, J . M.; Quin˜oa´, E.; Riguera, R.
J . Am. Chem. Soc. 1998, 120, 877. (f) Tyrrell, E.; Tsang, M. W. H.;
Skinner, G. A.; Farwcett, J . Tetrahedron 1996, 52, 9841. (g) Hoye, T.
R.; Loltun, D. O. J . Am. Chem. Soc. 1998, 120, 4638.
(5) Model A has been used in ref 1. In the present study, models C
and D are built up so that the positive and negative ∆δ values are
always on the right and left sides of the models, respectively, as in
the case of model A.
(6) A part of the results has appeared in Yabuuchi, T.; Ooi, T.;
Kusumi, T. 2I08, The 41st Symposium on the Chemistry of Terpenes,
Essential Oils, and Aromatics, Summary Papers, Iwate, J apan, 1997.
(4) Nagai, Y.; Kusumi, T. Tetrahedron Lett. 1995, 36, 1853.
10.1021/jo991218a CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/30/1999

398 J . Org. Chem., Vol. 65, No. 2, 2000
Yabuuchi and Kusumi
F igu r e 1. Stable conformation of the PGME amide of R,R-
disubstituted acetic acid. The Newman model [E] is a view
from the direction A. Rotation around C1-C2 by 180° gives
another conformation, [F]. The gray circle represents the
methoxycarbonylphenylmethyl group of the PGME moiety.
discussed. When the methoxycarbonyphenylmethyl group
is represented by a gray circle, and the PGME amide is
viewed from the direction A, two major rotamers, [E] and
[F], can be drawn as in Figure 1. Rotamer [E] is more
stable than rotamer [F], in which steric repulsion be-
tween the bulky methoxycarbonyphenylmethyl group and
R1/R2 is anticipated.
This “molecular models consideration” can be extended
to the PGME amide of chiral â,â-disubstituted propionic
acid. In Figure 2, three staggered conformations of the
(R)-PGME amide, [G], [H], and [I], resulting from rotation
around C1-C2 and viewed from direction B, are il-
lustrated. Of the three rotamers, [I] must be the least
stable because the largest group on C-2 is placed between
R1 and R2. Rotamers [G] and [H] are in almost the same
energy level. Therefore, the PGME amide of â,â-disub-
stituted propionic acid can be considered to exist in
conformer [J ], which is an averaged conformation of [G]
and [H].
When the PGME amide of chiral â,â-disubstituted
propionic acid takes the conformation [J ], the absolute
configuration at the â-position of the propionic acid
should be determined in a way analogous to that of the
modified Mosher method using model C [note: ∆δ ) δ(R)
- δ(S)]. Before the validity of this assumption is demon-
strated, the reason this methodology is important will
be explained.
F igu r e 2. Ideal conformation of the (R)-PGME amide of â,â-
disubstituted propionic acid (top). Three Newman projection
models, [G], [H], and [I], resulting from rotation around C1-
C2 (bottom). The gray circle represents the methoxycarbon-
ylphenylmethyl moiety. The conformation [J ] is the averaged
conformation between two stable conformers, [G] and [H].
Model C, in which ∆δ ) δ(R) - δ(S), shows the absolute
configuration of the â,â-disubstituted propionic acid.
There are a number of natural products, especially
terpenoids, having a structure unit [K] (Figure 3). Four
terpenoids, having the unit [K] are shown. All of these
compounds possess only olefinic linkages as chemically
active functional groups, and there has been no conve-
nient method to elucidate the absolute configuration,
except for enantiospecific total syntheses or a series of
degradation reactions leading to known compounds. It
was noticed that the oxidative cleavage of the olefinic
bond of [K] would give rise to a chiral â,â-disubstituted
propionic acid. Therefore, if it can be established that the
PGME method is actually applicable to a chiral â,â-
disubstituted propionic acid, the PGME method can be
extended to such olefinic compounds by combination with
an oxidative cleavage of the olefinic bonds.
F igu r e 3. Four terpenes possessing unit [K]. Cleavage of the
olefinic bond of [K] by, e.g., ozone gives a â,â-disubstituted
propionic acid.
Carboxylic acids 1-4, with known absolute configura-
tions, were prepared from commercially available (1R)-
(+)-pinene, D-∆3-carene, (3aR)-(+)-sclareolide, and (R)-
(+)-citronellol by ozonolysis, hydrolysis, or oxidation,
respectively, as shown in Figure 4. They were converted
to (R)- and (S)-PGME amides, and the ∆δ values [δ(R)
(S)] were calculated. The results are shown in the
structures 1a -4a (Figure 4). Without exception, the
-
δ

PGME for Absolute Configuration Determination
J . Org. Chem., Vol. 65, No. 2, 2000 399
F igu r e 5. (Top) Two possible conformers of the (S)-PGME
amide of (3S)-3,7-dimethyl-6-octenoic acid. (Bottom) ∆δ values
obtained for the (S)-enantiomers of 3-methylpentanoic (5),
3-methylhexanoic (6), 3-methylheptanoic (7), and 3-ethylhep-
tanoic (8) acids.
The applicability of the extended PGME method to
acyclic compounds was further confirmed by employing
several synthetic carboxylic acids, 5-8. The ∆δ values
obtained for these long-chain carboxylic acids (Figure 5)
reinforce the validity of the PGME method for these â,â-
disubstituted propionic acids.
