MNBA-mediated β-lactone formation: Mechanistic studies and application for the asymmetric total synthesis of tetrahydrolipstatin

Article abstract of DOI:10.1021/jo300139r

Various β-lactones were prepared from β-hydroxycarboxylic acids by intramolecular dehydration condensation using MNBA, an effective coupling reagent, along with a nucleophilic catalyst. The transition state that provides the desired 4-membered ring model system is disclosed by density functional theory (DFT) calculations, and the structural features of the transition form are discussed. This method was successfully applied to the asymmetric total synthesis of tetrahydrolipstatin (THL), an antiobestic drug used in clinical treatment to inhibit the activity of pancreatic lipase.

Full text of DOI:10.1021/jo300139r

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pubs.acs.org/joc
MNBA-Mediated β-Lactone Formation: Mechanistic Studies and
Application for the Asymmetric Total Synthesis of
Tetrahydrolipstatin
Isamu Shiina,* Yuma Umezaki, Nobutaka Kuroda, Takashi Iizumi, Shunsuke Nagai, and Takashi Katoh
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601,
Japan
S
* Supporting Information
ABSTRACT: Various β-lactones were prepared from β-
hydroxycarboxylic acids by intramolecular dehydration con-
densation using MNBA, an effective coupling reagent, along
with a nucleophilic catalyst. The transition state that provides
the desired 4-membered ring model system is disclosed by
density functional theory (DFT) calculations, and the
structural features of the transition form are discussed. This method was successfully applied to the asymmetric total synthesis
of tetrahydrolipstatin (THL), an antiobestic drug used in clinical treatment to inhibit the activity of pancreatic lipase.
corresponding monosubstituted β-lactone 2a in 21% yield
under the forced reaction conditions (Scheme 1).10 On the
other hand, we fortunately obtained a trisubstituted β-lactone
2b in excellent yield when 3-hydroxy-2,2-dimethyl-5-phenyl-
pentanoic acid (1b) was used as the substrate (89%). In the
latter reaction, the Thorpe−Ingold effect might dramatically
increase the reaction rate of the cyclization of the β-
hydroxycarboxylic acid 1b including a gem-dimethyl group at
the α-position of the carbonyl group.11 Next, stereoisomeric β-
hydroxycarboxylic acids (1c and 1d) were synthesized from syn-
and anti-aldols derived from 3-phenylpropanal with propanoic
acid derivatives, and these seco-acids were subjected to the
MNBA lactonization as shown in Scheme 1.10 A significant
difference between the reactivities of 1c and 1d was observed,
and the desired diastereomers of the β-lactones (2c and 2d, R1
= Me for 2d) were obtained from 1c and 1d in 13% and 69%
yields, respectively. It is easily anticipated that the formation of
the transition state for the unstable structure of the cis-2,3-
disubstituted 4-membered ring in 2c is more disfavored
compared to the formation of the transition state for the
more stable structure of the trans-2,3-disubstituted 4-membered
ring in 2d. We also discovered that the anti-β-hydroxycarboxylic
acid 1e, possessing a longer alkyl chain at the α-position, is
more preferable for the formation of the trans-2,3-disubstituted
β-lactone 2e, and a higher yield was attained for the synthesis of
2e from 1e using the MNBA lactonization depicted in Scheme
1 (83%, R1 = C6H13).10
INTRODUCTION
■
In 2004, we developed an effective lactonization using 2-
methyl-6-nitrobenzoic anhydride (MNBA) in the presence of a
nucleophilic catalyst, such as 4-(dimethylamino)pyridine
(DMAP) or 4-(dimethylamino)pyridine N-oxide (DMAPO),
under mild reaction conditions.1 This protocol was successfully
applied to the preparation of several cyclic compounds having a
variety of ring sizes, such as 2-hydroxy-24-oxooctacosanolide
(29-membered lactone),2 2-hydroxytetracosanolide (25-mem-
bered lactone),3 (9E)-isoambrettolide (17-membered lactone),4
erythronolide A (14-membered lactone),5 2-epibotcinolide (9-
membered lactone),6 and octalactins A and B (8-membered
lactone).7 Although these large- and medium-ring compounds
could be easily synthesized from the corresponding seco-acids
by MNBA lactonization as shown in the above instances,8 there
has been no report on the production of small ring compounds,
such as 3- or 4-membered lactones, using MNBA.9 Therefore,
we decided to determine the efficiency of the MNBA
lactonization for the preparation of 4-membered compounds
(β-lactones) starting from the corresponding β-hydroxycarbox-
ylic acids by this intramolecular dehydration coupling process.
Several benzylic-type β-hydroxycarboxylic acids (1f−h) were
further prepared by the aldol reaction of benzaldehyde with
suitable nucleophiles, such as acetic acid or 2-methylpropanoic
acid derivatives.10 Similar tendencies were observed during the
4-membered ring formation starting from 1f−h with those
RESULTS AND DISCUSSION
■
Systematic Studies of the Generation of the 4-
Membered Ring Compounds Using MNBA Lactoniza-
tion. First, 3-hydroxy-5-phenylpentanoic acid (1a), which was
prepared from 3-phenylpropanal with ethyl acetate by the aldol
reaction, was treated with MNBA and DMAP to provide the
Received: January 26, 2012
Published: May 3, 2012
© 2012 American Chemical Society
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Theoretical Studies of the MNBA-Mediated β-Lac-
tone-Forming Reactions. In order to clarify the significant
difference in the reactivities among several seco-acids during
the formation of the 4-membered ring systems, we have tried to
disclose the reaction mechanism that produces the several
multisubstituted β-lactones from the corresponding model
seco-acids based on theoretical calculations.12,13 It has already
been reported that the rapid formation of the mixed anhydride
(MA) from the seco-acid with MNBA is the initial step in the
MNBA-mediated coupling reaction, and the successive
nucleophilic addition of DMAP to MA provides the key
intermediate zwitterionic species as shown in Scheme 3. Next,
Scheme 1. MNBA Lactonization To Form a Variety of β-
Lactones Derived from 3-Phenylpropanal
Scheme 3. Reaction Pathway of the MNBA Lactonization To
Form β-Lactones from 3-Hydroxycarboxylic Acids (Seco-
Acids)
starting from 1a−e as shown in Scheme 2 (cf. Scheme 1). For
instance, the MNBA lactonization of 3-hydroxy-2,2-dimethyl-3-
Scheme 2. MNBA Lactonization To Form a Variety of β-
Lactones Derived from Benzaldehyde
the intramolecular transacylation proceeds by the attack of
oxygen in the activated hydroxyl group on the carbonyl carbon
in the acylpyridinium part to provide the desired β-lactone in
high yield.1a It was also disclosed by Zipse et al. that the
deprotonation of the hydroxyl group with the acyl anion part in
the zwitterionic species to form the new oxygen−carbon bond
is the rate-determining step in this transacylation process.14
Determination of the transition state forming the model β-
lactone (2S) from 3-hydroxypropanoic acid (1S) via the
zwitterionic species (INT-S) was carried out by using density
functional theory (DFT) calculations at the B3LYP/6-31G*//
B3LYP/6-31G* level.12 We succeeded in obtaining the
plausible transition structure (TS-S) as shown in Scheme 4,
and the nature of this stationary point was verified through
calculation of the vibrational frequency spectrum (ν = 221i
cm−1).15 The distance of the forming C−O bond (between
carbonyl carbon of the acid component and oxygen of hydroxy
in seco-acid) is 1.821 Å, and the distance of the cleaved O−H
bond (between oxygen and hydrogen in hydroxy) is 1.402 Å.
phenylpropanoic acid (1f) smoothly proceeded to afford the
trisubstituted β-lactone 2f in excellent yield (90%). When anti-
aldol derivatives (1g and 1h) were used as seco-acids for the
MNBA lactonization, it was also found that the desired trans-
2,3-disubstituted β-lactones (2g and 2h, R2 = Me for 2g, R2 =
C6H13 for 2h) were provided in good to high yields (69% and
81%, respectively).
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Scheme 4. Reaction Pathway and the Calculated Transition
State (TS-S) To Form Propan-3-olide (2S) from 3-
Hydroxypropanoic Acid (1S)
Scheme 5. Properties of Transition Structure (TS-S),
Structure Just before TS-S, and Structure Just after TS-S:
a
a
Left column, bond density surface selected for limited electrons in
total for showing bonding in the transition state (electron density, 0.08
electrons/au3). Right column, electron density selected for limited
electrons in total for showing atomic connectivity with local ionization
potential map (electron density, 0.08 electrons/au3).
one of the N-methyl groups in the pyridinium salt (2.622 and
2.766 Å, respectively). Furthermore, an intrinsic reaction
coordinate (IRC) analysis showed that the initial complex
(IC-S) will be first produced via the transition structure (TS-S),
and then it transforms into the more stable complex (SC-S), a
conformer of IC-S, as depicted in Scheme 4.15
Other transition states TSs-A−D, TS-T, TS-U, and TS-I that
form the model β-lactones 2A−D, 2T, 2U, and 2I from the
corresponding 3-hydroxypropanoic or 3-hydroxybutanoic acids
1A−D, 1T, 1U, and 1I were also determined at the same level
(B3LYP/6-31G*//B3LYP/6-31G*) by using DFT calcula-
tions, and all of the transition states and intermediates are
represented in Scheme 6.15 The three-dimensional structures of
the transition states TSs-A−D, TS-T, TS-U, and TS-I including
several bond distances are figured in Scheme 7. Furthermore,
the reaction coordinate profiles (MA of seco-acid → INT →
TS → IC → SC → β-lactone) for the MNBA lactonization of
the model seco-acids 1A−D, 1T, 1U, and 1I are graphically
summarized in Scheme 8 with the calculated relative enthalpies
(ΔH298.15) in Table 1. It should be noted that the structures of
the model seco-acids 1A−D correspond to those of the
experimentally examined seco-acids 1a−d in Scheme 1, and the
order of the reactivities of 1a−d (chemical yields of β-lactones
2a−d at rt; 5% (2a), 89% (2b), 13% (2c), 69% (2d)) is
correctly predicted by the result of the calculations as shown in
Table 1 (ΔH[rel (INTs)] of TSs-A−D; 14.14 kcal/mol (TS-A),
6.88 kcal/mol (TS-B), 12.69 kcal/mol (TS-C), 9.49 kcal/mol
The frequency analysis of TS-S revealed that the nucleophilic
attack of the alcohol on the carbonyl group and the
deprotonation of the hydroxyl group with the 2-methyl-6-
nitrobenzoate anion proceeded under a concerted reaction
mechanism because the C−O bond-forming step and the O−H
bond-cleaving process simultaneously occurred (Scheme 5).
The 2-methyl-6-nitrobenzoate moiety has a rigid structure in
which the conformation is restricted by the attractive
interaction between oxygen in the benzoate carbonyl group
and hydrogen at C-2 of the pyridinium salt (2.269 Å) as well as
the coordination of oxygens in the nitro group to hydrogen in
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Scheme 6. Reaction Pathway and the Calculated Transition States (TSs-A−D, TS-T, TS-U, and TS-I) To Form β-Lactones
(2A−D, 2T, 2U, and 2I) from 3-Hydroxycarboxylic Acids (1A−D, 1T, 1U, and 1I)
(TS-D)).16 The distances of the forming C−O bonds in TS-B,
TS-D, TS-T, and TS-I (1.867, 1.855, 1.871, and 1.928 Å,
respectively) are apparently longer than those in TS-S, TS-A,
TS-C, and TS-U (1.821, 1.825, 1.840, and 1.857 Å,
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Scheme 7. Three-Dimensional Transition Structures (TSs-A−D, TS-T, TS-U, and TS-I) To Form β-Lactones (2A−D, 2T, 2U,
and 2I) from 3-Hydroxycarboxylic Acids (1A−D, 1T, 1U, and 1I)
respectively); therefore, it might be anticipated that the former
transition states (TS-B, TS-D, TS-T, and TS-I) have structures
similar to those of the reactants, while the latter transition states
(TS-S, TS-A, TS-C, and TS-U) resemble the products
according to the Hammond postulate.17 Our calculated results
showed that the earlier transition states, such as TS-B, TS-D,
TS-T, and TS-I, can release a small strain energy during the
early stage in the transformation to afford the desired β-
lactones, although other later transition states, such as TS-S,
TS-A, TS-C, and TS-U, accumulate an excess energy until the
new oxygen−carbon bond-forming reaction begins in the late
stage.
This categorization finally prompted us to prepare a 2,2,3,3-
tetrasubstituted seco-acid 1i for the attempt to examine the
synthetic efficiency of a highly branched β-lactone 2i with four
alkyl substituents on the 4-membered ring as shown in Scheme
9. The preferred calculated results of the model compound 1I, a
low enthalpy of the transition state TS-I (ΔH[rel (INT‑I)] = 7.50
kcal/mol) and forming a C−O bond with a long distance in
TS-I (1.928 Å), suggest that easy ring closure of the seco-acid
1i should occur to form the desired β-lactone 2i via an early
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Scheme 8. Reaction Coordinates To Form β-Lactones (2A−D, 2S−U, and 2I) from 3-Hydroxycarboxylic Acids (1A−D, 1S−U,
and 1I)
Table 1. Calculated Relative Enthalpies (ΔH) (in kcal mol−1) of the Transition States and Intermediates for the Formation of
Lactones 2A−D, 2S−U, and 2I from 3-Hydroxycarboxylic Acids (1A−D, 1S−U, and 1I) at 298.15 K at the B3LYP/6-31G*//
B3LYP/6-31G* Level of Theory
DMAP + MA from 1A-D, 1S−U, 11 INT-A-D INT−
TS-A-D TS−
IC-A-D IC−
SC-A-D SC−
DMAP + 2A-D, 2S−U, 21 + 2-Me-6-
NO2C6H3CO2H (product)
(reactant)
S-U INT-I
S-U TS-I
S-U IC-I
S-U SC-I
S
7.64
6.73
0.73
6.47
2.42
0.90
6.80
0.56
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
15.83
14.14
6.88
0.32
−2.77
−11.65
−3.79
−9.09
−7.90
−4.85
−14.61
−8.08
−10.43
−19.91
−11.68
−16.28
−16.40
−12.52
−20.95
16.54
14.13
4.69
A
B
C
D
T
U
I
12.69
9.49
13.00
7.88
9.00
7.48
14.58
7.50
12.22
2.28
ϕC1−C2−C3 (Thorpe−Ingold effect) as shown above (vide
supra).11 Actually, the calculated bond angles ϕC1−C2−C3 of
INT-B (105.38°) derived from 1B, INT-T (108.41°) derived
from 1T, and INT-I (106.80°) derived from 1I are much
smaller than those of the intermediates INT-S (111.16°)
derived from 1S, INT-A (112.23°) derived from 1A, and INT-
U (113.22°) derived from 1U as depicted in Schemes 4 and 6.
