Ring-Closing Strategy Utilizing Nitrile α-Anions: Chiral Synthesis of (+)-Norchrysanthemic Acid and Expeditious Asymmetric Total Synthesis of (+)-Grandisol

Article abstract of DOI:10.1002/ejoc.201801160

Chiral syntheses of two distinct small cycloalkanes, (1R,3R)-(1Z)-norchrysanthemic acid and (+)-grandisol, were performed by characteristic ring-closing methodologies using carbanions at the α-position of nitriles (nitrile α-anions). (i) (1R,3R)-(1Z)-Norchrysanthemic acid, a highly potent ingredient of synthetic pyrethroid containing a cyclopropane structure, was synthesized from readily available (S)-epoxide derived from 3-methyl-but-2-en-1-ol in 7 steps in 23 % overall yield and with > 98 % ee. This sequence involves a trans-selective cyclopropane formation using the nitrile α-anion of (S)-3-mesyloxynitrile as the key step. The present chiral synthesis was performed with effective stereocontrol of both the chirality in the 1,3-positions on the cyclopropane and the Z-geometry of the propenyl group. (ii) (+)-Grandisol, an insect sex pheromone possessing a characteristic cyclobutane structure, was synthesized from commercially available cyclopropyl methyl ketone (route A) or from commercially available 3-cyanopropylzinc bromide and 1-bromo-1-methylpropene (route B) in 10 or 8 steps in 6 % or 8 % overall yield and with 80 % ee. This sequence involves a Shi asymmetric epoxidation of a trisubstituted olefin and a straightforward Stork-type asymmetric cyclobutane formation with clean S_N2 stereoinversion using the nitrile α-anion of the chiral epoxynitrile. The present expedient method is the second asymmetric total synthesis starting from achiral compounds.

Full text of DOI:10.1002/ejoc.201801160

A Journal of
Accepted Article
Title: Ring-Closing Strategy Utilizing Nitrile α-Anions: Chiral Synthesis
of (+)-Norchrysanthemic Acid and Expeditious Asymmetric Total
Synthesis of (+)-Grandisol
Authors: Yoo Tanabe, Tetsuya Fujiwara, Tomohito Okabayashi, Yuji
Takahama, and Noritada Matsuo
This manuscript has been accepted after peer review and appears as an
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using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801160
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801160
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10.1002/ejoc.201801160
European Journal of Organic Chemistry
FULL PAPER
Ring-Closing Strategy Utilizing Nitrile α-Anions: Chiral Synthesis
of (+)-Norchrysanthemic Acid and Expeditious Asymmetric Total
Synthesis of (+)-Grandisol
Tetsuya Fujiwara,[a] Tomohito Okabayashi,[a] Yuji Takahama,[a] Noritada Matsuo,[a] Yoo Tanabe*[a]
position of carbonyl compounds (aldehydes, ketones, esters,
Abstract: Chiral syntheses of two distinct small cycloalkanes,
(1R,3R)-(1Z)-norchrysanthemic acid and (+)-grandisol, were
performed by characteristic ring-closing methodologies using
carbanions at the α-position of nitriles (nitrile α-anions).
amides, and their derivatives) (pKa = ca. 19~30), however, less
attention has been focused on nitrile α-anions (pKa = ca. 31~32).
Moreover, limited effort has been invested in an enantioselective
version with nitrile α-anions.[5] Our object in this report is a
couple of chiral syntheses of small cycloalkanes utilizing
characteristic properties of nitrile α-anions as the key strategy.
Chiral chrysanthemic acid (1a)[6] and grandisol (2)[7] are well-
recognized natural products with the smallest three- and four-
membered ring carbocycles, respectively, highlighted in organic
chemistry textbooks and encyclopedias (Figure 1).[8] 1a is the
primary acid ingredient of natural pyrethroid insecticides and (+)-
2 is an insect sex pheromone of the cotton boll weevil.
(i) (1R,3R)-(1Z)-Norchrysanthemic acid, a highly potent ingredient of
synthetic pyrethroid containing
a cyclopropane structure, was
synthesized from readily available (S)-epoxide derived from 3-
methyl-but-2-en-1-ol in 7 steps in 23% overall yield and with >98%
ee.
