Divergent asymmetric total synthesis of all four pestalotin diastereomers from (R)-glycidol

Article abstract of DOI:10.3390/molecules25020394

All four chiral pestalotin diastereomers were synthesized in a straightforward and divergent manner from common (R)-glycidol. Catalytic asymmetric Mukaiyama aldol reactions of readily-available bis(TMSO)diene (Chan’s diene) with (S)-2-benzyloxyhexanal der

Full text of DOI:10.3390/molecules25020394

molecules
Article
Divergent Asymmetric Total Synthesis of All Four
Pestalotin Diastereomers from (R)-Glycidol
Mizuki Moriyama, Kohei Nakata, Tetsuya Fujiwara and Yoo Tanabe *
Department of Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda,
Hyogo 669-1337, Japan; dbe04644@kwansei.ac.jp (M.M.); knakata01@okuno.co.jp (K.N.);
tt_fujiwara@jp.daicel.com (T.F.)
* Correspondence: tanabe@kwansei.ac.jp; Tel.: +81-79-565-8394
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Rafael Chinchilla
Received: 28 December 2019; Accepted: 13 January 2020; Published: 17 January 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: All four chiral pestalotin diastereomers were synthesized in a straightforward and
divergent manner from common (R)-glycidol. Catalytic asymmetric Mukaiyama aldol reactions
of readily-available bis(TMSO)diene (Chan’s diene) with (S)-2-benzyloxyhexanal derived from
(R)-glycidol produced a syn-aldol adduct with high diastereoselectivity and enantioselectivity
using a Ti(iOPr)4/(S)-BINOL/LiCl catalyst. Diastereoselective Mukaiyama aldol reactions mediated
by catalytic achiral Lewis acids directly produced not only a (10S,6S)-pyrone precursor via the
syn-aldol adduct using TiCl4, but also (10S,6R)-pyrone precursor via the antialdol adduct using
ZrCl4, in a stereocomplementary manner. A Hetero-Diels-Alder reaction of similarly available
mono(TMSO)diene (Brassard’s diene) with (S)-2-benzyloxyhexanal produced the (10S,6S)-pyrone
precursor promoted by Eu(fod)3 and the (10S,6R)-pyrone precursor Et2AlCl. Debenzylation of the
(10S,6S)-precursor and the (10S,6R)-precursor furnished natural (
unnatural (+)-epipestalotin (99% ee, 7 steps), respectively. Mitsunobu inversions of the obtained
)-pestalotin and (+)-epipestalotin successfully produced the unnatural (+)-pestalotin (99% ee,
9 steps) and ( )-epipestalotin (99% ee, 9 steps), respectively, in a divergent manner. All four of
−
)-pestalotin (99% ee, 7 steps) and
(
−
−
the obtained chiral pestalotin diastereomers possessed high chemical and optical purities (optical
rotations, 1H-NMR, 13C-NMR, and HPLC measurements).
Keywords: asymmetric total synthesis; divergent synthesis; pyran-2-one; pestalotin; epipestalotin;
asymmetric Mukaiyama aldol reaction; hetero Diels-Alder reaction; Mitsunobu inversion; Chan’s
diene; Brassard’s diene
1. Introduction
Products possessing the 4-methoxy-5,6-dihydroxy-pyran-2-one structure are distributed in
nature [
dihydromethylsitan, etc. [
of ( )-epipestalotin, (+)-pestalotin, and (+)-epipestalotin (Figure 1). (
Pesalotia cryptomeriaecola Sawada by Kimura and Tamura’s group; it possesses distinctive bioactivity
as a gibberellin synergist [ ]. Independently, the same compound was isolated from unidentified
penicillium species as a minor component (code number: LLP-880α) by Ellestad’s group [6].
1
], including the (i) kavalactone series, such as kavain, methylsitan, dihydrokavain,
], and (ii) ( )-pestalotin [ ], with the three unnatural diastereomers
)-Pestalotin was isolated from
2
−
3
−
−
3–5
Molecules 2020, 25, 394; doi:10.3390/molecules25020394
www.mdpi.com/journal/molecules

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Figure 1. Natural and the related unnatural products of 4-methoxy-5,6-dihydroxy-pyran-2-one.
(
−
)-Pestalotin has received considerable attention as a synthetic target due to its characteristic
structure, which includes two consecutive stereogenic centers. Several asymmetric total syntheses of
)-pestalotin have therefore been performed to date, and the features are described in chronologic
(−
order of their development: (i) Dianion addition using ethyl acetoacetate with aldehyde containing a
1,3-dithian group, and successive asymmetric reduction using a chiral lithium hydro aluminate derived
from chiral diamino tartrate, but with ca. 10% ee (Seebach’s group) [
resolution of allyl alcohol producing ( )-pestalotin and diastereomeric (
pool synthesis starting from glycel aldehyde acetonide derived from d-mannitol to produce antipodal
(+)-pestalotin and (+)-epipestalotin (Mori’s group) [ ]; (iii) Derivatization of chiral diethyl tartarate and
7]; (ii) Sharpless asymmetric kinetic
−
−
)-epipestalotin, and chiral
8,9
the incorporation of a tosyl group as a latent scaffold (Masaki’s group) [10]; (iv) Asymmetric reduction
using (S)-alpine-borane reagent of ethynyl ketone intermediate and successive hetero-Diels-Alder
reaction with Brassard’s siloxydiene [11] (Midland and Graham) [12]; (v) Chiral pool synthesis
using unnatural (S)-norleucine, associated with successive syn-diastereoselective Mukaiyama aldol
additions using Chan’s 1,3-disiloxydiene [13] (Hagiwara’s group) [14,15]; (vi) Cycloaddition strategy
for chiral 1,2-diol with chiral induction utilizing Oppolzer’s camphor sultum (Curran and Zhang) [16];
(vii) Sharpless asymmetric dihydroxylation of ester including a non-conjugated ene-yne precursor
(Wang and Shen) [17]; and (viii) Sharpless asymmetric dihydroxylation of ethyl heptenoate and
successive
A review of these fruitful works revealed that the synthesis of all four pestalotin diastereomers
is limited to the report by Mori’s group [ ]. The syntheses are somewhat lengthy [( )-pestalotin: 8
steps, 4% overall yield; ( )-epipestalotin: 6 steps, 9% overall yield; (+)-pestalotin: 10 steps, 1% overall
β-ketoester formation via Birch reduction of the m-methoxyphenyl ring (Rao’s group) [18].
9
−
−
yield; (+)-epipestalotin: 10 steps, 3% overall yield], and commence with two quite different starting
compounds. Nonetheless, this work contributed significantly to clarifying the stereostructure-activity
relationship of these families; 10S configuration in the side chain was critical for the synergistic mode
of action for gibberellin [6,9].
On the other hand, there are three natural 3-acyl-4-hydroxy-5,6-dihydroxy-pyran-2-one products
relevant to 4-methoxy-5,6-dihydroxy-pyran-2-ones: (R)-podoblastins [19], (R)-lachnelluloic acid [20],
and alternaric acid [21] (Figure 2). We previously reported asymmetric total syntheses of all these
natural products utilizing a catalytic asymmetric Mukaiyama aldol reaction and an asymmetric
Ti-Claisen condensation as the crucial steps [22,23].