These results are easily correlated with the structures of seco-
acids; that is, 1B, 1T, and 1I have the gem-dimethyl group at
the α-position of the carbonyl group, although 1S, 1A, and 1U
have no substituent at the same position. On the other hand,
the calculated bond angle ϕC1−C2−C3 of INT-D derived from
the anti-compound 1D (113.20°) is similar to those of INT-S
(111.16°), INT-A (112.23°), and INT-U (113.22°) as well as
that of INT-C (109.65°) derived from syn-compound 1C.
Therefore, the conformational advantage of the transition state
TS-D for cyclization might arise from not only the substituent
effect of the methyl group at the C-2 position but also the
Scheme 9. Synthesis of the Fully Substituted β-Lactone (2i)
from 2,2,3,3-Tetrasubstituted 3-Hydroxycarboxylic Acid (1i)
Using MNBA Lactonization
transition state similar to that of TS-I. Actually, the very
effective MNBA-mediated lactonization of 1i proceeded under
the same reaction conditions, which were used in Schemes 1
and 2, and the corresponding fully substituted β-lactone 2i was
produced as expected in excellent yield (95%) according to the
theoretical prediction.18
A gem-dimethyl group at the α-position of the carbonyl
group produces strain which forces a decrease in the bond angle
Table 2. Yields of Lactones 2a−d and 2i and Calculated Relative Gibbs Free Energies (ΔG) (in kcal mol−1), Enthalpies (ΔH)
(in kcal mol−1), and Products of Entropies and Temperature (TΔS) (in kcal mol−1) for the Transition States TS-A−D, TS-S−U,
and TS-I at 298.15 K at the B3LYP/6-31G*//B3LYP/6-31G* Level of Theory
TS-B
TS-I
TS-T
TS-D
TS-C
TS-A
TS-U
TS-S
yield (%)
ΔG
ΔH
89 (2b)
6.56
95 (2i)
7.16
69 (2d)
9.32
13 (2c)
12.66
12.69
0.03
5 (2a)
14.04
14.14
0.10
8.84
9.00
0.16
14.50
14.58
0.08
15.80
15.83
0.03
6.88
7.50
9.49
TΔS
0.32
0.34
0.17
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Scheme 10. Comparison of Yields of Lactones 2a−d and 2i with Thermodynamic Potentials of the Model Lactonization To
Form (2A−D, 2S−U, and 2I) via the Transition States TS-A−D, TS-S−U, and TS−I
suitable direction of the additional methyl group at the C-3
position in INT-D. These structural restrictions in the reactants
1B, 1D, 1T, and 1I will allow the stability of the early transition
states TS-B, TS-D, TS-T, and TS-I to increase. Profiles of the
relative Gibbs free energies (ΔG) and enthalpies (ΔH) of
transition states TS-A−D, TS-S−U, and TS-I are summarized
in Table 2 and illustrated in Scheme 10. Apparently, these
potentials for the transition states TS-B, TS-D, TS-T, and TS-I
are lower (<10 kcal/mol) than those for the transition states
TS-S, TS-A, TS-C, and TS-U (>12 kcal/mol). Although the
participation of entropy to Gibbs free energy is not so large in
every case, certainly larger products of entropies and temper-
ature (TΔS) are observed for the transition states TS-B, TS-D,
TS-T, and TS-I compared with those for the transition states
TS-S, TS-A, TS-C, and TS-U. These extensive properties might
be also accounted for by the easy cyclization of seco-acids 1b,
1d, and 1i to afford the corresponding 2,2,3-trisubstituted β-
lactone 2b, trans-2,3-disubstituted β-lactone 2d, and 2,2,3,3-
tetrasubstituted β-lactone 2i in good yields.
Asymmetric Total Synthesis of Tetrahydrolipstatin
(THL). On the basis of the above systematic studies for the
generation of the 4-membered ring compounds, it was
determined that trans-2,3-disubstituted, 2,2,3-trisubstituted, or
2,2,3,3-tetrasubstituted β-lactones were easily generated from
the corresponding seco-acids by the MNBA lactonization.
Therefore, we further planned the total synthesis of
(−)-tetrahydrolipstatin ((−)-THL) (3)19,20 including the
trans-2,3-disubstituted β-lactone part according to our con-
tinuous efforts for the synthesis of useful organic molecules.
(−)-THL (3) has been used in clinical treatment as an
antiobestic drug called Orlistat or Xenical, which effectively
functions to inhibit the activity of pancreatic lipase. It is well-
known that the hydroxyl group in the serine moiety in lipase
reacts with the β-lactone residue in 3 to form the corresponding
ester; hence, the reaction process of the lipase-catalyzed
hydrolysis of triglycerides would be prevented in the presence
of 3 in vivo.21
Scheme 11. Retrosynthetic Analysis of
(−)-Tetrahydrolipstatin ((−)-THL) (3)
diastereoselective Mukaiyama aldol reaction of the aldehyde
B with ketene silyl acetal to form a seco-acid C,23 and (iii) the
MNBA lactonization of C to form a β-lactone 5.1 General
methods for the transformation of the precursor 5 with an α-
amino acid 4 into (−)-THL (3) have already been established
by other groups;20a therefore, preparation of the β-lactone 5 is
the crucial objective for us in these synthetic studies.
First, the racemic propargyl alcohol ( )-6 was obtained from
dodecanal with trimethylsilylacetylene according to the known
conventional method via two steps including the alkynylation of
dodecanal.24 Then, the kinetic resolution of ( )-6 using 3-
phenylpropanoic acid (0.7 equiv) and pivalic anhydride (0.75
equiv) with 5 mol % of (S)-benzotetramisole ((S)-BTM)25 was
attempted (Scheme 12, eq 1)22 to produce both the
corresponding (S)-ester (56% ee) and the recovered alcohol
(R)-6 (84% ee) in good yields (58% and 39%, respectively)
with moderate enantioselectivities (s = 9).26 We have already
established the remarkable asymmetric esterification using
diphenylacetic acid as an acyl donor with racemic 2-hydroxy
esters to afford the optically active compounds possessing
excellent enantiopurities;27 therefore, we next tried to improve
the selectivity of the kinetic resolution of the racemic propargyl
alcohol ( )-6 using diphenylacetic acid as an acyl donor instead
of using 3-phenylpropanoic acid (Scheme 12, eq 2).
Fortunately, the selective factor drastically improved and
reached a higher value (s = 34) with the enhanced
Scheme 11 shows our designed asymmetric synthesis of 3
including three notable methodologies, that is, (i) the
asymmetric esterification of the racemic secondary alcohol to
form a chiral protected propargyl alcohol A,22 (ii) the
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Scheme 12. Production of Chiral Alcohol (R)-6 by Kinetic Resolution of Racemic Alcohol ( )-6 via Asymmetric Esterification
Scheme 13. Total Synthesis of (−)-Tetrahydrolipstatin ((−)-THL) (3)
enantioselectivities of (S)-7 (80% ee) and the recovered (R)-6
(96% ee) in good yields (55% and 43%, respectively) when
using diphenylacetic acid.
the formed β-hydroxyester 11 was attained according to the
former established method to exclusively provide the desired
trisubstituted benzyl hexadecanoate 12.20x,z,29
As shown in Scheme 13, the multigram scale synthesis of the
optically pure (R)-6 was also carried out by the kinetic
resolution of a large amount of ( )-6 (6.00 g) using
diphenylacetic acid with (S)-BTM, and a sufficient amount
(2.43 g) of the desired chiral propargyl alcohol (R)-6 was
obtained in good yield (41% from ( )-6) with a very high
enantiopurity (99% ee, s = 34) via single operation.
Installation of the PMB protective group onto the alcohol
(R)-6 and the following hydroboration of the resulting alkyne 8
provided the chiral aldehyde 9 in good yield from (R)-6. The
Mukaiyama aldol reaction of the β-alkoxyaldehyde 9 with
ketene silyl acetal 10, which was prepared from benzyl acetate,
mediated by TiCl2(OiPr)2 smoothly proceeded to afford the
desired anti-1,3-diol unit 11 with a high stereoselectivity (anti/
syn = 94/6).28 The anti-selective alkylation at the α-position of
After hydrolysis of the benzyl ester 12 with lithium
hydroxide, the intramolecular dehydration condensation of
the resulting seco-acid was eventually examined using MNBA
(1.3 equiv) combined with a catalytic amount of DMAP (0.2
equiv) and triethylamine (6.0 equiv), and the desired trans-2,3-
disubstituted β-lactone 13 was readily produced in excellent
yield (91%) by this facile procedure. On the other hand, we
revealed that the MNBA lactonization using an excess amount
of DMAP (6.0 equiv) in the absence of triethylamine also
produced the β-lactone 13 in a similar satisfactory yield
(92%).30−33 Finally, sequential transformations of 13 by
deprotection of the PMB group and the Mitsunobu reaction
of the formed alcohol 5 with α-amino acid 4 furnished the
targeted molecule (−)-THL (3) in a very high yield. All
spectral data including the optical rotation of synthetic 3
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17.0 Hz, 1H, 2-H), 1.85 (dddd, J = 5.5, 8.5, 9.5, 14.0 Hz, 1H, 4-H),
1.74 (dddd, J = 4.0, 7.0, 9.5, 14.0 Hz, 1H, 4-H), 1.27 (t, J = 7.0 Hz, 3H,
OEt); 13C NMR (125 MHz, CDCl3) δ 172.8, 141.7, 128.4, 128.3,
125.8, 67.1, 60.6, 41.3, 38.1, 31.7, 14.1; HRMS (ESI-TOF) calcd for
C13H18O3Na (M + Na+) 245.1148, found 245.1151.
corresponded to those of reported (−)-THL (our synthetic
sample; [α]22D −32.5 (c 1.17, CHCl3); lit.19d [α]20D −32.0 (c 1,
CHCl3); lit.20i [α]25 −33.04 (c 0.79, CHCl3); lit.20n [α]20
D
D
−32.0 (c 0.74, CHCl3); lit.20x [α]26D −31 (c 0.1, CHCl3)), and
all the absolute configurations of the stereogenic centers at C-2,
C-3, and C-5 positions were unequivocally determined by this
identification.
3-Hydroxy-5-phenylpentanoic Acid (1a). To a solution of ethyl
3-hydroxy-5-phenylpentanoate (754 mg, 3.39 mmol) in aqueous
methanol (33.9 mL with 1% water) at room temperature was added
potassium carbonate (938 mg, 6.79 mmol). After the reaction mixture
had been stirred for 20 h at 65 °C, it was concentrated under reduced
pressure. The residue including a small amount of methanol was
diluted with water, and then it was extracted with chloroform/ethanol
= 7/3 and dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by
recrystallization from dichloromethane to afford 1a (460 mg, 70%) as
a white solid: mp 126−130 °C; IR (KBr) 3223, 1681 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.31−7.16 (m, 5H, Ph), 4.05 (dddd, J = 3.5, 4.0,
8.5, 8.5 Hz, 1H, 3-H), 2.82 (ddd, J = 5.5, 9.5, 14.5 Hz, 1H, 5-H), 2.72
(ddd, J = 7.0, 9.0, 14.5 Hz, 1H, 5-H), 2.59 (dd, J = 3.5, 17.0 Hz, 1H, 2-
H), 2.52 (dd, J = 8.5, 17.0 Hz, 1H, 2-H), 1.88 (dddd, J = 5.5, 8.5, 9.0,
14.0 Hz, 1H, 4-H), 1.78 (dddd, J = 4.0, 7.0, 9.5, 14.0 Hz, 1H, 4-H);
13C NMR (100 MHz, DMSO-d6) δ 173.2, 142.4, 128.5, 128.5, 125.8,
66.8, 42.9, 39.0, 31.5; HRMS (ESI-TOF) calcd for C11H14O3Na (M +
Na+) 217.0835, found 217.0840.
CONCLUSION
■
In summary, we have developed a convenient method for the
preparation of several β-lactones, representative of small ring
compounds, having trans-2,3-disubstituted, 2,2,3-trisubstituted,
or 2,2,3,3-tetrasubstituted patterns by using the MNBA-
mediated cyclization. The effective MNBA-mediated ring
closures of seco-acids, 3-hydroxy-2,2-dimethyl-5-phenylpenta-
noic acid (1b) and 3-hydroxy-2,2-dimethyl-3-methyl-5-phenyl-
pentanoic acid (1i), were demonstrated to afford the
corresponding 2,2,3-trisubstituted β-lactone 2b and 2,2,3,3-
tetrasubstituted β-lactone 2i in high yields (89% and 95%,
respectively). These experimental results were theoretically
explained by a mechanistic study by using DFT calculations for
the cyclization of the model seco-acids 1B and 1I to form β-
lactones 2B and 2I through the low energy transition states TS-
B and TS-I. We also achieved the enantioselective total
synthesis of (−)-tetrahydrolipstatin ((−)-THL) (3), an
antiobestic agent used in clinical treatments, by the MNBA
lactonization of the corresponding seco-acid to provide the β-
lactone moiety of 3 under mild reaction conditions. Two other
key steps, i.e., (i) the asymmetric esterification of diphenylacetic
acid with a large amount of the racemic secondary propargyl
alcohol ( )-6 and (ii) the diastereoselective Mukaiyama aldol
reaction of the aldehyde 9 with ketene silyl acetal 10 derived
from benzyl acetate, were employed for the construction of the
main skeleton of 3.