This sequence involves a trans-selective cyclopropane
formation using the nitrile α-anion of (S)-3-mesyloxynitrile as the key
step. The present chiral synthesis was performed with effective
stereocontrol of both the chirality in the 1,3-positions on the
cyclopropane and the Z-geometry of the propenyl group.
Norchrysanthemic acid (1b) (R=H) is
a potential acid
(ii) (+)-Grandisol, an insect sex pheromone possessing
a
component in metofluthrin,[9] which was recently developed as a
distinctive synthetic analogue of 1a. We first focused our
attention on a chiral synthesis of 1b, aimed at process chemistry,
which is closely connected with our longstanding interests in
synthetic chemistry for cyclopropane transformations[10] and
characteristic cyclobutane structure, was synthesized from
commercially available cyclopropyl methyl ketone (route A) or from
commercially available 3-cyanopropylzinc bromide and 1-bromo-1-
methylpropene (route B) in 10 or 8 steps in 6% or 8% overall yield
and with 80% ee. This sequence involves a Shi asymmetric
epoxidation of a trisubstituted olefin and a straightforward Stork-type
asymmetric cyclobutane formation with clean SN2 stereoinversion
using the nitrile α-anion of the chiral epoxynitrile. The present
expedient method is the second asymmetric total synthesis starting
from achiral compounds.
related studies of novel chiral pyrethroids.[11]
Next, we
envisaged a concise asymmetric total synthesis of (+)-grandisol.
Both chiral syntheses involve a common strategy, i.e. a clean
intramolecular SN2 ring-closings (A and B) based on the
distinctive properties of compact and linear nitrile α-anions
(Scheme 1).
Introduction
Carbanions at the α-position of nitriles (nitrile α-anions) serve
as useful C-C bond-forming tools in organic syntheses.[1] Due to
the feasible generation of these species using strong bases
(LDA, MHMDS, NaH, etc.), alkylation and addition reactions
using nitrile α-anions with their corresponding electrophiles are
well-recognized methodology.
Thorpe-Ziegler condensation
between nitriles [2] and conjugate addition of cyanohydrin ether
anions with enones as an umpolung methodology[3] are
representative reactions. Notable studies of the utilization of
nitrile anions are documented with regard to the stereoselective
C-C bond-forming reactions.[4]
Figure 1. Representative examples of cyclopropane and cyclobutane.
Compared with the privileged carbanion chemistry at the α-
[a]
T. Fujiwara, T. Okabayashi, Dr Y. Takahama, Dr. N. Matsuo, Prof.
Dr. Y. Tanabe
Department of Chemistry, School of Science and Technology
Kwansei Gakuin University
2-1 Gakuen, Sanda, Hyogo 669-1337 (Japan)
E-mail: tanabe@kwansei.ac.jp
HP: http://sci-tech.ksc.kwansei.ac.jp/~tanabe/index.html
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801160
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FULL PAPER
Conversion of nitrile in chiral cyclopropane (1R,3R)-7 to
carboxylic group, followed by careful Lindlar reduction within 20
min produced the desired chiral norchrysanthemic acid
[(1R,3R)-1b] in an overall 70% yield with nearly perfect Z-
selectivity.[15] The present chiral synthesis of 1b was performed
in 23% overall yield and with >98% ee through 7 steps with
effective stereocontrol both of chirality in 1,3-positions on the
cyclopropane and of Z-geometry of propenyl group.
Scheme 1. Nitrile α-anion ring-closing strategy for chiral syntheses (A) and (B).
Scheme 2. Chiral synthesis of norchrysanthemic acid (1b). [a] Propyne (7.0
eq.), nBuLi (3.5 equiv) / THF, ‒78 °C to 20 °C, 14 h, 96%; [b] TsCl (1.5 eq.),
Et3N (1.5 eq.), N-methylimidazole (0.2 equiv) / toluene, 20 °C, 1 h; [c] KCN
(3.0 equiv), TBAB (0.1 equiv) / DMSO, 60 °C, 14 h, 77% in 2 steps; [d] MsCl
(1.5 equiv), Et3N (1.5 equiv), N-methylimidazole (1.5 equiv) / toluene, 20 °C,
1.5 h; [e] NaHMDS (1.2 equiv) / THF‒CPME (1:2), ‒78 oC to 0 °C, 2 h, 53% in
2 steps with cis-7 (13%); [f] KOH (4.0 equiv) / ethylene glycol, reflux, 14 h,
79%; [g] H2, Pd/BaSO4 (1.2 equiv), quinolone (6.0 equiv) / hexane, 20 °C, 20
min, 89%.