This methodology has been quickly applied to absolute
configuration determination of some complex marine
natural products.7
Ap p lica t ion t o r-Oxy-r,r-Disu b st it u t ed Acet ic
Acid s. When an oxy group is present at C-1 of the PGME
amide, conformation [L] will become much more stable
than [M], resulting from rotation around the C1-C2 bond,
owing to the strong dipole-dipole repulsion between the
electronegative oxygens, together with the steric interac-
tion of the bulky PGME moiety with R1 and R2 in the
latter conformation. This consideration suggests that the
PGME method is also possible for the absolute configu-
ration determination of various types of quaternary R-oxy
carboxylic acids by means of model D [∆δ ) δ(S) - δ(R)].5
F igu r e 4. (Top) Transformation of (1R)-(+)-R-pinene, D-∆3-
carene, (3aR)-(+)-sclareolide, and (R)-(+)-citronellol to the
corresponding â,â-disubstituted propionic acids. (Bottom) ∆δ
[δ(R) - δ(S)] values obtained for the PGME amides 1a -4a .
positive and negative ∆δ values are oriented systemati-
cally on the right and left sides of the PGME plane,
respectively, and the absolute configurations deduced
from these results were identical with the known ones,
thus suggesting the validity of this extended use of the
PGME method.
It should be emphasized that the PGME method can
be applied to the acyclic carboxylic acid 4. The PGME
amide of 4 [in Figure 5, the (S)-PGME amide is shown]
can exist in, besides 4[J ] (Figure 2), the conformation
4[Zig], in which the PGME moiety is a zigzag extension
of the long aliphatic chain. Even in 4[Zig], however, the
methyl group is oriented in the same side of the phenyl
group, and it experiences an upfield anisotropic shift. The
4-methyl-3-pentenyl chain is situated on the PGME plane
in 4[Zig], the ∆δ values of its protons being null.
At first, the validity of the PGME method was exam-
ined by using acyclic R-oxy-R,R-disubstituted acetic acids.
The linear carboxylic acids of type [N] were synthesized
in racemic forms,8 and the racemates were optically
resolved (Figure 6). One example is as follows: 2-Pen-
tanone was treated with tribromomethane and KOH in
water to give rac-2-hydroxy-2-methylpentanoic acid (9).
The racemic mixture was condensed with (S)-PGME
(PyBOP, HOBT, and N-methylmorpholine), and the
resulting diastereomeric mixture (10a ) was separated by
silica gel column chromatography. One diastereomer, the
first-eluting one, was treated with 10 M KOH in metha-

400 J . Org. Chem., Vol. 65, No. 2, 2000
Yabuuchi and Kusumi
F igu r e 6. (Top) Reactions a and b to give R-oxy carboxylic
acids of type [N] are shown. (Bottom) Scheme to afford
2-hydroxy-2-methylhexanoic acid (9) and optical resolution of
it by (S)-PGME. Structure 10a exhibits the ∆δ values obtained
for (S)-9 ()11).
F igu r e 7. ∆δ values obtained for the acyclic R-hydroxy (12-
15), R-methoxy (16-20), and R-acetoxy (21-25) R,R-disubsti-
tuted acetic acids.
values [δ(S) - δ(R)] were calculated by subtracting the
proton chemical shifts of (R)-10-(S)-PGME from those
of (S)-10-(S)-PGME. [Note that the NMR spectrum of
(R)-10-(S)-PGME is identical with that of its enantiomer,
(S)-10-(R)-PGME.] The results are shown in 10a , which
is consistent with the (S)-configuration of 11.
In a similar manner, R-hydroxy-, methoxy-, and ac-
etoxy-R,R-disubstituted acetic acids of type [N] were
examined, and the results are summarized in Figure 7.
Without exception, the PGME method was found to be
valid for determining the absolute configurations of these
acyclic carboxylic acids. The ∆δ values of these R-oxy
quaternary acids are significantly larger than those of
R,R-disubstituted acetic acids, which implied that con-
formation [L] was actually predominant.
Versatility of the PGME method was further confirmed
when it was applied to natural R-oxy carboxylic acids 26-
29 (Figure 8). As can been seen in structures 26a -29a ,
the absolute configurations predicted by the ∆δ values
are all identical with the known absolute stereochemis-
try.
An interesting example of this PGME method is
shown: A methyl vinyl carbinol moiety, included in a
compound such as sclareol (30), is frequently encoun-
tered, particularly in terpenoids. Because it usually exists
at the terminus of the terpenoid side chain, as understood
by biosynthetic consideration, even the stereochemistry
relative to the cyclic moiety is extremely difficult to be
nol, and the specific rotation of the obtained carboxylic
acid (11), [R]365 -18.3° (c 0.08, H2O), was compared to
that of (S)-2-hydroxy-2-methylbutanoic acid, [R]365 -24.3°
(c 2.07, H2O).9 From this result, the first-eluting diaste-
reomer was proved to be (S)-10-(S)-PGME and the
second-eluting one to be (R)-10-(S)-PGME. The ∆δ
(7) (a) Sasaki, K.; Onodera, H.; Yasumoto, T. Enantiomer 1998, 3,
59. (b) Sasaki, K.; Satake, M.; Yasumoto, T. Biosci. Biotechnol.
Biochem. 1997, 61, 1783.