5-Phenylpentan-3-olide (2a).35 To a solution of MNBA (115
mg, 0.334 mmol), DMAP (6.3 mg, 0.052 mmol), and triethylamine
(0.210 mL, 1.51 mmol) in dichloromethane (12.9 mL) at 50 °C was
slowly added a solution of 1a (50.0 mg, 0.257 mmol) in THF (5.1
mL) with a mechanically driven syringe over a 12 h period. After the
reaction mixture had been stirred for 1 h at 50 °C, saturated aqueous
sodium hydrogen carbonate was added at 0 °C. The mixture was
extracted with dichloromethane, and the organic layer was washed
with brine and dried over sodium sulfate. After filtration of the mixture
and evaporation of the solvent, the crude product was purified by thin-
layer chromatography on silica (eluant; hexane/ethyl acetate = 3/1) to
1
afford 2a (9.5 mg, 21%) as a colorless oil: IR (neat) 1824 cm−1; H
NMR (500 MHz, CDCl3) δ 7.33−7.17 (m, 5H, Ph), 4.50 (dddd, J =
4.5, 5.5, 6.0, 8.0 Hz, 1H, 3-H), 3.48 (dd, J = 6.0, 16.0 Hz, 1H, 2-H),
3.03 (dd, J = 4.5, 16.0 Hz, 1H, 2-H), 2.83 (ddd, J = 5.5, 9.0, 14.0 Hz,
1H, 5-H), 2.72 (ddd, J = 7.5, 8.0, 14.0 Hz, 1H, 5-H), 2.20 (dddd, J =
5.5, 8.0, 8.0, 14.0 Hz, 1H, 4-H), 2.07 (dddd, J = 5.5, 7.5, 9.0, 14.0 Hz,
1H, 4-H); 13C NMR (100 MHz, CDCl3) δ 168.0, 140.0, 128.7, 128.4,
126.4, 70.4, 42.9, 36.4, 31.3; HRMS (ESI-TOF) calcd for C11H12O2Na
(M + Na+) 199.0730, found 199.0726.
EXPERIMENTAL SECTION
■
1
General Information. H and 13C NMR spectra were recorded
with chloroform (in CDCl3) or dimethyl sulfoxide (in DMSO-d6) as
internal standards. In some cases, 1H NMR assignments were
supported by appropriate homonuclear correlation experiments
(COSY).
Ethyl 3-Hydroxy-2,2-dimethyl-5-phenylpentanoate. To a
solution of diisopropylamine (0.628 mL, 4.47 mmol) in THF (34
mL) at 0 °C was added butyllithium in hexane (1.59 M, 2.60 mL, 4.13
mmol). The reaction mixture was stirred for 15 min at 0 °C, and then
ethyl 2-methylpropanoate (0.547 mL, 4.10 mmol) was added at −78
°C. After the reaction mixture had been stirred for 30 min, a solution
of 3-phenylpropanal (500 mg, 3.73 mmol) in THF (3 mL) was added
at −78 °C. The reaction mixture was stirred for 1.5 h, and then
saturated aqueous ammonium chloride was added. The mixture was
extracted with ethyl acetate, and the organic layer was washed with
brine and dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by column
chromatography on silica (eluant; hexane/ethyl acetate = 10/1) to
afford ethyl 3-hydroxy-2,2-dimethyl-5-phenylpentanoate (933 mg,
All reactions were carried out under argon atmosphere in dried
glassware unless otherwise noted. Dichloromethane was distilled from
diphosphorus pentoxide, then calcium hydride, and dried over MS 4 Å,
benzene and toluene were distilled from diphosphorus pentoxide, and
dried over MS 4 Å, and THF and diethyl ether were distilled from
sodium/benzophenone immediately prior to use.
Ethyl 3-Hydroxy-5-phenylpentanoate.34 To a solution of
diisopropylamine (0.650 mL, 4.62 mmol) in THF (37.3 mL) at 0
°C was added butyllithium in hexane (1.59 M, 2.60 mL, 4.13 mmol).
The reaction mixture was stirred for 15 min at 0 °C, and then ethyl
acetate (0.400 mL, 4.09 mmol) was added at −78 °C. After the
reaction mixture had been stirred for 30 min, 3-phenylpropanal (0.490
mL, 3.73 mmol) was added at −78 °C. The reaction mixture was
stirred for 2 h, and then saturated aqueous ammonium chloride was
added. The mixture was extracted with ethyl acetate, and the organic
layer was washed with brine and dried over sodium sulfate. After
filtration of the mixture and evaporation of the solvent, the crude
product was purified by column chromatography on silica (eluant;
hexane/ethyl acetate = 10/1) to afford ethyl 3-hydroxy-5-phenyl-
pentanoate (754 mg, 91%) as a colorless oil: IR (neat) 3445, 1733
cm−1; 1H NMR (500 MHz, CDCl3) δ 7.31−7.16 (m, 5H, Ph), 4.17 (q,
J = 7.0 Hz, 2H, OEt), 4.02 (dddd, J = 3.0, 4.0, 8.5, 9.0 Hz, 1H, 3-H),
2.83 (ddd, J = 5.5, 9.5, 14.0 Hz, 1H, 5-H), 2.70 (ddd, J = 7.0, 9.5, 14.0
Hz, 1H, 5-H), 2.51 (dd, J = 3.0, 17.0 Hz, 1H, 2-H), 2.44 (dd, J = 9.0,
1
quant) as a colorless oil: IR (neat) 3456, 1720 cm−1; H NMR (300
MHz, CDCl3) δ 7.33−7.15 (m, 5H, Ph), 4.14 (q, J = 7.2 Hz, 2H,
OEt), 3.62 (ddd, J = 2.1, 6.9, 10.5 Hz, 1H, 3-H), 2.96 (ddd, J = 5.1,
9.9, 13.8 Hz, 1H, 5-H), 2.65 (ddd, J = 6.9, 9.6, 13.8 Hz, 1H, 5-H), 2.65
(d, J = 6.9 Hz, 1H, OH), 1.83−1.70 (m, 1H, 4-H), 1.69−1.54 (m, 1H,
4-H), 1.25 (t, J = 7.2 Hz, 3H, OEt), 1.19 (s, 3H, 2-Me), 1.16 (s, 3H, 2-
Me); 13C NMR (125 MHz, CDCl3) δ 177.5, 142.0, 128.3, 128.2,
125.6, 75.7, 60.4, 46.8, 33.6, 32.7, 21.8, 20.4, 13.9; HRMS (ESI-TOF)
calcd for C15H22O3Na (M + Na+) 273.1461, found 273.1448.
3-Hydroxy-2,2-dimethyl-5-phenylpentanoic Acid (1b). To a
solution of ethyl 3-hydroxy-2,2-dimethyl-5-phenylpentanoate (933 mg,
3.73 mmol) in aqueous methanol (37.2 mL with 1% water) at room
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Featured Article
temperature was added potassium carbonate (1.03 g, 7.45 mmol).
After the reaction mixture had been stirred for 2 h at 65 °C, it was
concentrated under reduced pressure. The residue including a small
amount of methanol was diluted with water, and then it was extracted
with chloroform/ethanol = 7/3 and dried over sodium sulfate. After
filtration of the mixture and evaporation of the solvent, the crude
product was purified by column chromatography on silica (eluant;
chloroform/ethanol = 15/1) to afford 1b (662 mg, 80%) as a colorless
oil: IR (neat) 3436, 1703 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.31−
7.18 (m, 5H, Ph), 3.66 (dd, J = 2.0, 10.5 Hz, 1H, 3-H), 2.95 (ddd, J =
5.0, 10.0, 14.0 Hz, 1H, 5-H), 2.67 (ddd, J = 7.0, 9.5, 14.0 Hz, 1H, 5-H),
1.84 (dddd, J = 2.0, 7.0, 10.0, 14.0 Hz, 1H, 4-H), 1.68 (dddd, J = 5.0,
9.5, 10.5, 14.0 Hz, 1H, 4-H), 1.24 (s, 3H, 2-Me), 1.19 (s, 3H, 2-Me);
13C NMR (100 MHz, CDCl3) δ 183.4, 141.8, 128.4, 128.4, 125.9, 76.0,
47.0, 33.3, 32.8, 22.7, 19.9; HRMS (ESI-TOF) calcd for C13H18O3Na
(M + Na+) 245.1148, found 245.1142.
1.25 mmol) and 30% hydrogen peroxide in water (0.42 mL). After the
reaction mixture had been stirred for 24 h at room temperature, 1.0 M
hydrochloric acid was added at 0 °C. The acidified mixture (pH = 3)
was extracted with ethyl acetate, and the organic layer was washed with
brine and dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by column
chromatography on silica (eluant; chloroform/methanol = 30/1) to
afford 1c (109 mg, 83%) as a white solid: [α]22 +25.7 (c 0.987,
D
1
CHCl3); mp 77−78 °C; IR (KBr) 3381, 1705 cm−1; H NMR (500
MHz, CDCl3) δ 7.34−7.20 (m, 5H, Ph), 3.99 (ddd, J = 3.5, 3.5, 9.5
Hz, 1H, 3-H), 2.89 (ddd, J = 5.5, 9.5, 14.0 Hz, 1H, 5-H), 2.71 (ddd, J =
7.0, 9.5, 14.0 Hz, 1H, 5-H), 2.65 (dq, J = 3.5, 7.5 Hz, 1H, 2-H), 1.87
(dddd, J = 5.5, 9.5, 9.5, 14.0 Hz, 1H, 4-H), 1.76 (dddd, J = 3.5, 7.0, 9.5,
14.0 Hz, 1H, 4-H), 1.25 (d, J = 7.5 Hz, 3H, 2-Me); 13C NMR (125
MHz, CDCl3) δ 181.0, 141.5, 128.4, 128.4, 125.9, 71.1, 44.2, 35.3,
32.2, 10.4; HRMS (ESI-TOF) calcd for C12H16O3Na (M + Na+)
231.0992, found 231.1001.
2,2-Dimethyl-5-phenylpentan-3-olide (2b). To a solution of
MNBA (101 mg, 0.292 mmol), DMAP (5.5 mg, 0.045 mmol), and
triethylamine (0.190 mL, 1.37 mmol) in dichloromethane (13.5 mL)
at room temperature was slowly added a solution of 1b (50.6 mg,
0.228 mmol) in dichloromethane (9.0 mL) with a mechanically driven
syringe over a 12 h period. After the reaction mixture had been stirred
for 1 h at room temperature, saturated aqueous sodium hydrogen
carbonate was added at 0 °C. The mixture was extracted with
dichloromethane, and the organic layer was washed with brine and
dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by thin-
layer chromatography on silica (eluant; hexane/ethyl acetate = 3/1) to
(2S,3R)-2-Methyl-5-phenylpentan-3-olide (2c):38 To a solu-
tion of MNBA (104 mg, 0.301 mmol), DMAP (5.6 mg, 0.046 mmol),
and triethylamine (0.193 mL, 1.39 mmol) in dichloromethane (17
mL) at room temperature was slowly added a solution of 1c (48.2 mg,
0.231 mmol) in dichloromethane (6.2 mL) with a mechanically driven
syringe over a 12 h period. After the reaction mixture had been stirred
for 1 h at room temperature, saturated aqueous sodium hydrogen
carbonate was added at 0 °C. The mixture was extracted with
dichloromethane, and the organic layer was washed with brine and
dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified twice by
thin-layer chromatography on silica (eluant; hexane/ethyl acetate = 3/
1 and hexane/chloroform =1/5) to afford 2c (5.6 mg, 13%) as a
colorless oil: [α]23D +53.0 (c 0.640, CHCl3) [lit.38 [α]D1−47.2 (c 2.04,
CHCl3) for ent-2c (>99% ee)]; IR (neat) 1820 cm−1; H NMR (500
MHz, CDCl3) δ 7.34−7.18 (m, 5H, Ph), 4.56 (ddd, J = 4.0, 6.5, 10.0
Hz, 1H, 3-H), 3.74 (dq, J = 6.5, 8.0 Hz, 1H, 2-H), 2.88 (ddd, J = 5.0,
8.5, 14.0 Hz, 1H, 5-H), 2.71 (ddd, J = 7.5, 9.0, 14.0 Hz, 1H, 5-H), 2.09
(dddd, J = 4.0, 8.5, 9.0, 13.5 Hz, 1H, 4-H), 1.96 (dddd, J = 5.0, 7.5,
10.0, 13.5 Hz, 1H, 4-H), 1.27 (d, J = 8.0 Hz, 3H, 2-Me); 13C NMR
(100 MHz, CDCl3) δ 172.5, 140.4, 128.6, 128.5, 126.4, 74.6, 47.2,
32.0, 31.5, 8.1; HRMS (ESI-TOF) calcd for C12H14O2Na (M + Na+)
213.0886, found 213.0878.
1
afford 2b (41.5 mg, 89%) as a colorless oil: IR (neat) 1821 cm−1; H
NMR (500 MHz, CDCl3) δ 7.34−7.18 (m, 5H, Ph), 4.24 (dd, J = 4.5,
9.5 Hz, 1H, 3-H), 2.86 (ddd, J = 4.5, 9.5, 14.0 Hz, 1H, 5-H), 2.69
(ddd, J = 7.5, 9.0, 14.0 Hz, 1H, 5-H), 2.07 (dddd, J = 4.5, 9.0, 9.5, 14.0
Hz, 1H, 4-H), 1.97 (dddd, J = 4.5, 7.5, 9.5, 14.0 Hz, 1H, 4-H), 1.39 (s,
3H, 2-Me), 1.24 (s, 3H, 2-Me); 13C NMR (125 MHz, CDCl3) δ 175.3,
140.4, 128.6, 128.4, 126.3, 82.4, 53.3, 32.5, 31.7, 22.5, 16.3; HRMS
(ESI-TOF) calcd for C13H16O2Na (M + Na+) 227.1043, found
227.1034.