Results and Discussion
Despite both academic and industrial demands for the
synthesis of norchrysanthemic acid (1b), only two methods have
been reported to date. (i) (+)-3-Carene, a natural chiral pool
compound, was transformed to 1b in ca. 10% overall yield with
Z:E = 90:10 in 8 steps.[9a,d,e] This method requires two
ozonolysis steps and Wittig reaction, both of which are quite
Table 1. Cyclopropane formation of nitrile α-anion of (+)-6.
undesirable for the process production.
(ii) Racemic
chrysanthemic acid [(+)-1a] was converted to (+)-1b in ca. 15%
overall yield with Z:E = 96:4 in 3 steps.[9f] This short-step
method employed TBHP/catalytic SeO2‒oxidation in ionic liquid
and decarboxylation using Cu2O/quinoline reagent.
The
method provided racemic compound (+)-1b with steps that
would be challenging to implement in an industrial setting.
Our chiral synthetic route to 1b is depicted in Scheme 1.
Readily available epoxy alcohol (S)-3 (>98% ee), which was
derived from prenyl alcohol by the standard Sharpless
asymmetric epoxidation,[12] was treated with more than two
equivalents of LiC≡CH. The desired clean SN2 epoxy-ring-
opening proceeded regioselectively to give diol (R)-4 in 96%
Entry Base
Solvent
THF
THF
THF
(2-Me)THF
CPME[c]
THF/CPME[c] (1 / 2)
Yield / %[a]
cis / trans[b]
45 : 55
42 : 58
47 : 53
24 : 76
26 : 74
20 : 80
1
2
3
4
5
6
LDA
LiHMDS
NaHMDS
24
22
30
32
46
66
[a] From diol (±)-5. [b] Determined by 1H NMR of the crude product. [c]
yield.
Notably, the plausible but undesirable Payne
cyclopentyl methyl ether.
rearrangement of (S)-3b was completely circumvented during
the reaction.[13] Selective monotosylation of primary alcohol in
(R)-4 using TsCl/Et3N/cat. N-methylimidazole reagent,[14] and
successive cyanation (KCN/cat. TBAB) gave nitrile (S)-5.
Powerful mesylation (MsCl/Et3N/N-methylimidazole)[15] of the
tertiary alcohol (S)-5 afforded cyanated mesylate precursor (S)-6.
The key trans-selective ring-construction was examined using
(+)-6 (Table 1). Among several metal amide base and ether
solvent systems screened, NaHMDS/CPME (cyclopentyl methyl
ether)-THF (2:1) afforded the best results, producing
cyclopropane 7 in 66% yield (cis/trans = 20 : 80) from (S)-5
(entry 6). This conditions was adopted for chiral precursor (S)-6.
This trans-selectivity is probably accounted for the
thermodynamic stability.
We next envisaged another elaborated strategy for clean SN2
inversion of nitrile α-anions aimed at expeditious asymmetric
total synthesis of (+)-grandisol 2. Chiral synthesis of (+)-2 has
received considerable attention because of its simple but unique
cyclobutane
structure
possessing
condensed
methyl,
hydroxyethyl, and isopropenyl groups. A literature survey for the
chiral total syntheses of (+)-2 revealed 13 examples, categorized
into (i) standard optical resolution and kinetic resolution
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10.1002/ejoc.201801160
European Journal of Organic Chemistry
FULL PAPER
methods,[16-19] (ii) transformations of natural and unnatural chiral
pools,[20-27] and (iii) utilization of catalytic asymmetric
cycloaddition starting from achiral olefins.[28]
Our retrosynthetic strategy for (+)-2 is illustrated in Scheme 3.
The key feature involves (i) cyclobutane formation using chiral
epoxide 17 by a revised Stork’s racemic total synthesis of (+)-
2,[29] (ii) Shi’s asymmetric epoxidation of olefin intermediate 15,
and (iii) alternative syntheses of nitrile 11 (Routes A and B).