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Figure 2. All three 3-acyl-5,6-dihydro-2H-pyran-2-one natural products.
Consistent with our expeditious total syntheses of all these compounds, we envisaged a divergent
synthetic access to all four chiral pestalotin diastereomers starting from a common and readily-available
chiral building block, i.e., (R)-glycidol.
2. Results and Discussion
2.1. General Strategy for the Total Syntheses of All Four Pestalotin Diastereomers
A couple of the present divergent strategies involve a catalytic asymmetric and a diastereoselective
Mukaiyama aldol addition, and a diastereoselective hetero-Diels-Alder reaction, followed by a
Mitsunobu inversion as the crucial steps (Scheme 1). (R)-Glycidol is transformed to a common
starting (S)-2-benzyloxyhexanal (
anti-selective Mukaiyama aldol additions of readily-available bis(TMSO)diene (so-called Chan’s
diene) 13] with (S)-aldehyde produce stereocomplementary chiral aldol adducts syn- and
anti- , respectively. Alternatively, syn- and anti-selective hetero-Diels-Alder reactions of similarly
available mono(TMSO)diene (so-called Brassard’s diene) 11 24] with produce diastereomeric chiral
pyrone-adducts syn- and anti- , respectively. Following a conventional synthetic procedure [15], syn-
and anti- are transformed to ( )-pestalotin and (+)-epipestalotin, respectively. Mitsunobu inversions
of (−)-pestalotin and (+)-epipestalotin produce (−)-epipestalotin and (+)-pestalotin, respectively.
1) by the epoxide opening with a Grignard reagent. Syn- and
2
[
1
3
3
4
[
,
1
5
5
3
3
−
Scheme 1. Strategies for asymmetric total syntheses of pestalotin diastereomers.

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2.2. Total Syntheses of All Four Pestalotin Diastereomers
Synthesis of (S)-2-benzyloxyhexanal (1)
(S)-2-Benzyloxyhexanal (
was converted to trityl ether
1
6
) was synthesized from (R)-glycidol as shown in Scheme 2. (R)-Glycidol
(or commercially available) as a crude solid, which was purified by
25] gave
, the trityl group was removed
in 92% yield (2 steps). Finally, TEMPO (or
in 86% (or 97%) yield. Because of its easier
recrystallization (83% yield). CuI-catalyzed Grignard reaction of n-PrMgBr with epoxide
secondary alcohol in 93% yield. After the benzyl group protection of
using a PTS H2O catalyst to afford primary alcohol
Swern) oxidation of produced (S)-2-benzyloxyhexanal
6 [
7
7
•
8
8
1
recrystallization purification procedure, trityl protection method was selected instead of an alternative
p-methoxybenzyl protective method. The present sequence (four steps and 61% overall yield) is
superior regarding steps and overall yield compared with the relevant reported route starting from
(S)-norleucine (five steps and 27% overall yield) [14].
Scheme 2. Synthesis of common (S)-α-benzyloxy aldehyde 1.
2.3. Catalytic Asymmetric and Diastereoselective Mukaiyama Aldol Reactions
With (S)-aldehyde
reaction using readily-available Chan’s diene
1
in hand, we next investigated a catalytic asymmetric Mukaiyama aldol
13] with (Scheme 3). For this purpose, we employed
2
[
1
the procedure applied for the asymmetric syntheses of (R)-podoblastin-S and (R)-lachnelluloic acid [22],
as well as that described in Organic Syntheses, recently [26]. The reaction by using catalysis of Ti(iOPr)4
(2 mol%)/(S)-BINOL (2 mol%)/LiCl (4 mol%) and subsequent treatment with PPTS/MeOH afforded the
desired aldol adduct syn-3 in 31% yield with high diastereoselectivity and enantioselectivity [syn/anti
= 93:7, 85% ee (C-5 position) by HPLC analysis].
Scheme 3. Catalytic asymmetric Mukaiyama aldol reaction.
Instead of (S)-BINOL, antipodal (R)-BINOL (6 mol %) was examined under identical conditions.
Expectedly, the results differed with regard to the yield and diastereoselectivity [syn/anti = 50:50, 89%
ee (syn), and 99% ee (anti) by HPLC analysis] (mismatching).

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Pyrone formation and successive O-methylation using syn-
produced 4-methoxy-5,6-dihydro-2H-pyran-2-one precursor (1’S,6S)-
steps (Scheme 4). Finally, Pd/C-catalyzed debenzylation of (10S,6S)-
3
according to the reported method [15
in 88% yield (dr = 91:9) in two
furnished ( )-pestalotin in 60%
]
5
5
−
yield and 99% ee (C-6 position) by HPLC analysis after recrystallization, together with a trace amount
of (+)-epipestalotin.
Scheme 4. Synthesis of (−)-pestalotin.
2.4. Diastereoselective Mukaiyama Aldol Reactions Promoted by Achiral Lewis Acids
Several simpler achiral Lewis acids were screened for diastereoselective Mukaiyama aldol reactions
(Table 1). Hagiwara’s pioneering work addressed Lewis acid-mediated crossed-aldol reactions between
1
and
but the anti-
ZnCl2). Taking this information into account, we reinvestigated this procedure with the aim of
enhancing stereocomplementary anti- selectivity. The salient features are as follows: (i) The amount
of TiCl4 (100 mol %) could be decreased to a catalytic amount (20 mol %), by which aldehyde was
2
to afford syn-
3
adducts [15]; TiCl4 (100 mol %) produced excellent syn-
3
diastereoselectivity,
3
selectivity was insufficient when using several other Lewis acids (BF3
•OEt2, Et2AlCl,
3
1
sufficiently consumed (entries 1–3). (ii) Notably, the aldol-step reaction mixture was directly treated
with PPTS/MeOH solution following the procedure mentioned described in Section 2.2 to furnish the
desired 4-methoxy-5,6-dihydro-2H-pyran-2-one precursor (10S,6S)-
5 smoothly with good syn-/anti-
selectivity and excellent enantioselectivity at the C6-position (entry 2). This one-pot furan formation is
the first finding among previously reported total syntheses. (iii) The use of other strong Lewis acids
such as AlCl3, SnCl4, and BF3
•
OEt2, did not afford fruitful results (entries 4–6). (iv) Fortunately, the
reaction using ZrCl4 switched the selectivity from syn- to anti- to afford (10S,6S)-
5
as a major product
with moderate diastereoselectivity but with excellent enantioselectivity (entry 8). (v) The use of mild
metal triflate reagents such as M(OTf)n (M = Sc, La, Cu) were examined next. In contrast to TiCl4 and
ZrCl4, Cu(OTf)2 produced a satisfactory yield with excellent syn-
(entry 11).
3 selectivity and enantioselectivity
2.5. Catalytic Diastereoselective Hetero-Diels-Alder Reaction
Next, our attention was focused on a hetero-Diels-Alder reaction between aldehyde
Brassard’s siloxydiene (
) [11] to construct pyrone precursors (10S,6S)- and (10S,6R)-
1
5
and
in a
4
5
straightforward manner, basically according to Midland’s protocol [12] (Scheme 2). The salient
features are as follows: (i) Several Lewis acid catalysts (TiCl4, AlCl3, SnCl4, BF3 OEt2, ZnCl2, and
•
MgCl2) were screened (Table 2). The reaction profile apparently differed from the result listed in
Table 1; i.e., both the yield and stereoselectivities were moderate to low (entries 1–5). (ii) Among metal
triflate catalysts M(OTf)n (M = Sc, La, Cu), only Sc(OTf)3 afforded moderate result (entry 6), and, in
contrast to our expectation Cu(OTf)2 afforded a disappointing result (entry 8). (iii) A reinvestigation
of Midland’s best conditions using “chiral” Eu(hfc)3 revealed good selectivity for (1’S,6S)-5 (entry
9). (iv) Notably, the use of more inexpensive and accessible “achiral” Eu(fod)3 produced superior
diastereoselectivity and enantioselectivity (entry 10).