S-Ethyl (2S,3R)-3-Hydroxy-2-methyl-5-phenylpentane-
thioate.36,37 To tin(II) trifluoromethanesulfonate (592 mg, 1.42
mmol) at room temperature were added a solution of (S)-1-methyl-2-
(1-naphthylaminomethyl)pyrrolidine (404 mg, 1.68 mmol) in
dichloromethane (8.9 mL) and tributyltin fluoride (479 mg, 1.54
mmol). A solution of (Z)-1-ethylthio-1-(trimethylsiloxy)propene (271
mg, 1.55 mmol) in dichloromethane (2 mL) and a solution of 3-
phenylpropanal (173 mg, 1.29 mmol) in dichloromethane (2 mL)
were successively added at −78 °C. The reaction mixture was stirred
for 13 h at −78 °C, and then saturated aqueous sodium hydrogen
carbonate was added. The mixture was filtered through a short pad of
Celite, and the filtrate was extracted with dichloromethane. The
organic layer was washed with water and brine and dried over sodium
sulfate. After filtration of the mixture and evaporation of the solvent,
the crude product was purified by thin-layer chromatography on silica
(eluant; hexane/ethyl acetate = 3/1) to afford S-ethyl (2S,3R)-3-
hydroxy-2-methyl-5-phenylpentanethioate (171 mg, 52%, 92% ee, syn/
anti = 100/0) as a colorless oil: HPLC (CHIRALCEL OB-H, i-PrOH/
hexane = 1/19, flow rate =1.0 mL/min); tR = 9.02 min (96.0%), tR =
Ethyl (2R*,3R*)-3-Hydroxy-2-methyl-5-phenylpentanoate.39
To a solution of diisopropylamine (0.12 mL, 0.854 mmol) in THF
(3.8 mL) at 0 °C was added butyllithium in hexane (2.69 M, 0.310
mL, 0.834 mmol). After the reaction mixture had been stirred for 15
min at 0 °C, a solution of ethyl 3-hydroxy-5-phenylpentanoate (53.1
mg, 0.239 mmol) in THF (1 mL) was added at −78 °C. The reaction
mixture was stirred for 30 min at −78 °C and for 1 h at −45 °C, and
then a solution of iodomethane (0.150 mL, 2.41 mmol) in HMPA
(0.420 mL, 2.41 mmol) was added at −45 °C. After the reaction
mixture had been stirred for 1 h at −45 °C, saturated aqueous
ammonium chloride was added. The mixture was extracted with ethyl
acetate, and the organic layer was washed with brine and dried over
sodium sulfate. After filtration of the mixture and evaporation of the
solvent, the crude product was purified by thin-layer chromatography
on silica (eluant; hexane/ethyl acetate = 4/1) to afford ethyl
(2R*,3R*)-3-hydroxy-2-methyl-5-phenylpentanoate (47.8 mg, 85%,
anti/syn = 100/0) and recovered ethyl 3-hydroxy-5-phenylpentanoate
(2.4 mg, 5%) as colorless oils. Ethyl (2R*,3R*)-3-hydroxy-2-methyl-
5-phenylpentanoate: IR (neat) 3437, 1727 cm−1; 1H NMR (500
MHz, CDCl3) δ 7.31−7.17 (m, 5H, Ph), 4.17 (q, J = 7.0 Hz, 2H,
OEt), 3.67 (dddd, J = 3.0, 7.0, 7.0, 9.5 Hz, 1H, 3-H), 2.87 (ddd, J =
5.5, 10.0, 14.0 Hz, 1H, 5-H), 2.72 (d, J = 7.0 Hz, 1H, OH), 2.70 (ddd,
J = 6.5, 9.5, 14.0 Hz, 1H, 5-H), 2.52 (dq, J = 7.0, 7.5 Hz, 1H, 2-H),
1.82 (dddd, J = 3.0, 6.5, 10.0, 13.5 Hz, 1H, 4-H), 1.74 (dddd, J = 5.5,
9.5, 9.5, 13.5 Hz, 1H, 4-H), 1.27 (t, J = 7.0 Hz, 3H, OEt), 1.21 (d, J =
7.5 Hz, 3H, 2-Me); 13C NMR (125 MHz, CDCl3) δ 176.0, 141.9,
128.4, 128.3, 125.8, 72.6, 60.5, 45.2, 36.6, 31.9, 14.2, 14.1; HRMS
(ESI-TOF) calcd for C14H20O3Na (M + Na+) 259.1305, found
259.1314.
17.47 min (4.0%); [α]22 +57.2 (c 0.840, CHCl3); IR (neat) 3446,
D
1
1677 cm−1; H NMR (500 MHz, CDCl3) δ 7.34−7.16 (m, 5H, Ph),
3.94 (dddd, J = 3.0, 3.0, 3.5, 9.5 Hz, 1H, 3-H), 2.92−2.85 (m, 2H,
SEt), 2.92−2.82 (m, 1H, 5-H), 2.72−2.62 (m, 2H, 2-H, 5-H), 2.48 (br
d, J = 3.0 Hz, 1H, OH), 1.82 (dddd, J = 5.5, 9.5, 10.0, 14.0 Hz, 1H, 4-
H), 1.68 (dddd, J = 3.5, 6.5, 10.0, 14.0 Hz, 1H, 4-H), 1.25 (t, J = 7.5
Hz, 3H, SEt), 1.24 (t, J = 7.5 Hz, 3H, 2-Me); 13C NMR (125 MHz,
CDCl3) δ 204.2, 141.7, 128.4, 128.4, 125.8, 71.3, 53.0, 35.8, 32.2, 23.2,
14.5, 11.5; HRMS (ESI-TOF) calcd for C14H20O2SNa (M + Na+)
275.1076, found 275.1078.
(2S,3R)-3-Hydroxy-2-methyl-5-phenylpentanoic Acid (1c).
To a solution of S-ethyl (2S,3R)-3-hydroxy-2-methyl-5-phenylpenta-
nethioate (158 mg, 0.627 mmol) in THF (11.8 mL) and water (3.9
mL) at room temperature were added lithium hydroxide (30.0 mg,
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(2R*,3R*)-3-Hydroxy-2-methyl-5-phenylpentanoic Acid
(1d). To a solution of ethyl (2R*,3R*)-3-hydroxy-2-methyl-5-
phenylpentanoate (91.8 mg, 0.388 mmol) in methanol (0.97 mL)
and THF (1.94 mL) at room temperature was added lithium
hydroxide in water (4.00 M, 0.970 mL, 3.88 mmol). The reaction
mixture was stirred for 30 min at room temperature and then 1.0 M
hydrochloric acid was added at 0 °C. The acidified mixture (pH = 1)
was extracted with diethyl ether and the organic layer was washed with
brine and dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by thin-layer
chromatography on silica (eluant; chloroform/methanol/formic acid =
900/100/3) to afford 1d (79.1 mg, 98%) as a white solid: mp 71−72
°C; IR (KBr) 3390, 1709 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.31−
7.18 (m, 5H, Ph), 3.72 (ddd, J = 3.0, 7.0, 9.0 Hz, 1H, 3-H), 2.87 (ddd,
J = 5.5, 10.0, 14.0 Hz, 1H, 5-H), 2.72 (ddd, J = 7.0, 9.5, 14.0 Hz, 1H, 5-
H), 2.59 (dq, J = 7.0, 7.0 Hz, 1H, 2-H), 1.88 (dddd, J = 3.0, 7.0, 10.0,
14.0 Hz, 1H, 4-H), 1.80 (dddd, J = 5.5, 9.0, 9.5, 14.0 Hz, 1H, 4-H),
1.26 (d, J = 7.0 Hz, 3H, 2-Me); 13C NMR (125 MHz, CDCl3) δ 181.0,
141.6, 128.4, 128.4, 125.9, 72.6, 45.3, 36.2, 31.8, 14.1; HRMS (ESI-
TOF) calcd for C12H16O3Na (M + Na+) 231.0992, found 231.0997.
(2R*,3R*)-2-Methyl-5-phenylpentan-3-olide (2d).40 To a
solution of MNBA (140 mg, 0.406 mmol), DMAP (7.6 mg, 0.062
mmol), and triethylamine (0.260 mL, 1.88 mmol) in dichloromethane
(25 mL) at room temperature was slowly added a solution of 1d (65.0
mg, 0.312 mmol) in dichloromethane (6.2 mL) with a mechanically
driven syringe over a 12 h period. After the reaction mixture had been
stirred for 1 h at room temperature, saturated aqueous sodium
hydrogen carbonate was added at 0 °C. The mixture was extracted
with dichloromethane, and the organic layer was washed with brine
and dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by thin-layer
chromatography on silica (eluant; hexane/ethyl acetate =3/1) to afford
(2R*,3R*)-2-Hexyl-5-phenylpentanoic Acid (1e). To a solution
of ethyl (2R*,3R*)-2-hexyl-5-phenylpentanoate (98.2 mg, 0.320
mmol) in methanol (0.8 mL) and THF (1.6 mL) at room temperature
was added lithium hydroxide in water (4.00 M, 0.800 mL, 3.20 mmol).
The reaction mixture was stirred for 18 h at room temperature and
then 1.0 M hydrochloric acid was added at 0 °C. The acidified mixture
(pH = 4) was extracted with ethyl acetate, and the organic layer was
washed with brine and dried over sodium sulfate. After filtration of the
mixture and evaporation of the solvent, the crude product was purified
by thin-layer chromatography on silica (eluant; chloroform/methanol/
formic acid = 900/100/3) to afford 1e (78.9 mg, 88%) as a colorless
oil: IR (neat) 3417, 1712 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.33−
7.15 (m, 5H, Ph), 3.77−3.68 (m, 1H, 3-H), 2.86 (ddd, J = 5.5, 9.0,
14.0 Hz, 1H, 5-H), 2.71 (ddd, J = 7.0, 9.5, 14.0 Hz, 1H, 5-H), 2.48
(ddd, J = 5.0, 5.5, 10.0 Hz, 1H, 2-H), 1.91−1.78 (m, 2H, 1′-H), 1.78−
1.67 (m, 1H, 4-H), 1.67−1.56 (m, 1H, 4-H), 1.38−1.17 (m, 8H, 2′-H
3′-H, 4′-H, 5′-H), 0.87 (t, J = 7.0 Hz, 3H, 6′-H); 13C NMR (125 MHz,
CDCl3) δ 180.4, 141.6, 128.4, 128.4, 125.9, 71.6, 51.3, 37.0, 31.9, 31.5,
29.3, 29.1, 27.2, 22.5 (1′ to 5′), 14.0 (6′); HRMS (ESI-TOF) calcd for
C17H26O3Na (M + Na+) 301.1774, found 301.1780.
(2R*,3R*)-2-Hexyl-5-phenylpentan-3-olide (2e). To a solution
of MNBA (56.8 mg, 0.165 mmol), DMAP (3.1 mg, 0.025 mmol), and
triethylamine (0.110 mL, 0.794 mmol) in dichloromethane (10 mL) at
room temperature was slowly added a solution of 1e (35.4 mg, 0.127
mmol) in dichloromethane (2.7 mL) with a mechanically driven
syringe over a 12 h period. After the reaction mixture had been stirred
for 1 h at room temperature, saturated aqueous sodium hydrogen
carbonate was added at 0 °C. The mixture was extracted with
dichloromethane, and the organic layer was washed with brine and
dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by thin-
layer chromatography on silica (eluant; hexane/ethyl acetate = 6/1) to
1
2d (40.7 mg, 69%) as a colorless oil: IR (neat) 1823 cm−1; H NMR
1
afford 2e (27.6 mg, 83%) as a colorless oil: IR (neat) 1820 cm−1; H
(500 MHz, CDCl3) δ 7.33−7.18 (m, 5H, Ph), 4.17 (ddd, J = 4.0, 5.5,
8.0 Hz, 1H, 3-H), 3.20 (dq, J = 4.0, 7.5 Hz, 1H, 2-H), 2.83 (ddd, J =
5.5, 8.5, 14.0 Hz, 1H, 5-H), 2.71 (ddd, J = 8.0, 8.0, 14.0 Hz, 1H, 5-H),
2.20 (dddd, J = 5.5, 8.0, 8.0, 14.5 Hz, 1H, 4-H), 2.09 (dddd, J = 5.5,
8.0, 8.5, 14.5 Hz, 1H, 4-H), 1.32 (d, J = 7.5 Hz, 3H, 2-Me); 13C NMR
(125 MHz, CDCl3) δ 171.8, 140.0, 128.6, 128.3, 126.4, 78.6, 50.8,
35.8, 31.3, 12.4; HRMS (ESI-TOF) calcd for C12H14O2Na (M + Na+)
213.0886, found 213.0876.
NMR (500 MHz, CDCl3) δ 7.34−7.17 (m, 5H, Ph), 4.22 (ddd, J =
4.0, 5.5, 9.0 Hz, 1H, 3-H), 3.18 (ddd, J = 4.0, 7.0, 8.5 Hz, 1H, 2-H),
2.82 (ddd, J = 5.0, 9.0, 14.0 Hz, 1H, 5-H), 2.70 (ddd, J = 7.5, 8.5, 14.0
Hz, 1H, 5-H), 2.18 (dddd, J = 5.0, 8.5, 9.0, 14.0 Hz, 1H, 4-H), 2.07
(dddd, J = 5.5, 7.5, 9.0, 14.0 Hz, 1H, 4-H), 1.78 (dddd, J = 5.5, 7.0,
10.0, 14.0 Hz, 1H, 1′-H), 1.67 (dddd, J = 5.0, 8.5, 9.5, 14.0 Hz, 1H, 1′-
H), 1.46−1.20 (m, 8H, 2′-H 3′-H, 4′-H, 5′-H), 0.88 (t, J = 7.0 Hz, 3H,
6′-H); 13C NMR (125 MHz, CDCl3) δ 171.3, 140.1, 128.6, 128.3,
126.3, 77.1, 56.2, 36.1, 31.4, 31.3, 28.8, 27.7, 26.8, 22.4, 14.0; HRMS
(ESI-TOF) calcd for C17H24O2Na (M + Na+) 283.1669, found
283.1678.