Scheme 4. Synthesis of key chiral epoxide 17. [a] MeMgI (1.1 eq.) / Et2O, 0
oC, 1 h, 20 oC, 1 h. Work up with 30% H2SO4 aq., 84%; [b] DBU (2.0 eq.) /
toluene, 80 oC, 1 h, 78%; [c] NaCl / DMSO, 150 oC, 4 h, 86%; [d] Pd(PPh)4 (1
mol%) / THF, 50 oC, 3 h, 86%; [e] LDA (1.1 eq.) / THF-HPMA (5:1), ‒78 oC, 0.5
h, 20 oC, 14 h, 58% with 15’ (20%); [f] 16 (30 mol%), Oxone (1.38 eq.), K2CO3
(5.8 eq.), Bu4NHSO4 (4 mol%), / MeCN‒DMM (1 / 2), 0 - 5 oC, 1.5 h, 96%; [g]
cat. PPTS (0.1 eq.) / MeOH 20 oC, 1 h, PhCOCl, DMAP (0.1 eq.) / pyridine, 20
oC, 14 h, 47%.
Scheme 3. Retrosynthetic pathway for grandisol (+)-(2).
The crucial cyclobutane formation using nitrile α-anion
generated from (+)-17 was investigated (Table 2). Among
several base reagents and conditions screened, the reaction of
(+)-17 with LiHMDS at 60 oC in toluene solvent successfully
afforded the desired cyclobutane (+)-19 with its diastereomer
(+)-19’ in 83% yield (dr = ca. 6:4) (entry 1).[34,35] Slightly inferior
results were obtained when using a TMEDA additive and using
NaHMDS and KHMDS bases (entries 2, 4, 5).
Scheme 4 depicts the synthetic route to the key chiral epoxide
precursor 17. Grignard reaction of MeMgI with commercially
available cyclopropyl methyl ketone 8, followed by treatment
with H2SO4/H2O gave homoallyl iodide 9 via a Juria-type
cyclopropane-cleavage.[30] Alkylation of ethyl cyanoacetate with
9 and successive Krapcho decarboxylation[31] afforded olefinic
nitrile 11[32] in 67% overall yield (Route A). Notably, Negishi
cross-coupling using commercially available Zn reagent 12 with
vinyl bromide 13 directly produced 11 in 86% yield (Route B).
Monoalkylation of 11 with THP-protected bromide 14 gave nitrile
15 with a small amount of dialkylated byproduct 15’, which was
Table 2. Cyclobutane formation of nitrile α-anion of (+)-17.
easily removed by column chromatography.
15 was
successfully converted to the chiral epoxide (R)-17 by Shi’s
asymmetric epoxidation[33] using the mannitol-derived catalyst 16
in 96% yield with ca. 80% ee. To accurately determine the
enantioselectivity, (R)-17 was converted to benzoate derivative
18 in 2 steps. Fortuitously, this Shi’s standard protocol matched
for the desired “natural” grandisol (+)-2 (vide infra).
Entry Base
Solvent
toluene
Yield / %[a]
(+)-19 / (+)-19’
60 : 40
53 : 47
51 : 49
54 : 46
1
2
3
4
5
LiHMDS
83
65[b]
72
THF
toluene
NaHMDS
KHMDS
40
65
50 : 50
[a] Isolated yield. [b] 3.0 equiv of TMEDA was used.
The final stage of the asymmetric total synthesis of (+)-2 is
depicted in Scheme 5. Compared with the original Stork’s
approach[29] and Guerrero group’s extensive studies[35] using
racemic epoxynitrile substrates, the present designed route is
more straightforward, because it eliminates oxidation of the
secondary alcohol and Wittig olefination steps. In addition, Shi’s
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10.1002/ejoc.201801160
European Journal of Organic Chemistry
FULL PAPER
asymmetric epoxidation using tri-substituted olefins generally
produces higher enantioselectivity than when using di-
substituted olefins.[33] This background led us to use chiral
epoxynitrile (R)-17.
reactions. This protocol provides a new access for preparing a
useful chiral cyclopropane and cyclobutane synthons.