(8) Yabuuchi, T.; Kusumi, T. Chem. Pharm. Bull. 1999, 47, 684.
(9) Corey, E. J .; Paul, F. Tetrahedron Lett. 1987, 25, 2801.

PGME for Absolute Configuration Determination
J . Org. Chem., Vol. 65, No. 2, 2000 401
acid (36) were subjected to the PGME method. The ∆δ
values denoted in 33a -36a are in accordance with those
expected from their absolute configurations.
F igu r e 8. Application of the PGME method to natural
products possessing an R-oxy-R,R-disubstituted acetic acid
moiety.
solved. In many terpenoids, the stereochemistry of the
methyl vinyl carbinol moiety has remained unsolved. An
oxidative cleavage of the vinyl group, however, will give
an R-hydroxy carboxylic acid, the absolute configuration
of which will be conveniently determined by the PGME
method.
Sclareol (30) was treated with ozone in a mixed solvent
(MeOH:AcOH ) 2:1) at -78 °C, and the subsequent
workup with hydrogen peroxide at -78 °C afforded the
carboxylic acid 31 in good yield. The quaternary R-hy-
droxycarboxylic acid 31 was condensed with (S)- and (R)-
PGME to give 32-(S) and 32-(R). The ∆δ values calcu-
lated from the chemical shifts of each diastereomer are
illustrated in 32a . Only the methyl group at the R-posi-
tion has negative ∆δ values, and the other protons have
positive ∆δ values. These results led to the (R)-configu-
ration at the carbinol carbon, which was coincident with
the known absolute configuration. The configuration of
many terpenoids having a methyl vinyl carbinol system
can, therefore, be elucidated by means of the PGME
method.
Ap p lica t ion t o r-Oxy-r-m on osu b st it u t ed Acet ic
Acid . On the basis of considerations similar to those for
R-oxy-R,R-disubstituted acetic acid, we deduced that the
PGME method might be applied to an R-oxy-R-monosub-
stituted acetic acid by utilizing model D, in which one of
the R-substituents is a hydrogen.
Con clu sion s
The PGME method, using (R)- and (S)-phenylglycine
methyl esters, originally developed for elucidating the
absolute configuration of R,R-disubstituted acetic acids,
is applicable to â,â-disubstituted acetic acids [model C:
∆δ ) δ(R) - δ(S)], R-oxy-R,R-disubstituted acetic acids
[model D: ∆δ ) δ(S) - δ(R)], and R-oxy-R-monosubstituted
acetic acids (model D).10 Because a carboxylic acid is
(10) The 1H NMR spectra were recorded for the 1-15 mM solutions
of the PGME amides. The concentration of the solution did not affect
the magnitude of the ∆δ values.
L-Leucic acid (33), (S)-(+)-5-oxo-2-tetrahydrofurancar-
boxylic acid (34), L-leucic acid acetate (35), and L-glyceric

402 J . Org. Chem., Vol. 65, No. 2, 2000
Yabuuchi and Kusumi
Meth yl (1′R,2R,2′R,4a ′S,8a ′S)-[2′-Hyd r oxy-5′,5′,8a ′-tr i-
m et h ylp er h yd r on a p h t h yl)a cet a m id o]p h en ylet h a n oa t e
(3a -R). Anal. Calcd for C25H37NO4: C, 72.26; H, 8.97; N, 3.37.
Found: C, 72.38; H, 9.10; N, 3.36.
(3R)-3,7-Dim eth yl-6-octen oic Acid (4). (S)-(+)-Citronellol
(200 mg, 1.3 mmol) was treated with J ones reagent (8 N, 5
mL) at room temperature for 2 h. After addition of isopropyl
alcohol, the solution was concentrated. Hydrochloric acid (5%;
20 mL) was added to the residue, and the mixture was
extracted with ethyl acetate three times. The organic layer
was dried over anhydrous Na2SO4 and concentrated, affording
the carboxylic acid 4 (217 mg, 98%). Anal. Calcd for C10H18O2:
C, 70.55; H, 10.66. Found: C, 70.51; H, 10.53.
Met h yl (2S,3′R)-(3,7-Dim et h yl-6-oct en a m id o)p h en yl-
eth a n oa te (4a -S). Anal. Calcd for C19H27NO3: C, 71.89; H,
8.57; N, 4.41. Found: C, 71.68; H, 8.55; N, 4.46.
Met h yl (2R,3′R)-(3,7-Dim et h yl-6-oct en a m id o)p h en yl-
eth a n oa te (4a -R). Anal. Calcd for C19H27NO3: C, 71.89; H,
8.57; N, 4.41. Found: C, 71.64; H, 8.46; N, 4.43.
3-Meth ylp en ta n oic Acid (5). A mixture of racemic 2-me-
thylbutanoic acid (1 g, 8.6 mmol) and thionyl chloride (3 mL,
34 mmol) was refluxed at 90 °C for 3 h. After thionyl chloride
was removed by evaporation with benzene, the residue was
dissolved in dry ether (10 mL). The solution was added to an
excess (>10 mol equiv) of the diazomethane in ether (50 mL),
and the mixture was stirred for 15 h at room temperature.