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Table 1. Catalytic diastereoselective Mukaiyama aldol reaction.
ee/% a)
ee/% a)
(10S,6S)-5 (10S,6R)-5
Lewis
Entry
Yield/%
3–5
Syn-3/
Temp./◦C
(10S,6S)-5/(10S,6R)-5 a)
Acid
Anti-3a)
syn-3
anti-3
ND b)
1
2
3
4
5
TiCl4
20–25
0–5
−20
0–5
0–5
0–5
0–5
0–5
7
0
23
trace
33
trace
21
trace
32
trace
53
33
49
31
trace
0
trace
43
41
5
-
60:40
87:13
62:38
-
-
-
33:67
35:65
-
-
-
-
-
-
-
98
-
87
-
98
-
95
91
>98
-
-
-
-
55:45
-
60:40
-
33:67
-
56:44
-
90
ND b)
ND b)
AlCl3
SnCl4
-
70
-
-
-
6
BF3
ZrCl4
•
OEt2
-
7 c)
8 c)
9 c)
10 c)
11 c)
ND b)
ND b)
>98
-
ND b)
-
-
-
-
-
>98
Sc(OTf)3
La(OTf)3
Cu(OTf)2
-
-
–
-
-
-
trace
5
93:7
98
a) Concerning the C6-position. Determined by HPLC analysis (DAICEL Chiralcel AD-3). b) Not determined due to
the HPLC peak overlap of 3 and 5. c) PPTS/MeOH step: 40–45 ◦C.
Table 2. Stereoselective catalytic hetero-Diels-Alder reaction using Brassard’s siloxydiene.
Yield/% a)
(10S,6S)-5/(10S,6R)-5 a)
Entry
Lewis Acid
Temp./◦C
1
2
TiCl4
SnCl4
19
22
55:45
3
4
BF3•OEt2
complex mixtures
ZnCl2
33
58:42
64:36
79:21
5
6
7
8
9
10
MgCl2
31
Sc(OTf)3
La(OTf)3
Cu(OTf)2
Eu(hfc)3
Eu(fod)3
−78 to 20–25
37
complex mixtures
complex mixtures
41
88 (95% ee) b):12
0–5 to 20–25
0–5
67 c)
98 (>98% ee) b):2
a) Determined by 1H-NMR analysis. b) Concerning the C6-position. c) Isolated.
According to Midland’s report, stereocomplementary (10S,6R)-diastereoselective reaction using
Et2AlCl catalyst was examined to obtain pyrone (10S,6R)-
in our hands (Scheme 5). Due to the subtle
reported conditions, the reaction was hardly reproducible, and our best result was addressed; the
obtained crude product contained considerable amounts of aldol-type compound with the desirable
product (10S,6R)- was converted to (10S,6R)-
. Compound by PPTS/toluene under reflux conditions,
albeit in poor yield (12%).
5
9
5
9
5

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Scheme 5. (10S,6R)-Diastereoselective hetero-Diels-Alder reaction using Brassard’s siloxydiene.
Finally, debenzylation of (10S,6S)-
5
and (1’S,6R)-
5
using the H2/Pd(OH)2-C catalyst produced
( )-pestalotin and (+)-epipestalotin, respectively, in good yield and with excellent optical purities
−
(Scheme 6). Gratifyingly, Mitsunobu inversions of (
−
)-pestalotin and (+)-epipestalotin smoothly
proceeded to furnish (+)-epipestalotin and (
inversion step increases the value of the whole synthesis by a convergent process. Physical and spectral
data (mp, optical rotation, 1H-NMR) of all four pestalotin diastereomers matched completely with
Mori’s reported data [
the experimental and in the ESI, respectively. The present divergent methodology is superior compared
with Mori’s approach to the only reported total synthesis of all four pestalotin families [ ] in the
−
)-pestalotin, respectively (Scheme 6). The present
9
]. Additional 13C-NMR spectral data and HPLC measurements are described in
9
following respects: (i) common (R)-glycidol starting compound, (ii) short syntheses (7 and 9 steps),
and (iii) higher total yield.
Scheme 6. Final stage of the total synthesis all four pestalotin diastereomers.
3. Materials and Methods
All reactions were carried out in oven-dried glassware under an argon atmosphere. Flash column
chromatography was performed with silica gel 60 (230–400 mesh ASTM, Merck, Darmstadt, Germany).
TLC analysis was performed on Merck 0.25 mm Silicagel 60 F254 plates. Melting points were determined
on a hot stage microscope apparatus (ATM-01, AS ONE, Osaka, Japan) and were uncorrected. NMR
spectra were recorded on a JEOLRESONANCE EXC-400 or ECX-500 spectrometer (JEOL, Akishima,
Japan) operating at 400 MHz or 500 MHz for 1H-NMR, and 100 MHz and 125 MHz for 13C NMR.
Chemical shifts (δ
ppm) in CDCl3 were reported downfield from TMS (=0) for 1H-NMR. For 13C-NMR,
chemical shifts were reported in the scale relative to CDCl3 (77.00 ppm) as an internal reference.
Mass spectra were measured on a JMS-T100LC spectrometer (JEOL, Akishima, Japan). HPLC data
were obtained on a SHIMADZU (Kyoto, Japan) HPLC system (consisting of the following: LC-20AT,
CMB20A, CTO-20AC, and detector SPD-20A measured at 254 nm) using Chiracel AD-H or Ad-3
column (Daicel, Himeji, Japan, 25 cm) at 25 ◦C. Optical rotations were measured on a JASCO DIP-370
(Na lamp, 589 nm).

