Diastereoselective preparation of (R)- and (S)-2-methoxy-2-phenylpent-3- ynoic acids and their use as reliable chiral derivatizing agents

Article abstract of DOI:10.1021/jo2016554

Benzoyl-S,O-acetals 1a and 1b were used as chiral auxiliaries to achieve the diastereoselective preparation of both enantiomers of 2-methoxy-2- phenylpent-3-ynoic acids (MPPAs). The latter were condensed with several chiral secondary alcohols and some primary amines to evaluate their potential as chiral derivatizing agents (CDAs). The ¹H NMR spectra of the corresponding esters and amides showed strong consistency with the absolute configuration of the carbinol and amine moieties, whose observed ΔδL₁ and ΔδL₂ values were in the ranges of 0.1-0.4 and 0.02-0.12 ppm, respectively.

Full text of DOI:10.1021/jo2016554

Article
pubs.acs.org/joc
Diastereoselective Preparation of (R)- and (S)-2-Methoxy-2-
phenylpent-3-ynoic Acids and Their Use as Reliable Chiral
Derivatizing Agents
Salvador Perez-Estrada,† Pedro Joseph-Nathan,‡ Hugo A. Jimenez-Vazquez,† Manuel E. Medina-Lopez,†
́
́
́
́
Francisco Ayala-Mata,† and L. Gerardo Zepeda*,†
†Departamento de Química Organ
Prol. de Carpio y Plan de Ayala, Mex
‡Departamento de Química, Centro de Investigacion
Mexico, D.F., 07000 Mexico
́
ica, Escuela Nacional de Ciencias Biolog
ico, D.F., 11340 Mexico
y de Estudios Avanzados del Instituto Politec
́
icas, Instituto Politec
́
nico Nacional,
́
́
́
nico Nacional, Apartado 14-740,
́
S
* Supporting Information
ABSTRACT: Benzoyl-S,O-acetals 1a and 1b were used as chiral auxiliaries to achieve the diastereoselective preparation of both
enantiomers of 2-methoxy-2-phenylpent-3-ynoic acids (MPPAs). The latter were condensed with several chiral secondary
alcohols and some primary amines to evaluate their potential as chiral derivatizing agents (CDAs). The 1H NMR spectra of the
corresponding esters and amides showed strong consistency with the absolute configuration of the carbinol and amine moieties,
whose observed ΔδL1 and ΔδL2 values were in the ranges of 0.1−0.4 and 0.02−0.12 ppm, respectively.
practical protocol for the synthesis of new CDAs (R)-(+)-2 and
(S)-(−)-2 and a representative number of examples supporting
its use as a very reliable alternative for determining the absolute
configuration of chiral secondary carbinols and chiral primary
amines.
INTRODUCTION
The use of chiral derivatizing agents (CDAs) is one of the most
reliable and effective methods to determine the absolute
■
1
configuration of chiral alcohols and amines by H NMR. Since
the pioneer work of Mosher1 describing the use of α-methoxy-
α-trifluoromethylphenylacetic acid (MTPA) as the first
prototype of a CDA, a diversity of Mosher analogues have
been developed and used in the assignment of the absolute
configuration of a wide variety of chiral alcohol and amine
derivatives, among other compounds.2 During the course of our
work focused on the development of new chiral auxiliaries
derived from (1R)-(−)-myrtenal, we described the synthesis of
benzoyl-S,O-acetals 1a and 1b as well as their use to obtain
either enantiomer of chiral α-hydroxyacids through a highly
diastereoselective process.3a Taking advantage of this highly
stereocontrolled process, we envisioned the diastereoselective
synthesis of the new enantiomeric pair of 2-methoxy-2-
phenylpent-3-ynoic acids (α,α,α-methoxyphenylpropynylacetic
acids, MPPAs) (R)-(+)-2 and (S)-(−)-2 as strong candidates
for use as CDAs to determine the absolute configuration of
chiral alcohols and amines. The main structural feature of
these CDAs is the simultaneous presence of propynyl and
phenyl groups at C-2, which in principle would exert opposite
anisotropic effects on substituents L1 and L2 present at the
carbinol and amine fragments, thus inducing optimal
discrimination of such groups by means of their relative
chemical shifts (Figure 1). Herein we describe an easy and
RESULTS AND DISCUSSION
■
The preparation of thioacetals 1a and 1b was efficiently
achieved according to the synthetic protocol developed by our
research group.3a−c These compounds were treated with
MeCCMgBr to give the corresponding carbinols 3a and
3b in quantitative yield and >99:1 dr (Scheme 1), with a
stereochemistry in agreement with the Cram chelated model,
which states that the Grignard reagent is preferably coordinated
with oxygen instead of sulfur, thus giving, for instance the
nucleophilic addition mainly through the re face of the carbonyl
group of thioacetal 1a.4 After successive treatment of 3a and 3b
with NaH and CH3I, diastereomeric methylethers 3c and 3d
were obtained in yields higher than 95% without the need of
any particular purification protocol for the last two steps.
Hydrolysis of thioacetals 3c and 3d was readily accomplished
with NCS and AgNO3 in CH3CN/H2O, affording the
corresponding aldehydes. The crude products were oxidized
to the MPPAs (R)-(+)-2 and (S)-(−)-2 with Jones reagent
Received: August 11, 2011
Published: January 3, 2012
© 2012 American Chemical Society
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Figure 1. Syn and anti periplanar perspective views of the diastereomeric pair of esters and amides formed by condensation of CDAs (R)-(+)-2a and
(S)-(−)-2b with chiral secondary carbinols and primary amines, respectively, and their expected ΔδSR and ΔδRS values for ligands L1 and L2.
a
Scheme 1. Reaction Sequence Yielding MPPAs (R)-(+)-2 and (S)-(−)-2
a
(i) MeCCMgBr, THF, −78 °C (>99%). (ii) NaH, MeI, THF, rt (>95%). (iii) (a) NCS, AgNO3, MeCN/H2O; (b) CrO3, H2SO4/H2O.
(R)-(+)-2: [α]25 = +42.6° (c 1.51, CHCl3); (S)-(−)-2: [α]25 = −42.4° (c 1.65, CHCl3).
D
D
(CrO3 in H2O/H2SO4) and easily purified by conversion to
the sodium salt, washing with Et2O/hexanes (1:1) and back-
conversion to the free acid using 10% aq HCl solution.
It must be mentioned that preparation of the corresponding
esters from (R)-MPPA or (S)-MPPA gave a diastereomeric
mixture ranging from 79:21 to 97:3 and 87:13 to 97:3, re-
that should be highlighted from Table 1. In addition, the size
and systematic relative signs of the ΔδSR values, which range
from 0.1 to ca. 0.4 ppm for the α positions at ligands L1 and L2,
allowed for a very reliable assignment of the absolute
configuration of the tested carbinols. Two additional facts
must be emphasized: (a) when L1 or L2 is or possesses an
aromatic group, this is mostly under the protective anisotropic
effect of the MPPA’s phenyl group (structures 4−6), as was
corroborated through NOE experiments (Supporting Informa-
tion), making these CDAs especially effective for this kind of
alcohol, and (b) in cases where no hydrogen atom is present at
the α position, the protective anisotropic effect of the phenyl
group of the MPPA moiety was efficiently transmitted to the β,
γ, or even more remote positions (structures 4, 6, 12, 13, and
16). Just to provide a graphical example, Figure 2 illustrates
sections of the 1H NMR spectra for esters prepared by
condensing (3R)-hydroxytetrahydrofuran with the (R)- and
(S)-MPPAs (upper and lower traces, respectively). As can be
seen, the chemical shifts (ΔδSR) pattern obtained from both
compounds clearly correlates with the absolute configuration of
the alcohol used. The same trend was observed for all esters
synthesized in this work; the full set of NMR spectra is
provided in the Supporting Information.
In addition, we consider it useful to extend the scope of this
method to determine the absolute configuration of chiral
primary amines, since they represent an important group of
compounds widely found in pharmaceutical formulations and
in nature (i.e., alkaloids, amino acids) or even as frequent tar-
gets in asymmetric synthesis. In this case, the available chiral
primary amines were methylbenzyl amine, norbornyl amine,
and the methyl esters of L-valine and L-serine, whose cor-
responding amides 24−27 were prepared using BOP as coupl-
ing reagent and DEA as a catalyst. It is important to note that
1
spectively, as can be observed in their corresponding H NMR
spectra (Supporting Information). This result must be either in
direct connection with the combined optical purity5 of both
tested carbinols and amines (sold as 95−99% purum, labeled as
the sum of enantiomers) and MPPA acids (R)-(+)-2 and (S)-
(−)-2, as well as the presence of some level of kinetic re-
solution. For instance, the later event was particularly pronoun-
ced in the preparation of (R)-MPPA and (S)-MPPA bornyl
esters 12a (dr 87:13) and 12b (dr 79:21).
According to the protocol for determining the absolute
configuration of secondary alcohols via the double derivatiza-
tion Mosher method,1,2,6 the relative sign of the chemical shift
1
difference for ligands L1 and L2 (ΔδSR), obtained from H
NMR spectra of the R*O-(S)-MPPA and R*O-(R)-MPPA
esters (4−23), will indicate the absolute configuration of the
chiral carbinol. As can be seen, these alcohols comprise a wide
structural diversity including cyclic, open chain, and benzylic
secondary alcohols. The numbers attached to structures (4−23)
in Table 1 reveal all ΔδSR values obtained from the synthesized
R*O-(S)-MPPA and R*O-(R)-MPPA pairs of esters, where
blue (positive) values are those resulting from ΔδSR(L2) =
[δ(L2) R*O-(S)-MPPA] − [δ(L2) R*O-(R)-MPPA] and red
(negative) values result from ΔδSR(L1) = [δ(L1) R*O-(S)-
MPPA] − [δ(L1) R*O-(R)-MPPA].
Complete consistency between the known absolute config-
uration of the tested carbinols and the ΔδSR values for ligands
L1 and L2 belonging to their respective esters is the first point
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a
Table 1. Representative MPPA Esters and Amides of Chiral Alcohols and Amines, of Known Absolute Configuration
a
Negative (red) and positive (blue) values are ΔδSR values for molecular regions representing ligands L1 and L2, respectively, which systematically
agree with the absolute configuration of tested chiral alcohols and amines. Projections of esters R*O-(S)-MPPA and R*O-(R)-MPPA 4−23, as well
as amides R*NH-(S)-MPPA and R*NH-(R)-MPPA 24−27, are shown in the more stable syn-periplanar (spO, vide infra) and anti-periplanar (ap-Z)2
conformations, respectively. All chemical shifts were recorded in CDCl3 at rt.
conformational analysis of Mosher amides reveals (vide infra)
that the main conformer corresponds to an anti-periplanar
(ap-Z) arrangement (Figure 1).2 Consequently, to maintain Δδ
negative values in ligand L1 and positive in ligand L2, NMR data
must be interpreted as ΔδRS(L1) = [δ(L1) R*NH-(R)-MPPA] −
[δ(L1) R*NH-(S)-MPPA] and ΔδRS(L2) = [δ(L2) R*NH-(R)-
MPPA] − [δ(L2) R*NH-(S)-MPPA], respectively, since in the
resulting ap-Z conformation the relative orientation of phenyl
and propynyl groups, in relation to ligands L1 and L2, are
opposite as compared with the main conformer of the
corresponding esters (Figure 1).
The last row in Table 1 shows the resulting amides along with
their ΔδRS values. In this case, these values are smaller than the
corresponding ΔδSR values for esters as the distance between the
anisotropic groups and ligands L1 and L2 is larger in the ap-Z con-
formation in comparison with the corresponding sp conformation.
However, all ΔδRS values were completely consistent with the
known absolute configuration of the used amines and amino acids.
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L-valine-R* 27, where R* is the corresponding CDA to be used
for comparison. It should be noted that the absolute Δδ values
are shown for convenience, thus comparing only their
magnitudes. As can be seen, the absolute values induced by
MPPA are very similar to those obtained when using its
analogues MPA2 and CFTA7 and clearly improve the values
obtained when using MTPA2,8 and MAA.2,9
It is well-known that the success of this methodology for the
assignment of absolute configuration relies on the assumption
that conformers such as those shown in Figure 1 are the
predominant ones within the overall conformational distribu-
tion of esters and amides.2,6 For instance, MTPA esters give rise
to six conformers out of which the syn- (sp1) and anti-
periplanar (ap1) are the most abundant ones.2 According to
previous theoretical studies of MTPA esters,2−6 a thorough
conformational search was carried out on (S)-s-Bu-(R)-MPPA
and (S)-s-Bu-(S)-MPPA esters (22).10 The search showed that
the sec-butyl fragment conformation in both esters is essentially
the same as that shown in Figure 1, that is, the C−H bond of
the secondary carbon is coplanar and syn with respect to the
carbonyl CO bond. In addition, it was found that rotation of
the OC−Cα bond in each ester leads to two distinct sets of
conformers (Figure 3). The most stable set corresponds to the
approximately syn-periplanar arrangement of the methoxy
group with respect to the carbonyl group, which is designated
as the sp(O) conformer (Figure 3).
Figure 2. Spectral regions for esters 14a and 14b formed with (3R)-3-
hydroxyfurane and (R)-MPPA (top) and (S)-MPPA (bottom) acids,
respectively. See Table 1 for the corresponding ΔδSR values.
Table 2 shows a comparison between the ΔδSR values ob-
tained in this work and those ΔδSR values obtained by using the
most known phenyl-derived CDAs bearing the same carbinol
and amine moiety: (R)-menthol-R* 10, (R)-phenetole-R* 6,
(R)-borneol-R* 12, s-BuO-R* 22, i-PrO-R* 23, methylbenzyl
amine-R* 24, (+)-2-bornyl amine-R* 25, L-serine-R* 26, and
Table 2. ΔδSR or ΔδRS Absolute Values for Esters and Amides Derived from Some of the Most Common Described Phenyl-
Containing CDAs and Their Comparison with ΔδSR and ΔδRS Values Obtained in This Work
a
CDA, ΔδSR or ΔδRS (ppm)
b
c
alcohol/amine
i-PrOH
substituent
MTPA
0.07
MPA
MAA
CFTA
0.14
MPPA
0.09
Me
0.12
0.13
0.11
0.23
0.21
0.26
0.05
0.15
0.05 (0.082)
0.006 (0.093)
s-BuOH
H-1
0.08
0.12
H-3
0.05/0.04
0.11
0.10/0.11
0.22
H-4
0.009 (0.147)
0.024 (0.183)
0.019 (0.154)
0.003 (0.035
0.005 (0.074)
0.21
(R)-menthol
Me-8
Me-9
Me-10
Me
0.17
0.21
0.21
0.04
0.25
0.24
0.07
0.06
0.05
(R)-phenetol
(R)-borneol
0.06
0.10
0.11
H-ortho
H-3
0.03
0.25
0.26
0.10
0.39
0.06
0.27
0.33
0.28
H-4
0.03
(0.043)
0.10
0.06
Me-10
H-3
0.08
0.0035 (0.134)
0.22
0.21
(+)-2-bornyl amine
L-valine methyl ester
L-serine methyl ester
0.07
0.048/0.071
0.013
H-4
0.02
Me-8
Me-10
OMe
H-3
0.022
0.078
0.017
0.084
0.189
0.08
0.0146
0.037
0.08
Me (i-Pr)
Me (i-Pr)
OMe
H-3
0.111
0.103
0.022
0.07
0.026
0.095/0.083
a
All ΔδSR and ΔδRS values were obtained in CDCl3 and are expressed as absolute values. Comparative values of CDAs other than MPPA were taken
b
c
from ref 2. Values for MPA correspond to ΔδRS. Values in brackets were obtained in CCl4.
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Figure 3. Relative energies (kcal/mol) between syn-periplanar sp(O) and sp(C) conformers of (S)-s-Bu-(R)-MPPA ester obtained through Cα-CO
and Cα-Ph rotations. The aromatic carbon labeled with a yellow dot shows the equivalence between both conformers sp(O), as well as between both
conformers sp(C), in the range 0−180° and 180−360°. The relative stability of these four conformers is also shown in the contour plots of the potential
energy surface illustrated at the left-hand side of this figure.