The solution was concentrated, and the residue was refluxed
in a mixture of 10% silver nitrate solution (10 mL) and
concentrated, NH4OH (20 mL) for 6 h. The reaction mixture
was washed with ether. After acidification with 1 M HCl, the
product was extracted with ethyl acetate three times, affording
crude 2-methylpentanamide (1.24 g) after evaporation of the
solvent. The product was refluxed with 3 M KOH (20 mL) for
20 h. After washing of the mixture with ether, acidification
with 12 M HCl, and extraction with ethyl acetate, racemic
3-methylpentanoic acid 9 (0.99 g, 89%) was obtained as a pale
yellow oil. This material was purified by bulb-to-bulb distil-
lation (150 °C, 5 Torr). Anal. Calcd for C6H12O2: C, 62.04; H,
10.41. Found: C, 62.28; H, 10.34.
derived from various kinds of synthons such as an ester,
primary alcohol, and olefin, the PGME method can be
extended to the absolute configuration determination of
compounds without a carboxyl group by combination with
the appropriate chemical reactions.
Exp er im en ta l Section
Ma ter ia ls. (S)- and (R)-PGME, (1R)-(+)-R-pinene, D-∆3-
carene, (3aR)-(+)-sclareolide, (R)-(+)-citronellol, (1R,3R,4R,5R)-
(-)-quinic acid (deacetylated 26), (S)-(-)-camphoric acid (27),
chlorogenic acid (deacetylated 28), (R)-(+)-Trolox (29), sclareol
(30), L-leucic acid (33), (S)-(+)-5-oxo-2-tetrahydrofurancar-
boxylic acid (34), and L-glyceric acid (deacetylated 36) were
purchased from Aldrich, and were used without purification.
Gen er a l P r oced u r e To P r ep a r e th e (S)- a n d (R)-P GME
Am id es of a Ca r boxylic Acid . To a stirred solution of a
carboxylic acid (0.39 mmol) and (S)-PGME (0.49 mmol) in dry
DMF (2 mL) were successively added PyBOP (0.49 mmol),
HOBT (0.49 mmol), and N-methylmorpholine (270 µL) at 0
°C. After the mixture was stirred at room temperature for 3
h, ethyl acetate was added, and the resulting solution was
successively washed with 5% HCl, saturated NaHCO3 solution,
and brine. The organic layer was dried over anhydrous Na2-
SO4 and concentrated to give a residue which was chromato-
graphed on silica gel with 3:1 hexanes-ethyl acetate as
developing solvent to afford the (S)-PGME amide in 70-80%
yield.
(1S,3S)-(3-Acetyl-2,2-d im eth ylcyclobu tyl)a cetic Acid
(1). Into a solution of (1R)-(+)-pinene (500 mg) in methanol
(20 mL) cooled to -78 °C was bubbled ozone gas for 20 min.
After addition of triphenylphosphine (2 g) and ether (5 mL)
and stirring for 1 h, 0.1 M HCl was added and the mixed
solution was extracted with ethyl acetate three times. The
extract was treated with J ones reagent (8 N, 10 mL) at room
temperature for 1 h. After addition of 2-propanol and removal
of the solvent, 0.1 M HCl was added to the residue, and the
solution was extracted with ethyl acetate. Drying over Na2-
SO4 and concentration afforded the carboxylic acid 1 (510 mg,
75%) as a colorless oil. Anal. Calcd for C10H16O3: C, 65.19; H,
8.75. Found: C, 65.13; H, 8.72.
The carboxylic acids 6, 7, and 8 were obtained by the same
procedure.
3-Meth ylh exa n oic Acid (6). Anal. Calcd for C7H14O2: C,
64.58; H, 10.84. Found: C, 64.41; H, 10.56.
3-Meth ylh ep ta n oic Acid (7). Anal. Calcd for C8H16O2: C,
66.63; H, 11.18. Found: C, 66.81; H, 11.21.
3-Eth ylh ep ta n oic Acid (8). Anal. Calcd for C9H18O2: C,
68.42; H, 11.66. Found: C, 64.41; H, 10.56.
Meth yl (1′S,2S,3′S)-[(3-Acetyl-2,2-d im eth ylcyclobu tyl)-
a ceta m id o]p h en yleth a n oa te (1a -S). Anal. Calcd for C19H25
-
NO4: C, 38.86; H, 7.60; N, 4.23. Found: C, 38.61; H, 7.67; N,
4.41.
Meth yl (1′S,2R,3′S)-[(3-Acetyl-2,2-d im eth ylcyclobu tyl)-
a ceta m id o]p h en yleth a n oa te (1a -R). Anal. Calcd for C19H25
-
Sep a r a tion of th e Dia ster eom er s of th e (S)-P GME
Am id es 5a -8a . The (S)-PGME amides 5a -8a were prepared
according to the general procedure. Each diastereomer was
separated by HPLC (LiChrosorb, 2:1 to 3:1 hexanes-ethyl
acetate) except for 8a which was subjected to recycling HPLC.
In each case, the first-eluting compound was deduced to be
the (S)-PGME amide of the (R)-carboxylic acid, because the
(S)-PGME amide of (3R)-3,7-dimethyl-6-octenoic acid (4) eluted
faster than the (S)-PGME amide of (3S)-4.
Meth yl (2S,3′S)-(3′-Meth ylp en ta n a m id o)p h en yleth a -
n oa te (5a -S). Anal. Calcd for C15H21NO3: C, 68.42; H, 8.04;
N, 5.32. Found: C, 68.53; H, 8.36; N, 5.41.