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(R)-2-((trityloxy)methyl)oxirane (6)
TrCl (15.3 g, 55 mmol) in CH2Cl2 (35 mL) was added to a stirred solution of (R)-(+)-glycidol
(3.70 g, 50 mmol) and Et3N (13.9 mL, 100 mmol) and DMAP (61 mg, 0.5 mmol) in CH2Cl2 (15 mL) at
0–5 ◦C under an Ar atmosphere, followed by stirring at 20–25 ◦C for 24 h. The mixture was quenched
with sat. NH4Cl aq., which was extracted three times with Et2O. The combined organic phase was
washed with water, brine, dried (Na2SO4), and concentrated. The obtained crude solid was purified by
recrystallization from MeOH (100 mL) to give the desired product 6 (13.1 g, 83%).
Colorless crystals, mp 99–100 ◦C [lit. [25], 100 ◦C (EtOH)]; 1H-NMR (400 MHz, CDCl3):
δ = 2.63
(dd, J = 2.3 Hz, 5.0 Hz, 1H), 2.78 (dd, J = 4.6, 1H), 3.09–3.18 (m, 2H), 3.32 (dd, J = 2.3 Hz, 10.0 Hz, 1H),
7.20–7.35 (m, 10H), 7.42–7.50 (m, 5H); 13C-NMR (100 MHz, CDCl3):
127.8 (6C), 128.6 (6C), 143.8.
δ = 44.6, 51.0, 64.7, 86.6, 127.0 (3C),
(S)-1-(Trityloxy)hexan-2-ol (7)
1-Bromopropane (8.60 mL, 95 mmol) was gradually added to a stirred Mg granular (2.31 g,
95 mmol) and a small amounts of I2 in THF (60 mL) at 20–25 ◦C under an Ar atmosphere, and the
mixture was stirred for 0.5 h at 20–25 ◦C. CuI (143 mg, 0.80 mmol) was added, the mixture was cooled
down to 6 (12.1 g, 38 mmol) in THF (100 mL) was added to the mixture at
40 ◦C and (S)-oxirane
−
the same temperature, followed by stirring for 2 h. The mixture was quenched with sat. NH4Cl aq.,
which was extracted three times with AcOEt. The combined organic phase was washed with water,
brine, dried (Na2SO4), and concentrated. The obtained crude product was purified by SiO2–column
chromatography (hexane/AcOEt = 15/1) to give the desired alcohol 7 (12.7 g, 93%).
Pale yellow oil; 1H-NMR (400 MHz, CDCl3):
δ = 0.86 (t, J = 6.9 Hz, 3H), 1.16–1.46 (m, 6H), 2.30 (d,
J = 3.7 Hz, 1H), 3.02 (dd, J = 7.8 Hz, 9.2 Hz, 1H), 3.18 (dd, J = 3.2 Hz, 9.2 Hz, 1H), 3.72–3.80 (m, 1H),
7.19–7.35 (m, 10H), 7.40–7.47 (m, 5H); 13C-NMR (100 MHz, CDCl3):
86.6, 127.0 (3C), 127.8 (6C), 128.6 (6C), 143.8.
δ = 13.9, 22.6, 27.6, 33.0, 67.7, 70.9,
(S)-2-(Benzyloxy)hexan-1-ol (8) [15]
A mixture of benzyl bromide (4.85 mL, 41 mmol) and (S)-alcohol
7 (12.4 g, 34 mmol) in DMF
(25 mL) were added to a stirred suspension of NaH (60%; 2.04 mg, 51 mmol) in DMF (10 mL) at 0–5 ◦C
under an Ar atmosphere. TBAI (126 mg, 0.3 mmol) was added to the mixture and the mixture was
allowed to warm up to 20–25 ◦C, followed by stirring for 1 h. The mixture was quenched with MeOH
and K2CO3, which was extracted three times with AcOEt. The combined organic phase was washed
with water, brine, dried (Na2SO4), and concentrated. The obtained crude oil (15.6 g) was used for the
next step without purification.
TsOH H2O (647 mg, 3.4 mmol) was added to a solution of the oil (15.6 g) in MeOH (70 mL) at
·
20–25 ◦C under an Ar atmosphere, and the mixture was stirred for 1 h at the same temperature. The
mixture was quenched with sat. NaHCO3 aq. and concentrated, which was extracted three times with
AcOEt. The combined organic phase was washed with water, brine, dried (Na2SO4), and concentrated.
The obtained crude product was purified by SiO2–column chromatography (hexane/AcOEt = 15:1–3:1)
to give 8 (6.52 g, 92% for 2 steps, >98% ee).

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Yellow oil; [α]2D4 +21.4 (c 1.16, CHCl3) [lit. [15], [α]Dunknown +22.3 (c 1.13, CHCl3)]; H-NMR
(400 MHz, CDCl3): = 0.90 (t, J = 6.9 Hz, 3H), 1.23–1.40 (m, 4H), 1.44–1.71 (m, 2H), 1.93 (brs, 1H),
3.47–3.58 (m, 2H), 3.65–3.75 (m, 1H), 4.54 (d, J = 11.5 Hz, 1H), 4.63 (d, J = 11.5 Hz, 1H), 7.27–7.39 (m,
5H); 13C NMR (500 MHz, CDCl3):
= 13.8, 22.6, 27.3, 30.3, 63.9, 71.3, 79.7, 127.4, 127.6 (2C), 128.2 (2C),
1
δ
δ
138.3. HPLC analysis (AD-H, flow rate 1.00 mL/min, solvent: hexane/2-propanol = 30/1) tR(racemic) =
9.33 min and 10.27 min. tR[(S)-form] = 8.95 min.
(S)-2-(Benzyloxy)hexanal (1) [15]
TEMPO (106 mg, 0.68 mmol) and KBr (407 mg, 3.◦4 mmol) was added to a stirred solution of
alcohol
8 (7.08 g, 34 mmol) in CH2Cl2 (34 mL) at 0–5 C under an Ar atmosphere. A mixture of
NaOCl aq. (1.5 M, 34 mL, 51 mmol), NaHCO3 (6.7 g, 80 mmol), and Na2CO3 (318 mg, 3 mmol) in
water (220 mL), was added to the solution at same temperature. The mixture was allowed to warm
to 20–25 ◦C, followed by stirring at the same temperature for 1 h. The mixture was quenched with
water, which was extracted twice with CH2Cl2. The combined organic phase was washed with water,
brine, dried (Na2SO4), and concentrated. The obtained crude oil was purified by Florisil® column
chromatography (hexane/AcOEt = 5:1) to give the desired product 1 (6.04 g, 86%).
Yellow oil; [α]2D4
−
81.2 (c 1.08, CHCl3) [lit. [15], [α]Dunknown
−
86.1 (c 0.98, CHCl3)]; H-NMR
1
(500 MHz, CDCl3):
δ = 0.90 (t, J = 7.5 Hz, 3H), 1.24–1.49 (m, 4H), 1.69 (q, J = 6.9 Hz, 13.8 Hz, 2H), 3.76
(t, J = 6.3 Hz, 1H), 4.54 (d, J = 11.5 Hz, 1H), 4.68 (d, J = 11.5 Hz, 1H), 7,27–7.41 (m, 5H), 9.66 (s, 1H); 13
NMR (125 MHz, CDCl3): δ = 13.7, 22.3, 26.7, 29.6, 72.3, 83.3, 127.8, 127.9, 128.4, 137.3, 203.6.
An alternative method is following:
C
DMSO (4.26 mL, 60 mmol) in CH2Cl2 (20 mL) was added slowly to a stirred solution of oxalyl
dichloride (3.43 mL, 40 mmol) in CH2Cl2 (60 mL) at
78 ◦C under an Ar atmosphere. After the mixture
was stirred for 5 min, (4.22 g, 20 mmol) in CH2Cl2 (20 mL) was added and the mixture was stirred for
−
8
0.5 h at the same temperature. Et3N (16.6 mL, 120 mmol) was added to the mixture and the mixture
was allowed to warm up to 0–5 ◦C over a period of 1 h, followed by stirring for 1 h at 0–5 ◦C. The
mixture was quenched with water, which was extracted three times with Et2O. The combined organic
phase was washed with a large amounts of water, brine, dried (Na2SO4), and concentrated. The
obtained crude product was purified by SiO2–column chromatography (hexane/AcOEt = 25/1) to give
the desired product 1 (3.99 g, 97%).
Methyl (5S,6S)-6-(benzyloxy)-5-hydroxy-3-oxodecanoate (syn-3) [15]
Preparation for Ti-BINOL solution: A suspension of Ti(OiPr)4 (2.9 mg, 10 µmol), and (S)-BINOL
(2.8 mg, 10 µmol) in THF (0.4 mL) was stirred stirred at 20–25 ◦C under an Ar atmosphere for 1 h.
Asymmetric Mukaiyama aldol reaction: Ti-BINOL solution was added to a stirred suspension of
aldehyde
1
(103 mg, 0.50 mmol) and LiCl (0.85 mg, 20
µ
mol) in THF (0.5 mL) at 20–25 ◦C under an Ar
(260 mg, 1.0 mmol)
atmosphere, followed by stirring at the same temperature for 0.5 h. Chan’s diene
2
in THF (0.3 mL) was added slowly to the mixture, which was stirred for 14 h. PPTS (25 mg, 0.10 mmol)
in MeOH (1.0 mL) was added to the mixture, followed by stirring at the same temperature for 2 h. The
resulting mixture was quenched with sat. NaHCO3 aq., which was extracted three times with Et2O.
The combined organic phase was washed with water, brine, dried (Na2SO4), and concentrated. The
obtained crude oil was purified by SiO2–column chromatography (hexane/AcOEt = 8/1) to give the
desired product syn-3 (85% ee, dr 93:7, 51 mg, 31%).