In the second set, the 1-propynyl group also attains a syn-
periplanar position with respect to the carbonyl, and therefore
this one was designated as the sp(C) conformer. Although in
both conformations the phenyl group would exert similar
shielding effects on both L1 and L2 groups, a fact that would
lead to poor ΔδSR values and to an inaccurate assignment of the
absolute configuration, the relative stability of the sp(O) and
sp(C) conformers is such that, according to B3LYP/6-31G(d)
relative energies, the total population of the sp(O) conformers
of the (S)-s-Bu-(R)-MPPA is 90%. For the (S)-s-Bu-(S)-MPPA
diastereomer, the population of the sp(C) conformers is lower,
about 71%. The predominance of the sp(O) conformers in both
derivatives would lead to sufficiently large ΔδSR values with the
expected sign, which would be expected to correlate with the
correct absolute configuration of the carbinol moiety. Figure 3
also shows the relative stability between sp(O) and sp(C)
conformers (0.41 kcal/mol), which were generated by rotating
Cα−Ph and Cα−CO bonds while maintaining the conformation
of the carbinol moiety unchanged;11 the resulting potential
energy surface from this conformational search are also illu-
strated in both 3D and contour plots perspectives. Interestingly,
the corresponding anti-periplanar conformers where the OMe
group is anti to the carbonyl (Figure 1) are almost negligible in
this case, resulting in a clear contrast with CDAs bearing OMe
group at Cα, for instance, MPA.
Concerning amides, a conformational search of the amide
derived from (R)-sec-butyl amine and (R)-MPPA acid, by using
the Monte Carlo method and the Molecular Mechanics Force
Field MMFF94 (Spartan 10, V1.0.1), afforded 15 conformers
under 10 kcal/mol, from which ca. 19% adopt an ap-Z con-
formation in a similar way as MPA amide derivatives behave,2
while the remaining ca. 81% takes an sp(C) arrangement related
to the sp(C) conformer found for MPPA esters (Figure 3).
In Figure 4 are shown the structures of both conformers; in
the former one the OMe and CO groups are anti-
periplanar, while in the later the propynyl and CO groups are
syn-periplanar. It can be observed that the anisotropic
Figure 4. (a) ap-Z and (b) sp(C) conformers found for MPPA-amides.
MMFF (Monte Carlo) calculations showed that sp(C) is the major
conformer.
contribution of the propynyl group should be lower in
conformer sp(C); however, the phenyl group orientation is
always on the same side of ligand L1 in both conformers, thus
maintaining a consistent shielding effect. No sp(O) conformer
similar to that for esters was found under the above energy
range.
CONCLUSIONS
■
Although currently there are growing alternatives to determine
the absolute configuration of chiral compounds, e.g., vibrational
circular dichroism (VCD),12 the combined double derivatiza-
tion and NMR measurements so far remains one of the most
reliable methodologies to accomplish this task. In this sense,
this work contributes with a robust protocol for the synthesis of
novel (R)- and (S)-MPPAs and introduces their use as CDAs in
the assignment of the absolute configuration of a representative
number of chiral secondary alcohols. The ΔδSR values were all
in agreement with the correct absolute configuration of the
carbinol moiety. The magnitude of the ΔδSR values found (0.1−
0.4 ppm) for all R*O-(S)-MPPA and R*O-(R)-MPPA esters
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1H, J = 9.9, 5.1 Hz, H-10a), 3.76 (dq, 1H, J = 9.6, 7.1 Hz, H-1′a),
3.71 (s, 1H, OH), 3.61 (t, 1H, J = 9.9 Hz, H-10b), 3.41 (ddd, 1H, J =
9.5, 8.7. 5.7 Hz, H-3), 3.22 (dq, 1H, J = 9.6, 7.1 Hz, H-1′b), 2.59 (m,
1H, H-4e), 2.41 (dtd, 1H, J = 9.8, 6.1, 2.1 Hz, H-7e), 2.24 (td, 1H, J =
6.1, 1.8 Hz, H-1), 2.12 (ddd, 1H, J = 13.4, 5.7, 2.5 Hz, H-4a), 2.12 (m,
1H, H-2), 2.94 (tt, 1H, J = 6.1, 2.5 Hz, H-5), 1.93 (s, 3H, Me-15), 1.21
(s, 3H, Me-9), 1.02 (d, 1H, J = 9.8 Hz, H-7a), 0.96 (t, 3H, J = 7.1 Hz,
(4−23) is very similar to those described for the most
recommended CDA, MPA2 and CFTA.7 However, it must
be emphasized that synthesis of the latter involves a more
elaborated protocol, comprising resolution of a racemic mix-
ture, than preparation of MPPA and, in contrast to MPA,
MPPA esters were successfully prepared under different
reaction conditions without racemization because of their lack
of “racemizable” alpha protons. Our acids are particularly
suitable for the assignment of absolute configuration of chiral
α-aryl secondary alcohols in cases where other CDA fails2,9b,13
and are comparable with CFTA in this regard. Finally, all above
results strongly indicate that the structural features of MPPA
acids, bearing the two divergent anisotropic phenyl and
propynyl groups, ensures an sp(O) conformational predom-
inance, thus rendering easily measurable ΔδSR values with the
correct signs, which in turn allows for the unequivocal
assignment of the absolute configuration of secondary
alcohols. The shown MPPA amine derivatives 24−27 also dem-
onstrated that the present method offers a reliable alternative
to determine the absolute configuration of chiral primary
amines.
H-2′), 0.96 (s, 3H, Me-8), 0.89 (s, 9H, t-Bu), 0.06 (s, 6H, Me2-Si). 13
C
NMR (75.4 MHz, CDCl3): δ 141.5 (C-i), 127.8 (C-p), 127.6 (C-m),
126.6 (C-o), 94.5 (C-11), 82.6 (C-13), 80.1 (C-14), 73.9 (C-12), 65.7
(C-1′), 65.6 (C-10), 52.6 (C-2), 42.2 (C-1), 42.2 (C-5), 39.3 (C-4),
38.4 (C-6), 35.7 (C-3), 33.4 (C-7), 27.6 (Me-9), 26.0 (t-Bu), 23.4
(Me-8), 18.4 (C-Si), 14.4 (Me-2′), 4.0 (Me-15), −5.2 (Me-Si), −5.3
(Me-Si). IR (CH2Cl2) νmax: 3446, 3060, 2928, 2855, 1470, 1449, 1385,
1361, 1254, 108, 837, 777, 698 cm−1. MS (EI) m/z (%): 485 ([M −
OH]+·, 6.2), 456 ([M − EtOH]+·, 12.1), 357 ([M − PhC(OH)-
CCMe]+·, 24), 265 (44), 135 (100). HRFABMS calcd for
C29H46O3SSi + Na: 525.2835, found 525.2825.
(1S,2R,3S,5R)-2-(O-tert-Butyldimethylsilyloxymethylen)-6,6-
dimethyl-3-[(1S,2S)-1-ethoxy-2-phenyl-2-hydroxy-3-pentyn-1-
sulfanyl)]-bicyclo-[3.1.1]-heptane (3b). Obtained in 98% yield
(>99:<1 dr) as colorless syrup (Rf 0.32, hexane/ethyl ether 9:1).
[α]23D = +36.6 (c 0.624, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.71
(m, 2H, H-o), 7.33 (m, 3H, H-m,p), 4.47 (s, 1H, H-11), 3.84 (dq, 1H,
J = 9.4, 7.1 Hz, H-1′a), 3.73 (s, 1H, OH), 3.62 (dd, 1H, J = 9.6, 5.3 Hz,
H-10a), 3.43 (t, 1H, J = 9.6 Hz, H-10b), 3.25 (dq, 1H, J = 9.4, 7.1 Hz,
H-1′b), 2.77 (ddd, 1H, J = 9.8, 7.9, 5.7 Hz, H-3), 2.58 (m, 1H, H-4e),
2.38 (dtd, 1H, J = 9.8, 6.1, 1.7 Hz, H-7e), 2.16 (ddd, 1H, J = 11.1, 5.7,
2.7 Hz, H-4a), 2.04 (m, 1H, H-1), 2.04 (m, 1H, H-2), 1.93 (tt, 1H, J =
6.1, 2.7 Hz, H-5), 1.91 (s, 3H, Me-15), 1.18 (s, 3H, Me-9), 1.04 (d,
1H, J = 9.8 Hz, H-7a), 1.03 (t, 3H, J = 7.1 Hz, Me-2′), 0.90 (s, 9H,
t-Bu), 0.87 (s, 3H, Me-8), 0.07 (s, 3H, Me-Si), 0.06 (s, 3H, Me-Si).
13C NMR (75.4 MHz, CDCl3): δ 141.4 (C-i), 127.7 (C-p), 127.5 (C-m),
126.6 (C-o), 94.9 (C-11), 82.0 (C-13), 80.0 (C-14), 74.8 (C-12), 65.7
(C-10), 65.3 (C-1′), 52.7 (C-2), 42.3 (C-1), 42.1 (C-5), 39.1 (C-4),
38.1 (C-6), 36.9 (C-3), 33.1 (C-7), 27.5 (Me-9), 26.0 (t-Bu), 23.3
(Me-8), 18.4 (C-Si), 14.4 (Me-2′), 3.9 (Me-15), −5.2 (Me-Si), −5.3
(Me-Si). IR (CH2Cl2) νmax: 3460, 3060, 2927, 2855, 1472, 1450, 1385,
1361, 1254, 1079, 837, 777, 699 cm−1. MS (EI) m/z (%): 485 ([M −
OH]+·, 3.5), 456 ([M − EtOH]+·, 8.8), 357 ([M − PhC(OH)-
CCMe]+·, 41.8), 265 (42.4), 135 (100). HRFABMS calcd for
C29H46O3SSi + Na: 525.2835, found 525.2839.
Preparation of S,O-Acetals 3c and 3d. To a solution of alcohol
3a (4.05 g, 8.0 mmol) and methyl iodide (3.43 g, 24.2 mmol) in dry
THF (20 mL) was added sodium hydride (644 mg, 60% dispersion in
mineral oil, 16.1 mmol) under N2 atmosphere. The reaction mixture
was stirred for 2 h at room temperature and quenched with methanol.
Saturated aqueous NH4Cl and NaCl were added successively and
extracted with ethyl ether. The ethereal layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude mix-
ture was filtered through a silica gel column (hexane/ethyl ether 9:1)
affording methyl ether 3c (4.04 g, >95%) as a colorless oil.
(1S,2R,3S,5R)-2-(O-tert-Butyldimethylsilyloxymethylen)-6,6-
dimethyl-3-[(1R,2R)-2-methoxy-1-ethoxy-2-phenyl-3-pentyn-1-
sulfanyl)]-bicyclo-[3.1.1]-heptane (3c). Obtained in 97% yield
(>99:<1 dr) as colorless syrup (Rf 0.54, hexane/ethyl ether 9:1).
[α]25D = +53.3 (c 0.59, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.63
(m, 2H, H-o), 7.33 (m, 3H, H-m,p), 4.64 (s, 1H, H-11), 3.80 (dd, 1H,
J = 9.8, 4.3 Hz, H-10a), 3.58 (dq, 1H, J = 9.6, 7.1 Hz, H-1′a), 3.56 (t,
1H, J = 9.8 Hz, H-10b), 3.23 (dq, 1H, J = 9.6, 7.1 Hz, H-1′b), 3.23 (s,
3H, OMe), 3.06 (ddd, 1H, J = 9.5, 8.3, 5.8 Hz, H-3), 2.46 (m, 1H,
H-4e), 2.35 (dtd, 1H, J = 9.6, 6.0, 1.9 Hz, H-7e), 2.24 (td, 1H, J = 6.0,
2.0 Hz, H-1), 2.11 (ddd, 1H, J = 13.8, 5.8, 2.7 Hz, H-4a), 2.05 (m, 1H,
H-2), 2.01 (s, 3H, Me-15), 1.90 (tt, 1H, J = 6.0, 2.7 Hz, H-5), 1.18 (s,
3H, Me-9), 1.06 (d, 1H, J = 9.6 Hz, H-7a), 0.92 (s, 3H, Me-8), 0.92 (t,
3H, J = 7.1 Hz, Me-2′), 0.87 (s, 9H, t-Bu), 0.04 (s, 6H, Me2-Si). 13C
NMR (75.4 MHz, CDCl3): δ 139.6 (C-i), 127.9 (C-p), 127.8 (C-m),
127.7 (C-o), 92.3 (C-11), 86.1 (C-13), 82.9 (C-14), 76.2 (C-12), 65.6
(C-1′), 65.3 (C-10), 52.2 (OMe), 52.1 (C-2), 42.2 (C-5), 41.9 (C-1),
38.5 (C-6), 34.4 (C-4), 34.9 (C-3), 33.0 (C-7), 27.6 (Me-9), 26.0
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out under a
nitrogen atmosphere in oven- or flame-dried glassware, unless the
reaction procedure states otherwise. Tetrahydrofuran (THF) and
ether (Et2O) were distilled from sodium−benzophenone in a
continuous still under an atmosphere of nitrogen. Dichloromethane
was distilled from calcium hydride in a still under an atmosphere of
nitrogen. Room temperature reactions were carried out between 20
and 25 °C, and reactions at −78 °C were carried out in an acetone−
dry ice bath. Analytical thin-layer chromatography (TLC) was
performed using precoated TLC plates with Silica Gel 60 F254 and
visualized using combinations of UV, anisaldehyde, and ceric
ammonium molybdate (CAM) staining. Flash column chromatog-
raphy was performed using silica gel (230−400 mesh) as the stationary
phase. Proton magnetic resonance spectra were recorded at 300 and
500 MHz, as specified. Carbon magnetic resonance spectra were
recorded at 75 and 125 MHz, as specified. Chemical shifts were
reported in δ units relative to tetramethylsilane using the residual
solvent signal for reference (CDCl3 Δδ 7.27 and 77.0 ppm for proton
1
and carbon, respectively). Peak assignments of the H and 13C NMR
spectra were confirmed by using 2D NMR experiments (gCOSY,
NOESY-1D, gHSQC, and gHMBC). IR spectral data were obtained
using CH2Cl2 as solvent. Optical rotations were measured in solutions
of CHCl3 using the sodium D line (589 nm). High resolution mass
spectral data were obtained using either of the following ionization
methods: HREIMS, HRESIMS (Micro-TOF), or HRFABMS.
Preparation of S,O-Acetals 3a and 3b. A solution of S,O-acetals
1a and 1b (3.75 g, 8.0 mmol) in dry THF (32 mL) at −78 °C was
treated with propynylmagnesium bromide (32 mL, 0.5 M in THF,
16.1 mmol) and stirred at −78 °C for 2 h. The reaction mixture was
quenched with aqueous NH4Cl (3 mL). The resulting mixture was
allowed to warm to room temperature, diluted with saturated solution
of NaCl, and extracted with diethyl ether. The ethereal layer was dried
(Na2SO4) and concentrated to give the corresponding pure alcohols
3a or 3b (3.88 g, >99%, dr > 99:<1) as colorless oils. When the
reaction was performed with the mixture of both S,O-acetals 1a and
1b, a mixture of the above carbinols was obtained. The two products
were separated by flash column chromatography (silica gel 230−400,
hexane/diethyl ether 93:7).
(1S,2R,3S,5R)-2-(O-tert-Butyldimethylsilyloxymethylen)-6,6-
dimethyl-3-[(1R,2R)-1-ethoxy-2-phenyl-2-hydroxy-3-pentyn-1-
sulfanyl)]-bicyclo-[3.1.1]-heptane (3a). Obtained in 96% yield
(>99:<1 dr) as colorless syrup (Rf 0.44, hexane/ethyl ether 9:1).
[α]23D = +35.6 (c 0.535, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.70
(m, 2H, H-o), 7.31 (m, 3H, H-m,p), 4.47 (s, 1H, H-11), 3.83 (dd,
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Article
(t-Bu), 23.3 (Me-8), 18.3 (C-Si), 14.8 (Me-2′), 4.0 (Me-15), −5.1
(Me-Si), −5.3 (Me-Si). IR (CH2Cl2) νmax: 3060, 2928, 2855, 1471,
1447, 1387, 1362, 1255, 1075, 837, 775, 699 cm−1. MS (EI) m/z (%):
485 ([M − OMe]+·, 5.3), 357 ([M − PhC(OMe)CCMe]+·, 42.6), 265
(52.8), 159 (100) 135 (99.1). HRFABMS calcd for C30H48O3SSi +
Na: 539.2991, found 539.3011.