Ethyl (2R*,3R*)-2-Hexyl-5-phenylpentanoate. To a solution of
diisopropylamine (0.250 mL, 1.78 mmol) in THF (6.9 mL) at 0 °C
was added butyllithium in hexane (1.57 M, 1.11 mL, 1.74 mmol). The
reaction mixture was stirred for 15 min at 0 °C, and then a solution of
ethyl 3-hydroxy-5-phenylpentanoate (110 mg, 0.496 mmol) in THF (3
mL) was added at −78 °C. The reaction mixture was stirred for 1 h at
−78 °C and for 1 h at −45 °C, and then a solution of iodohexane
(0.730 mL, 4.96 mmol) in HMPA (0.860 mL, 4.94 mmol) was added.
After the reaction mixture had been stirred for 2 h at −45 °C,
saturated aqueous ammonium chloride was added. The mixture was
extracted with ethyl acetate, and the organic layer was washed with
brine and dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by thin-layer
chromatography on silica (eluant; hexane/ethyl acetate = 3/1) to
afford ethyl (2R*,3R*)-2-hexyl-5-phenylpentanoate (98.2 mg, 65%,
anti/syn = 100/0) and recovered ethyl 3-hydroxy-5-phenylpentanoate
(28.5 mg, 26%) as colorless oils. Ethyl (2R*,3R*)-2-hexyl-5-
phenylpentanoate: IR (neat) 3448, 1720 cm−1; 1H NMR (300
MHz, CDCl3) δ 7.33−7.15 (m, 5H, Ph), 4.20 (qd, J = 7.2, 10.8 Hz,
1H, OEt), 4.16 (qd, J = 7.2, 10.8 Hz, 1H, OEt), 3.68 (dddd, J = 4.5,
5.1, 8.4, 8.7 Hz, 1H, 3-H), 2.86 (ddd, J = 6.3, 9.0, 14.1 Hz, 1H, 5-H),
2.69 (ddd, J = 7.5, 9.3, 14.1 Hz, 1H, 5-H), 2.65 (d, J = 8.4 Hz, 1H,
OH), 2.43 (ddd, J = 5.1, 5.4, 9.0 Hz, 1H, 2-H), 1.86−1.66 (m, 3H, 4-
H, 1′-H), 1.66−1.53 (m, 1H, 4-H), 1.34−1.20 (m, 8H, 2′-H, 3′-H, 4′-
H, 5′-H), 1.28 (t, J = 7.2 Hz, 3H, OEt), 0.88 (t, J = 7.2 Hz, 3H, 6′-H);
13C NMR (75 MHz, CDCl3) δ 175.6, 141.8, 128.3, 128.3, 125.7, 71.5,
60.3, 50.9, 37.4, 32.0, 31.5, 29.5, 29.0, 27.1, 22.4, 14.2, 13.9; HRMS
(ESI-TOF) calcd for C19H30O3Na (M + Na+) 329.2087, found
329.2093.
Ethyl 3-Hydroxy-2,2-dimethyl-3-phenylpropanoate.41 To a
solution of diisopropylamine (0.675 mL, 4.80 mmol) in THF (37.0
mL) at 0 °C was added butyllithium in hexane (1.57 M, 2.83 mL, 4.44
mmol). The reaction mixture was stirred for 15 min at 0 °C, and then
ethyl isobutyrate (0.592 mL, 4.43 mmol) was added at −78 °C. After
the reaction mixture had been stirred for 30 min, benzaldehyde (0.374
mL, 3.70 mmol) was added at −78 °C. The reaction mixture was
stirred for 1 h, and then saturated aqueous ammonium chloride was
added. The mixture was extracted with diethyl ether, and the organic
layer was washed with brine and dried over sodium sulfate. After
filtration of the mixture and evaporation of the solvent, the crude
product was purified by thin-layer chromatography on silica (eluent;
hexane/ethyl acetate = 4/1) to afford ethyl 3-hydroxy-2,2-dimethyl-3-
phenylpropanoate (803 mg, 98%) as a colorless oil: IR (neat) 3487,
1
1717 cm−1; H NMR (400 MHz, CDCl3) δ 7.35−7.23 (m, 5H, Ph),
4.89 (d, J = 4.0 Hz, 1H, 3-H), 4.19 (q, J = 7.2 Hz, 2H, OEt), 3.13 (d, J
= 4.0 Hz, 1H, OH), 1.27 (t, J = 7.2 Hz, 3H, OEt), 1.14 (s, 3H, 2-Me),
1.12 (s, 3H, 2-Me); 13C NMR (100 MHz, CDCl3) δ 177.7, 140.0,
127.63, 127.63, 127.60, 78.6, 60.8, 47.5, 22.9, 19.0, 14.0; HRMS (ESI-
TOF) calcd for C13H18O3Na (M + Na+) 245.1148, found 245.1138.
3-Hydroxy-2,2-dimethyl-3-phenylpropanoic Acid (1f).42 To a
solution of ethyl 3-hydroxy-2,2-dimethyl-3-phenylpropanoate (263
mg, 1.18 mmol) in methanol (3.0 mL) and THF (6.0 mL) at 0 °C was
added lithium hydroxide in water (4.00 M, 3.00 mL, 12.0 mmol). The
reaction mixture was stirred for 10 h at room temperature and then 1.0
M hydrochloric acid was added at 0 °C. The acidic mixture (pH = 4)
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was extracted with ethyl acetate, and the organic layer was washed with
brine and dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by
recrystallization from dichloromethane to afford 1f (195 mg, 85%) as a
128.4, 128.1, 128.0, 127.9, 126.6, 76.2, 66.4, 47.2, 14.4; HRMS (ESI-
TOF) calcd for C17H18O3Na (M + Na+) 293.1148, found 293.1148.
(2R*,3S*)-3-Hydroxy-2-methyl-3-phenylpropanoic Acid
(1g).44 To a solution of benzyl (2R*,3S*)-3-hydroxy-2-methyl-3-
phenylpropanoate (65.1 mg, 0.241 mmol) in methanol (0.6 mL) and
THF (1.2 mL) at 0 °C was added lithium hydroxide in water (4.00 M,
0.600 mL, 2.40 mmol). After the reaction mixture had been stirred for
3 h at room temperature, 1.0 M hydrochloric acid was added at 0 °C.
The acidified mixture (pH = 4) was extracted with ethyl acetate and
the organic layer was dried over sodium sulfate. After filtration of the
mixture and evaporation of the solvent, the crude product was purified
by thin-layer chromatography on silica (eluant; hexane/ethyl acetate =
4/1) to afford 1g (195 mg, 85%) as a white solid: mp 96−97 °C; IR
1
white solid: mp 134−135 °C; IR (KBr) 3383, 1697 cm−1: H NMR
(400 MHz, CDCl3) δ 7.38−7.28 (m, 5H, Ph), 4.95 (s, 1H, 3-H), 2.17
(s, 1H, OH), 1.18 (s, 3H, 2-Me), 1.18 (s, 3H, 2-Me); 13C NMR (100
MHz, CDCl3) δ 182.4, 139.5, 128.1, 128.0, 127.7, 78.5, 47.5, 23.3,
18.7; HRMS (ESI-TOF) calcd for C11H14O3Na (M + Na+) 217.0835,
found 217.0833.
2,2-Dimethyl-3-phenylpropan-3-olide (2f). To a solution of
MNBA (92.4 mg, 0.268 mmol), DMAP (5.0 mg, 0.041 mmol), and
triethylamine (0.170 mL, 1.23 mmol) in dichloromethane (17.8 mL)
at room temperature was slowly added a solution of 1f (40.1 mg, 0.206
mmol) in THF (2.8 mL) and dichloromethane (2.8 mL) with a
mechanically driven syringe over a 12 h period. After the reaction
mixture had been stirred for 1 h at room temperature, saturated
aqueous sodium hydrogen carbonate was added at 0 °C. The mixture
was extracted with dichloromethane, and the organic layer was washed
with brine and dried over sodium sulfate. After filtration of the mixture
and evaporation of the solvent, the crude product was purified by thin-
layer chromatography on silica (eluant; hexane/ethyl acetate = 9/1) to
1
(KBr) 3383, 1713 cm−1; H NMR (500 MHz, CDCl3) δ 7.38−7.20
(m, 5H, Ph), 4.75−4.60 (m, 1H, 3-H), 2.85−2.70 (m, 1H, 2-H), 1.00−
0.86 (m, 3H, 2-Me); 13C NMR (100 MHz, CDCl3) δ 182.4, 141.5,
128.4, 127.9, 127.0, 77.2, 48.1, 14.5; HRMS (ESI-TOF) calcd for
C10H12O3Na (M + Na+) 203.0679, found 203.0670.
(2R*,3S*)-2-Methyl-3-phenylpropan-3-olide (2g).45 To a
solution of MNBA (72.5 mg, 0.211 mmol), DMAP (4.0 mg, 0.032
mmol), and triethylamine (0.130 mL, 0.938 mmol) in dichloro-
methane (12.0 mL) at room temperature was slowly added a solution
of 1g (29.2 mg, 0.162 mmol) in dichloromethane (4.2 mL) with a
mechanically driven syringe over a 12 h period. After the reaction
mixture had been stirred for 1 h at room temperature, saturated
aqueous sodium hydrogen carbonate was added at 0 °C. The mixture
was extracted with dichloromethane, and the organic layer was washed
with brine and dried over sodium sulfate. After filtration of the mixture
and evaporation of the solvent, the crude product was purified by
column chromatography on silica (eluant; hexane/ethyl acetate/
triethylamine = 50/10/1) to afford 2g (18.0 mg, 69%) as a colorless
1
afford 2f (32.6 mg, 90%) as a colorless oil: IR (neat) 1828 cm−1; H
NMR (500 MHz, CDCl3) δ 7.47−7.24 (m, 5H, Ph), 5.32 (s, 1H, 3-
H), 1.58 (s, 3H, 2-Me), 0.90 (s, 3H, 2-Me); 13C NMR (125 MHz,
CDCl3) δ 175.0, 135.3, 128.6, 128.4, 125.1, 82.8, 56.6, 22.4, 17.9;
HRMS (ESI-TOF) calcd for C11H12O2Na (M + Na+) 199.0730, found
199.0729.
Benzyl 3-Hydroxy-3-phenylpropanoate. To a solution of
diisopropylamine (90.0 μL, 0.640 mmol) in THF (5.0 mL) at 0 °C
was added butyllithium in hexane (1.57 M, 0.390 mL, 0.612 mmol).
The reaction mixture was stirred for 15 min at 0 °C, and then benzyl
acetate (83.0 μL, 0.597 mmol) was added at −78 °C. After the
reaction mixture had been stirred for 30 min, benzaldehyde (50.0 μL,
0.495 mmol) was added at −78 °C. The reaction mixture was stirred
for 1 h, and then saturated aqueous ammonium chloride was added.
The mixture was extracted with ethyl acetate, and the organic layer was
washed with brine and dried over sodium sulfate. After filtration of the
mixture and evaporation of the solvent, the crude product was purified
by thin-layer chromatography on silica (eluent; hexane/ethyl acetate =
4/1) to afford benzyl 3-hydroxy-3-phenylpropanoate (130 mg, quant)
1
oil: IR (neat) 1824 cm−1; H NMR (300 MHz, CDCl3) δ 7.46−7.35
(m, 5H, Ph), 5.16 (d, J = 4.2 Hz, 1H, 3-H), 3.59 (dq, J = 4.2, 7.5 Hz,
1H, 2-H), 1.54 (d, J = 7.5 Hz, 3H, 2-Me); 13C NMR (125 MHz,
CDCl3) δ 171.7, 137.1, 129.1, 128.9, 125.5, 79.1, 54.6, 12.6; HRMS
(ESI-TOF) calcd for C10H10O2Na (M + Na+) 185.0573, found
185.0580.
Ethyl 3-Hydroxy-3-phenylpropanoate.41,46 To a solution of
diisopropylamine (0.90 mL, 6.40 mmol) in THF (24.7 mL) at 0 °C
was added butyllithium in hexane (2.69 M, 2.30 mL, 6.19 mmol). The
reaction mixture was stirred for 20 min at 0 °C, and then ethyl aceate
(0.580 mL, 5.93 mmol) was added at −78 °C. After the reaction
mixture had been stirred for 30 min, benzaldehyde (0.500 mL, 4.95
mmol) was added at −78 °C. The reaction mixture was stirred for 1 h,
and then saturated aqueous ammonium chloride was added. The
mixture was extracted with diethyl ether, and the organic layer was
washed with brine and dried over sodium sulfate. After filtration of the
mixture and evaporation of the solvent, the crude product was purified
by thin-layer chromatography on silica (eluent; hexane/ethyl acetate =
4/1) to afford ethyl 3-hydroxy-3-phenylpropanoate (936 mg, 97%) as
1
as a colorless oil: IR (neat) 3451, 1734 cm−1; H NMR (500 MHz,
CDCl3) δ 7.40−7.27 (m, 10H, Ph, Ph), 5.18 (d, J = 13.5 Hz, 1H, Bn),
5.16 (d, J = 13.5 Hz, 1H, Bn), 5.16 (ddd, J = 3.5, 3.5, 8.5 Hz, 1H, 3-H),
3.15 (d, J = 3.5 Hz, 1H, OH), 2.84 (dd, J = 8.5, 17.0 Hz, 1H, 2-H),
2.78 (dd, J = 3.5, 17.0 Hz, 1H, 2-H); 13C NMR (100 MHz, CDCl3) δ
172.1, 142.4, 135.5, 128.6, 128.5, 128.3, 128.2, 127.8, 125.6, 70.3, 66.6,
43.3; HRMS (ESI-TOF) calcd for C16H16O3Na (M + Na+) 279.0992,
found 279.0998.