Cyclobutane formation using (R)-17 under the optimized
conditions in Table 2 (entry 1) afforded the desired product
(1R,2S)-19 in a total yield of 83% with the diastereomer
(1R,2R)-19’[36] with c.a. 6:4 ratio. DIBAL reduction of (1R,2S)-19
gave aldehyde (1R,2S)-20, which was subjected to Wolff-
Kishner reduction using H2NNH2/aqueous KOH to furnish
Experimental Section
General Remarks: All reactions were carried out in oven-dried
glassware under an argon atmosphere. Flash column chromatography
was performed with silica gel Merck 60 (230-400 mesh ASTM). TLC
analysis was performed on 0.25 mm Silicagel Merck 60 F254 plates.
Melting points were determined on a hot stage microscope apparatus
(AS ONE, ATM-01) and were uncorrected. NMR spectra were recorded
on a JEOL DELTA 300 or JEOLRESONANCE ECX-500 spectrometer,
cyclobutane (1R,2S)-21 in 73% yield in
2
steps.[29,37]
Dehydration of (1R,2S)-21 using SOCl2/pyridine afforded key
precursor (1R,2S)-22 with a minor byproduct 22’ in a total yield
of 75%. Deprotection of the THP group using Dowex 50Wx8[38]
gave the desired crude (+)-grandisol 2, which was purified by p-
nitrobenzoylation and a deprotection sequence to remove
alcohol derived from 22’. Eventually, (+)-grandisol 2 was
synthesized in 40% yield from (1R,2S)-21 (80% ee based on
the PNB ester). The present work is the second example of
catalytic asymmetric synthesis in 10 steps (Route A) or 8 steps
(Route B) in total 6% or 8% overall yield with 80% ee.
Compared with the first method requiring 17 steps,[28] the
present synthesis is expeditious.
1
operating at 300 MHz or 500 MHz for H NMR and 75 MHz or 120 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. IR
Spectra were recorded on a JASCO FT/IR-5300 spectrophotometer.
Mass spectra were measured on a JEOL JMS-T100LC spectrometer.
HPLC data were obtained on a SHIMADZU HPLC system (consisting of
the following: SLC-10A, DGU-4A, LC-10AD, SIL-10A, CTO-10A and
detector SPD-10AV measured at 254 nm) using DAISEL Chiracel OD-H
column (25 cm) at 30 ˚C.
(S)-(3,3-dimethyloxiran-2-yl)methanol (2)
LiOH (1.33 g, 55.5 mmol) in H2O (40 mL) was added to a
stirred suspension of ester (1; >98% ee, 9.28 g, 37 mmol)
in THF (55 mL) at 0 – 5 ºC under an Ar atmosphere,
followed by being stirred at the same temperature for 0.5 h. The solution
was diluted with Et2O (90 mL) and CH2Cl2 (180 mL). Na2SO4 (45 g) was
added to the stirred mixture, followed by being stirred at the same
temperature for 20 min. The mixture was filtered and the filtrate was
concentrated under reduced pressure. The obtained crude oil was
purified by distillation to give the desired product (3.06 g, 81%).colorless
25
oil; bp 175 – 180 ºC / 2.9 kPa. [α]D –9.1 (c 1.0, CHCl3); 1H NMR (400
MHz, CDCl3): δ = 1.31 (s, 3H), 1.35 (s, 3H), 1.71 (br s, 1H), 2.99 (dd, J =
4.0 Hz, 6.9 Hz, 1H), 3.69 (dd, J = 6.9 Hz, Jgem = 12.0 Hz, 1H), 3.85 (dd,
J = 4.0 Hz, Jgem = 12.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 18.8,
24.8, 58.9, 61.4, 63.8; IR (neat): νmax = 3391, 2970, 2930, 1456, 1379,
1252, 1096, 1030, 856 cm-1.