(1S,2R,3S,5R)-2-(O-tert-Butyldimethylsilyloxymethylen)-6,6-
dimethyl-3-[(1S,2S)-2-methoxy-1-ethoxy-2-phenyl-3-pentyn-1-
sulfanyl)]-bicyclo-[3.1.1]-heptane (3d). Obtained in 98% yield
(>99:<1 dr) as colorless syrup starting from tertiary alcohol 3b and
(S)-(−)-2-Methoxy-2-phenylpent-3-ynoic Acid. Obtained in
91% yield (91:09 er)5 as colorless syrup [α]25 = −42.4 (c 1.65,
D
CHCl3). 1H NMR (500 MHz, CDCl3): δ 9.22 (s, 1H, OH), 7.65 (m,
2H, H-o), 7.36 (m, 3H, H-m,p), 3.36 (s, 3H, OMe), 2.01 (s, 3H, Me-5).
13C NMR (125 MHz, CDCl3): δ 171.4 (C-1), 136.6 (C-i), 129.2
(C-p), 128.5 (C-o), 126.9 (C-m), 86.9 (C-3), 80.0 (C-4), 73.2 (C-2),
52.8 (OMe), 3.8 (Me-5). IR (CH2Cl2) νmax: 2939.4, 1737.7, 1450.3,
1215.2, 1093.8, 698.4 cm−1. MS (EI) m/z (%): 204 ([M]+·, 4.1), 189
([M − Me]+·, 2.6), 173 ([M − OMe]+·, 39.2), 159 ([M − CO2H]+·,
100), 115 (16.1). HRESIMS calcd for C12H12O3 + H: calcd 205.0864,
found 205.0861.
following the methodology for the synthesis of ether 3c. (Rf 0.51,
1
hexane/ethyl ether 9:1). [α]25 = +186.8 (c 0.48, CHCl3). H NMR
D
Preparation of MPPA Esters 4−23. To a solution of acids (R)-
(+)-2 or (S)-(−)-2 (1 equiv), the chiral alcohol (1.1 quiv), and DMAP
(1.5 equiv) in dry dichloromethane (5 mL/50 mg of the acid) was
added 1.1 equiv of DCC at room temperature. The reaction mixture
was stirred for 24 h, then filtered, diluted with dichloromethane, and
washed with aqueous 5% HCl. The organic layer was dried over
Na2SO4, filtered, and evaporated to dryness to give the crude product.
Column chromatography of the crude product on silica (230−400
mesh) and hexane/ethyl ether as eluant gave the corresponding esters
R*O-(S)-MPPA and R*O-(R)-MPPA.
(1S)-1-Indanyl (R)-2-Methoxy-2-phenylpent-3-ynoate 4a.
Obtained in 56% yield as colorless syrup (Rf 0.47 hexane/AcOEt/
Et2O 85:10:5); dr 95:5. [α]24D = −2.8 (c 0.29, CHCl3). 1H NMR (500
MHz, CDCl3): δ 7.64 (m, 2H, H-o), 7.30 (m, 3H, H-m,p), 7.22 (m,
2H, H-4′,5′), 7.10 (td, 1H, J = 6.9, 2.5 Hz, H-6′), 7.02 (d, 1H, J = 6.9
Hz, H-7′), 6.18 (dd, 1H, J = 7.1, 4.7 Hz, H-1′), 3.38 (s, 3H, OMe),
3.02 (ddd, 1H, J = 16.0, 8.6, 5.4 Hz, H-3a′), 2.82 (ddd, 1H, J = 16.0,
8.4, 5.4 Hz, H-3b), 2.48 (dddd, 1H, J = 13.8, 8.4, 7.1, 5.4 Hz, H-2a′),
2.02 (dddd, 1H, J = 13.8, 8.6, 5.9, 4.7 Hz, H-2b′), 1.98 (s, 3H, Me-5).
13C NMR (125 MHz, CDCl3): δ 169.4 (C-1), 144.0 (C-i′), 140.3
(C-i′), 138.2 (C-i), 128.8 (C-p), 128.5 (C-5′), 128.1 (C-m), 126.6
(C-o), 126.5 (C-6′), 125.2 (C-7′), 124.6 (C-4′), 85.7 (C-3), 80.5 (C-4),
80.0 (C-1′), 74.4 (C-2), 53.0 (OMe), 31.9 (C-2′), 30.0 (C-3′), 3.8
(Me-5). IR (CH2Cl2) νmax: 1737, 1236, 1093, 756 cm−1. MS (EI) m/z
(%): 159 ([M − CO2C9H9]+·, 100), 128 (2.7), 117 ([indanyl]+·, 20),
105 (5), 67 (2.5). HRESIMS: calcd for C21H20O3 + Na: 343.1310,
found 343.1316.
(1S)-1-Indanyl (S)-2-Methoxy-2-phenylpent-3-ynoate 4b.
Obtained in 49% yield as colorless syrup (Rf 0.47 hexane/AcOEt/
Et2O 85:10:5); dr 93:7. [α]25D = +1.2 (c 0.31, CHCl3). 1H NMR (500
MHz, CDCl3): δ 7.66 (m, 2H, H-o), 7.32 (m, 3H, H-m,p), 7.28 (m,
2H, H-5′,7′), 7.23 (m, 1H, H-4′), 7.18 (m, 1H, H-6′), 6.21 (dd, 1H, J =
7.1, 4.4 Hz, H-1′), 3.39 (s, 3H, OMe), 2.96 (ddd, 1H, J = 16.1, 8.6, 5.6
Hz H-3a′), 2.80 (ddd, 1H, J = 16.0, 8.3, 5.8 Hz, H-3b′), 2.41 (dddd,
1H, J = 13.8, 8.3, 7.1, 5.6 Hz, H-2a′), 1.96 (s, 3H, Me-5), 1.86 (dddd,
1H, J = 13.8, 8.6, 5.8, 4.4 Hz, H-2b′). 13C NMR (125 MHz, CDCl3): δ
169.4 (C-1), 144.1 (C-i′), 140.4 (C-i′), 138.1 (C-i), 128.8 (C-p), 128.6
(C-5′), 128.1 (C-m), 126.7 (C-o), 126.6 (C-6′), 125.3 (C-7′), 124.6
(C-4′), 85.8 (C-3), 80.5 (C-4), 80.0 (C-1′), 74.4 (C-2), 53.0 (OMe),
31.8 (C-2′), 30.0 (C-3′), 3.7 (Me-5). IR (CH2Cl2) νmax: 1737, 1236,
1093, 757 cm−1. MS (EI) m/z (%): 159 ([M − CO2C9H9]+·, 100), 128
(2.7), 117 ([indanyl]+·, 15), 105 (5), 67 (0.7). HRESIMS: calcd for
C21H20O3 + Na: 343.1310, found 343.1311.
(300 MHz, CDCl3): δ 7.64 (m, 2H, H-o), 7.31 (m, 3H, H-m,p), 4.56
(s, 1H, H-11), 3.78 (dd, 1H, J = 10.1, 3.9 Hz, H-10a), 3.75, (dq, 1H,
J = 9.4, 7.0 Hz, H-1′a), 3.50 (t, 1H, J = 10.1 Hz, H-10b), 3.31 (dq, 1H,
J = 9.4, 7.0 Hz, H-1′b), 3.26 (s, 3H, OMe), 2.85 (ddd, 1H, J = 9.8, 8.3,
6.1 Hz, H-3), 2.54 (m, 1H, H-4e), 2.37 (tdt, 1H, J = 10.0, 6.0, 1.8 Hz,
H-7e), 2.23 (td, 1H, J = 6.0, 1.9 Hz, H-1), 2.17 (ddd, 1H, J = 13.7, 6.1,
2.6 Hz, H-4a), 2.01 (m, 1H, H-2), 2.01 (s, 3H, Me-15), 1.92 (tt, 1H,
J = 6.0, 2.6 Hz, H-5), 1.19 (s, 3H, Me-9), 1.01 (d, 1H, J = 10.0 Hz,
H-7a), 1.00 (t, 3H, J = 7.0 Hz, Me-2′), 0.92 (s, 3H, Me-8), 0.90 (s, 9H,
t-Bu), 0.06 (s, 6H, Me2-Si). 13C NMR (75.4 MHz, CDCl3): δ 139.3
(C-i), 128.0 (C-p), 127.8 (C-m), 127.5 (C-o), 92.9 (C-11), 85.3
(C-13), 83.6 (C-14), 76.6 (C-12), 65.1 (C-10), 64.8 (C-1′), 52.8 (C-2);
52.1 (OMe), 42.3 (C-5), 41.9 (C-1), 38.8 (C-4), 38.4 (C-6), 37.0
(C-3), 33.4 (C-7), 27.7 (Me-9), 26.0 (t-Bu), 23.2 (Me-8), 18.4 (C-Si),
14.5 (Me-2′), 3.9 (Me-15), −5.1 (Me-Si), −5.2 (Me-Si). IR (CH2Cl2)
νmax: 3060, 2928, 2855, 1471, 1448, 1386, 1362, 1254, 1080, 837, 775,
706 cm−1. MS (EI) m/z (%): 485 ([M − OMe]+·, 10.5), 357 ([M −
PhC(OMe)CCMe]+·, 52.6), 265 (51.8), 159 (100) 135 (99.7).
HRFABMS calcd for C30H48O3SSi + Na: 539.2991, found 539.3010.
Preparation of MTPA Acids (R)-(+)-2 and (S)-(−)-2. A suspen-
sion of NCS (1.9 g, 14.4 mmol) and AgNO3 (2.5 g, 14.4 mmol) in
CH3CN/H2O 1:1 (18.0 mL) cooled at 0 °C was added to a solution of
adducts 3c or 3d (3.7 g, 7.2 mmol) in CH3CN (18.0 mL) previously
cooled at 0 °C. The reaction mixture was stirred for 10 min at 0 °C
and quenched by successively adding saturated solutions of NaCl,
Na2SO3, and NaHCO3 (3.0 mL). The slurry was filtered in vacuo,
solids were washed with cold diethyl ether, and then the filtrate was
diluted with saturated NaHCO3 and extracted with diethyl ether. The
combined organic layers were washed with saturated aqueous NaCl
and dried over Na2SO4, and the solvent was distilled in a rotary
evaporator at 46 °C and atmospheric pressure. The residue was dis-
solved in 200 mL of acetone, cooled at 0 °C, and treated with Jones’
reagent (10.6 mL, 1.16 M (7.0 g of CrO3, 6.0 mL of H2SO4 and water
to make up 60.0 mL of solution), 14.4 mmol). The reaction mixture
was stirred for 1 h at the same temperature and quenched with
isopropanol; the clear supernatant was decanted and evaporated to
give the crude product. The residue was dissolved in ethyl ether and
washed with water, and then the organic layer was dried (Na2SO4),
filtered, and concentrated to dryness. The crude product was dissolved
in hexane/ethyl ether 1:1 and transferred to a separatory funnel,
saturated aqueous NaHCO3 was added until no gas was produced, and
if necessary water was added in order to make a suitable volume. Then
the aqueous layer was washed with hexane/ethyl ether 1:1 (2 × 30 mL),
acidified with concentrated HCl (pH = 3), and extracted with hexane/
ethyl ether/dichloromethane 1:1:1. The organic layer was dried over
Na2SO4, filtered, and concentrated to dryness to yield acid (R)-(+)-2
(1.32 g, 90% yield) as a colorless syrup.
(1R,2S)-1-(2-Phenyl)cyclohexanyl (R)-2-Methoxy-2-phenyl-
pent-3-ynoate 5a. Obtained in 43% yield as colorless syrup (Rf
1
0.51 hexane-Et2O 4:1) ; dr 97:3. [α]25 = −47.2 (c 0.37, CHCl3). H
D
NMR (500 MHz, CDCl3): δ 7.41 (m, 2H, H-o), 7.23 (m, 3H, H-m,p),
7.23 (m, 3H, H-m′), 7.17 (m, 2H, H-o′,p′), 5.03 (td, 1H, J = 10.8, 4.4
Hz, H-1′), 3.17 (s, 3H, OMe), 2.69 (ddd, 1H, J = 12.7, 10.8, 3.8 Hz,
H-2′), 1.97 (m, 1H, H-6e′), 1.90 (m, 1H, H-3e′), 1.84 (s, 3H, Me-5),
1.78 (m, 1H, H-4e′), 1.74 (m, 1H, H-5e′), 1.52 (qd, 1H, J = 12.7, 3.5 Hz,
H-3a′), 1.43 (qt, 1H, J = 12.7, 3.2 Hz, H-5a′), 1.30 (qt, 1H, J = 12.7,
3.3 Hz, H-4a′), 1.25 (m, 1H, H-6a′). 13C NMR (125 MHz, CDCl3): δ
168.5 (C-1), 142.8 (C-i′), 138.2 (C-i), 128.3 (C-p′), 128.1 (C-m),
128.0 (C-o), 127.5 (C-o′), 126.4 (C-m′), 126.3 (C-p), 85.2 (C-3),
80.2 (C-4), 77.6 (C-1′) 74.2 (C-2), 52.8 (OMe), 49.3 (C-2′), 34.0
(C-3′), 31.5 (C-6′), 25.6 (C-4′), 24.5 (C-5′), 3.6 (Me-5). IR (CH2Cl2)
νmax: 2932, 1739, 1449, 1239, 1091, 757, 697 cm−1. HREIMS calcd for
C24H26O3: 362.1882, found 362.1880.
(R)-(+)-2-Methoxy-2-phenylpent-3-ynoic Acid. Obtained in
90% yield (91:09 er)5 as colorless syrup [α]25 = +42.6 (c 1.51,
D
1
CHCl3). H NMR (500 MHz, CDCl3): δ 9.22 (s, 1H, OH), 7.65 (m,
2H, H-o), 7.36 (m, 3H, H-m,p), 3.36 (s, 3H, OMe), 2.01 (s, 3H, Me-5).
13C NMR (125 MHz, CDCl3): δ 171.4 (C-1), 136.6 (C-i), 129.2
(C-p), 128.5 (C-o), 126.9 (C-m), 86.9 (C-3), 80.0 (C-4), 73.2 (C-2),
52.8 (OMe), 3.8 (Me-5). IR (CH2Cl2) νmax: 2939.6, 1738.9, 1450.3,
1215.6, 1093.9, 698.6 cm−1. MS (EI) m/z (%): 204 ([M]+·, 5.3), 189
([M − Me]+·, 4.1), 173 ([M − OMe]+·, 42.9), 159 ([M − CO2H]+·,
100), 115 (20.2). HRESIMS calcd for C12H12O3 + H: 205.0864, found
205.0859.
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Article
(1R,2S)-1-(2-Phenyl)cyclohexanyl (S)-2-Methoxy-2-phenyl-
pent-3-ynoate 5b. Obtained in 40% yield as colorless syrup (Rf 0.51
hexane-Et2O 4:1); dr 96:4. [α]24D = −34.3 (c 0.36, CHCl3). 1H NMR
(500 MHz, CDCl3): δ 7.32 (m, 2H, H-o), 7.21 (m, 1H, H-p′), 7.14
(m, 3H, H-m,p), 7.14 (m, 2H, H-m′), 7.02 (m, 2H, H-o′), 5.03 (td,
1H, J = 10.8, 4.3 Hz, H-1′), 3.06 (s, 3H, OMe), 2.63 (ddd, 1H, J =
12.6, 10.8, 3.7 Hz, H-2′), 2.06 (m, 1H, H-6e′), 1.95 (m, 1H, Me-5),
1.87 (s, 3H, H-3e′), 1.81 (m, 1H, H-4e′), 1.74 (m, 1H, H-5e′), 1.48
(qd, 1H, J = 12.6, 3.7 Hz, H-3a′), 1.45 (qt, 1H, J = 12.6, 3.6 Hz, H-5a′),
1.36 (m, 1H, H-6a′), 1.30 (qt, 1H, J = 12.6, 3.6 Hz, H-4a′). 13C NMR
(125 MHz, CDCl3): δ 168.7 (C-1), 142.7 (C-i′), 138.1 (C-i), 128.2
(C-m), 128.1 (C-p′), 127.9 (C-o), 127.2 (C-o′), 126.24 (C-m′), 126.18
(C-p), 85.2 (C-3), 80.4 (C-4), 77.7 (C-1′) 74.8 (C-2), 52.8 (OMe),
49.2 (C-2′), 34.2 (C-3′), 31.5 (C-6′), 25.6 (C-4′), 24.5 (C-5′), 3.7 (Me-
5). IR (CH2Cl2) νmax: 2932, 1739, 1239, 1091, 757, 697 cm−1.