Molecules 2020, 25, 394
10 of 16
25
Pale yellow oil; [α]]
+1.0 (c 1.0, CHCl3) [lit. [15], [α]uDnknown +1.2 (c 1.00, CHCl3)]; 85% ee; HPLC
analysis (AD-3, flow ratDe 1.00 mL/min, solvent: hexane/2-propanol = 30:1) tR(racemic) = 13.51 min,
1
14.13 min, 18.89 min and 19.82 min. tR[(5S,6S)-form] = 18.69 min. H-NMR (500 MHz, CDCl3):
δ =
0.91 (t, J = 6.9 Hz, 3H), 1.24–1.70 (m, 6H), 2.62–2.64 (m, 1H), 2.71-2.74 (m, 1H), 3.34–3.37 (m, 1H), 3.477
(s, 1H), 3.480 (s, 1H), 3.73 (s, 3H), 4.13–4.18 (m, 1H), 4.49 (d, J = 11.5 Hz, 1H), 4.63 (d, J = 11.5 Hz, 1H),
7.28–7.37 (m, 5H); 13C-NMR (125 MHz, CDCl3):
127.8, 127.9, 128.4, 138.2, 167.4, 202.7.
δ = 14.0, 22.8, 27.6, 29.3, 46.0, 49.6, 52.3, 68.3, 72.2, 80.8,
(E)-((1,3-dimethoxybuta-1,3-dien-1-yl)oxy)trimethylsilane (4) (Brassard’s diene)
Concentrated H2SO4 (0.27 mL, 5.0 mmol) was added to a stirred mixture of methyl acetoacetate
(11.6g, 100 mmol) and trimethyl orthoformate (26.5 g, 250 mmol) at 0–5 ◦C under an Ar atmosphere,
followed by stirring at 20–25 ◦C for 24 h. K2CO3 (5.0 g) was added to the mixture, which was filtered
through a glass filter. The filtrate was concentrated under reduced pressure. The obtained crude oil
was purified by distillation (bp 72–75 ◦C/3.2 kPa) to give the desired (E)-methyl-3-methoxybut-2-enoate
(9.08 g, 70%).
nBuLi (1.63 M in hexane, 13.6 mL, 22 mmol) was added to stirred solution of iPr2NH (3.11 mL,
22 mmol) in THF (10 mL) at 0–5 ◦C under an Ar atmosphere, followed by stirring for 10 min. The
mixture was cooled down to
78 ◦C and (E)-methyl-3-methoxybut-2-enoate (2.22 g, 17 mmol) in THF
−
(4.0 mL) was added to the mixture, followed by stirring at the same temperature for 0.5 h. TMSCl
(2.58 mL, 20 mmol) in THF (3.0 mL) was added to the mixture at the same temperature and the mixture
was allowed to warm up to 0–5 ◦C over a period of 1 h. The mixture was concentrated and filtered
through Celite® (No.503) using a glass filter, and washing with hexane (10 mL
concentrated under reduced pressure and the obtained crude oil was purified by distillation to give
×
3). The filtrate was
the desired product 4 (2.62 g, 76%).
Colorless oil; bp 40–43 ◦C/50 Pa; 1H-NMR (400 MHz, CDCl3):
δ = 0.26 (s, 9H), 3.56 (s, 3H), 3.57 (s,
3H), 3.99 (t, J = 1.4 Hz, 1H), 4.03 (d, J = 1.4 Hz, 1H), 4.34 (d, J = 1.8, 1H); 13C NMR (100 MHz, CDCl3):
= 0.3, 54.0, 55.0, 75.5, 78.6, 158.7
δ
(S)-6-[(S)-1-(Benzyloxy)pentyl]-4-methoxy-5,6-dihydro-2H-pyran-2-one [(10S,6S)-5] [15]
(1) 1M-KOH aq. (0.37 mL) was added to a stirred solution of (5S,6S)-aldol adduct syn-3 (108 mg,
0.33 mmol) in MeOH (0.37 mL) at 20–25 ◦C under an Ar atmosphere, followed by stirring at the same
temperature for 3 h. The mixture was quenched with 1M-HCl aq., which was extracted twice with
AcOEt. The combined organic phase was washed with brine, dried (Na2SO4), and concentrated. The
obtained crude oil was purified by SiO2–gel column chromatography (hexane/AcOEt = 5/1–2/1) to give
the desired 4-hydroxy-5,6-dihydro-2H-pyran-2-one precursor (dr 93:7, 94 mg, 98%).
1H-NMR (500 MHz, CDCl3):
δ = 0.92 (t, J = 6.9 Hz, 3H), 1.28–1.40 (m, 4H), 1.71–1.77 (m, 2H),
2.58 (dd, J = 5.2 Hz, 17.2 Hz, 1H), 2.76 (dd, J = 5.2 Hz, 17.2 Hz, 1H), 3.30 (d, J = 20.1 Hz, 1H), 3.41 (d,
J = 20.1 Hz, 1H), 3.42–3.45 (m, 1H), 4.44 (d, J = 10.9 Hz, 1H), 4.59 (d, J = 10.9 Hz, 1H), 4.71–4.74 (m,
1H), 7.26–7.37 (m, 1H); 13C-NMR (125 MHz, CDCl3):
128.1, 128.2, 128.5, 136.9, 167.7, 199.4
δ = 13.9, 22.7, 27.5, 29.3, 40.6, 46.2, 72.3, 75.9, 80.0,
K2CO3 (80 mg, 0.58 mmol) was added to a stirred suspension of the precursor (85 mg, 029 mmol)
and Me2SO4 (55 mg, 0.44 mmol) in acetone (1.5 mL) at 20–25 ◦C under an Ar atmosphere, followed by