Benzyl (2R*,3S*)-3-Hydroxy-2-methyl-3-phenylpropa-
noate.43 To a solution of benzyl 3-hydroxy-3-phenylpropanoate
(65.2 mg, 0.254 mmol) in THF (5.1 mL) at −78 °C was added a
solution of LHMDS in THF (1.00 M, 0.890 mL, 0.890 mmol). The
reaction mixture was stirred for 30 min at −78 °C and for 1 h at −45
°C, and then a solution of iodomethane (0.160 mL, 2.57 mmol) in
HMPA (0.440 mL, 2.53 mmol) was added. After the reaction mixture
had been stirred for 1 h at −45 °C, saturated aqueous ammonium
chloride was added. The mixture was extracted with ethyl acetate, and
the organic layer was washed with brine and dried over sodium sulfate.
After filtration of the mixture and evaporation of the solvent, the crude
product was purified by thin-layer chromatography on silica (eluant;
hexane/ethyl acetate = 4/1) to afford benzyl (2R*,3S*)-3-hydroxy-2-
methyl-3-phenylpropanoate (20.8 mg, 30%, anti/syn = 100/0) and
recovered benzyl 3-hydroxy-3-phenylpropanoate (36.6 mg, 56%) as
colorless oils. Benzyl (2R*,3S*)-3-hydroxy-2-methyl-3-phenylpropa-
1
a colorless oil: IR (neat) 3454, 1732 cm−1; H NMR (500 MHz,
CDCl3) δ 7.41−7.27 (m, 5H, Ph), 5.14 (ddd, J = 3.5, 4.0, 8.5 Hz, 1H,
3-H), 4.19 (q, J = 7.5 Hz, 2H, OEt), 3.25 (d, J = 3.5 Hz, 1H, OH),
2.76 (dd, J = 8.5, 16.0 Hz, 1H, 2-H), 2.71 (dd, J = 4.0, 16.0 Hz, 1H, 2-
H), 1.27 (t, J = 7.5 Hz, 3H, OEt); 13C NMR (125 MHz, CDCl3) δ
172.1, 142.6, 128.3, 127.6, 125.5, 70.1, 60.7, 43.3, 14.0; HRMS (ESI-
TOF) calcd for C11H14O3Na (M + Na+) 217.0835, found 217.0834.
Ethyl (2R*,3S*)-2-Hexyl-3-hydroxy-3-phenylpropanoate. To
a solution of ethyl 3-hydroxy-5-phenylpropanoate (250 mg, 1.29
mmol) in THF (6.4 mL) at −78 °C was added a solution of LHMDS
in THF (1.00 M, 4.50 mL, 4.50 mmol). The reaction mixture was
stirred for 1 h at −78 °C and for 1 h at −45 °C, and then a solution of
iodohexane (1.90 mL, 12.9 mmol) in HMPA (2.24 mL, 11.6 mmol)
was added. After the reaction mixture had been stirred for 40 min at
−45 °C, saturated aqueous ammonium chloride was added. The
mixture was extracted with ethyl acetate, and the organic layer was
washed with brine and dried over sodium sulfate. After filtration of the
mixture and evaporation of the solvent, the crude product was purified
by thin-layer chromatography on silica (eluant; hexane/ethyl acetate =
4/1) to afford ethyl (2R*,3S*)-2-hexyl-3-hydroxy-3-phenylpropanoate
1
noate: IR (neat) 3464, 1734 cm−1; H NMR (500 MHz, CDCl3) δ
7.39−7.28 (m, 10H, Ph), 5.19 (d, J = 13.5 Hz, 1H, Bn), 5.16 (d, J =
13.5 Hz, 1H, Bn), 4.79 (dd, J = 5.0, 8.5 Hz, 1H, 3-H), 2.91 (d, J = 5.0
Hz, 1H, OH), 2.89 (qd, J = 7.5, 8.5 Hz, 1H, 2-H), 1.05 (d, J = 7.5 Hz,
1H, 2-Me); 13C NMR (75 MHz, CDCl3) δ 175.5, 141.5, 135.7, 128.5,
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(43.1 mg, 12%, anti/syn = 100/0) and recovered ethyl 3-hydroxy-5-
phenylpropanoate (202 mg, 81%) as colorless oils. Ethyl (2R*,3S*)-2-
hexyl-3-hydroxy-3-phenylpropanoate: IR (neat) 3464, 1734 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.30−7.18 (m, 5H, Ph), 4.71 (dd, J =
6.5, 7.5 Hz, 1H, 3-H), 4.09 (qd, J = 7.0, 12.5 Hz, 1H, OEt), 4.07 (qd, J
= 7.0, 12.5 Hz, 1H, OEt), 2.83 (d, J = 6.5 Hz, 1H, OH), 2.66 (ddd, J =
4.0, 7.5, 9.5 Hz, 1H, 2-H), 1.57−1.47 (m, 1H, 1′-H), 1.28−1.20 (m,
1H, 1′-H), 1.19−1.05 (m, 11H, OEt, 2′-H, 3′-H, 4′-H, 5′-H), 0.76 (t, J
= 7.5 Hz, 3H, 6′-H); 13C NMR (125 MHz, CDCl3) δ 175.4, 142.1,
128.4, 127.9, 126.4, 75.3, 60.5, 53.0, 31.5, 29.6, 29.0, 27.0, 22.5, 14.2,
14.0; HRMS (ESI-TOF) calcd for C17H26O3Na (M + Na+) 301.1774,
found 301.1762.
2,2,3-Trimethyl-5-phenylpentan-3-olide (2i).9f To a solution
of MNBA (82.6 mg, 0.240 mmol), DMAP (4.5 mg, 0.037 mmol), and
triethylamine (0.150 mL, 1.08 mmol) in dichloromethane (14.0 mL)
at room temperature was slowly added a solution of 1i (43.6 mg, 0.185
mmol) in dichloromethane (4.5 mL) with a mechanically driven
syringe over a 12 h period. After the reaction mixture had been stirred
for 1 h at room temperature, saturated aqueous sodium hydrogen
carbonate was added at 0 °C. The mixture was extracted with
dichloromethane, and the organic layer was washed with brine and
dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by thin-
layer chromatography on silica (eluant; hexane/ethyl acetate = 4/1) to
afford 2i (38.1 mg, 95%) as a white solid: mp 50−52 °C; IR (neat)
(2R*,3S*)-2-Hexyl-3-hydroxy-3-phenylpropanoic Acid (1h).
To a solution of ethyl (2R*,3R*)-2-hexyl-3-phenylpropanoate (32.9
mg, 0.118 mmol) in methanol (0.6 mL) and THF (1.2 mL) at 0 °C
was added lithium hydroxide in water (4.00 M, 0.600 mL, 2.40 mmol).
After the reaction mixture had been stirred for 30 min at room
temperature, 1.0 M hydrochloric acid was added at 0 °C. The acidified
mixture (pH = 4) was extracted with ethyl acetate, and the organic
layer was dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by thin-layer
chromatography on silica (eluant; chloroform/methanol = 9/1) to
afford 1h (29.0 mg, 98%) as a colorless oil: IR (neat) 3397, 1704
1
1805 cm−1; H NMR (500 MHz, CDCl3) δ 7.33−7.18 (m, 5H, Ph),
2.74 (ddd, J = 5.0, 13.5, 13.5 Hz, 1H, 5-H), 2.68 (ddd, J = 5.0, 12.0,
13.5 Hz, 1H, 5-H), 2.17 (ddd, J = 5.0, 12.0, 14.5 Hz, 1H, 4-H), 2.06
(ddd, J = 5.0, 13.5, 14.5 Hz, 1H, 4-H), 1.59 (s, 3H, 3-Me), 1.36 (s, 6H,
2-Me); 13C NMR (75 MHz, CDCl3) δ 175.6, 141.0, 128.6, 128.1,
126.2, 85.0, 54.8, 38.7, 30.5, 20.2, 19.3, 18.4; HRMS (ESI-TOF) calcd
for C14H18O2Na (M + Na+) 241.1199, found 241.1192.
1-Trimethylsilyltetradec-1-yn-3-ol.24 To a solution of trime-
thylsilylacetylene (9.23 g, 94.0 mmol) in THF (100 mL) at −78 °C
was added butyllithium in hexane (2.69 M, 34.9 mL, 94.0 mmol). After
the reaction mixture had been stirred for 1 h at −23 °C, a solution of
dodecanal (15.7 g, 85.2 mmol) in THF (42 mL) was added at −78 °C.
The reaction mixture was stirred for 1 h at −23 °C and then saturated
aqueous ammonium chloride was added. The mixture was extracted
with ethyl acetate, and the organic layer was washed with water and
brine and dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by column
chromatography on silica (eluant; hexane/ethyl acetate = 40/1) to
afford 1-trimethylsilyltetradec-1-yn-3-ol (21.8 g, 90%) as a colorless
oil: IR (neat) 3340 cm−1; 1H NMR (500 MHz, CDCl3) δ 4.35 (dt, J =
6.0, 6.0 Hz, 1H, 3-H), 1.73 (br d, J = 6.0, 1H, OH), 1.72−1.63 (m, 2H,
4-H), 1.49−1.37 (m, 2H, 5-H), 1.36−1.20 (m, 16H, 6-H, 7-H, 8-H, 9-
H, 10-H, 11-H, 12-H, 13-H), 0.88 (t, J = 6.0 Hz, 3H, 14-H), 0.17 (s,
9H, TMS); 13C NMR (125 MHz, CDCl3) δ 107.0, 89.2, 62.9, 37.7,
31.9, 29.6, 29.6, 29.5, 29.5, 29.3, 29.2, 25.1, 22.7, 14.1, −0.1; HRMS
(ESI-TOF) calcd for C17H34OSiNa (M + Na+) 305.2271, found
305.2275.
1
cm−1; H NMR (500 MHz, CDCl3) δ 7.30−7.10 (m, 5H, Ph), 4.74−
4.53 (m, 1H, 3-H), 2.73−2.52 (m, 1H, 2-H), 1.48−1.34 (m, 1H, 1′-H),
1.27−1.13 (m, 1H, 1′-H), 1.15−0.93 (m, 11H, OEt, 2′-H, 3′-H, 4′-H,
5′-H), 0.72 (t, J = 7.5 Hz, 3H, 6′-H); 13C NMR (125 MHz, CDCl3) δ
181.9, 141.9, 128.3, 127.8, 127.0, 75.9, 54.2, 31.6, 29.7, 29.2, 27.2, 22.6,
14.0; HRMS (ESI-TOF) calcd for C15H22O3Na (M + Na+) 273.1461,
found 273.1472.
(2R*,3S*)-2-Hexyl-3-phenylpropan-3-olide (2h). To a solution
of MNBA (60.6 mg, 0.176 mmol), DMAP (3.3 mg, 0.027 mmol), and
triethylamine (0.110 mL, 0.794 mmol) in dichloromethane (10.0 mL)
at room temperature was slowly added a solution of 1h (33.9 mg,
0.135 mmol) in dichloromethane (3.5 mL) with a mechanically driven
syringe over a 12 h period. After the reaction mixture had been stirred
for 1 h at room temperature, saturated aqueous sodium hydrogen
carbonate was added at 0 °C. The mixture was extracted with
dichloromethane, and the organic layer was washed with brine and
dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by column
chromatography on silica (eluant; hexane/ethyl acetate/triethylamine
= 50/10/1) to afford 2h (25.4 mg, 81%) as a colorless oil: IR (neat)
Tetradec-1-yn-3-ol (( )-6). To a solution of 1-trimethylsilylte-
tradec-1-yn-3-ol (533 mg, 1.90 mmol) in methanol (6.3 mL) at room
temperature was added potassium carbonate (315 mg, 2.28 mmol).
After the reaction mixture had been stirred for 1 h at room
temperature, it was concentrated under reduced pressure. The residue
was diluted with water and extracted with diethyl ether, and the
organic layer was washed with brine and dried over sodium sulfate.
After filtration of the mixture and evaporation of the solvent, the crude
product was purified by thin-layer chromatography on silica (eluant;
hexane/ethyl acetate = 8/1) to afford ( )-6 (375 mg, 94%) as a white
solid: mp 32−33 °C; IR (KBr) 3363, 3309 cm−1; 1H NMR (500 MHz,
CDCl3) δ 4.36 (ddd, J = 2.5, 6.0, 7.5 Hz, 1H, 3-H), 2.45 (d, J = 2.5 Hz,
1H, 1-H), 1.93 (br s, 1H, OH), 1.77−1.63 (m, 2H, 4-H), 1.51−1.40
(m, 2H, 5-H), 1.37−1.19 (m, 16H, 6-H, 7-H, 8-H, 9-H, 10-H, 11-H,
12-H, 13-H), 0.88 (t, J = 6.0 Hz, 3H, 14-H), 13C NMR (125 MHz,
CDCl3) δ 85.1, 72.8, 62.3, 37.7, 31.9, 29.6, 29.6, 29.5, 29.5, 29.3, 29.2,
25.0, 22.7, 14.1; HRMS (ESI-TOF) calcd for C14H26ONa (M + Na+)
233.1876, found 233.1871.
(S)-1-Undecylprop-2-ynyl Diphenylacetate ((S)-7) and (R)-
Tetradec-1-yn-3-ol ((R)-6). To a solution of ( )-6 (6.00 g, 28.5
mmol) in diethyl ether (57 mL) at room temperature were
successively added diphenylacetic acid (4.24 g, 20.0 mmol),
diisopropylethylamine (7.45 mL, 42.8 mmol), (S)-BTM (360 mg,
1.43 mmol), and pivalic anhydride (4.07 mL, 21.4 mmol). After the
reaction mixture had been stirred for 12 h at room temperature,
saturated aqueous sodium hydrogen carbonate was added. The
mixture was extracted with ethyl acetate, and the organic layer was
washed with brine and dried over sodium sulfate. After filtration of the
mixture and evaporation of the solvent, the crude product was purified
by column chromatography on silica (eluant; hexane/ethyl acetate =
1
1826 cm−1; H NMR (300 MHz, CDCl3) δ 7.46−7.35 (m, 5H, Ph),
5.21 (d, J = 4.2 Hz, 1H, 3-H), 3.53 (ddd, J = 4.2, 6.6, 8.4 Hz, 1H, 2-H),
1.99 (dtd, J = 6.6, 9.0, 13.5 Hz, 1H, 1′-H), 1.88 (tdd, J = 6.0, 8.4, 13.5
Hz, 1H, 1′-H), 1.60−1.24 (m, 8H, 2′-H, 3′-H, 4′-H, 5′-H), 0.88 (t, J =
6.3 Hz, 3H, 6′-H); 13C NMR (75 MHz, CDCl3) δ 171.3, 137.3, 129.0,
128.9, 125.5, 77.7, 59.9, 31.4, 28.9, 28.1, 26.9, 22.5, 14.0; HRMS (ESI-
TOF) calcd for C15H20O2Na (M + Na+) 255.1356, found 255.1345.