HREIMS calcd for C24H26O3: 362.1882, found 362.1894.
J = 6.5 Hz, Me-10′), 0.89 (m, 1H, H-4a′). 13C NMR (125 MHz, CDCl3):
δ 168.8 (C-1), 145.3 (C-7′), 138.3 (C-i), 128.4 (C-p), 128.0 (C-m),
126.8 (C-o), 111.6 (C-8′), 85.4 (C-3), 80.4 (C-4), 75.6 (C-1′), 74.7
(C-2), 53.0 (OMe), 50.1 (C-2′), 39.7 (C-6′), 34.0 (C-4′), 31.3 (C-5′),
30.6 (C-3′), 22.0 (Me-10′), 19.4 (Me-9′), 3.8 (Me-5). IR (CH2Cl2)
νmax: 2926, 1737, 1240, 1095 cm−1. MS (EI) m/z (%): 159 ([M −
CO2C10H17]+·, 100), 128 (2.5), 105 (5), 81 (5), 67 (5.7). HRESIMS:
calcd for C22H28O3 + Na: 363.1936, found 363.1945.
(3S)-3-Octinyl (R)-2-Methoxy-2-phenylpent-3-ynoate 8a. Ob-
tained in 76% yield as colorless syrup (Rf 0.56 hexane/AcOEt/Et2O
1
85:10:5); dr 95:5. [α]24 = −49.3 (c 0.15, CHCl3). H NMR (300
D
MHz, CDCl3): δ 7.68 (m, 2H, H-o), 7.36 (m, 3H, H-m,p), 5.33 (td,
1H, J = 6.6, 2.2 Hz, H-3′), 3.42 (s, 3H, OMe), 2.36 (d, 1H, J = 2.2 Hz,
H-1′), 2.01 (s, 3H, Me-5), 1.74 (m, 2H, H-4′), 1.31 (m, 2H, H-5′), 1.24
(m, 2H, H-6′), 1.22 (m, 2H, H-7′), 0.86 (t, 3H, J = 6.7 Hz, H-8′). 13C
NMR (75.4 MHz, CDCl3): δ 168.5 (C-1), 137.8 (C-i), 128.7 (C-p),
128.2 (C-m), 126.6 (C-o), 85.9 (C-3), 80.4 (C-4), 80.2 (C-2′), 74.3
(C-2), 73.9 (C-1′), 65.3 (C-3′), 53.1 (OMe), 34.2 (C-4′), 31.0 (C-6′),
(1R)-1-(1-Phenyl)ethyl (R)-2-Methoxy-2-phenylpent-3-
ynoate 6a. Obtained in 48% yield as colorless syrup (Rf 0.4,
1
hexane/ethyl ether 4:1); dr 96:4. [α]24 = +15.1 (c 0.56, CHCl3). H
24.2 (C-5′), 22.4 (C-7′), 13.9 (Me-8′), 3.8 (Me-5). IR (CH2Cl2) νmax
:
D
2954, 2931, 1747, 1215, 1093 cm−1. HRESIMS: calcd for C20H24O3:
312.1725, found 312.1726.
NMR (300 MHz, CDCl3): δ 7.68 (m, 2H, H-o), 7.29 (m, 3H, H-m,p),
7.27 (m, 3H, H-m′,p′), 7.27 (m, 2H, H-o′), 5.88 (q, 1H, J = 6.6 Hz, H-
1′), 3.39 (s, 3H, OMe), 2.01 (s, 3H, Me-5), 1.38 (d, 3H, J = 6.6 Hz,
(3S)-3-Octinyl (S)-2-Methoxy-2-phenylpent-3-ynoate 8b. Ob-
13
́
Me-2). C NMR (75.4 MHz, CDCl3): δ 168.1 (C-1), 141.1 (C-i),
tained in 60% yield as colorless syrup (Rf 0.56 hexane/AcOEt/Et2O
1
85:10:5); dr 94:6. [α]19 = −33.1 (c 0.46, CHCl3). H NMR (300
138.0 (C-i), 128.6 (C-p), 128.3 (C-o′ or C-m), 128.2 (C-m or C-o′),
127.6 (C-p′), 126.6 (C-o), 125.6 (C-m′), 85.8 (C-3), 80.4 (C-4), 74.4
(C-2), 73.7 (C-1′), 53.0 (OMe), 21.9 (C-2′), 3.7 (C-5). IR (CH2Cl2)
νmax: 1746.6, 1450.1, 1238.2, 1094.1, 697.7 cm−1. MS (EI) m/z (%):
159 ([M − CO2C8H9]+·, 100), 128 (2.9), 115 (2.9), 105
D
MHz, CDCl3): δ 7.68 (m, 2H, H-o), 7.35 (m, 3H, H-m,p), 5.33 (td,
1H, J = 6.5, 2.2 Hz, H-3′), 3.40 (s, 3H, OMe), 2.43 (d, 1H, J = 2.2 Hz,
H-1′), 2.03 (s, 3H, Me-5), 1.64 (m, 2H, H-4′), 1.18 (m, 2H, H-7′), 1.16
(m, 2H, H-6′), 1.13 (m, 2H, H-5′), 0.81 (t, 3H, J = 6.7 Hz, H-8′). 13C
NMR (75.4 MHz, CDCl3): δ 168.3 (C-1), 137.9 (C-i), 128.7 (C-p),
128.2 (C-m), 126.7 (C-o), 86.2 (C-3), 80.4 (C-4), 80.2 (C-2′), 73.9
(C-2), 73.9 (C-1′), 65.3 (C-3′), 53.3 (OMe), 34.2 (C-4′), 30.9 (C-6′),
([PHCHMe]+·, 15.7), 77 (2.6). HRESIMS calcd for C20H20O3
+
Na: 331.1310, found 331.1311.
(1R)-1-(1-Phenyl)ethyl (S)-2-Methoxy-2-phenylpent-3-
ynoate 6b. Obtained in 44% yield as colorless syrup (Rf 0.4,
24.0 (C-5′), 22.3 (C-7′), 13.8 (Me-8′), 3.8 (Me-5). IR (CH2Cl2) νmax
:
hexane/ethyl ether 4:1); dr 95:05. [α]24 = +186.8 (c 0.42, CHCl3).
2954, 2932, 1748, 1210, 1094 cm−1. HRESIMS: calcd for C20H24O3:
312.1725, found 312.1727.
D
1H NMR (300 MHz, CDCl3): δ 7.63 (m, 2H, H-o), 7.32 (m, 3H,
H-m,p), 7.19 (m, 3H, H-m′,p′), 7.01 (m, 2H, H-o′), 5.85 (q, 1H, J =
6.6 Hz, H-1′), 3.37 (s, 3H, OMe), 2.03 (s, 3H, Me-5), 1.48 (d, 3H, J =
6.6 Hz, Me-2′). 13C NMR (75.4 MHz, CDCl3): δ 168.4 (C-1), 140.9
(2S)-2-Penten-4-yl (R)-2-Methoxy-2-phenylpent-3-ynoate 9a.
Obtained in 45% yield as colorless syrup (Rf 0.50 hexane/AcOEt/
1
Et2O 85:10:5); dr 95:5. [α]21 = +13.0 (c 0.24, CHCl3). H NMR
D
́
(C-i), 137.9 (C-i), 128.6 (C-p), 128.1 (C-m), 128.1 (C-m′), 127.5
(300 MHz, CDCl3): δ 7.66 (m, 2H, H-o), 7.33 (m, 3H, H-m,p), 5.45
(m, 1H, H-4′), 4.95 (q, 1H, J = 6.2 Hz, H-2′), 4.89 (dd, 1H, J = 2.2,
1.1 Hz, H-5a′), 4.85 (m, 1H, H-5b′), 3.39 (s, 3H, OMe), 2.17 (m, 2H,
H-3′), 2.02 (s, 3H, Me-5), 1.19 (d, 3H, J = 6.3 Hz, Me-1′). 13C NMR
(75.4 MHz, CDCl3): δ 168.8 (C-1), 138.2 (C-i), 133.0 (C-4′), 128.5
(C-p), 128.1 (C-m), 126.7 (C-o), 117.7 (C-5′), 85.6 (C-3), 80.4 (C-4),
74.5 (C-2), 72.1 (C-2′), 53.0 (OMe), 39.8 (C-3′), 19.0 (Me-1′), 3.7
(Me-5). IR (CH2Cl2) νmax: 1739, 1239, 1093 cm−1. MS (EI) m/z (%):
159 ([M − CO2C10H17]+·, 100), 128 (2.7), 115 (3.7), 105 (4.9),
67 (4.6). HRESIMS: calcd for C17H20O3 + Na: 295.1310, found
295.1314.
(C-p′), 126.8 (C-o), 125.5 (C-o′), 85.8 (C-3), 80.3 (C-4), 74.3 (C-2), 73.8
(C-1′), 53.4 (OMe), 21.9 (C-2′), 3.8 (C-5). IR (CH2Cl2) νmax: 1747.8,
1450.2, 1239.1, 1095.7, 697.7 cm−1. MS (EI) m/z (%): 159 ([M −
CO2C8H9]+·, 100), 128 (2.8), 115 (2.8), 105 ([PHCHMe]+·, 16.2), 77
(2.4). HRESIMS calcd for C20H20O3 + Na: 331.1310, found 331.1308.
(1R,2S,5R)-1-Isopulegoyl (R)-2-Methoxy-2-phenylpent-3-
ynoate 7a. Obtained in 40% yield as colorless syrup (Rf 0.39
hexane-Et2O 4:1); dr 97:3. [α]22D = −11.2 (c 0.32, CHCl3). 1H NMR
(500 MHz, CDCl3): δ 7.64 (m, 2H, H-o), 7.31 (m, 3H, H-m,p), 4.79
(td, 1H, J = 11.0, 4.4 Hz, H-1′), 4.66 (m, 1H, H-8a′), 4.64 (m, 1H, H-
8b′), 3.37 (s, 3H, OMe), 2.11 (ddd, 1H, J = 12.6, 11.0, 3.7 Hz, H-2′),
1.97 (s, 3H, Me-5), 1.81 (dtd, 1H, J = 12.2, 4.4, 1.8 Hz, H-6e′), 1.67
(m, 1H, H-3e′), 1.63 (m, 1H, H-4e′), 1.58 (dd, 3H, J = 1.4, 0.8 Hz,
Me-9′), 1.49 (ddqd, 1H, J = 16.5, 13.2, 6.6, 4.4 Hz, H-5′), 1.34 (m, 1H,
H-3a′), 0.87 (m, 1H, H-6a′), 0.87 (m, 1H, H-4a′), 0.85 (d, 3H, J = 6.6
Hz, Me-10′). 13C NMR (125 MHz, CDCl3): δ 168.7 (C-1), 145.6 (C-
7′), 138.4 (C-i), 128.4 (C-p), 128.0 (C-m), 126.6 (C-o), 111.7 (C-8′),
85.3 (C-3), 80.4 (C-4), 75.6 (C-1′), 74.7 (C-2), 52.9 (OMe), 50.3 (C-
2′), 39.5 (C-6′), 34.0 (C-4′), 31.2 (C-5′), 30.5 (C-3′), 21.9 (Me-10′),
19.5 (Me-9′), 3.7 (Me-5). IR (CH2Cl2) νmax: 1927, 1738, 1241, 1093
cm−1. MS (EI) m/z (%): 159 ([M − CO2C10H17]+·, 100), 128 (2.7),
105 (5), 81 (5), 67 (6.7). HRESIMS: calcd for C22H28O3 + Na:
363.1936, found 363.1946.
(2S)-2-Penten-4-yl (S)-2-Methoxy-2-phenylpent-3-ynoate 9b.
Obtained in 52% yield as colorless syrup (Rf 0.50 hexane/AcOEt/
1
Et2O 85:10:5); dr 94:6. [α]23 = +9.1 (c 0.12, CHCl3). H NMR
D
(300 MHz, CDCl3): δ 7.66 (m, 2H, H-o), 7.34 (m, 3H, H-m,p), 5.67
(ddt, 1H, J = 17.1, 10.2, 7.0 Hz, H-4′), 5.03 (ddt, 1H, J = 10.2, 1.9, 1.5
Hz, H-5b′), 4.99 (m, 1H, H-5a′), 4.96 (q, 1H, J = 6.3 Hz, H-2′), 3.39
(s, 3H, OMe), 2.26 (m, 2H, H-3′), 2.00 (s, 3H, Me-5), 1.08 (d, 3H, J =
6.3 Hz, Me-1′). 13C NMR (75.4 MHz, CDCl3): δ 168.8 (C-1), 138.2
(C-i), 133.2 (C-4′), 128.2 (C-p), 128.1 (C-m), 126.6 (C-o), 117.7 (C-5′),
85.5 (C-3), 80.4 (C-4), 74.6 (C-2), 72.0 (C-2′), 53.0 (OMe), 39.9 (C-3′),
18.9 (Me-1′), 3.7 (Me-5). IR (CH2Cl2) νmax: 1740, 1241, 1094 cm−1. MS
(EI) m/z (%): 159 ([M − CO2C10H17]+·, 100), 128 (3.0), 115 (2.2),
105 (5.3), 67 (6.4). HRESIMS: calcd for C17H20O3 + Na: 295.1310,
found 295.1316.
(1R,2S,5R)-1-Isopulegoyl (S)-2-Methoxy-2-phenylpent-3-
ynoate 7b. Obtained in 38% yield as colorless syrup (Rf 0.42
hexane-Et2O 4:1); dr 93:7. [α]24D = −11.6 (c 0.08, CHCl3). 1H NMR
(500 MHz, CDCl3): δ 7.61 (m, 2H, H-o), 7.30 (m, 3H, H-m,p), 4.76
(td, 1H, J = 11.0, 4.4 Hz, H-1′), 4.41 (m, 1H, H-8a′), 4.37 (m, 1H, H-
8b′), 3.36 (s, 3H, OMe), 2.01 (m, 1H, H-2′), 2.01 (s, 3H, Me-5), 1.95
(dtd, 1H, J = 12.0, 4.0, 1.6 Hz, H-6e′), 1.63 (m, 1H, H-3e′), 1.59 (m,
1H, H-4e′), 1.51 (m, 1H, H-5′), 1.38 (dd, 3H, J = 1.4, 0.8 Hz, Me-9′),
1.29 (m, 1H, H-3a′), 1.01 (q, 1H, J = 12.0 Hz, H-6a′). 0.90 (d, 3H,
(1S,2R,5S)-Menthyl (R)-2-Methoxy-2-phenylpent-3-ynoate 10a.