Molecules 2020, 25, 394
11 of 16
stirring at the same temperature for 14 h. The mixture was quenched with water, which was extracted
three times with Et2O. The combined organic phase was washed with brine, dried (Na2SO4), and
concentrated. The obtained crude oil was purified by SiO2–gel column chromatography (hexane/AcOEt
= 6/1–4/1) to give the desired product (10S,6S)-5 (dr 91:9, 79 mg, 89%).
Pale yellow oil; [α]2D5 −93.7 (c 0.72, CHCl3)]. [lit. [15], [α]unknown −99.1 (c 0.93, CHCl3)].
D
(2) TiCl4 (0.02 mL, 0.2 mmol) was added to a solution of aldehyde 1 (206 mg, 1.0 m mol) in CH2Cl2
(3.0 mL) at 0–5 ◦C under an Ar atmosphere, followed by stirring at the same temperature for 10 min.
Chan’s diene (61 % purity, 520 mg, 1.2 mmol) was added to the mixture, which was stirred at 0–5 ◦C
for 5 min and at 20–25 ◦C for 1 h. MeOH (2 mL) and PPTS (125 mg, 0.5 mmol) was successively added
to the mixture, followed by stirring at the same temperature for 2 h. The mixture was quenched with
sat. NaHCO3 aq., which was filtered through Celite®. The filtrate was extracted twice with AcOEt,
and the combined organic phase was washed with water, brine dried (Na2SO4), and concentrated. The
obtained crude oil was purified by SiO2-column chromatography (hexane/AcOEt = 4:1) to give the
desired product (1’S,6S)-5 [165 mg, 49%, 91% ee, dr = 87:13].
(3) Aldehyde
Eu(fod)3 (104 mg, 0.1 mmol) in CH2Cl2 (1.0 mL) at 0–5 ◦C under an Ar atmosphere, followed by stirring
at the same temperature for 5 min. Brassard’s diene (607 mg, 3.0 mmol) in CH2Cl2 (2.0 mL) was
1 (413 mg, 2.0 mmol) in CH2Cl2 (1.0 mL) was added to a stirred suspension of
4
added to the mixture at the same temperature, followed by stirring for 2 h. The mixture was quenched
with water, which was extracted three times with AcOEt. The combined organic phase was washed
with water, brine, dried (Na2SO4), and concentrated. The obtained crude product was purified by
SiO2–column chromatography (hexane/AcOEt = 3/1) to give the desired product [(1’S,6S)-5] (370 mg,
67%, >98% ee, dr = 98:2). HPLC analysis (AD-3, flow rate 1.00 mL/min, solvent: hexane/2-propanol
1
= 30:1) tR(racemic) = 23.25 min and 24.77 min. tR[(1S,6S)-form] = 25.53 min.; H-NMR (500 MHz,
CDCl3):
δ = 0.89 (t, J = 6.9 Hz, 3H), 1.25–1.72 (m, 6H), 2.26 (dd, J = 4.0 Hz, 17.2 Hz, 1H), 2.70 (ddd,
J = 1.7 Hz, 13.2 Hz, 17.2 Hz, 1H), 3.58–3.61 (m, 1H), 3.74 (s, 3H), 4.52 (dt, J = 4.0 Hz, 13.2 Hz, 1H), 4.62
(d, J = 11.5 Hz, 1H), 4.66 (d, J = 11.5 Hz, 1H), 5.13 (d, J = 1.7 Hz, 1H), 7.27–7.36 (m, 5H); 13C NMR
(125 MHz, CDCl3):
167.0, 173.3.
δ = 14.0, 22.7, 27.9, 28.4, 29.3, 56.1, 72.9, 76.3, 79.0, 90.2, 127.8, 127.9, 128.4, 138.1,
(−)-Pestalotin; (S)-6-[(S)-1-Hydroxypentyl]-4-methoxy-5,6-dihydro-2H-pyran-2-one [9]
A suspension of benzyl ether [(1S,6S)- ] (448 mg, 1.5 mmol) and 20% Pd(OH)2/C (53 mg, 0.08 mmol)
5
in AcOEt (15 mL), equipped with a H2 balloon, was stirred at 20–25 ◦C for 1 h. The mixture was filtered
through Celite® (No.503) using glass filter and the filtrate was concentrated under reduced pressure.
The obtained crude solid (384 mg) was purified by SiO2–column chromatography (hexane/AcOEt =
3:2) to give the desired (−)-pestalotin (283 mg, 88%, >98% ee, dr = >98:2).
Colorless crystals; mp 84–86 ◦C (lit. [
90.2 (c 1.17, MeOH)]; HPLC analysis (AD-3, flow rate 1.00 mL/min, solvent: hexane/2-propanol =
30:1) tR(racemic) = 45.23 min and 48.13 min. tR[(1S,6S)-form] = 45.85 min.; 1H-NMR (500 MHz, CDCl3):
= 0.92 (t, J = 6.9 Hz, 3H), 1.30–1.67 (m, 6H), 2.07 (brs, 1H), 2.25 (dd, J = 4.0 Hz, 17.2 Hz, 1H), 2.80 (ddd,
9
], 85.8–86.0 ◦C); [α]D25 ], [α]D21
91.9 (c 0.44, MeOH) [lit. [9
−
−
δ
J = 1.7 Hz, 12.6 Hz, 17.2 Hz, 1H), 3.61–3.64 (m, 1H), 3.76 (s, 3H), 4.30 (dt, J = 4.0 Hz, 12.6 Hz, 1H), 5.15
(d, J = 1.7 Hz, 1H); 13C-NMR (125 MHz, CDCl3):
δ = 13.9, 22.6, 27.6, 29.6, 32.4, 56.1, 72.4, 78.4, 90.0,
166.7, 173.1.