Meth yl (2S,3′R)-(3′-Meth ylp en ta n a m id o)p h en yleth a -
n oa te (5a -R). Anal. Calcd for C15H21NO3: C, 68.42; H, 8.04;
N, 5.32. Found: C, 68.51; H, 8.24; N, 5.45.
Meth yl (2S,3′S)-(3′-Meth ylh exn am ido)ph en yleth an oate
(6a -S). Anal. Calcd for C16H23NO3: C, 69.29; H, 8.36; N, 5.05.
Found: C, 69.41; H, 8.41; N, 5.33.
Meth yl (2S,3′R)-(3′-Meth ylh exn am ido)ph en yleth an oate
(6a -R). Anal. Calcd for C16H23NO3: C, 69.29; H, 8.36; N, 5.05.
Found: C, 69.45; H, 8.39; N, 5.02.
Meth yl (2S,3′S)-(3′-Meth ylh ep ta n a m id o)p h en yleth a -
n oa te (7a -S). Anal. Calcd for C17H25NO3: C, 70.07; H, 8.65;
N, 4.81. Found: C, 70.21; H, 8.57; N, 4.79.
Meth yl (2S,3′R)-(3′-Meth ylh ep ta n a m id o)p h en yleth a -
n oa te (7a -R). Anal. Calcd for C17H25NO: C, 70.07; H, 8.65; N,
4.81. Found: C, 70.18; H, 8.55; N, 4.68.
NO4: C, 38.86; H, 7.60; N, 4.23. Found: C, 38.66; H, 7.62; N,
4.39.
(1S,3S)-[2,2-Dim eth yl-3-(2-oxop r op yl)cyclop r op yl]a ce-
tic Acid (2). Anal. Calcd for C10H16O3: C, 65.19; H, 8.75.
Found: C, 65.16; H, 8.61.
Meth yl (1′S,2S,3′S)-[2′,2′-Dim eth yl-3′-(2-oxop r op yl)cy-
clop r op yl]p h en yleth a n oa te (2a -S). Anal. Calcd for C19H25
-
NO4: C, 38.86; H, 7.60; N, 4.23. Found: C, 38.71; H, 7.45; N,
4.36.
Meth yl (1′S,2R,3′S)-[2′,2′-Dim eth yl-3′-(2-oxop r op yl)cy-
clop r op yl]p h en yleth a n oa te (2a -R). Anal. Calcd for
C
19H25NO4: C, 38.86; H, 7.60; N, 4.23. Found: C, 38.82; H,
7.78; N, 4.31.
(1R,2R,4a S,8a S)-(2-H yd r oxy-5,5,8a -Tr im et h ylp er h y-
d r on a p h th yl)a cetic Acid (3). (3aR)-(+)-Sclareolide (100 mg,
0.4 mmol) in methanol (3 mL) was added to 3 M KOH, and
the mixture was refluxed for 20 h. The reaction mixture was
washed with ether, and the aqueous layer was acidified with
12 M HCl. The product was extracted with ethyl acetate three
times. The organic layer was dried over anhydrous Na2SO4
and concentrated, affording the carboxylic acid 3 (103 mg, 96%)
as a colorless oil. Anal. Calcd for C16H28O3: C, 71.60; H, 10.51.
Found: C, 71.28; H, 10.60.
Meth yl (1′R,2S,2′R,4a ′S,8a ′S)-[2′-Hyd r oxy-5′,5′,8a ′-tr i-
m et h ylp er h yd r on a p h t h yl)a cet a m id o]p h en ylet h a n oa t e
(3a -S). Anal. Calcd for C25H37NO4: C, 72.26; H, 8.97; N, 3.37.
Found: C, 72.34; H, 9.12; N, 3.39.

PGME for Absolute Configuration Determination
J . Org. Chem., Vol. 65, No. 2, 2000 403
Meth yl (2S,3′S)-(3′-Meth yloctan am ido)ph en yleth an oate
(8a -S). Anal. Calcd for C18H27NO3: C, 70.59; H, 8.91; N, 4.59.
Found: C, 70.39; H, 8.66; N, 4.58.
Met h yl (2S,2′R)-(2′-Met h oxy-2′-m et h ylp en t a n a m id o)-
p h en yleth a n oa te (17-R): MS (EI) m/z 293 (M+); HRMS (EI)
calcd for C16H23NO4 293.1626, found 293.1627.
Met h yl (2S,2′S)-(2′-Met h oxy-2′-m et h ylh exa n a m id o)-
p h en yleth a n oa te (18-S): MS (EI) m/z 307 (M+); HRMS (EI)
calcd for C17H25NO4 307.1782, found 307.1780.
Met h yl (2S,3′R)-(3′-Met h yloct a n a m id o)p h en ylet h a -
n oa te (8a -R). Anal. Calcd for C18H27NO3: C, 70.59; H, 8.91;
N, 4.59. Found: C, 70.51; H, 8.88; N, 4.57.
Met h yl (2S,2′R)-(2′-Met h oxy-2′-m et h ylh exa n a m id o)-
p h en yleth a n oa te (18-R): MS (EI) m/z 307 (M+); HRMS (EI)
calcd for C17H25NO4 307.1782, found 307.1807.
Meth yl (2S,2′S)-(2′-Eth yl-2′-m eth oxyp en ta n a m id o)p h e-
n yleth a n oa te (19-S): MS (EI) m/z 307 (M+); HRMS (EI) calcd
for C17H25NO4 307.1782, found 307.1788.