Obtained in 45% yield as colorless syrup (Rf 0.54, hexane/ethyl ether
1
4:1); dr 95:5. [α]24 = +63.9 (c 0.52, CHCl3). H NMR (500 MHz,
D
CDCl3): δ 7.65 (m, 2H, H-o), 7.32 (m, 3H, H-m,p), 4.60 (td, 1H, J =
11.6, 4.3 Hz, H-1′), 3.38 (s, 3H, OMe), 2.03 (s, 3H, Me-5), 1.96 (tdt,
1H, J = 11.6, 4.2, 1.9 Hz, H-6a′), 1.63 (m, 1H, H-4a′), 1.56 (dq, 1H, J =
13.2, 3.3 Hz, H-3a′), 1.45 (m, 1H, H-5′), 1.26 (tt, 1H, J = 11.6, 2.6 Hz,
H-2′), 1.09 (sept-d, 1H, J = 7.0, 2.6 Hz, H-7′), 0.98 (q, 1H, J = 11.6 Hz,
1647
dx.doi.org/10.1021/jo2016554 | J. Org. Chem. 2012, 77, 1640−1652

The Journal of Organic Chemistry
Article
H-6b′), 0.93 (dq, 1H, J = 13.2, 3.0 Hz, H-3b′), 0.88 (d, 3H, J = 6.6 Hz,
Me-10′), 0.82 (m, 1H, H-4b′), 0.61 (d, 3H, J = 7.0 Hz, Me-8′), 0.43
(d, 3H, J = 7.0 Hz, Me-9′). 13C NMR (125 MHz, CDCl3): δ 168.8
(C-1), 138.2 (C-i), 128.5 (C-p), 128.0 (C-m), 126.8 (C-o), 85.7 (C-3),
80.3 (C-4), 76.1 (C-1′), 74.4 (C-2), 52.9 (OMe), 46.8 (C-2′), 40.1 (C-
6′), 34.1 (C-4′), 31.3 (C-5′), 25.3 (C-7′), 22.9 (C-3′), 21.9 (C-10′),
20.5 (C-9′), 15.6 (C-8′), 3.8 (Me-5). IR (CH2Cl2) νmax: 2953.2,
1741.1, 1449.5, 1240−5, 1096.4, 1012.9 cm−1. MS (EI) m/z (%): 311
([M − OMe]+·, 2.4), 159 ([M − CO2C10H19]+·, 100), 128 (2.3), 115
(2.5), 105 (3.1). HRESIMS calcd for C22H30O3 + Na: 365.2092, found
365.2098.
Me-10′), 0.63 (dd, 1H, J = 13.9, 3.79 Hz, H-3b′). 13C NMR (75.4
MHz, CDCl3): δ 169.4 (C-1), 138.3 (C-i), 128.5 (C-p), 128.1 (C-m),
126.6 (C-o), 85.4 (C-3), 81.4 (C-2′), 80.3 (C-4), 74.6 (C-2), 53.0
(OMe), 49.0 (C-7′), 47.7 (C-1′), 44.7 (C-4′), 36.0 (C-3′), 27.7 (C-6′),
26.8 (C-5′), 19.5 (Me-9′), 18.8 (Me-8′), 13.3 (Me-10′), 3.7 (Me-5). IR
(CH2Cl2) νmax: 2953.8, 1741.9, 1450.8, 1241.2, 1097.8, 1021.4 cm−1.
MS (EI) m/z (%): 159 ([M − CO2C10H17]+·, 100), 128 (3.5), 115
(3.1), 105 (3.7), 81 (5.5), 67 (4.7). HRESIMS calcd for C22H28O3 +
Na: 363.1936, found 363.1940.
(1S,2R)-Bornyl (S)-2-Methoxy-2-phenylpent-3-ynoate 12b.
Obtained in 49% yield as colorless syrup (Rf 0.42, hexane/ethyl
1
(1S,2R,5S)-Menthyl (S)-2-Methoxy-2-phenylpent-3-ynoate
ether 4:1); dr 71:29. [α]24 = −28.8 (c 0.56, CHCl3). H NMR (300
D
10b. Obtained in 50% yield as colorless syrup (Rf 0.54, hexane/
MHz, CDCl3): δ 7.70 (m, 2H, H-o), 7.34 (m, 3H, H-m,p), 4.81 (ddd,
1H, J = 10.0, 3.0, 2.0 Hz, H-2′), 4.42 (s, 3H, OMe), 2.29 (m, 1H, H-
3a′), 2.03 (s, 3H, Me-5), 1.72 (m, 1H, H-6a′), 1.63 (m, 1H, H-5a′),
1.63 (m, 1H, H-4′), 1.14 (m, 1H, H-5b′), 1.14 (m, 1H, H-6b′), 0.91
(dd, 1H, J = 13.7, 3.8 Hz, H-3b′), 0.84 (s, 3H, Me-9′), 0.81 (s, 3H, Me-
8′), 0.58 (s, 3H, Me-10′). 13C NMR (75.4 MHz, CDCl3): δ 169.4 (C-
1), 138.4 (C-i), 128.5 (C-p), 128.1 (C-m), 126.1 (C-o), 85.5 (C-3),
81.5 (C-2′), 80.4 (C-4), 74.5 (C-2), 53.0 (OMe), 48.9 (C-7′), 47.7 (C-
1′), 44.7 (C-4′), 36.2 (C-3′), 27.8 (C-6′), 26.7 (C-5′), 19.5 (Me-9′),
18.8 (Me-8′), 13.1 (Me-10′), 3.7 (Me-5). IR (CH2Cl2) νmax: 2953.8,
1741.9, 1450.9, 1241.9, 1097.7, 1021.5 cm−1. MS (EI) m/z (%): 159
([M − CO2C10H17]+·, 100) 128 (2.3), 105 (2.6), 81 (2.2), 67 (2.3).
HRESIMS calcd for C22H28O3 + Na: 363.1936, found 363.1935.
(1R,2S,4S)-2-Fenchyl (R)-2-Methoxy-2-phenylpent-3-ynoate
1
ethyl ether 4:1); dr 91:9. [α]26 = +63.0 (c 0.24, CHCl3). H NMR
D
(500 MHz, CDCl3): δ 7.65 (m, 2H, H-o), 7.33 (m, 3H, H-m,p), 4.67
(td, 1H, J = 10.9, 4.4 Hz, H-1′), 3.39 (s, 3H, OMe), 1.99 (s, 3H, Me-5),
1.79 (m, 1H, H-6a′), 1.76 (sept-d, 1H, J = 7.0, 2.8 Hz, H-7′), 1.62
(m, 1H, H-4a′), 1.60 (m, 1H, H-3a′), 1.43 (m, 1H, H-5′), 1.36 (tt, 1H,
J = 11.7, 3.1 Hz, H-2′), 1.00 (qd, 1H, J = 13.0, 3.3 Hz, H-3b′), 0.83 (d,
3H, J = 6.5 Hz, Me-10′), 0.82 (d, 3H, J = 7.0 Hz, Me-8′), 0.79 (m, 1H,
H-6b′), 0.79 (m, 1H, H-4b′), 0.67 (d, 3H, J = 7.0 Hz, Me-9′). 13C
NMR (125 MHz, CDCl3): δ 168.8 (C-1), 138.3 (C-i), 128.5 (C-p),
128.1 (C-m), 126.5 (C-o), 85.4 (C-3), 80.4 (C-4), 76.1 (C-1′), 74.8
(C-2), 52.9 (OMe), 47.0 (C-2′), 39.9 (C-6′), 34.1 (C-4′), 31.3 (C-5′),
25.9 (C-7′), 23.3 (C-3′), 21.9 (C-10′), 20.6 (C-9′), 16.1 (C-8′), 3.6
(Me-5). IR (CH2Cl2) νmax: 2954, 1739, 1450, 1240, 1095, cm−1.
HREIMS calcd for C22H30O3: 342.2195, found 342.2207.
13a. Obtained in 42% yield as colorless syrup (Rf 0.56 hexane/Et2O
1
(1R,2S,5R)-Menthyl (R)-2-Methoxy-2-phenylpent-3-ynoate
4:1); dr 88:12. [α]23 = +21.5 (c 0.28, CHCl3). H NMR (500 MHz,
D
11a. Obtained in 53% yield as colorless syrup (Rf 0.54, hexane/
CDCl3): δ 7.70 (m, 2H, H-o), 7.32 (m, 3H, H-m,p), 4.27 (d, 1H, J =
1.9 Hz, H-2′), 3.42 (s, 3H, OMe), 2.01 (s, 3H, Me-5), 1.67 (m, 1H, H-
4′), 1.62 (m, 1H, H-5a′), 1.51 (m, 1H, H-6a′), 1.49 (m, 1H, H-7a′),
1.38 (tdd, 1H, J = 12.4, 5.7, 4.0 Hz, H-5b′), 1.09 (dd, 1H, J = 10.4, 1.5
Hz, H-7b′), 1.06 (s, 3H, Me-9′), 0.90 (tdd, 1H, J = 12.4, 3.4, 2.0 Hz, H-
6b′), 0.71 (s, 3H, Me-10′), 0.69 (s, 3H, Me-8′). 13C NMR (125 MHz,
CDCl3): δ 169.6 (C-1), 138.6 (C-i), 128.5 (C-p), 128.1 (C-m), 126.7
(C-o), 87.6 (C-2′), 85.5 (C-3), 80.3 (C-4), 74.7 (C-2), 53.0 (OMe),
48.4 (C-1′), 48.3 (C-4′), 41.1 (C-7′), 39.7 (C-3′), 29.5 (Me-9′), 26.2
(C-6′), 25.7 (C-5′), 19.9 (Me-10′), 18.9 (Me-8′), 3.6 (Me-5). IR
(CH2Cl2) νmax: 2956, 1743, 1242, 1098 cm−1. MS (EI) m/z (%): 188
(4.3), 159 ([M − CO2C10H17]+·, 100), 128 (3.2), 105 (4.6), 81 (7.7),
67 (6.7). HRESIMS: calcd for C22H28O3 + Na: 363.1936, found
363.1946.
1
ethyl ether 4:1); dr 97:3. [α]24 = −51.4 (c 0.53, CHCl3). H NMR
D
(500 MHz, CDCl3): δ 7.65 (m, 2H, H-o), 7.33 (m, 3H, H-m,p), 4.67
(td, 1H, J = 11.3, 4.4 Hz, H-1′), 3.39 (s, 3H, OMe), 1.99 (s, 3H, Me-
5), 1.79 (m, 1H, H-6a′), 1.76 (sept-d, 1H, J = 7.0, 2.5 Hz, H-7′), 1.62
(m, 1H, H-4a′), 1.60 (m, 1H, H-3a′), 1.43 (m, 1H, H-5′), 1.36 (tt, 1H,
J = 11.3, 2.5 Hz, H-2′), 1.00 (qd, 1H, J = 13.0, 3.3 Hz, H-3b′), 0.83 (d,
3H, J = 6.5 Hz, Me-10′), 0.82 (d, 3H, J = 7.0 Hz, Me-8′), 0.79 (m, 1H,
H-6b′), 0.79 (m, 1H, H-4b′), 0.67 (d, 3H, J = 7.0 Hz, Me-9′). 13C
NMR (125 MHz, CDCl3): δ 168.8 (C-1), 138.3 (C-i), 128.5 (C-p),
128.1 (C-m), 126.5 (C-o), 85.4 (C-3), 80.4 (C-4), 76.1 (C-1′), 74.8
(C-2), 52.9 (OMe), 47.0 (C-2′), 39.9 (C-6′), 34.1 (C-4′), 31.3 (C-5′),
25.9 (C-7′), 23.3 (C-3′), 21.9 (C-10′), 20.6 (C-9′), 16.1 (C-8′), 3.6
(Me-5). IR (CH2Cl2) νmax: 29534.7 1740.4 1450.5, 1240.4, 1095.9,
999.0 cm−1. MS (EI) m/z (%): 311 ([M − OMe]+·, 2.3), 159 ([M −
CO2C10H19]+·, 100), 128 (2.8), 115 (2.3), 105 (2.6). HRESIMS calcd
for C22H30O3 + Na: 365.2092, found 365.2084.
(1R,2S,4S)-2-Fenchyl (S)-2-Methoxy-2-phenylpent-3-ynoate
13b. Obtained in 40% yield as colorless syrup (Rf 0.56 hexane/Et2O
1
4:1); dr 87:13. [α]22 = −8.1 (c 0.12, CHCl3). H NMR (500 MHz,
D
(1R,2S,5R)-Menthyl (S)-2-Methoxy-2-phenylpent-3-ynoate
CDCl3): δ 7.70 (m, 2H, H-o), 7.33 (m, 3H, H-m,p), 4.32 (d, 1H, J =
1.9 Hz, H-2′), 3.41 (s, 3H, OMe), 2.01 (s, 3H, Me-5), 1.63 (m, 1H, H-
6a′), 1.61 (m, 1H, H-4′), 1.51 (m, 1H, H-7a′), 1.48 (m, 1H, H-5a′),
1.35 (tdd, 1H, J = 12.4, 5.9, 4.0 Hz, H-5b′), 1.12 (dd, 1H, J = 10.3, 1.5
Hz, H-7b′), 1.003 (tdd, 1H, J = 12.4, 3.3, 2.1 Hz, H-6b′), 0.999 (s, 3H,
Me-8′), 0.98 (s, 3H, Me-9′), 0.25 (s, 3H, Me-10′). RMN 13C (125
MHz, CDCl3): δ 169.6 (C-1), 138.4 (C-i), 128.5 (C-p), 128.1 (C-m),
126.9 (C-o), 87.7 (C-2′), 85.5 (C-3), 80.3 (C-4), 74.8 (C-2), 53.0
(OMe), 48.6 (C-1′), 48.2 (C-4′), 41.1 (C-7′), 39.5 (C-3′), 29.5 (Me-
9′), 26.3 (C-6′), 25.6 (C-5′), 19.5 (Me-10′), 19.1(Me-8′), 3.6 (Me-5).
IR (CH2Cl2) νmax: 2956, 17343, 1242, 1098 cm−1. MS (EI) m/z (%):
188 (4.2), 159 ([M − CO2C10H17]+·, 100), 128 (3.0), 105 (4.9), 81
(7.5), 67 (6.5). HRESIMS: calcd for C22H28O3 + Na: 363.1936, found
363.1943.
11b. Obtained in 48% yield as colorless syrup (Rf 0.54, hexane/
1
ethyl ether 4:1); dr 93:7. [α]23 = −65.2 (c 0.18, CHCl3). H NMR
D
(500 MHz, CDCl3): δ 7.65 (m, 2H, H-o), 7.32 (m, 3H, H-m,p), 4.60
(td, 1H, J = 11.6, 4.2 Hz, H-1′), 3.38 (s, 3H, OMe), 2.03 (s, 3H, Me-5),
1.96 (dtd, 1H, J = 11.6, 4.2, 1.9 Hz, H-6a′), 1.63 (m, 1H, H-4a′),
1.56 (dq, 1H, J = 13.2, 3.3 Hz, H-3a′), 1.45 (m, 1H, H-5′), 1.26 (tt, 1H,
J = 11.6, 3.2 Hz, H-2′), 1.09 (sept-d, 1H, J = 7.0, 2.8 Hz, H-7′), 0.98 (q,
1H, J = 11.6 Hz, H-6b′), 0.93 (qd, 1H, J = 13.1, 3.0 Hz, H-3b′), 0.88
(d, 3H, J = 6.6 Hz, Me-10′), 0.82 (m, 1H, H-4b′), 0.61 (d, 3H, J = 7.0
Hz, Me- 8′), 0.43 (d, 3H, J = 7.0 Hz, Me-9′). 13C NMR (125 MHz,
CDCl3): δ 186.8 (C-1), 138.2 (C-i), 128.5 (C-p), 128.1 (C-m), 126.8
(C-o), 85.7 (C-3), 80.3 (C-4), 76.1 (C-1′), 74.4 (C-2), 52.9 (OMe),
46.8 (C-2′), 40.1 (C-6′), 34.1 (C-4′), 31.3 (C-5′), 25.3 (C-7′), 23.0 (C-
3′), 22.0 (C-10′), 20.5 (C-9′), 15.6 (C-8′), 3.8 (Me-5). IR (CH2Cl2)
νmax: 1254, 1740, 1450, 1240, 1096 cm−1. HREIMS calcd for
C22H30O3: 342.2195, found 342.2184.
(3R)-3-Tetrahydrofuranyl (R)-2-Methoxy-2-phenylpent-3-
ynoate 14a. Obtained in 21% yield as colorless syrup (Rf 0.16
hexane/AcOEt/CH2Cl2 8:1:1); dr 95:5. [α]23 = +17.0 (c 0.08,
D
(1S,2R)-Bornyl (R)-2-Methoxy-2-phenylpent-3-ynoate 12a.
CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.66 (m, 2H, H-o), 7.35 (m,
3H, H-m,p), 5.30 (ddt, 1H, J = 6.3, 4.7, 1.7 Hz, H-3′), 3.90 (dd, 1H, J =
10.6, 4.7 Hz, H-2a′), 3.77 (dd, 1H, J = 10.6, 1.7 Hz, H-2b′), 3.76 (td,
1H, J = 8.4, 3.8 Hz, H-5a′), 3.64 (td, 1H, J = 8.4, 6.5 Hz, H-5b′), 3.38
(s, 3H, OMe), 2.03 (m, 1H, H-4a′), 2.02 (s, 3H, Me-5), 1.74 (m, 1H,
H-4b′). 13C NMR (125 MHz, CDCl3): δ 169.1 (C-1), 137.9 (C-i),
128.7 (C-p), 128.3 (C-m), 126.7 (C-o), 86.0 (C-3), 80.3 (C-4), 76.4
(C-3′), 74.1 (C-2), 72.6 (C-2′), 66.9 (C-5′), 53.0 (OMe), 32.6 (C-4′),
Obtained in 41% yield as colorless syrup (Rf 0.42, hexane/ethyl
1
ether 4:1); dr 87:13. [α]24 = −7.4 (c 0.53, CHCl3). H NMR (300
D
MHz, CDCl3): δ 7.69 (m, 2H, H-o), 7.34 (m, 3H, H-m,p), 4.85 (ddd,
1H, J = 10.1, 3.1, 1.9 Hz, H-2′), 3.42 (s, 3H, OMe), 2.20 (m, 1H, H-
3a′), 2.02 (s, 3H, Me-5), 1.81 (ddd, 1H, J = 13.1, 9.3, 3.9 Hz, H-6a′),
1.63 (m, 1H, H-5a′), 1.57 (m, 1H, H-4′), 1.20 (m, 1H, H-6b′), 0.92
(m, 1H, H-5b′), 0.84 (s, 3H, Me-9′), 0.82 (s, 3H, Me-8′), 0.79 (s, 3H,
1648
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3.8 (C-5). IR (CH2Cl2) νmax: 1741, 1239, 1088 cm−1. HREIMS calcd
for C16H18O4: 274.1205, found 274.1213.
(C-8′), 169.9 (OCOMe), 169.4 (C-10′), 168.7 (C-1), 137.9 (C-i),
128.7 (C-p), 128.3 (C-m), 126.8 (C-o), 122.6 (C-9′), 86.6 (C-3), 80.1
(C-4), 76.6 (C-2′), 73.5 (C-2), 71.9 (C-4′), 65.7 (C-6′), 55.6 (C-1′),
53.3 (C-7′), 53.0 (OMe), 48.2 (C-11′), 37.5 (C-5′), 32.6 (C-3′), 26.3
(Me-14′), 23.2 (Me-15′), 21.1 (OCOMe), 20.2 (Me-12′), 19.0 (Me-
13′), 3.7 (Me-5). HREIMS calcd for C29H34O6: 478.2355, found
478.2351.
(3R)-3-Tetrahydrofuranyl (S)-2-Methoxy-2-phenylpent-3-
ynoate 14b. Obtained in 21% yield as colorless syrup (Rf 0.16
hexane/AcOEt/CH2Cl2 8:1:1); dr 96:4. [α]26 = −5.0 (c 0.13,
D
CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.66 (m, 2H, H-o), 7.35 (m,
3H, H-m,p), 5.29 (m, 1H, H-3′), 3.85 (dd, 1H, J = 10.6, 4.8 Hz, H-2a′),
3.81 (td, 1H, J = 8.5, 3.9 Hz, H-5a′), 3.77 (td, 1H, J = 8.5, 6.5 Hz, H-
5b′), 3.59 (dd, 1H, J = 10.6, 0.6 Hz, H-2b′), 3.39 (s, 3H, OMe), 2.10
(m, 1H, H-4a′), 2.02 (s, 3H, Me-5), 1.96 (m, 1H, H-4b′). 13C NMR
(125 MHz, CDCl3): δ 169.2 (C-1), 137.8 (C-i), 128.7 (C-p), 128.3
(C-m), 126.7 (C-o), 86.9 (C-3), 80.3 (C-4), 76.4 (C-3′), 74.2 (C-2),
72.6 (C-2′), 66.9 (C-5′), 53.0 (OMe), 32.7 (C-4′), 3.7 (C-5). IR
(CH2Cl2) νmax: 1740, 1218, 1085 cm−1. HREIMS calcd for C16H18O4:
274.1205, found 274.1212.
3α-Tibolol-3-yl (R)-2-Methoxy-2-phenylpent-3-ynoate 17a.
Obtained in 14% yield as colorless syrup (Rf 0.23 hexane/acetone 4:1);
dr 97:3. [α]26 = +178.0 (c 0.08, CHCl3). 1H NMR (500 MHz,
D
CDCl3): δ 7.67 (m, 2H, H-o), 7.34 (m, 3H, H-m,p), 4.90 (dddd, 1H,
J = 11.4, 9.1, 5.7, 3.4 Hz, H-3′), 3.39 (s, 3H, OMe), 2.57 (s, 1H, H-19′),
2.29 (ddd, 1H, J = 13.8, 9.5, 5.6 Hz, H-16a′), 2.19 (m, 1H, H-4a′), 2.09
(m, 1H, H-1a′), 2.02 (s, 3H, Me-5), 1.97 (m, 1H, H-16b′), 1.92 (m,
1H, H-1b′), 1.78 (m, 1H, H-2a′), 1.55 (m, 1H, H-4b′), 1.40 (m, 1H, H-
2b′), 1.13 (qd, 1H, J = 13.0, 3.9 Hz, H-11b′), 0.85 (s, 3H, Me-21′), 0.76
(d, 3H, J = 7.0 Hz, Me-20′). 13C NMR (125 MHz, CDCl3): δ 169.0
(C-1), 138.4 (C-i), 128.6 (C-10′), 128.5 (C-p), 128.2 (C-m), 126.7
(C-o), 123.4 (C-5′), 87.6 (C-18′), 85.6 (C-3), 80.5 (C-4), 79.9 (C-17′),
74.6 (C-2), 73.8 (C-19′), 72.8 (C-3′), 53.0 (OMe), 47.4 (C-13′), 46.2
(C-14′), 41.6 (C-8′), 39.7 (C-9′), 39.0 (C-16′), 38.5 (C-4′), 36.0 (C-
6′), 33.0 (C-12′), 28.0 (C-2′), 27.1 (C-7′), 26.0 (C-1′), 25.2 (C-11′),
22.0 (C-15′), 12.81 (Me-20′), 12.79 (Me-21′), 3.8 (Me-5). HREIMS
calcd for C33H40O4: 500.2927, found 500.2946.
3α-Tiboloyl (S)-2-Methoxy-2-phenylpent-3-ynoate 17b. Ob-
tained in 15% yield as colorless syrup (Rf 0.22 hexane/acetone 4:1).
[α]25D = +28.0 (c 0.10, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.67
(m, 2H, H-o), 7.34 (m, 3H, H-m,p), 4.89 (dddd, 1H, J = 11.4, 9.1, 5.7,
3.4 Hz, H-3′), 3.39 (s, 3H, OMe), 2.57 (s, 1H, H-19′), 2.29 (ddd, 1H,
J = 13.8, 9.5, 5.6 Hz, H-16a′), 2.14 (m, 1H, H-1a′), 2.11 (m, 1H, H-4a′),
2.02 (s, 3H, Me-5), 1.95 (m, 1H, H-1b′), 1.92 (m, 1H, H-2a′), 1.58 (m,
1H, H-2b′), 1.48 (m, 1H, H-4b′), 1.14 (qd, 1H, J = 13.0, 3.8 Hz, H-
11b′), 0.84 (s, 3H, Me-21′), 0.73 (d, 3H, J = 7.0 Hz, Me-20′). 13C NMR
(125 MHz, CDCl3): δ 169.0 (C-1), 138.4 (C-i), 128.6 (C-10′), 128.5
(C-p), 128.2 (C-m), 126.7 (C-o), 123.5 (C-5′), 87.6 (C-18′), 85.6 (C-3),
80.5 (C-4), 79.9 (C-17′), 74.7 (C-2), 73.8 (C-19′), 72.8 (C-3′), 53.0
(OMe), 47.4 (C-13′), 46.2 (C-14′), 41.6 (C-8′), 39.7 (C-9′), 39.0 (C-
16′), 38.5 (C-4′), 35.8 (C-6′), 33.0 (C-12′), 28.1 (C-2′), 27.1 (C-7′), 26.1
(C-1′), 25.2 (C-11′), 22.0 (C-15′), 12.81 (Me-20′), 12.79 (Me-21′), 3.8
(Me-5). IR (CH2Cl2) νmax: 3293, 2935, 1738, 1245, 1094 cm−1.
HREIMS calcd for C33H40O4: 500.2927, found 500.2909.
(2R)-2-(1-Methyloxycarbonyl)butyl (R)-2-Methoxy-2-phenyl-
pent-3-ynoate 15a. Obtained in 20% yield as colorless syrup (Rf
1
0.16 hexane/acetone 9:1); 94:6. [α]20 = −1.4 (c 0.24, CHCl3). H
D
NMR (500 MHz, CDCl3): δ 7.66 (m, 2H, H-o), 7.33 (m, 3H, H-m,p),
5.18 (tt, 1H, J = 7.7, 5.3 Hz, H-3′), 3.60 (s, 3H, OMe′), 3.39 (s, 3H,
OMe), 2.59 (dd, 1H, J = 15.6, 7.7 Hz, H-2a′), 2.50 (dd, 1H, J = 15.6,
5.3 Hz, H-2b′), 2.01 (s, 3H, Me-5′), 1.51 (m, 2H, H-4′), 0.62 (t, 3H,
J = 7.4 Hz, Me-5′). 13C NMR (125 MHz, CDCl3): δ 170.4 (C-1′),
168.7 (C-1), 138.2 (C-i), 128.6 (C-p), 128.2 (C-m), 126.7 (C-o), 85.7
(C-3), 80.3 (C-4), 74.3 (C-2), 73.6 (C-3′), 53.0 (OMe), 51.6 (OMe′),
38.5 (C-2′), 26.6 (C-4′), 8.8 (C-5′), 3.7 (C-5). IR (CH2Cl2) νmax: 1742,
1237, 1091 cm−1. HREIMS calcd for C18H22O5: 318.1467, found
318.1472.
(2R)-2-(1-Methyloxycarbonyl)butyl (S)-2-Methoxy-2-phenyl-
pent-3-ynoate 15b. Obtained in 20% yield as colorless syrup
(Rf 0.17 hexane/acetone 9:1); 91:9. [α]25D = −32.5 (c 0.06, CHCl3). 1H
NMR (500 MHz, CDCl3): δ 7.65 (m, 2H, H-o), 7.33 (m, 3H, H-m,p),
5.19 (tt, 1H, J = 7.8, 5.2 Hz, H-3′), 3.43 (s, 3H, OMe′), 3.38 (s, 3H,
OMe), 2.48 (dd, 1H, J = 15.7, 7.8 Hz, H-2a′), 2.40 (dd, 1H, J = 15.7,
5.2 Hz, H-2b′), 2.01 (s, 3H, Me-5′), 1.63 (m, 2H, H-4′), 0.85 (t, 3H,
J = 7.4 Hz, Me-5′). 13C NMR (125 MHz, CDCl3): δ 170.3 (C-1′),
168.6 (C-1), 138.1 (C-i), 128.5 (C-p), 128.1 (C-m), 126.7 (C-o), 85.6
(C-3), 80.3 (C-4), 74.5 (C-2), 73.3 (C-3′), 52.9 (OMe), 51.6 (OMe′),
38.2 (C-2′), 26.7 (C-4′), 8.9 (C-5′), 3.7 (C-5). IR (CH2Cl2) νmax: 1740,
1238, 1091 cm−1. HREIMS calcd for C18H22O5: 318.1467, found
318.1473.
3β-Tiboloyl (R)-2-Methoxy-2-phenylpent-3-ynoate 18a. 1H
NMR (500 MHz, CDCl3): δ 7.68 (m, 2H, H-o), 7.36 (m, 3H, H-m,p),
5.12 (m, 1H, H-3′), 3.44 (s, 3H, OMe), 2.61 (s, 1H, H-19′), 2.34 (m,
1H, H-16a′), 2.03 (m, 1H, H-6a′), 2.18 (m, 1H, H-1a′), 2.05 (s, 3H,
Me-5), 2.04 (m, 1H, H-4a′), 2.01 (m, 1H, H-16′), 2.00 (m, 1H, H-11′),
2.03 (m, 1H, H-6a′), 1.95 (m, 1H, H-2a′), 1.80 (m, 1H, H-4b′), 1.78
(m, H-7b′), 1.76 (m, 1H, H-1b′), 1.61−1.72 (m, 4H, H-14′, H-15a′, H-
9′, H-12b′), 1.61 (m, 1H, H-2b′), 1.42 (H-6b′), 1.37 (m, 1H, H-8),
1.36 (m, 1H, H-15b′), 1.14 (m, 1H, H-11b′), 0.95 (s, 3H, Me-21′),
0.77 (d, 3H, J = 7.0 Hz, Me-20′). 13C NMR (125 MHz, CDCl3): δ
168.95 (C-1), 138.54 (C-i), 128.39 (C-10′), 128.23 (C-p), 128.08
(C-m), 126.58 (C-o), 121.87 (C-5′), 87.58 (C-18′), 85.25 (C-3), 80.39
(C-2), 79.89 (C-17′), 74.63 (C-4), 73.90 (C-19′), 70.94 (C-3′), 53.05
(OMe), 47.42 (C-13′), 46.20 (C-14′), 41.69 (C-8′), 39.64 (C-9′),
38.99 (16′), 38.55 (C-6′), 35.16 (C-4′), 33.10 (C-12′), 27.10 (C-7′),
26.58 (C-1′), 25.27 (C-11′), 22.53 (C-2′), 22.05 (C-5′), 12.90 (Me-
20′,21′), 3.78 (Me-5). HREIMS calcd for C33H40O4: 500.2927, found
500.2929.
Longipinenoyl (R)-2-Methoxy-2-phenylpent-3-ynoate 16a.
Obtained in 14% yield as colorless syrup (Rf 0.22 hexane/acetone 4:1);
dr 93:7. [α]25 = +60.0 (c 0.03, CHCl3). 1H NMR (500 MHz,
D
CDCl3): δ 7.72 (m, 2H, H-o), 7.36 (m, 2H, H-m), 7.30 (m, 1H, H-p),
5.75 (q, 1H, J = 1.5 Hz, H-9′), 5.00 (t, 1H, J = 3.4 Hz, H-2′), 4.86 (dd,
1H, J = 11.9, 1.8 Hz, H-4′), 3.46 (s, 3H, OMe), 3.04 (dd, 1H, J = 6.7,
0.9 Hz, H-7′), 2.57 (d, 1H, J = 6.7 Hz, H-11′), 2.24 (s, 1H, H-6′), 2.15
(ddd, 1H, J = 15.1, 11.9, 3.4 Hz, H-3a′), 2.02 (s, 3H, Me-5), 2.00 (d,
3H, J = 1.5 Hz, Me-15′), 1.98 (s, 3H, OAc′), 1.85 (ddd, 1H, J = 15.1,
3.4, 1.8 Hz, H-3b′), 0.96 (s, 3H, Me-13′), 0.84 (s, 3H, Me-14′), 0.78
(s, 3H, Me-12′). 13C NMR (125 MHz, CDCl3): δ 202.5 (C-8′), 170.0
(OCOMe), 169.2 (C-10′), 169.1 (C-1′), 137.8 (C-i), 128.6 (C-p),
128.3 (C-m), 126.8 (C-o), 122.8 (C-9′), 86.2 (C-3), 80.7 (C-4),
76.9 (C-2′), 74.6 (C-2), 72.1(C-4′), 65.7 (C-6′), 56.0 (C-1′), 53.40
(C-7′), 53.36 (OMe), 48.3 (C-11′), 37.5 (C-5′), 32.4 (C-3′), 26.3
(Me-14′), 23.3 (Me-15′), 21.0 (OCOMe), 20.5 (Me-12′), 19.3
(Me-13′), 3.7 (Me-5). HREIMS calcd for C29H34O6: 478.2355, found
478.2358.
Longipinenoyl (S)-2-Methoxy-2-phenylpent-3-ynoate 16b.