Molecules 2020, 25, 394
12 of 16
(R)-6-[(S)-1-(Benzyloxy)pentyl]-4-methoxy-5,6-dihydro-2H-pyran-2-one [(1’S,6R)-5]
(1) Aldehyde
1 (206 mg, 1.0 mmol) was added to a stirred suspension of ZrCl4 (47 mg, 0.2 mmol)
in CH2Cl2 (0.9 mL) at 0–5 ◦C under an Ar atmosphere. After 10 min, Chan’s diene (ca. 60% purity;
520 mg, 1.2 mmol) was added to the mixture, which was allowed to warm up to 20–25 ◦C, followed by
stirring for 1 h. MeOH (2.0 mL) and PPTS (125 mg 0.5 mmol) was successively added to the solution,
followed by stirring at 40–45 ◦C for 14 h. Sat. NaHCO3 aq. solution was added to the mixture, which
was filtered through Cerite®. The filtrate was extracted twice with AcOEt, and the combined organic
phase was washed with water, brine dried (Na2SO4), and concentrated. The obtained crude oil was
purified by SiO2-column chromatography (hexane/AcOEt = 4:1) to give the desired product (10S,6R)-
(126 mg, 41%, >98% ee, dr = 35:65).
5
Colorless oil. HPLC analysis (AD-3, flow rate 1.00 mL/min, solvent: hexane/2-propanol = 30:1)
tR(racemic) = 17.72 min and 19.60 min. tR[(1S,6R)-form] = 18.10 min.; 1H-NMR (500 MHz, CDCl3):
δ
= 0.89 (t, J = 6.9 Hz, 3H), 1.29-1.64 (m, 6H), 2.35 (dd, J = 4.0 Hz, 17.2 Hz, 1H), 2.81 (ddd, J = 1.7 Hz,
12.6 Hz, 17.2 Hz, 1H), 3.74 (s, 3H), 3.73-3.78 (m, 1H), 4.39 (dt, J = 4.0, 12.6, 1H), 4.63 (d, J = 11.5, 1H),
4.74 (d, J = 11.5, 1H), 5.14 (d, J = 1.7, 1H), 7.28-7.35 (m, 5H ); 13C-NMR (125 MHz, CDCl3):
δ = 13.9,
22.6, 27.4, 27.9, 30.7, 56.0, 73.3, 78.4, 79.1, 90.0, 127.6, 127.8, 128.3, 138.3, 167.0, 173.4.
(2) Et2AlCl (1.0 M, 0.6 mL, 0.6 mmol) was added to a stirred solution of aldehyde
1
4
(103 mg,
(202 mg,
◦
0.5 mmol) in CH2Cl2 (0.5 mL) at
0.6 mmol) in CH2Cl2 (0.5 mL) was added to the mixture, which was stirred for 14 h at the same
temperature. The mixture was allowed to warm up to
mixture was quenched by MeOH, which was extracted three times with AcOEt. The combined organic
phase was washed with water, brine, dried (Na2SO4), and concentrated. The obtained crude product
was purified by SiO2-column chromatography (hexane/AcOEt = 5/1) to give a mixture of aldol adduct
and (10S,6R)-
5 (45:55, 48 mg, 30%). The mixture (48 mg) and PPTS (2 mg, 0.007 mmol) in toluene
−
78 C under an Ar atmosphere. After 5 min, diene
◦
−
30 C, followed by stirring for 14 h. The
9
(1.4 mL), was added at 80–85 ◦C for 1 h under an Ar atmosphere. After cooling to room temperature,
water was added to the mixture, which was extracted twice with AcOEt. The combined organic
phase was washed with water and brine, dried (Na2SO4), and concentrated. The obtained crude solid
purified by SiO2-column chromatography (hexane/AcOEt = 5/1) to give the desired product (1’S,6R)-
5
(23 mg, 2 steps 15%, ca. 30% of (1’S,6S)-5 was contained).
(+)-Epipestalotin; (R)-6-[(S)-1-Hydroxypentyl]-4-methoxy-5,6-dihydro-2H-pyran-2-one [9]
A suspension of benzyl ether [(1S,6R)-5] (365 mg, 1.2 mmol) and 20% Pd(OH)2/C (42 mg, 0.06 mmol)
in AcOEt (12 mL), equipped with a H2 balloon, was stirred stirred at 20–25 ◦C for 1 h. The mixture was
filtered through Celite® (No.503) using glass filter and the filtrate was concentrated under reduced
pressure. The obtained crude solid was purified SiO2–column chromatography (hexane/AcOEt = 3/2)
to give the desired (+)-epipestalotin (187 mg, 71%, >98% ee, dr = 98:2).
Colorless crystals; mp 92–94 ◦C (lit. [
9
], 93.0–94.0 ◦C); [α]D20 + 75.3 (c 0.39, MeOH) [lit. [
9
], [α]1D7
+
75.9 (c 0.39, MeOH)]; >99% ee; HPLC analysis (AD-3, flow rate 1.00 mL/min, solvent: hexane/2-propanol
1
= 25:1) tR(racemic) = 33.00 min and 35.46 min. tR[(1S,6R)-form] = 34.81 min.; H NMR (500 MHz,
CDCl3):
δ = 0.92 (t, J = 6.9 Hz, 3H), 1.30–1.56 (m, 6H), 2.04 (brs, 1H), 2.24 (dd, J = 4.0 Hz, 17.2 Hz, 1H),