(R)-3-methyl-2-(prop-1-yn-1-yl)butane-1,3-diol (3)
nBuLi (1.63 M in hexane, 65.0 mL, 106 mmol) was
added to a stirred solution of propyne (8.47 g, 211
mmol) in THF (80 mL) at -78 ºC under an Ar
atmosphere, followed by being stirred at the same
temperature for 0.5 h. (S)-epoxide (2; 3.08 g, 30.2
Scheme 5. Asymmetric total synthesis of (+)-grandisol (2). [a] LiHMDS (3.0
eq.) / toluene, 60 oC, 0.5 h, 83%. dr = 6 : 4; [b] DIBAL (4.0 eq.) / toluene, 0 oC
to 20 oC, 6 h; [c] H2NNH2 / H2O (3.0 eq.), KOH (4.5 eq.) / diethyleneglycol 200
oC, 3 h, 73% in 2 steps; [d] SOCl2 (1.2 eq.) / pyridine, 0 oC, 2 h, 75%; [e]
Dowex 50Wx8 / MeOH, 20 oC, 14 h; [f] PNBCl (1.5 eq.), Py (2.0 eq.), DMAP
(0.1 eq.) / CH2Cl2, 20 oC, 1 h. [g] LiOH (2.0 eq.) / THF‒H2O (1.5:1), 20 oC, 14
h.
mmol) in THF (10 mL) was added slowly to the mixture at the same
temperature, which was stirred for 0.5 h. The mixture was allowed to
warm up to 20 – 25 ºC, and stirred for 14 h. The mixture was quenched
with water, which was extracted three times with Et2O (50 mL × 3). The
combined organic phase was washed with brine, dried (Na2SO4) and
concentrated. The obtained crude oil was purified by SiO2-gel column
chromatography (hexane-Et2O = 3 : 1) to give the desired product (4.12 g,
96%).
Conclusion
pale yellow oil; [α]D25 +9.2 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ =
1.33 (s, 6H), 1.76 (br s, 1H), 1.85 (d, J = 3.0 Hz, 3H), 1.94 (br s, 2H),
3.76–3.85 (m, 2H); 13C NMR (100 MHz, CDCl3): δ = 3.5, 26.5, 28.5, 45.5
63.3, 73.0, 76.7, 80.3; IR (neat): νmax = 3333, 2972, 2922, 2886, 1377,
1364, 1173, 1148, 1063, 1028 cm-1; HRMS (ESI): m/z calcd for C8H14O2
[M + Na]+ 165.0891; found: 165.0896.
We achieved a couple of chiral syntheses of (1R,3R)-
norchrysanthemic acid and an expedient asymmetric total
synthesis of (+)-grandisol, both utilizing distinctive ring-closing
methodologies with nitrile -anions. The present small-ring
formation involves different types of clean intramolecular SN2
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10.1002/ejoc.201801160
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FULL PAPER
Determination of ee 3 by the derivatization to (R)-2-(2-
By-product: colorless oil; 1H NMR (400 MHz; CDCl3): δ = 1.42 (s, 6H),
hydroxypropan-2-yl)pent-3-yn-1-yl benzoate
1.69 (br s, 1H), 1.98 (s, 3H), 5.31 (s, 1H), 5.46 (s, 1H).
PhCOCl (93 mg, 0.66 mmol) was added to a stirred
solution of (R)-1,3-diol (3; 63 mg, 0.44 mmol), pyridine
(70 mg, 0.88 mmol), DMAP (5 mg, 0.044mmol) in
(1R,3R)-2,2-dimethyl-3-(prop-1-yn-1-yl)cyclopropane-1-carbonitrile
(7)
CH2Cl2 (1.0 mL) at 0 – 5 ºC under an Ar atmosphere,
A solution of MsCl (2.00 g, 17.4 mmol) in toluene (10
followed by being stirred at 20 – 25 ºC for 1 h. The
mL) was added to a stirred suspension of (S)-nitrile (5;
mixture was quenched with water, which was extracted twice with CH2Cl2.
The combined organic phase was washed with sat. NaHCO3 aq., water,
brine, dried (Na2SO4) and concentrated. The obtained crude oil was was
purified by SiO2-gel column chromatography (hexane-AcOEt = 15 : 1 –
10 : 1) to give the desired benzoate (87 mg, 80%).
1.76 g, 11.6 mmol), N-methylimidazole (1.43 g, 17.4
mmol), and Et3N (1.77 mg, 17.4 mmol) in toluene (25
mL) at 20 – 25 ºC under an Ar atmosphere, followed by being stirred for
at the same temperature for 1.5 h. The mixture was quenched with 1M-
HCl aqueous solution, which was extracted twice with AcOEt. The
combined organic phase was washed with brine, dried (Na2SO4) and
concentrated. The obtained crude mesylate (6; 2.40 g) was used for the
next step without purification.