Met h yl (2S,2′R)-(2′-E t h yl-2′-m et h oxyp en t a n a m id o)-
p h en yleth a n oa te (19-R): MS (EI) m/z 307 (M+); HRMS (EI)
calcd for C17H25NO4 307.1782, found 307.1785.
Met h yl (2S,2′S)-(2′-Met h oxy-2′-m et h yloct a n a m id o)-
p h en yleth a n oa te (20-S): MS (EI) m/z 335 (M+); HRMS (EI)
calcd for C19H29NO4 335.2095, found 335.2091.
Met h yl (2S,2′R)-(2′-Met h oxy-2′-m et h yloct a n a m id o)-
p h en yleth a n oa te (20-R): MS (EI) m/z 335 (M+); HRMS (EI)
calcd for C19H29NO4 335.2093, found 335.2091.
Con d en sa tion of r-Acetoxy-r,r-d isu bstitu ted Acetic
Acid s. The procedures are similar to those of quaternary
R-hydroxycarboxylic acids described above.
Meth yl (2S,2′S)-(2′-Acetoxy-2′-m eth ylbu ta n a m id o)p h e-
n yleth a n oa te (21-S): MS (EI) m/z 307 (M+); HRMS (EI) calcd
for C16H21NO5 307.1418, found 307.1418.
Meth yl (2S,2′R)-(2′-Acetoxy-2′-m eth ylbu ta n a m id o)p h e-
n yleth a n oa te (21-R): MS (EI) m/z 307 (M+); HRMS (EI) calcd
for C16H21NO5 307.1418, found 307.1411.
Met h yl (2S,2′S)-(2′-Acet oxy-2′-m et h ylp en t a n a m id o)-
p h en yleth a n oa te (22-S): MS (EI) m/z 321 (M+); HRMS (EI)
calcd for C17H23NO5 321.1575, found 321.1577.
Met h yl (2S,2′R)-(2′-Acet oxy-2′-m et h ylp en t a n a m id o)-
p h en yleth a n oa te (22-R): MS (EI) m/z 321 (M+); HRMS (EI)
calcd for C17H23NO5 321.1575, found 321.1570.
Meth yl (2S,2′S)-(2′-Acetoxy-2′-m eth ylh exa n a m id o)p h e-
n yleth a n oa te (23-S): MS (EI) m/z 335 (M+); HRMS (EI) calcd
for C18H25NO5 335.1731, found 335.1733.
Met h yl (2S,2′R)-(2′-Acet oxy-2′-m et h ylh exa n a m id o)-
p h en yleth a n oa te (23-R): MS (EI) m/z 335 (M+); HRMS (EI)
calcd for C18H25NO5 335.1731, found 335.1735.
Meth yl (2S,2′S)-(2′-Acetoxy-2′-eth ylp en ta n a m id o)p h e-
n yleth a n oa te (24-S): MS (EI) m/z 335 (M+); HRMS (EI) calcd
for C18H25NO5 335.1731, found 335.1729.
Meth yl (2S,2′R)-(2′-Acetoxy-2′-eth ylp en ta n a m id o)p h e-
n yleth a n oa te (24-R): MS (EI) m/z 335 (M+); HRMS (EI) calcd
for C18H25NO5 335.1731, found 335.1728.
Meth yl (2S,2′S)-(2′-Acetoxy-2′-m eth ylocta n a m id o)p h e-
n yleth a n oa te (25-S): MS (EI) m/z 363 (M+); HRMS (EI) calcd
for C20H29NO5 363.2044, found 363.2041.
Meth yl (2S,2′R)-(2′-Acetoxy-2′-m eth ylocta n a m id o)p h e-
n yleth a n oa te (25-R): MS (EI) m/z 363 (M+); HRMS (EI) calcd
for C20H29NO5 363.2044, found 363.2040.
Con d en sa tion of Na tu r a l P r od u cts Ha vin g a n r-Oxy
Moiety w ith (S)- a n d (R)-P GME. (1R,3R,4R,5R)-(-)-Quinic
acid (100 mg, 0.52 mmol) and chlorogenic acid (100 mg, 0.282
mmol) were converted to the corresponding tetraacetyl quinic
acids (166 mg) and tetraacetyl chlorogenic acid (159 mg) by
treatment with acetic anhydride and pyridine. These two
acetylated acids, (S)-(-)-camphanic acid, and (R)-(+)-Trolox
were condensed with (S)- and (R)-PGME according to the
general procedure.
Meth yl (1′R′,2S,3′R,4′R,5′R)-P h en yl-(1′,3′,4′,5′-tetr a a c-
etoxycycloh exan ecar boxam ido)eth an oate (26a-S): HRMS
(EI) calcd for C24H29NO11 507.1739, found 507.1733.
Meth yl (1′R′,2R,3′R,4′R,5′R)-P h en yl-(1′,3′,4′,5′-tetr a a c-
etoxycycloh exan ecar boxam ido)eth an oate (26a-R): HRMS
(EI) calcd for C24H29NO11 507.1739, found 507.1738.
Meth yl (1′R,2S,4′R)-(2′-Oxa -3′-oxo-4′,7′,7′-tr im eth ylbi-
cyclo[2.2.1]h ep ta n eca r boxa m id o)p h en yleth a n oa te (27a -
S): HRMS (EI) calcd for C19H23NO5 345.1612, found 345.1611.