3β-Tiboloyl (S)-2-Methoxy-2-phenylpent-3-ynoate 18b. Ob-
tained in 18% yield as colorless syrup. 1H NMR (500 MHz, CDCl3): δ
7.68 (m, 2H, H-o), 7.36 (m, 3H, H-m,p), 5.10 (m, 1H, H-3′), 3.43 (s,
3H, OMe), 2.61 (s, 1H, H-19′), 2.34 (m, 1H, H-16a′), 2.15 (m, 1H,
H-6a′), 2.11 (m, 1H, H-4a′), 2.05 (s, 3H, Me-5), 1.99 (m, 1H, H-16b′),
1.91 (m, 1H, H-1a′), 1.91 (m, 1H, H-11a′), 1.86 (m, 1H, H-2a′), 1.98
(m, 1H, H-4b′), 1.80 (m, H-7b′), 1.76 (m, 1H, H-1b′), 1.61−1.75 (m,
4H, H-14′, H-15a′, H-9′, H-12b′), 1.56 (m, 1H, H-2b′), 1.50 (H-6b′),
1.42 (m, 1H, H-8), 1.35 (m, 1H, H-15b′), 1.08 (m, 1H, H-11b′), 0.93
(s, 3H, Me-21′), 0.78 (d, 3H, J = 7.0 Hz, Me-20′). 13C NMR (125
MHz, CDCl3): δ 169.05 (CO), 138.52 (C-i), 128.47 (C-10′),
Obtained in 14% yield as colorless syrup (Rf 0.22 hexane/acetone 4:1);
dr 95:5. [α]23 = +86.7 (c 0.11, CHCl3). 1H NMR (500 MHz,
D
CDCl3): δ 7.71 (m, 2H, H-o), 7.34 (m, 2H, H-m), 7.28 (tt, 1H, J = 7.3,
1.3 Hz, H-p), 5.69 (q, 1H, J = 1.5 Hz, H-9′), 5.12 (dd, 1H, J = 12.0, 1.8
Hz, H-4′), 4.86 (t, 1H, J = 3.1 Hz, H-2′), 3.44 (s, 3H, OMe), 3.01 (dd,
1H, J = 6.8 Hz, H-7′), 2.52 (d, 1H, J = 6.8 Hz, H-11′), 2.23 (s, 1H, H-
6′), 2.20 (ddd, 1H, J = 15.1, 12.0, 3.1 Hz, H-3a′), 2.07 (s, 3H, Me-5),
2.05 (s, 3H, OAc′), 2.03 (ddd, 1H, J = 15.1, 3.1, 1.8 Hz, H-3b′), 1.96
(d, 3H, J = 1.5 Hz, Me-15′), 0.99 (s, 3H, Me-13′), 0.88 (s, 3H,
Me-14′), 0.32 (s, 3H, Me-12′). 13C NMR (125 MHz, CDCl3): δ 202.4
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128.37 (C-p), 128.11 (C-m), 126.69 (C-o), 121.99 (C-5′), 87.57
(C-18′), 85.49 (C-3), 80.57 (C-2), 79.90 (C-17′), 74.63 (C-4), 73.91
(C-19′), 71.21 (C-3′), 53.06 (OMe), 47.40 (C-13′), 46.19 (C-14′),
41.80 (C-8′), 39.52 (C-9′), 38.98 (C-16′), 38.72 (C-6′), 35.38 (C-4′),
33.06 (C-12′), 27.15 (C-7′), 26.52 (C-1′), 25.35 (C-11′), 22.51 (C-2′),
22.06 (C-15′), 12.97 (Me-20′), 12.86 (C-21′), 3.82 (Me-5). HREIMS
calcd for C33H40O4: 500.2927, found 500.2929.
41.15 (C-5′), 39.39 (C-4′), 37.11 (C-6′), 32.46 (C-7′), 26.79 (M2−9′),
18.75 (Me-8′), 3.77 (Me′5). HREIMS calcd for C23H30O4: 370.2144,
found 370.2144.
10-[10-Methyl-3,10-dihydroxy]-pinanyl (S)-2-Methoxy-2-
phenylpent-3-ynoate 21b and 3-[10-Methyl-3,10-dihydroxy]-
pinanyl (S)-2-Methoxy-2-phenylpent-3-ynoate 20b. Obtained in
16% yield as a mixture of esters at C-3 and C-10 position (colorless
syrup), which were difficult to separate by column chromatography;
3β-Cholesteryl (R)-2-Methoxy-2-phenylpent-3-ynoate 19a.
Obtained in 32% yield as colorless syrup. 1H NMR (500 MHz,
CDCl3): δ 7.67 (m, 2H, H-o), 7.34 (m, 3H, H-o, H-p), 5.31 (m, 1H,
H-6′), 4.63 (m, 1H, H-3′), 2.19 (m, 1H, H-4a′), 2.17 (m, 1H, H-4b′),
1.89−2.04 (m, 2H, H-7a′, H12a′), 1.84 (m, 1H, H-16a), 1.80 (m, 1H,
H-2a′), 1.58 (m, 1H, H-2b′), 1.29−1.60 (m, 9H, H-1′a, H-15′a,b, H-
7′b, H-25′, H-8′, H-20′, H-11′a,b), 1.24 (m, 1H, H-16b), 0.89−1.19 (m,
9H, H-1′b, H-12b′, H-23′a,b, H-24′a,b, H-17′, H-14′, H-9′), 0.97 (s, 3H,
Me-19′), 0.90 (d, 3H, J = 7.0 Hz, Me-21′), 0.87 (d, 3H, J = 7.1 Hz, Me-
26′), 0.86 (d, 3H, J = 7.1 Hz, Me-27′), 0.66 (s, 3H, Me-18′). 13C NMR
(125 MHz, CDCl3): 168.84 (C-1), 139.34 (C-5′), 138.40 (C-i), 128.56
(C-p), 128.18 (C-o), 126.67 (C-m), 122.81 (C-6′), 85.62 (C-3), 80.54
(C-2), 75.82 (C-3′), 74.69 (C-4), 56.66 (C-14′), 56.12 (C-17′), 49.97
(C-9′), 42.30 (C-13′), 39.71 (C-12′), 39.51 (C-24′), 37.52 (C-4′),
36.86 (C-10′), 36.54 (C-1′), 36.17 (C-22′), 35.78 (C-20′), 31.87
(C-7′), 31.82 (C-8′), 28.21 (C-16′), 28.01 (C-25′), 27.34 (C-2′), 24.26
(C-15′), 23.82 (C-23′), 22.81 (C-26′), 22.55 (C-27′), 21.02 (C-11′),
19.31 (C-19′), 18.71 (C-21′), 11.84 (C-18′), 3.84 (C-5). HREIMS calcd
for C33H40O4: 572.4230, found 572.4214.
3β-Cholesteryl (S)-2-Methoxy-2-phenylpent-3-ynoate 19b.
Obtained in 32% yield as colorless syrup. 1H NMR (500 MHz,
CDCl3): δ 7.67 (m, 2H, H-o), 7.34 (m, 3H, H-o, H-p), 5.34 (m, 1H,
H-6′), 4.64 (m, 1H, H-3′), 2.31 (m, 1H, H-4a′), 2.27 (m, 1H, H-4b′),
1.89−2.04 (m, 2H, H-7a′, H12a′), 1.84 (m, 1H, H-16a), 1.69 (m, 1H,
H-2a′), 1.43 (m, 1H, H-2b′), 1.29−1.60 (m, 9H, H-1′a, H-15′a,b, H-
7′b, H-25′, H-8′, H-20′, H-11′a,b), 1.24 (m, 1H, H-16b), 0.89−1.19 (m,
9H, H-1′b, H-12b′, H-23′a,b, H-24′a,b, H-17′, H-14′, H-9′), 0.97 (s, 3H,
Me-19′), 0.90 (d, 3H, J = 7.0 Hz, Me-21′), 0.87 (d, 3H, J = 7.1 Hz, Me-
26′), 0.86 (d, 3H, J = 7.1 Hz, Me-27′), 0.66 (s, 3H, Me-18′). 13C NMR
(125 MHz, CDCl3): 168.82 (C-1), 139.41 (C-5′), 138.39 (C-i), 128.55
(C-p), 128.17 (C-o), 126.67 (C-m), 122.79 (C-6′), 85.63 (C-3), 80.52
(C-2), 75.78 (C-3′), 74.67 (C-4), 56.66 (C-14′), 56.12 (C-17′), 49.96
(C-9′), 42.30 (C-13′), 39.70 (C-12′), 39.51 (C-24′), 37.61 (C-4′),
36.82 (C-10′), 36.54 (C-1′), 36.17 (C-22′), 35.77 (C-20′), 31.88 (C-
7′), 31.83 (C-8′), 28.21 (C-16′), 28.00 (C-25′), 27.25 (C-2′), 24.26 (C-
15′), 23.82 (C-23′), 22.81 (C-26′), 22.55 (C-27′), 21.01 (C-11′), 19.31
(C-19′), 18.70 (C-21′), 11.84 (C-18′), 3.84 (C-5). HREIMS calcd for
C39H56O3: 572.4230, found 572.4244.
1
therefore, their H data were assigned without previous separation by
performing homonuclear 2D NMR experiments. Data for compound
21b: 1H NMR (500 MHz, CDCl3): δ 7.62−7.69 (m, 2H, H-o), 7.29−
7.39 (m, 3H, H-m, H-p), 5.00 (m, 1H, H-10′), 4.01 (m, 1H, H-3′), 3.40
(s, 3H, OMe), 2.53 (m, 1H, H-4′ec), 2.32 (m, 1H, H-7ec), 2.01 (s, 3H,
CCMe), 1.97 (m, 1H, H-2′), 1.90 (m, 1H, H-1′), 1.83 (m, 1H, H-5′),
1.72 (m, 1H, H-4′ax), 1.16 (d, 3H, J = 7.1 Hz, Me-11′), 1.07 (s, 3H,
Me-9′), 1.01 (d, 1H, J = 9.7 Hz, H-7′ax), 0.83 (s, 3H, Me-8′). Data for
1
compound 20b: H NMR (500 MHz, CDCl3): δ 7.62−7.69 (m, 2H,
H-o), 7.29−7.39 (m, 3H, H-m, H-p), 4.97 (m, 1H, H-3′), 3.72 (m, 1H,
H-10′), 3.38 (s, 3H, OMe), 2.54 (m, 1H, H-4′ec), 2.30 (m, 1H, H-7ec),
2.03 (s, 3H, CCMe), 1.95 (m, 1H, H-2′), 1.82 (m, 1H, H-5′), 1.27 (m,
1H, H-4′ax), 1.16 (d, 3H, J = 7.1 Hz, Me-11′), 1.20 (s, 3H, Me-9′),
1.01 (d, 1H, J = 9.7 Hz, H-7′ax), 0.87 (s, 3H, Me-8′). HREIMS calcd
for C23H30O4: 370.2144, found 370.2155.
2-Butyl (R)-2-Methoxy-2-phenylpent-3-ynoate 22a. Obtained
1
in 54% yield as colorless syrup (Rf 0.46, hexane/ethyl ether 4:1). H
NMR (300 MHz, CDCl3): δ 7.67 (m, 2H, H-o), 7.33 (m, 3H, H-m,p),
4.84 (sext, 1H, J = 6.2 Hz, H-2′), 3.39 (s, 3H, OMe), 2.02 (s, 3H, Me-
5), 1.49 (m, 2H, H-3′), 1.06 (d, 3H, J = 6.2 Hz, H-1′), 0.83 (t, 3H, J =
7.5 Hz, H-4′). 13C NMR (75.4 MHz, CDCl3): δ 169.1 (C-1), 138.3
(C-i), 128.5 (C-p), 128.1 (C-m), 126.6 (C-o), 85.5 (C-3), 80.4 (C-4),
74.5 (C-2), 74.2 (C-2′), 52.9 (OMe), 28.5 (C-3′), 19.0 (C-1′), 9.2 (C-
4′), 3.8 (C-5).
2-Butyl (R)-2-methoxy-2-phenylpent-3-ynoate 22b. Obtained
in 54% yield as epimer of 22a at the carbinol moiety; colorless syrup
1
(Rf 0.46, hexane/ethyl ether 4:1). H NMR (300 MHz, CDCl3): δ
7.67 (m, 2H, H-o), 7.33 (m, 3H, H-m,p), 4.84 (sext, 1H, J = 6.2 Hz, H-
2′), 3.39 (s, 3H, OMe), 2.01 (s, 3H, Me-5), 1.49 (m, 2H, H-3′), 1.18
(d, 3H, J = 6.2 Hz, H-1′), 0.62 (t, 3H, J = 7.5 Hz, H-4′). 13C NMR
(75.4 MHz, CDCl3): δ 169.1 (C-1), 138.3 (C-i), 128.5 (C-p), 128.1
(C-m), 126.7 (C-o), 85.6 (C-3), 80.4 (C-4), 74.7 (C-2), 74.3 (C-2′),
52.9 (OMe), 28.6 (C-3′), 19.1 (C-1′), 9.4 (C-4′), 3.8 (C-5).
Isopropyl (R)-2-Methoxy-2-phenylpent-3-ynoate 23. Ob-
tained in 48% yield as colorless syrup (Rf 0.43, hexane/ethyl ether
1
4:1). [α]24 = +7.2 (c 0.37, CHCl3). H NMR (300 MHz, CDCl3): δ
D
7.67 (m, 2H, H-o), 7.37 (m, 3H, H-m,p), 5.02 (sept, 1H, J = 6.2 Hz,
H-2′), 3.39 (s, 3H, OMe), 2.02 (s, 3H, Me-5), 1.21 (d, 3H, J = 6.2 Hz,
Me-1′), 1.12 (d, 3H, J = 6.2 Hz, Me-3′). 13C NMR (75.4 MHz,
CDCl3): δ 168.9 (C-1), 138.2 (C-i), 128.5 (C-p), 128.1 (C-m), 126.6
(C-o), 74.5 (C-2), 69.8 (C-2′), 52.9 (OMe), 21.4 (Me-1′), 21.2 (Me-
3′), 3.8 (Me-5). IR (CH2Cl2) νmax: 2981.9, 1740.8, 1450.7, 1243.6,
1094.5 cm−1. MS (EI) m/z (%): 215 ([M − OMe]+·, 15.4), 159 ([M −
CO2CH(CH3)2]+·, 100), 128 (3.6), 115 (3.4), 105 (3.7). HRESIMS
calcd for C15H18O3 + Na: 269.1150, found 269.1153.
Preparation of MPPA Amides 24−27. To a solution of (R)-
(+)-2 or (S)-(−)-2 (1 equiv), the chiral amine (1.1 quiv), and TEA
(1.1 equiv) in dry dichloromethane (5 mL/50 mg of the acid) was
added 1.1 equiv of BOP at room temperature. The reaction mixture
was stirred for 24 h, diluted with dichloromethane, and washed with
aqueous 5% HCl. The organic layer was dried over Na2SO4, filtered,
and evaporated to dryness to give the crude product, which was
purified by silica gel (230−400 mesh) column chromatography using
hexane/ethyl ether as eluent to give the corresponding R*NH-(S)-
MPPA and R*NH-(R)-MPPA amides.
3-[10-Methyl-3,10-dihydroxy]-pinanyl (R)-2-Methoxy-2-
phenylpent-3-ynoate 20a. Obtained in 27% yield as colorless syrup.
1H NMR (500 MHz, CDCl3): δ 7.67 (m, 2H, H-o), 7.28−7.37 (m,
3H, H-m, H-p), 4.89 (m, 1H, H-3′), 3.59 (m, 1H, H-10′), 3.38 (s, 3H,
OMe), 2.63 (m, 1H, H-4′ec), 2.40 (m, 1H, H-7ec), 2.30 (m, 1H, H-1′),
2.03 (s, 3H, CCMe), 1.91 (m, 1H, H-5′), 1.75 (m, 1H, H-2′), 1.63 (m,
1H, H-4′ax), 1.21 (s, 3H, Me-9′), 1.04 (d, 1H, J = 9.7 Hz, H-7′ax), 0.86
(s, 3H, Me-8′), 0.57 (d, 3H, J = 7.1 Hz, Me-11′). 13C NMR (125 MHz,
CDCl3): δ 168.57 (CO), 137.83 (C-i), 128.64 (C-p), 128.16 (C-m),
126.88 (C-o), 85.87 (C-3), 80.30 (C-4), 74.30 (C-2), 70.73 (C-3′),
69.23 (10′), 55.91 (C-2′), 52.94 (OMe), 41.35 (C-5′), 41.02 (C-1′),
37.86 (C-6′), 35.92 (C-4′), 32.18 (C-7′), 27.09 (Me-9′), 23.78 (Me-8′),
21.45 (m-11′), 3.74 (CCMe). HREIMS calcd for C23H30O4: 370.2144,
found 370.2158.