Molecules 2020, 25, 394
13 of 16
2.84 (ddd, J = 1.7 Hz, 12.6 Hz, 17.2 Hz, 1H), 3.76 (s, 3H), 3.94–3.97 (m, 1H), 4.34 (dt, J = 3.4 Hz, 12.6 Hz,
1H), 5.14 (d, 1.7 Hz, 1H); 13C NMR (125 MHz, CDCl3):
89.7, 167.1, 173.5.
δ = 13.8, 22.4, 26.8, 27.7, 31.4, 56.0, 71.3, 78.7,
(−)-Epipestalotin; (S)-6-[(R)-1-Hydroxypentyl]-4-methoxy-5,6-dihydro-2H-pyran-2-one [9]
DEAD (40% in toluene, 0.91 mL, 2.0 mmol) was added slowly to a stirred mixture of ( )-pestalotin
−
(214 mg, 1.0 mmol) and 4-nitrobenzoic acid (334 mg, 2.0 mmol) and PPh3 (525 mg, 2.0 mmol) in toluene
(10 mL) at 0–5 ◦C under an Ar atmosphere, followed by stirring at 20–25 ◦C for 6 h. The mixture was
quenched with water, which was extracted three times with AcOEt. The combined organic phase
was washed with sat. NaHCO3 aq., brine, dried (Na2SO4), and concentrated. The obtained crude
product was purified by SiO2–column chromatography (hexane/AcOEt = 3:1) to give a mixture of the
desired ( )-Epipestalotin and diethyl hydrazodicarboxylate, which was used in the next step without
−
further purification.
A suspension of the mixture and K2CO3 (138 mg, 1.0 mmol) in MeOH (10 mL) was stirred at
20–25 ◦C under an Ar atmosphere for 10 min. The mixture was filtered through Celite® (No.503) using
a glass filter washing with AcOEt (5 mL
×
3). The filtrate was concentrated under reduced pressure
and the obtained crude oil, which was purified by SiO2–column chromatography (hexane/AcOEt = 2:1)
to give the desired (−)-epipestalotin (133 mg, 62% for 2 steps, >98% ee, dr = >98:2).
Colorless crystals; mp 89–91 ◦C (lit. [
9
], 90.7–91.2 ◦C); [α]D20 ], [α]D17
75.8 (c 0.58, MeOH) [lit. [9
−
−
75.6 (c 0.58, MeOH)]; HPLC analysis (AD-3, flow rate 1.00 mL/min, solvent: hexane/2-propanol = 25:1)
tR(racemic) = 33.00 min and 35.46 min. tR[(1R,6S)-form] = 32.31 min.; 1H-NMR (500 MHz, CDCl3):
δ
=
0.92 (t, J = 6.9 Hz, 3H), 1.30–1.55 (m, 6H), 2.04 (brs, 1H), 2.24 (dd, J = 4.0 Hz, 17.2 Hz, 1H), 2.84 (ddd,
J = 1.7 Hz, 12.6 Hz, 17.2 Hz, 1H), 3.76 (s, 3H), 3.94–3.97 (m, 1H), 4.34 (dt, J = 3.4 Hz, 12.6 Hz, 1H), 5.14
(d, J = 1.7 Hz, 1H); 13C-NMR (125 MHz, CDCl3):
δ = 13.8, 22.4, 26.8, 27.7, 31.4, 56.0, 71.3, 78.7, 89.7,
167.1, 173.5.
(+)-Pestalotin; (R)-6-[(R)-1-Hydroxypentyl]-4-methoxy-5,6-dihydro-2H-pyran-2-one [9]
Following the procedure for the preparation of ( )-epipestalotin, the reaction of (+)-epipestalotin
−
(107 mg, 0.5 mmol) using DEAD (40% in toluene, 0.45 mL, 1.0 mmol), 4-nitrobenzoic acid (167 mg,
1.0 mmol), PPh3 (262 mg, 1.0 mmol), and K2CO3 (69 mg, 0.5 mmol) give the desired (+)-pestalotin
(72 mg, 67% for 2 steps, >98% ee, dr > 98:2,).
Colorless crystals; mp 82–84 ◦C (lit. [ ], 83.0–84.5 ◦C); [α]2D0 +97.5 (c 0.65, MeOH) [lit. [ ], [α]D17
9 9
+88.7 (c 0.65, MeOH)]; HPLC analysis (AD-3, flow rate 1.00 mL/min, solvent: hexane/2-propanol = 30:1)
tR(racemic) = 45.23 min and 48.13 min. tR[(1R,6R)-form] = 49.57 min; 1H-NMR (500 MHz, CDCl3):
δ
=
0.92 (t, J = 6.9 Hz, 3H), 1.30–1.67 (m, 6H), 2.07 (brs, 1H), 2.25 (dd, J = 4.0 Hz, 17.2 Hz, 1H), 2.80 (ddd,
J = 1.7 Hz, 12.6 Hz, 17.2 Hz, 1H), 3.61–3.64 (m, 1H), 3.76 (s, 3H), 4.30 (dt, J = 4.0 Hz, 12.6 Hz, 1H), 5.15
(d, J = 1.7 Hz, 1H); 13C-NMR (125 MHz, CDCl3):
δ = 13.9, 22.6, 27.6, 29.6, 32.4, 56.1, 72.4, 78.4, 90.0,
166.7, 173.1.

Molecules 2020, 25, 394
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4. Conclusions
We achieved an asymmetric total synthesis of all four chiral pestalotin diastereomers using
common and commercially-available (R)-glycidol as the starting compound. The present synthesis
involves a couple of divergent strategies, including syn- and anti-selective Mukaiyama aldol additions
and hetero-Diels-Alder reactions.
Catalytic asymmetric Mukaiyama aldol reactions of readily-available bis(TMSO)diene (Chan’s
diene) with (S)-2-benzyloxyhexanal derived from (R)-glycidol afforded a syn-aldol adduct with high
diastereoselectivity and enantioselectivity. Diastereoselective Mukaiyama aldol reactions mediated by
catalytic achiral Lewis acids directly produced not only a (10S,6S)-pyrone precursor via the syn-aldol
adduct using TiCl4, but also (10S,6R)-pyrone precursor derived from an antialdol adduct using ZrCl4
in a stereocomplementary manner.
A hetero-Diels-Alder reaction of similarly available mono(TMSO)diene (Brassard’s diene) with
(S)-2-benzyloxyhexanal produced the (1’S,6S)-pyrone precursor promoted by Eu(fod)3 and the
(10S,6R)-pyrone precursor EtAlCl2.
Debenzylation of (10S,6S)-and (10S,6R)-precursors furnished natural (
−
)(
)-epipestalotin were
)-pestalotin and (+)-epipestalotin, respectively,
−
)-pestalotin and
unnatural (+)-epipestalotin, respectively. The unnatural (+)-pestalotin and (
−
successfully synthesized by Mitsunobu inversion of (
−
in a divergent manner. All four chiral pestalotin diastereomers obtained possessed high chemical and
optical purities (optical rotations, 1H-NMR, 13C-NMR, and HPLC measurements).
The present divergent method affords concise access to asymmetric syntheses directed for these
types of compounds with consecutive chiral dihydroxy groups, and is useful for accessible asymmetric
Mukaiyama aldol reactions and relevant hetero-Diels-Alder reactions.
Copies of the 1H, 13C-NMR spectra for compounds syn-
(+)-epipestalotin are available in the Supplementary Information.
chromatogram of ( )- , (S)- , ( )- , syn- , ( )- , (1’S,6R)- , (
, (10S,6S)-
)-pestalotin, ( )-epipestalotin, (+)-epipestalotin, and ( )-epipestalotin are available in the
Supplementary Information.
3
, (10S,6S)-
5
, (
−
)-pestalotin, (10S,6R)-
Copies of the HPLC
)-pestalotin, (+)-pestalotin,
5,
±
8
8
±
3
3
±
5
5
5
±
(−
±
−
Supplementary Materials: The following are available online. Supplementary 1: 1H, 13C-NMR spectra for
compounds syn- , ( , (+)-epipestalotin, Supplementary 2: HPLC chromatogram of
, (10S,6S)- )-pestalotin, (10S,6R)-
)- , (S)- , ( )- , syn- , ( )- , (1’S,6R)- , ( )-pestalotin, (+)-pestalotin, ( )-pestalotin, ( )-epipestalotin,
, (10S,6S)-
(+)-epipestalotin, and (−)-epipestalotin.
3
3
5
±
−
5
±
(±
8
8
±
3
5
5
5
−
±
Author Contributions: M.M., K.N., and T.F. contributed the majority of experiments. Y.T. conceived and designed
the project, and prepared the whole manuscript. All authors have read and agreed to the published version of
the manuscript.
Funding: This research was partially supported by Grant-in-Aids for Scientific Research on Basic Area (B)
“18350056”, Basic Areas (C) 15K05508, and Priority Areas (A) “17035087” and “18037068”, and Exploratory
Research “17655045” from the Ministry of Education, Culture, Sports, Science and Technology (MEXT).
Acknowledgments: We thank Momoyo Kawamoto and Daiki Ueura in our laboratory for their help of
some experiments.
Conflicts of Interest: The authors declare no conflict of interest.
Dedication: This article is dedicated to the late professor Teruaki Mukaiyama who deceased in 2018 and the late
professor Kenji Mori who deceased in 2019. One of the authors (Y.T) offer his warmest congratulations to Professor
Ben L. Feringa (University of Groningen, The Netherlands) on being awarded the 2016 Nobel Prize in Chemistry.
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