Meth yl (1′R,2R,4′R)-(2′-Oxa -3′-oxo-4′,7′,7′-tr im eth ylbi-
cyclo[2.2.1]h ep ta n eca r boxa m id o)p h en yleth a n oa te (27a -
R): HRMS (EI) calcd for C19H23NO5 345.1614, found 345.1611.
2-Hyd r oxy-2-m eth ylp en ta n oic Acid (9). 2-Pentanone (2
mL, 22.0 mmol) and tribromomethane (20 mL) were placed in
a three-necked flask equipped with a magnetic stirrer and a
dropping funnel. To this solution was slowly added KOH (30
g) in methanol (30 mL). The resulting mixture was stirred
vigorously for 1 h. Water was added to the suspension, and
the solution was washed with two portions of ether. The
aqueous layer was collected and acidified with 12 M HCl. The
resulting suspension was extracted with three portions of ethyl
acetate. The organic solution was dried over anhydrous Na2-
SO4 and concentrated to give 2.07 g (80%) of racemic 9: HRMS
(EI) calcd for C6H12O3 132.0786, found 132.0779. Anal. Calcd
for C6H12O3: C, 54.53; H, 9.15. Found: C, 54.63; H, 9.35.
Meth yl (2S,2′S)-(2′-Hyd r oxy-2′-m eth ylp en ta n a m id o)-
p h en yleth a n oa te [(S)-10-(S)-P GME]: HRMS (EI) calcd for
C
15H21NO4 279.1469, found 279.1463.
Meth yl (2S,2′R)-(2′-Hyd r oxy-2′-m eth ylp en ta n a m id o)-
p h en yleth a n oa te [(R)-10-(S)-P GME]: HRMS (EI) calcd for
C
15H21NO4 279.1469, found 279.1471.
Con d en sa tion of r-Hyd r oxy-r,r-d isu bstitu ted Acetic
Acid s w ith P GME. The general procedure is as follows: To
a solution of a mixture of racemic 2-hydroxy-2-methylbutanoic
acid (100 mg, 0.98 mmol) and (S)-PGME (245 mg, 1.23 mmol)
were successively added PyBOP (640 mg, 1.23 mmol), HOBT
(166 mg, 1.23 mmol), and N-methylmorpholine (0.2 mL) at 0
°C for 3 h. After addition of ethyl acetate, the reaction mixture
was washed with diluted HCl solution, saturated sodium
bicarbonate solution, and brine, and the organic layer was
dried over anhydrous Na2SO4. Concentration of the dried
solution and subsequent purification by preparative TLC
method afforded the respective diastereomers (12-S; 108 mg,
12-R; 113 mg, 85%).
Met h yl (2S,2′S)-(2′-H yd r oxy-2′-m et h ylb u t a n a m id o)-
p h en yleth a n oa te (12-S): MS (EI) m/z 265 (M+); HRMS (EI)
calcd for C14H19NO4 265.1313, found 265.1311.
Met h yl (2S,2′R)-(2′-H yd r oxy-2′-m et h ylb u t a n a m id o)-
p h en yleth a n oa te (12-R): MS (EI) m/z 265 (M+); HRMS (EI)
calcd for C14H19NO4 265.1313, found 265.1315.
Met h yl (2S,2′S)-(2′-H yd r oxy-2′-m et h ylh exa n a m id o)-
p h en yleth a n oa te (13-S): MS (EI) m/z 293 (M+); HRMS (EI)
calcd for C16H23NO4, 293.1626, found 293.1622.
Met h yl (2S,2′R)-(2′-H yd r oxy-2′-m et h ylh exa n a m id o)-
p h en yleth a n oa te (13-R): MS (EI) m/z 293 (M+); HRMS (EI)
calcd for C16H23NO4 293.1626, found 293.1629.
Meth yl (2S,2′S)-(2′-Eth yl-2′-h yd r oxyp en ta n a m id o)p h e-
n yleth a n oa te (14-S): MS (EI) m/z 293 (M+); HRMS (EI) calcd
for C16H23NO4 293.1626, found 293.1627.
Meth yl (2S,2′R)-(2′-Eth yl-2′-h yd r oxyp en ta n a m id o)p h e-
n yleth a n oa te (14-R): MS (EI) m/z 293 (M+); HRMS (EI) calcd
for C16H23NO4 293.1626, found 293.1621.
Met h yl (2S,2′S)-(2′-H yd r oxy-2′-m et h yloct a n a m id o)-
p h en yleth a n oa te (15-S): MS (EI) m/z 321 (M+); HRMS (EI)
calcd for C18H27NO4 321.1938, found 321.1933.
Met h yl (2S,2′R)-(2′-H yd r oxy-2′-m et h yloct a n a m id o)-
p h en yleth a n oa te (15-R): MS (EI) m/z 321 (M+); HRMS (EI)
calcd for C18H27NO4 321.1938, found 321.1934.
Con d en sa tion of r-Meth oxy-r,r-d isu bstitu ted Acetic
Acid s. The procedures are similar to those of quaternary
R-hydroxycarboxylic acids described above.
Met h yl (2S,2′S)-(2′-Met h oxy-2′-m et h ylb u t a n a m id o)-
p h en yleth a n oa te (16-S): MS (EI) m/z 279 (M+); HRMS (EI)
calcd for C15H21NO4 279.1469, found 279.1489.