10-[10-Methyl-3,10-dihydroxy]-pinanyl (R)-2-Methoxy-2-
phenylpent-3-ynoate 21a. Obtained in 29% yield as colorless
syrup. 1H NMR (500 MHz, CDCl3): δ 7.68 (m, 2H, H-o), 7.31−7.40
(m, 3H, H-m, H-p), 4.96 (m, 1H, H-10′), 3.97 (m, 1H, H-3′), 3.38 (s,
3H, OMe), 2.51 (m, 1H, H-4′ec), 2.13 (m, 1H, H-7ec), 2.04 (s, 3H,
CCMe), 1.89 (m, 1H, H-2′), 1.83 (m, 1H, H-5′), 1.69 (m, 1H, H-4′ax),
1.33 (d, 3H, J = 7.1 Hz, Me-11′), 1.28 (m, 1H, H-1′), 0.90 (s, 3H, Me-
9′), 0.89 (d, 1H, J = 9.7 Hz, H-7′ax), 0.76 (s, 3H, Me-8′). 13C NMR
(125 MHz, CDCl3): δ 168.60 (CO), 138.00 (C-i), 128.63 (C-p),
128.25 (C-m), 126.84 (C-o), 85.83 (C-3), 80.27 (C-4), 74.42 (C-10′),
74.28 (C-2), 65.74 (C-3′), 57.27 (C-2′), 53.39 (OMe), 41.29 (C-1′),
Amide of Methylbenzyl Amine and (R)-2-Methoxy-2-phenyl-
pent-3-ynoic 24a. Obtained in 64% yield as colorless syrup. 1H
NMR (300 MHz, CDCl3): δ 7.61 (2H, m, H-o), 7.33 (3H, m, H-m,p),
7.33 (5H, m, H-o′,m′,p′), 7.18 (1H, d, J = 8.0 Hz, NH), 5.08 (1H, dq,
J = 8.0, 6.9 Hz, H-1′), 3.27 (3H, s, OMe), 1.98 (3H, s, Me-5), 1.48
(3H, d, J = 6.9 Hz, Me-2′). 13C NMR (75.4 MHz, CDCl3): δ 168.4
(CO), 142.8 (C), 138.1 (C), 128.6 (CH), 128.4 (CH), 128.2 (CH),
1650
dx.doi.org/10.1021/jo2016554 | J. Org. Chem. 2012, 77, 1640−1652

The Journal of Organic Chemistry
Article
127.2 (CH), 126.8 (CH), 126.2 (CH), 85.7 (C), 81.0 (C), 74.8 (C),
52.4 (OCH3), 48.6 (CH), 21.5 (CH3), 3.8 (CH3). HRESI calcd for
C20H21O2 + Na: 330.1470, found 330.1474.
ACKNOWLEDGMENTS
■
L.G.Z. acknowledges financial support from CGPI/IPN (grants
20090454, 20100702) and CONACYT-Mexico (grants 44157-
Q and 105601). S.P.-E. and M.E.M.-L. thank CONACYT-
Mexico for fellowships. L.G.Z. and H.A.J.-V. are fellows of the
COFAA-IPN and EDI-IPN programs.
Amide of Methylbenzyl Amine and (S)-2-Methoxy-2-phenyl-
pent-3-ynoic Acid 24b. Obtained in 48% yield as colorless syrup. 1H
NMR (300 MHz, CDCl3): δ 7.54 (2H, m, H-o), 7.30 (3H, m, H-m,p),
7.30 (5H, m, H-o′,m′,p′), 7.19 (1H, d, J = 8.2 Hz, NH), 5.09 (1H, dq,
J = 8.2, 6.9 Hz, H-1′), 3.27 (3H, s, OMe), 2.02 (3H, s, Me-5), 1.54
(3H, d, J = 6.9 Hz, Me-2′). 13C NMR (75.4 MHz, CDCl3): δ 168.4
(CO), 142.9 (C), 138.0 (C), 128.5 (CH), 128.4 (CH), 128.2 (CH),
127.2 (CH), 126.8 (CH), 126.1 (CH), 85.7 (C), 81.1 (C), 74.9 (C),
52.3 (OCH3), 48.6 (CH), 21.5 (CH3), 3.9 (CH3). HRESI calcd for
C20H21NO2 + Na: 330.1470, found 330.1474.
Amide of 3-Norbornyl Amine and (R)-2-Methoxy-2-phenyl-
pent-3-ynoic Acid 25a. Obtained in 38% yield as colorless syrup. 1H
NMR (300 MHz, CDCl3): δ 2.18 (m, 1H, H-3a′), 2.01 (s, 3H,
CCMe), 1.78 (m, 1H, H-6a′), 1.65 (m, 1H, H-4′), 1.55 (m, 1H, H-5a′),
1.43 (m, 1H, H-6b′), 1.23 (m, 1H, H-5b′), 0.91 (s, 3H, Me-9′), 0.87
(s, 3H, Me-8′), 0.83 (s, 3H, Me-10′), 0.78 (dd, 1H, J = 4.1, 9.3 Hz, H-3b′).
HRESI calcd for C22H29NO2: 339.2198, found 339.2193.
Amide of 3-Norbornyl Amine and (S)-2-Methoxy-2-phenyl-
pent-3-ynoic Acid 25b. Obtained in 43% yield as colorless syrup. 1H
NMR (300 MHz, CDCl3): δ 2.34 (1H, m, H-3a′), 2.02 (s, 3H,
CCMe), 1.78 (m, 1H, H-6a′), 1.67 (m, 1H, H-4′), 1.53 (m, 1H, H-5a′),
1.40 (m, 1H, H-6b′), 1.24 (m, 1H, H-5b′), 0.91 (s, 3H, Me-9′), 0.86 (s,
3H, Me-8′), 0.85 (s, 3H, Me-10′), 0.69 (dd, 1H, J = 4.1, 9.3 Hz, H-3b′).
HRESI calcd for C22H29NO2: 339.2198, found 339.2205.
REFERENCES
■
(1) (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543−2549. (b) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512−519. (c) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem.
1973, 38, 2143−2147.
(2) For extensive reviews about state-of-the-art of CDAs, see:
(a) Seco, J. M.; Quinoa,
́
E.; Riguera, R. Chem. Rev. 2004, 104, 17−117.
(b) Wenzel, T. J.; Wilcox, J. D. Chirality 2003, 15, 256−270.
(3) (a) Perez-Estrada, S.; Lagunas-Rivera, S.; Vargas-Díaz, M. E.;
Velazquez-Ponce, P.; Joseph-Nathan, P.; Zepeda, L. G. Tetrahedron:
Asymmetry 2005, 16, 1837−1843. (b) Martínez-Ramos, F.; Vargas-
Díaz, M. E.; Chacon-García, L.; Tamariz, J.; Joseph-Nathan, P.;
Zepeda, L. G. Tetrahedron: Asymmetry 2001, 12, 3095. (c) Vargas-
Díaz, M. E.; Chacon-García, L.; Velazquez, P.; Tamariz, J.; Joseph-
Nathan, P.; Zepeda, L. G. Tetrahedron: Asymmetry 2003, 14, 3225.
(d) Chacon-García, L.; Lagunas-Rivera, S.; Perez-Estrada, S.; Vargas-
̃
́
́
́
́
́
́
́
Díaz, M. E.; Joseph-Nathan, P.; Tamariz, J.; Zepeda, L. G. Tetrahedron
Lett. 2004, 45, 2141.
Amide of L-valine and (R)-2-Methoxy-2-phenylpent-3-ynoic
Acid 27a. Obtained in 62% yield as colorless syrup. 1H NMR (300 MHz,
CDCl3): δ 7.64 (2H, m, H-o), 7.43 (1H, d, J = 9.1 Hz, NH), 7.37 (3H, m,
H-m,p), 4.51 (1H, dd, J = 9.1, 4.8 Hz, H-1′), 3.71 (3H, s, CO2Me), 3.31
(3H, s, OMe), 2.23 (1H, m, H-2′), 2.02 (3H, s, Me-5), 0.97 (3H, d, J = 6.9
Hz, Me-4′), 0.94 (3H, d, J = 6.9 Hz, Me-5′). 13C NMR (75.4 MHz, CDCl3):
δ 172.1 (CO), 169.4 (CO), 137.9 (C), 128.5 (CH), 128.2 (CH), 127.0
(CH), 85.9 (C), 81.1 (C), 74.9 (C), 57.0 (CH), 52.5 (CH3), 52.0 (CH3),
31.4 (CH), 18.9 (CH3), 17.7 (CH3), 3.8 (CH3). Rf = 0.61, 5% acetone/
chloroform. HRESI calcd for C18H23NO4 + H: 318.1705, found 318.1705.
Amide of L-valine and (S)-2-Methoxy-2-phenylpent-3-ynoic
Acid 27a. Obtained in 71% yield as colorless syrup. Rf = 0.61 in 5%
(4) (a) Cram, D. J.; Elhafez, F. A. J. Am. Chem. Soc. 1952, 74, 5828−
5835. (b) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81,
2748. (c) Cram, D. J.; Wilson, D. R. J. Am. Chem. Soc. 1963, 85, 1245−
1249.
(5) (1R)-(−)-Myrtenal ([α]20 = −15.0, neat) is commercially
D
available from two providers: (1) Penta Manufacturing Corp.
(Fairfield, NJ, USA) and (2) Aldrich-Aldrich Co, (St. Louis, MO,
USA). Only (1R)-(−)-myrtenal from the first provider was used to
synthesize S,O-acetals 1a and 1b. All commercial carbinols and amines
used to prepare R*O-(R)-MPPA 4a−23a and R*O-(S)-MPPA 4b−
23b esters and R*NH-(R)-MPPA 24a−27a and R*NH-(S)-MPPA
24b−27b amides are sold as 95−99% purum (sum of enantiomers,
GC) whose enantiomeric purity is not specified.
1
acetone/chloroform. 318.1709. H NMR (300 MHz, CDCl3): δ 7.62
(2H, m, H-o), 7.36 (3H, m, H-m,p), 7.36 (1H, d, J = 9.1 Hz, NH), 4.51
(1H, dd, J = 9.1, 4.9 Hz, H-1′), 3.75 (3H, s, CO2Me), 3.35 (3H, s,
OMe), 2.15 (1H, m, H-2′), 2.01 (3H, s, Me-5), 0.86 (3H, d, J = 6.9 Hz,
Me-4′), 0.83 (3H, d, J = 6.9 Hz, Me-5′). 13C NMR (75.4 MHz,
CDCl3): δ 172.1 (CO), 169.3 (CO), 138.4 (C), 128.5 (CH), 128.2
(CH), 126.6 (CH), 85.9 (C), 81.3 (C), 74.7 (C), 56.9 (CH), 52.6
(CH3), 52.1 (CH3), 31.6 (CH), 18.8 (CH3), 17.6 (CH3), 3.9 (CH3).
HRESI calcd for C18H23NO4 + H: 318.1705, found 318.1709.
Amide of L-serine (R)-2-Methoxy-2-phenylpent-3-ynoic Acid
́
(6) (a) Seco, J. M.; Quinoa, E.; Riguera, R. Tetrahedron: Asymmetry
̃
2001, 12, 2915−2925. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.;
Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092. (c) Latypov, Sh. K.;
Seco, J. M.; Quinoa, E.; Riguera, R. J. Org. Chem. 1996, 61, 8569−
8577. (d) Kusumi, T. Synth. Org. Chem. 1993, 51, 462. (e) Trost, B.
M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J. M.;
Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S. L.; Springer, J.
P. J. Org. Chem. 1986, 51, 2370−2374.
1
26a. Obtained in 32% yield as colorless syrup. H NMR (300 MHz,
(7) (a) Takeuchi, Y.; Konishi, M.; Hori, H.; Takahashi, T.; Kometani,
T.; Kirk, K. L. Chem. Commun. 1998, 365−366. (b) Takeuchi, Y.;
Konishi, M.; Hori, H.; Takahashi, T.; Kirk, K. L. Enantiomer 1999, 4,
339−344. (c) Takahashi, T.; Fukuishima, A.; Tanaka, Y.; Takeuchi, Y.;
Kabuto, K.; Kabuto, C. Chem. Commun. 2000, 788−789. (d) Fujiwara,
T.; Sasaki, M.; Omata, K.; Kabuto, C.; Kabuto, K.; Takeuchi, Y.
Tetrahedron: Asymmetry 2004, 15, 555−563. (e) Takeuchi, Y.; Hidehito
Fujisawa, H.; Noyori, R. Org. Lett. 2004, 6, 4607−4610.
(8) Omata, K.; Fujiwara, T.; Kabuto, K. Tetrahedron: Asymmetry
2002, 13, 1655−1662.
(9) (a) Kowalczyk, R.; Skarzewski, J. Tetrahedron 2005, 61, 623−628.
(b) Kowalczyk, R.; Skarzewski, J. Tetrahedron: Asymmetry 2006, 17,
1370−1379.
(10) The conformational search was carried out in both esters by
systematic rotation of all pertinent bonds at the HF/3-21G level of
ab initio theory. The resulting geometries were further optimized at the
HF/6-31G(d) and B3LYP/6-31G(d) levels of theory. Vibrational
frequencies were obtained on the minima thus obtained; only real
frequencies were obtained in all cases. Relative B3LYP/6-31G(d)
energies (ΔE0) were obtained considering the electronic energies of
the minima corrected by inclusion of zero-point energies (E0).
CDCl3): δ 4.51 (m, 1H, H-2′), 3.92 (1H, dd, J = 3.0, 9.1 Hz, 3-a′), 3.85
(1H, dd, J = 3.0, 9.1 Hz, H-3b′), 3.78 (s, 3H, COOMe), 3.31 (s, 3H,
OMe), 2.44 (bs, 1H, OH), 2.01 (s, 3H, CCMe). HRESI calcd for
C16H18NO4 − H2O: 288.1236, found 288.1250.
Amide of L-serine (S)-2-Methoxy-2-phenylpent-3-ynoic Acid
1
26b. Obtained in 27% yield as colorless syrup. H NMR (300 MHz,
CDCl3): δ 4.51 (m, 1H, H-2′), 4.02 (1H, dd, J = 3,0, 9.1 Hz, 3-a′), 3.93
(1H, dd, J = 3.0, 9.1 Hz, H-3b′), 3.75 (s, 3H, COOMe), 3.28 (s, 3H,
OMe), 2.44 (bs, 1H, OH), 2.01 (s, 3H, CCMe), 1.90 (bs, 1H, OH).
HRESI calcd for C16H20NO5: 306.1341, found 306.1352.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all relevant compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lzepeda@woodward.encb.ipn.mx.
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The Journal of Organic Chemistry
Article
Conformational populations were estimated from ΔE0 values of the
relevant conformers according to their Boltzmann distribution.
(11) The conformational search also showed that the phenyl group in
the acid moiety prefers a conformation in which the ring is coplanar
with the methoxy group. In the particular case of esters 22 there are
three sp(O) and three sp(C) conformers that differ mainly in the
conformation of the ethyl group of the sec-butyl fragment.
(12) Burgueno-Tapia, E.; Zepeda, L. G.; Joseph-Nathan, P.
̃
Phytochemistry 2010, 71, 1158−1161.
́
(13) (a) Seco, J. M.; Latipov, S.; Quinoa, E.; Riguera, R. Tetrahedron
̃
Lett. 1994, 35, 2921−2924. (b) Chataigner, I.; Lebreton, J.; Durand,
D.; Guingant, A.; Villieras, J. Tetrahedron Lett. 1998, 39, 1759−1762.
́
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