3-Hydroxy-2,2,3-trimethyl-5-phenylpentanoic Acid (1i). To a
solution of diisopropylamine (1.30 mL, 4.25 mmol) in THF (18.5
mL) at 0 °C was added butyllithium in hexane (1.57 M, 5.66 mL, 8.89
mmol). The reaction mixture was stirred for 15 min at 0 °C, and then
2-methylpropanoic acid (0.592 mL, 4.44 mmol) was added at −45 °C.
After the reaction mixture had been stirred for 2 h at 50 °C, 4-
phenylbutan-2-one (0.374 mL, 3.70 mmol) was added at −45 °C. The
reaction mixture was stirred for 2 h at −45 °C and for 1 h at 50 °C and
then 1.0 M hydrochloric acid was added at 0 °C. The mixture was
extracted with ethyl acetate, and the organic layer was washed with
brine and dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by column
chromatography on silica (eluent; chloroform/methanol = 20/1) to
afford 1i (607 mg, 70%) as a colorless oil: IR (neat) 3414, 1692 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.43−7.08 (m, 5H, Ph), 2.92−2.74
(m, 1H, 5-H), 2.74−2.55 (m, 1H, 5-H), 1.90−1.64 (m, 2H, 4-H), 1.26
(s, 3H, 3-Me), 1.22 (s, 3H, 2-Me), 1.20 (s, 3H, 2-Me); 13C NMR (100
MHz, CDCl3) δ 183.8, 142.5, 128.4, 128.3, 125.7, 77.2, 50.2, 38.9,
29.9, 21.5, 21.2, 21.1; HRMS (ESI-TOF) calcd for C14H20O3Na (M +
Na+) 259.1305, found 259.1296.
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50/1) to afford the corresponding ester (S)-7 (6.65 g, 58%, 74% ee) as
a colorless oil and the recovered optically active alcohol (R)-6 (2.43 g,
41%, 99% ee) as a white solid.
Benzyl (3S,5R)-5-(4-Methoxybenzyloxy)-3-hydroxyhexade-
canoate (11). To a solution of 9 (72.8 mg, 0.209 mmol) in toluene
(3.5 mL) at −78 °C was added a solution of TiCl2(-Oi-Pr)2 in toluene
(1.00 M, 0.520 mL, 0.520 mmol). The reaction mixture was stirred for
15 min at −78 °C, and then a solution of 1-benzyloxy-1-(t-
butyldimethylsiloxy)ethene (10) (144 mg, 0.543 mmol) in toluene
(0.7 mL) was added. After the reaction mixture had been stirred for 4
h at −78 °C, phosphate buffer (pH = 7) was added. The mixture was
extracted with dichloromethane and the organic layer was washed with
saturated aqueous ammonium chloride and brine, dried over sodium
sulfate. After filtration of the mixture and evaporation of the solvent,
(R)-Tetradec-1-yn-3-ol ((R)-6) [99% ee]:24 [α]22D +2.71 (c 1.10,
CHCl3). Enantiomeric excess of the optically active alcohol (R)-6 was
determined after converting into the corresponding ester (R)-7. HPLC
(CHIRALPAK OJ-H, i-PrOH/hexane =1/9, flow rate = 0.5 mL/min);
tR = 22.3 min (0.47%), tR = 26.0 min (99.53%).
(S)-1-Undecylprop-2-ynyl Diphenylacetate ((S)-7) [74% ee].
HPLC (CHIRALPAK OJ-H, i-PrOH/hexane = 1/9, flow rate = 0.5
mL/min); tR = 21.8 min (86.8%), tR = 26.7 min (13.2%); [α]22D −30.7
1
1
(c 1.22, CHCl3); IR (neat) 3302, 1743 cm−1; H NMR (500 MHz,
the crude product (anti/syn = 94/6, determined by H NMR) was
purified by thin-layer chromatography on silica (eluant; hexane/ethyl
acetate = 4/1) to afford anti-aldol 11 (90.2 mg, 87%) as a colorless oil:
[α]24D −13.7 (c 0.687, CHCl3); IR (neat) 3440, 1736 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.39−7.29 (m, 5H, Ph), 7.25 (d, J = 8.5 Hz, 2H,
PMP), 6.86 (d, J = 8.5 Hz, 2H, PMP), 5.15 (s, 2H, Bn), 4.51 (d, J =
11.0 Hz, 1H, PMB), 4.43 (d, J = 11.0 Hz, 1H, PMB), 4.35−4.28 (m,
1H, 3-H), 3.79 (s, 3H, OMe), 3.72−3.65 (m, 1H, 5-H), 3.31 (d, J =
4.0 Hz, 1H, OH), 2.51 (d, J = 6.0 Hz, 2H, 2-H), 1.73−1.45 (m, 4H, 4-
H, 6-H), 1.35−1.20 (m, 18H, 7-H, 8-H, 9-H, 10-H, 11-H, 12-H, 13-H,
14-H, 15-H), 0.88 (t, J = 7.0 Hz, 3H, 16-H); 13C NMR (75 MHz,
CDCl3) δ 172.3, 159.2, 135.7, 130.5, 129.5, 128.6, 128.3, 128.2, 113.8,
76.1, 71.0, 66.4, 65.3, 55.3, 41.9, 40.0, 33.6, 31.9, 29.8, 29.7, 29.6, 29.6,
29.6, 29.3, 25.2, 22.7, 14.1; HRMS (ESI-TOF) calcd for C31H46O5Na
(M + Na+) 521.3237, found 521.3263.
CDCl3) δ 7.28−7.18 (m, 10H, Ph), 5.36 (ddd, J = 2.5, 6.0, 7.5 Hz, 1H,
3-H), 4.99 (s, 1H, 2′-H), 2.38 (d, J = 2.5 Hz, 1H, 1-H), 1.74−1.63 (m,
2H, 4-H), 1.30−1.10 (m, 18H, 5-H, 6-H, 7-H, 8-H, 9-H, 10-H, 11-H,
12-H, 13-H), 0.83 (t, J = 7.5 Hz, 3H, 14-H); 13C NMR (125 MHz,
CDCl3) δ 171.4, 138.4, 138.4, 128.6, 128.6, 128.6, 128.5, 127.3, 127.2,
81.0, 73.7, 64.5, 56.9, 34.4, 31.9, 29.6, 29.6, 29.4, 29.4, 29.3, 28.9, 24.7,
22.7, 14.1; HRMS (ESI-TOF) calcd for C28H36O2Na (M + Na+)
427.2608, found 427.2628.
(R)-3-(4-Methoxybenzyloxy)tetradec-1-yne (8). To a suspen-
sion of sodium hydride (55% in paraffin liquid, 41.5 mg, 0.951 mmol)
in DMF (0.7 mL) at 0 °C was added a solution of (R)-6 (100 mg,
0.475 mmol) in DMF (1.7 mL). After the reaction mixture had been
stirred for 1 h at 0 °C, 4-methoxybenzyl chloride (0.0710 mL, 0.523
mmol) and tetrabutylammonium iodide (18.5 mg, 0.0475 mmol) were
added at 0 °C. The reaction mixture was stirred for 40 min at room
temperature and then saturated aqueous sodium hydrogen carbonate
was added at 0 °C. The mixture was extracted with diethyl ether, and
the organic layer was dried over sodium sulfate. After filtration of the
mixture and evaporation of the solvent, the crude product was purified
by thin-layer chromatography on silica (eluant; benzene/hexane = 2/
Benzyl (2S,3S,5R)-5-(4-Methoxybenzyloxy)-2-hexyl-3-hy-
droxyhexadecanoate (12). To a solution of 11 (32.4 mg, 0.0650
mmol) in THF (1.3 mL) at −78 °C was added a solution of LHMDS
in THF (1.00 M, 0.230 mL, 0.230 mmol). The reaction mixture was
stirred for 30 min at −78 °C and for 1 h at −45 °C, and then a
solution of iodohexane (0.0960 mL, 0.652 mmol) in HMPA (0.113
mL, 0.649 mmol) was added. After the reaction mixture had been
stirred for 3 h at −45 °C, saturated aqueous ammonium chloride was
added. The mixture was extracted with ethyl acetate, and the organic
layer was washed with brine and dried over sodium sulfate. After
filtration of the mixture and evaporation of the solvent, the crude
product was purified by thin-layer chromatography on silica (eluant;
hexane/ethyl acetate = 4/1) to afford 12 (20.6 mg, 55%, anti/syn =
100/0) and recovered 11 (12.7 mg, 39%) as colorless oils. Benzyl
(2S,3S,5R)-5-(4-methoxybenzyloxy)-2-hexyl-3-hydroxyhexadeca-
1) to afford 8 (150 mg, 96%) as a colorless oil: [α]22 +88.2 (c 1.13,
D
1
CHCl3); IR (neat) 3302 cm−1; H NMR (500 MHz, CDCl3) δ 7.30
(d, J = 8.5 Hz, 1H, PMP), 6.89 (d, J = 8.5 Hz, 1H, PMP), 4.74 (d, J =
11.0 Hz, 1H, PMB), 4.45 (d, J = 11.0 Hz, 1H, PMB), 4.05 (ddd, J =
2.5, 6.0, 7.5 Hz, 1H, 3-H), 3.81 (s, 3H, OMe), 2.46 (d, J = 2.5 Hz, 1H,
1-H), 1.81−1.68 (m, 2H, 4-H), 1.54−1.40 (m, 2H, 5-H), 1.39−1.18
(m, 16H, 6-H, 7-H, 8-H, 9-H, 10-H, 11-H, 12-H, 13-H), 0.89 (t, J =
6.5 Hz, 3H, 14-H); 13C NMR (125 MHz, CDCl3) δ 159.2, 130.0,
129.6, 113.8, 83.2, 73.6, 70.1, 68.1, 55.2, 35.6, 31.9, 29.6, 29.6, 29.6,
29.5, 29.3, 29.3, 25.2, 22.7, 14.1; HRMS (ESI-TOF) calcd for
C22H34O2Na (M + Na+) 353.2451, found 353.2460.
noate (12): [α]22 −17.0 (c 1.01, CHCl3); IR (neat) 3479, 1728
D
cm−1; 1H NMR (500 MHz, CDCl3) δ 7.38−7.28 (m, 5H, Ph), 7.24 (d,
J = 8.5 Hz, 2H, PMP), 6.84 (d, J = 8.5 Hz, 2H, PMP), 5.18 (d, J = 12.0
Hz, 1H, Bn), 5.15 (d, J = 12.0 Hz, 1H, Bn), 4.49 (d, J = 11.0 Hz, 1H,
PMB), 4.41 (d, J = 11.0 Hz, 1H, PMB), 4.00 (dddd, J = 2.5, 6.0, 6.5,
8.5 Hz, 1H, 3-H), 3.79 (s, 3H, OMe), 3.70−3.64 (m, 1H, 5-H), 3.06
(d, J = 6.0 Hz, 1H, OH), 2.45 (ddd, J = 4.5, 6.5, 9.5 Hz, 1H, 2-H),
1.71−1.42 (m, 6H, 4-H, 6-H, 1′-H), 1.35−1.15 (m, 26H, 7-H, 8-H, 9-
H, 10-H, 11-H, 12-H, 13-H, 14-H, 15-H, 2′-H, 3′-H, 4′-H, 5′-H), 0.88
(t, J = 7.0 Hz, 3H, 16-H), 0.86 (t, J = 7.0 Hz, 3H, 6′-H); 13C NMR
(125 MHz, CDCl3) δ 175.2, 159.2, 136.0, 130.6, 129.5, 128.5, 128.3,
128.2, 113.8, 76.2, 71.0, 69.5, 66.1, 55.2, 51.8, 38.6, 33.6, 31.9, 31.6,
29.8, 29.7, 29.6, 29.6, 29.6, 29.3, 29.2, 29.1, 27.3, 25.3, 22.7, 22.5, 14.1,
14.0; HRMS (ESI-TOF) calcd for C37H58O5Na (M + Na+) 605.4176,
found 605.4164.
(R)-3-(4-Methoxybenzyloxy)tetradecanal (9). To a solution of
8 (20.5 mg, 0.0621 mmol) in THF (1.2 mL) at 0 °C was added a
solution of catecholborane in THF (1.00 M, 0.560 mL, 0.560 mmol).
After the reaction mixture had been stirred for 3.5 h at 70 °C,
phosphate buffer (pH = 7) (2 mL) and a solution of sodium acetate
(229 mg, 2.79 mmol) in water (2 mL) were added at 0 °C. The
reaction mixture was stirred for 10 min at 0 °C, and then hydrogen
peroxide (30% in water, 1.25 mL, 12.4 mmol) was added. After the
reaction mixture had been stirred for 3 h at room temperature, the
aqueous layer was saturated by the addition of potassium carbonate.
The mixture was extracted with ethyl acetate, and the organic layer was
dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by thin-
layer chromatography on silica (eluant; hexane/ethyl acetate = 6/1) to
(2S,3S,5R)-5-(4-Methoxybenzyloxy)-2-hexyl-3-hydroxyhexa-
decanoic Acid. To a solution of 12 (19.2 mg, 0.0329 mmol) in
methanol (0.18 mL) and THF (0.35 mL) at room temperature was
added lithium hydroxide in water (4.00 M, 0.180 mL, 0.720 mmol).