Met h yl (2S,2′R)-(2′-Met h oxy-2′-m et h ylb u t a n a m id o)-
p h en yleth a n oa te (16-R): MS (EI) m/z 279 (M+); HRMS (EI)
calcd for C15H21NO4 279.1469, found 279.1473.
Meth yl (2S,2′S)-(2′-Meth oxy-2′-m eth ylp en ta n a m id o)-
p h en yleth a n oa te (17-S): MS (EI) m/z 293 (M+); HRMS (EI)
calcd for C16H23NO4 293.1626, found 293.1645.

404 J . Org. Chem., Vol. 65, No. 2, 2000
Yabuuchi and Kusumi
(S)-P GME Am id e of Ch lor ogen ic Acid (28a -S): HRMS
(EI) calcd for C23H27NO5 669.2057, found 669.2050.
(R)-P GME Am id e of Ch lor ogen ic Acid (28a -R): HRMS
(EI) calcd for C23H27NO5 669.2057, found 669.2058.
(2S,2′R)-(6′-Hyd r oxy-2′,5′,7′,8′-tetr a m eth ylch r om a n -2′-
ca r boxa m id o)p h en yleth a n oa te (29a -S): HRMS (EI) calcd
for C23H27NO5 397.1887, found 397.1871.
(2R,2′R)-(6′-Hyd r oxy-2′,5′,7′,8′-tetr a m eth ylch r om a n -2′-
ca r boxa m id o)p h en yleth a n oa te (29a -R): HRMS (EI) calcd
for C23H27NO5 397.1887, found 397.1886.
Ozon olysis of Scla r eol. A solution of sclareol (30; 50 mg,
0.16 mmol) in a mixed solvent (2:1 methanol-acetic acid) was
cooled to -78 °C in dry ice-methanol. Ozone was introduced
into the solution, and the reaction was monitored by TLC.
After 10 min, the bubbling of ozone was stopped, and hydrogen
peroxide (30%; 10 mL) was added to the solution. The mixture
was stirred for 1 h at -78 °C. Dilute HCl (5%; 30 mL) and
sodium sulfate (excess) were added to the solution, and the
mixture was extracted with ethyl acetate three times. After
the organic layer was dried over anhydrous Na2SO4, the
solution was concentrated, affording the carboxylic acid 31 (61
mg) as a colorless oil: HRMS (EI) calcd for C19H34O4 326.2457,
found 326.2455.
Meth yl (2S,2′S)-(2′-Hyd r oxy-4′-m eth ylp en ta n a m id o)-
p h en yleth a n oa te (33a -S): HRMS (EI) calcd for C15H21NO4
279.1469, found 279.1460.
Meth yl (2R,2′S)-(2′-Hyd r oxy-4′-m eth ylp en ta n a m id o)-
p h en yleth a n oa te (33a -R): HRMS (EI) calcd for C15H21NO4
279.1469, found 279.1455.
Meth yl (2S,2′S)-(5-Oxo-2-fu r a n ca r boxa m id o)p h en yle-
th a n oa te (34a -S): HRMS (EI) calcd for C14H15NO5 281.1262,
found 281.1256.
Met h yl (2S,2′R)-(5-Oxo-2-fu r a n ca r b oxa m id o)p h en yl-
eth a n oa te (34a -R): HRMS (EI) calcd for C14H15NO5 281.1262,
found 281.1266.
Met h yl (2S,2′S)-(2′-Acet oxy-4′-m et h ylp en t a n a m id o)-
p h en yleth a n oa te (35a -S): HRMS (EI) calcd for C17H23NO5
321.1575, found 321.1570.
Met h yl (2R,2′S)-(2′-Acet oxy-4′-m et h ylp en t a n a m id o)-
p h en yleth a n oa te (35a -R): HRMS (EI) calcd for C17H23NO5
321.1575, found 321.1577.
Meth yl (2S,2′S)-(2′,3′-Dia cetoxyp r op a n a m id o)p h en yl-
eth a n oa te (36a -S): HRMS (EI) calcd for C16H19NO3 273.1364,
found 273.1366.
Meth yl (2R,2′S)-(2′,3′-Dia cetoxyp r op a n a m id o)p h en yl-
eth a n oa te (36a -R): HRMS (EI) calcd for C16H19NO3 273.1364,
found 273.1365.
Meth yl (2S,2′R,2′′R,4a ′′S,8a ′′S)-[4′-(2′′-Hyd r oxy-2′′,5′′,5′′,-
8a ′′-tetr a m eth ylp er h yd r on a p h th yl)-2′-h yd r oxy-2′-m eth -
ylbu ta n a m id o]p h en yleth a n oa te (32a -S): HRMS (EI) calcd
for C28H43NO5 473.3138, found 473.3133.
Meth yl (2R,2′R,2′′R,4a′′S,8a′′S)-[4′-(2′′-Hydr oxy-2′′,5′′,5′′,-
8a ′′-tetr a m eth ylp er h yd r on a p h th yl)-2′-h yd r oxy-2′-m eth -
ylbu ta n a m id o]p h en yleth a n oa te (32a -R): HRMS (EI) calcd
for C28H43NO5 473.3138, found 473.3130.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
data of the compounds described in the Experimental Section
and numberings of the positions used for assignment of the
1H and 13C NMR signals. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O991218A