The reaction mixture was stirred for 2 h at 55 °C and then 1.0 M
hydrochloric acid was added at 0 °C. The acidified mixture (pH = 4)
was extracted with ethyl acetate and the organic layer was washed with
brine and dried over sodium sulfate. The crude product was purified
by thin-layer chromatography on silica (eluant; chloroform/methanol
= 9/1) to afford (2S,3S,5R)-5-(4-methoxybenzyloxy)-2-hexyl-3-
afford 9 (11.5 mg, 53%) as a colorless oil: [α]22 −13.9 (c 1.01,
D
1
CHCl3); IR (neat) 1726 cm−1; H NMR (300 MHz, CDCl3) δ 9.78
(dd, J = 2.1, 2.7 Hz, 1H, 1-H), 7.24 (d, J = 8.4 Hz, 2H, PMP), 6.87 (d,
J = 8.4 Hz, 2H, PMP), 4.50 (d, J = 11.1 Hz, 1H, PMB), 4.44 (d, J =
11.1 Hz, 1H, PMB), 3.92 (dtd, J = 4.8, 6.0, 7.2 Hz, 1H, 3-H), 3.80 (s,
3H, OMe), 2.66 (ddd, J = 2.7, 7.2, 16.2 Hz, 1H, 2-H), 2.54 (ddd, J =
2.1, 4.8, 16.2 Hz, 1H, 2-H), 1.71−1.60 (m, 1H, 4-H), 1.60−1.48 (m,
1H, 4-H), 1.46−1.06 (m, 18H, 5-H, 6-H, 7-H, 8-H, 9-H, 10-H, 11-H,
12-H, 13-H), 0.88 (t, J = 6.6 Hz, 3H, 14-H); 13C NMR (125 MHz,
CDCl3) δ 201.7, 159.2, 130.3, 129.3, 113.7, 73.9, 70.8, 55.1, 48.2, 34.2,
31.8, 29.6, 29.6, 29.5, 29.5, 29.5, 29.3, 25.0, 22.6, 14.0; HRMS (ESI-
TOF) calcd for C22H36O3Na (M + Na+) 371.2557, found 371.2543.
hydroxyhexadecanoic acid (16.2 mg, quant) as a colorless oil: [α]21
D
1
−23.0 (c 1.09, CHCl3); IR (neat) 3430, 1710 cm−1; H NMR (500
MHz, CDCl3) δ 7.25 (d, J = 9.0 Hz, 2H, PMP), 6.86 (d, J = 9.0 Hz,
2H, PMP), 4.49 (d, J = 11.0 Hz, 1H, PMB), 4.45 (d, J = 11.0 Hz, 1H,
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PMB), 4.12−3.98 (m, 1H, 3-H), 3.80−3.62 (m, 2H, 5-H), 3.78 (s, 3H,
OMe) 2.42−2.26 (m, 1H, 2-H), 1.80−1.43 (m, 6H, 4-H, 6-H, 1′-H),
1.43−1.10 (m, 26H, 7-H, 8-H, 9-H, 10-H, 11-H, 12-H, 13-H, 14-H,
15-H, 2′-H, 3′-H, 4′-H, 5′-H), 0.95−0.78 (m, 6H, 16-H, 6′-H); 13C
NMR (125 MHz, CDCl3) δ 179.4, 159.3, 130.3, 129.5, 113.8, 76.5,
71.1, 69.2, 55.2, 51.8, 38.2, 33.6, 31.9, 31.6, 29.8, 29.7, 29.6, 29.6, 29.6,
29.3, 29.3, 29.2, 27.2, 25.4, 22.7, 22.6, 14.1, 14.0; HRMS (ESI-TOF)
calcd for C30H52O5Na (M + Na+) 515.3707, found 515.3730.
8.22 (s, 1H, CHO), 5.90 (d, J = 8.5 Hz, 1H, NH), 5.03 (dddd, J = 4.0,
5.5, 6.5, 7.0 Hz, 1H, 5-H), 4.69 (ddd, J = 4.0, 8.5, 13.0 Hz, 1H, 2″-H),
4.29 (ddd, J = 4.5, 4.5, 8.0 Hz, 1H, 3-H), 3.21 (ddd, J = 4.0, 4.5, 11.5
Hz, 1H, 2-H), 2.16 (dt, J = 7.0, 8.0, 15.0 Hz, 1H, 4-H), 2.01 (dt, J =
4.0, 4.5, 15.0 Hz, 1H, 4-H), 1.85−1.50 (m, 6H, 6-H, 1′-H, 3″-H),
1.50−1.15 (m, 27H, 7-H, 8-H, 9-H, 10-H, 11-H, 12-H, 13-H, 14-H,
15-H, 2′-H, 3′-H, 4′-H, 5′-H, 4″-H), 1.05−0.82 (m, 12H, 16-H, 6′-H,
5″-H, 5″-H); 13C NMR (125 MHz, CDCl3) δ 171.9, 170.7, 160.6, 74.7,
72.7, 57.0, 49.6, 41.5, 38.7, 34.0, 31.9, 31.4, 29.6, 29.5, 29.4, 29.3, 29.3,
28.9, 27.6, 26.7, 25.1, 24.9, 22.8, 22.7, 22.5, 21.9, 21.7, 14.1, 14.0;
HRMS (ESI-TOF) calcd for C29H53O5NNa (M + Na+) 518.3816,
found 518.3809.
(2S,3S,5R)-5-(4-Methoxybenzyloxy)-2-hexyldecan-3-olide
(13). To a solution of MNBA (29.7 mg, 0.0863 mmol), DMAP (1.6
mg, 0.013 mmol), and triethylamine (0.0551 mL, 0.397 mmol) in
dichloromethane (4.6 mL) at room temperature was slowly added a
solution of (2S,3S,5R)-5-(4-methoxybenzyloxy)-2-hexyl-3-hydroxyhex-
adecanoic acid (32.7 mg, 0.0664 mmol) in dichloromethane (2 mL)
with a mechanically driven syringe over a 12 h period. After the
reaction mixture had been stirred for 1 h at room temperature,
saturated aqueous sodium hydrogen carbonate was added at 0 °C. The
mixture was extracted with dichloromethane, and the organic layer was
washed with brine and dried over sodium sulfate. After filtration of the
mixture and evaporation of the solvent, the crude product was purified
by thin-layer chromatography on silica (eluant; hexane/ethyl acetate =
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra on all compounds and Cartesian
coordinates for all calculated intermediates and transition
structures. This material is available free of charge via the
Internet at http://pubs.acs.org.
5/1) to afford 13 (28.7 mg, 91%) as a colorless oil: [α]21 −44.8 (c
AUTHOR INFORMATION
Corresponding Author
*E-mail: shiina@rs.kagu.tus.ac.jp.
D
■
1
1.00, CHCl3); IR (neat) 1823 cm−1; H NMR (500 MHz, CDCl3) δ
7.25 (d, J = 9.0 Hz, 2H, PMP), 6.88 (d, J = 9.0 Hz, 2H, PMP), 4.53 (d,
J = 11.0 Hz, 1H, PMB), 4.43 (dt, J = 4.0, 6.5 Hz, 1H, 3-H), 4.37 (d, J =
11.0 Hz, 1H, PMB), 3.81 (s, 3H, OMe), 3.58 (tt, J = 5.5, 6.5 Hz, 1H,
5-H), 3.20 (dt, J = 4.0, 7.5 Hz, 1H, 2-H), 1.92 (dd, J = 5.5, 6.5 Hz, 2H,
4-H), 1.80−1.71 (m, 1H, 1′-H), 1.70−1.58 (m, 2H, 6-H, 1′-H), 1.57−
1.48 (m, 1H, 6-H), 1.43−1.27 (m, 26H, 7-H, 8-H, 9-H, 10-H, 11-H,
12-H, 13-H, 14-H, 15-H, 2′-H, 3′-H, 4′-H, 5′-H), 0.90−0.86 (m, 6H,
16-H, 6′-H); 13C NMR (125 MHz, CDCl3) δ 171.7, 159.2, 130.5,
129.3, 113.8, 75.5, 75.4, 71.2, 56.6, 55.2, 39.8, 33.9, 31.9, 31.5, 29.7,
29.6, 29.6, 29.6, 29.3, 29.3, 28.9, 27.7, 26.7, 24.7, 22.7, 22.5, 14.1, 14.0;
HRMS (ESI-TOF) calcd for C30H50O4Na (M + Na+) 497.3601, found
497.3598.
ACKNOWLEDGMENTS
This study was supported by a Research Grant from The Naito
Foundation.
■
REFERENCES
■
(1) (a) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org.
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(2S,3S,5R)-5-Hydroxy-2-hexyldecan-3-olide (5).20n To a sol-
ution of 13 (17.3 mg, 0.0364 mmol) in ethanol (0.7 mL) at room
temperature was added palladium hydroxide on carbon (1.5 mg, 0.011
mmol). The reaction mixture was stirred for 2 h at room temperature
under hydrogen atmosphere. The mixture was filtered through a short
pad of Celite, and the filtrate was extracted with ethyl acetate. After
evaporation of the solvent, the residue was dried under reduced
pressure to afford 5. The crude product 5 was used in the following
reaction without further purification. For the analysis, the crude
product was purified by thin-layer chromatography on silica (eluant;
hexane/ethyl acetate = 5/1) to afford pure 5 as a colorless solid: [α]26
−37.9 (c 0.678, CHCl3); mp 57−58 °C; IR (KBr) 3340, 1813 cm−1D;
1H NMR (500 MHz, CDCl3) δ 4.50 (ddd, J = 4.0, 4.5, 8.5 Hz, 1H, 3-
H), 3.90−3.77 (m, 1H, 5-H), 3.26 (ddd, J = 3.5, 4.0, 11.0 Hz, 1H, 2-
H), 2.01−1.89 (m, 1H, 4-H), 1.89−1.70 (m, 3H, 4-H, 1′-H), 1.70−
1.21 (m, 28H, 6-H, 7-H, 8-H, 9-H, 10-H, 11-H, 12-H, 13-H, 14-H, 15-
H, 2′-H, 3′-H, 4′-H, 5′-H), 0.88 (t, J = 7.5 Hz, 3H, 16-H), 0.88 (t, J =
7.5 Hz, 3H, 6′-H); 13C NMR (125 MHz, CDCl3) δ 171.6, 75.6, 68.5,
56.6, 41.8, 38.1, 31.9, 31.5, 29.6, 29.6, 29.5, 29.5, 29.5, 29.3, 28.9, 27.7,
26.8, 25.4, 22.7, 22.5, 14.1, 14.0; HRMS (ESI-TOF) calcd for
C22H42O3Na (M + Na+) 377.3026, found 377.3026.
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olide ((−)-THL) (3).19,20 To a solution of crude 5 in THF (0.7 mL) at
0 °C were successively added N-formyl-L-leucine (4) (20.4 mg, 0.128
mmol), triphenylphosphine (28.7 mg, 0.109 mmol), and a solution of
DIAD in toluene (1.90 M, 0.0700 mL, 0.133 mmol). The reaction
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filtered though a short pad of silica gel with ethyl acetate. After
evaporation of the solvent, the crude product was purified twice by
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4/1 and hexane/diethyl ether = 1/2) to afford 3 (17.3 mg, 96% in two
steps) as a colorless oil: [α]22 −32.5 (c 1.17, CHCl3) [lit.19d [α]20
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D
D
−32.0 (c 1, CHCl3); lit.20i [α]25 −33.04 (c 0.79, CHCl3); lit.20n
D
[α]20 −32.0 (c 0.74, CHCl3); lit.20x [α]26 −31 (c 0.1, CHCl3)]; IR
D
D
(neat) 3329, 1822, 1738, 1678 cm−1; H NMR (500 MHz, CDCl3) δ
1
4899
dx.doi.org/10.1021/jo300139r | J. Org. Chem. 2012, 77, 4885−4901

The Journal of Organic Chemistry
Featured Article
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lactones 2a−i are included in the Supporting Information. Seco-acids
1a, 1b, and 1d−i and β-lactones 2a, 2b, and 2d−i were prepared as
racemic compounds, whereas the asymmetric Mukaiyama aldol
reaction was used for the preparation of chiral seco-acid 1c because
it is known that this method gives syn-aldols with perfect
diastereoselectivity. Mainly, a mixture of polymerized products was
obtained when seco-acid 1a was used for the lactonization. No
epimerization was observed at the C-2 positions of seco-acids 1c, 1d,
1g, and 1h to form the corresponding β-lactones 2c, 2d, 2g, and 2h
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=
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ΔH[rel
= 9.40 kcal/mol), TS-B; ΔH[rel
= 6.88 kcal/
(INT‑B′)]
(INT‑B)]
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Featured Article
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Rich, D. H. J. Am. Chem. Soc. 1985, 107, 4342−4343. (b) Colucci, W.
J.; Tung, R. D.; Petri, J. A.; Rich, D. H. J. Org. Chem. 1990, 55, 2895−
2903. See ref 20aa (eq 5).
(32) See also other methods for the formation of β-lactone part
involved in THL, such as the Yamaguchi method: Inanaga, J.; Hirata,
K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979,
52, 1989−1993. See ref 20y (eq 6).
(33) For other lactonizations used in the total synthesis of
tetrahydrolipstatin (THL), see refs 20a (Adam’s method; 40%
(three steps)) 20b, (Adam’s method; 61% (single step)) 20c,
(Adam’s method; 55% (two steps)) 20e, (Adam’s method; 70%
(three steps)) 20g, (Adam’s method; 69% (single step)) 20i, (Adam’s
method; 72% (two steps)) 20k, (Adam’s method; 76% (two steps))
20l, (Adam’s method; 84% (two steps)) 20m, (Adam’s method; 78%
(two steps)) 20n, (Adam’s method; 50% (three steps)) 20o, (Adam’s
method; 74% (single step)) 20q, (Adam’s method; 89% (single step))
20s, (Adam’s method; 66% (two steps)) 20t, (Adam’s method; 78%
(single step)) 20u, (Adam’s method; 78% (single step)) 20v, (Rich’s
BOPCl protocol; 75% (single step)) 20x, (Rich’s BOPCl protocol;
65% (single step)) 20y, (Yamaguchi method; 55% (single step)) 20z,
4901
dx.doi.org/10.1021/jo300139r | J. Org. Chem. 2012, 77, 4885−4901