Mesylate (6; 2.40 g) in CPME/THF (2 : 1, 10 mL) was added to a
stirred solution of NaHMDS (0.6 M in toluene, 21 mL, 12.6 mmol) in
CPME/THF (2 : 1, 96 mL) at –78 ºC under an Ar atmosphere, followed by
being stirred at the same temperature for 0.5 h. The mixture was allowed
to warm to 0 – 5 ºC, and was stirred for 2 h. The mixture was reversely
quenched with water, which was extracted twice with Et2O. The
combined organic phase was washed with brine, dried (Na2SO4) and
concentrated. The obtained crude oil was purified by SiO2-gelcolumn
chromatography (hexane-Et2O = 100 : 1) to give the desired product (812
mg, 53% for 2 steps).
1
colorless oil; [α]D25 +70.9 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3): δ =
1.36 (s, 3H), 1.37 (s, 3H), 1.83 (d, J = 2.3 Hz, 3H), 2.87–2.92 (m, 1H),
4.39 (dd, J = 7.8 Hz, Jgem = 10.8 Hz, 1H), 4.51 (dd, J = 6.0 Hz, Jgem =
10.8 Hz, 1H), 7.42–7.47 (m, 1H), 7.54–7.58 (m, 1H), 8.03–8.07 (m, 2H);
13C NMR (100 MHz, CDCl3): δ = 3.5, 27.2, 27.6, 44.0, 64.8, 71.5, 80.5,
128.4, 129.6, 130.1, 133.0, 166.4; IR (neat): νmax = 3485, 3067, 2974,
2920, 1717, 1450, 1377, 1273, 1129, 708 cm-1; HRMS (ESI): m/z calcd
for C15H18O3 [M + Na]+ 269.1152; found: 269.1154. >99% ee; HPLC
analysis (AD-H, flow rate 1.00 ml/min, solvent: hexane/2-propanol = 20/1)
tR(racemic) = 14.42 min and 16.60 min. tR[(R)-form] = 16.82 min.
(R)-2-(2-hydroxypropan-2-yl)pent-3-yn-1-yl
4-
methylbenzenesulfonate (4)
1
A solution of TsCl (6.45 g, 33.9 mmol) in toluene (10
mL) was added to a stirred solution of (R)-1,3-diol (3;
3.22 g, 22.6 mmol), N-methylimidazole (371 mg, 4.52
trans-7: H NMR (400 MHz, CDCl3): δ = 1.68 (s, 3H), 1.82 (s, 3H), 1.85
(d, J = 2.3 Hz, 3H), 2.59 (dd, J = 8.2 Hz, Jgem = 16.5 Hz, 1H), 2.75 (dd, J
= 5.0 Hz, Jgem = 16.5 Hz, 1H), 3.05 (s, 3H), 3.16–3.21 (m, 1H).
25
mmol), and Et3N (3.43 g, 33.9 mmol) in toluene (55 mL)
cis-7: pale yellow oil; [α]D +180.2 (c 1.0, CHCl3); 1H NMR (400 MHz,
at 20 – 25 ºC under an Ar atmosphere, followed by
CDCl3): δ = 1.26 (s, 3H), 1.29 (d, J = 5.2 Hz, 1H), 1.32 (s, 3H), 1.71–1.73
(m, 1H), 1.80 (d, J = 2.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 3.5,
18.4, 20.9, 22.3, 23.3, 26.0, 74.8, 77.5, 119.1; IR (neat): νmax = 2963,
2922, 2234, 1454, 1381, 1269, 1119, 1053, 1028 cm-1; HRMS (ESI): m/z
calcd for C9H11N [M + Na]+ 156.0789; found: 156.0786.
being stirred at the same temperature for 1 h. The mixture was
quenched with water, which was extracted twice with AcOEt. The
combined organic phase was washed with water, brine, dried (Na2SO4)
and concentrated. The obtained crude oil was purified by SiO2-gel
column chromatography (hexane-AcOEt = 15 : 1 - 3 :1) to give the
desired product (6.43 g, 96%).
(1R,3R)-2,2-dimethyl-3-(prop-1-yn-1-yl)cyclopropane-1-carboxylic
acid (8)[15]
1
white crystals; mp 78 – 80 ºC. [α]D25 +21.8 (c 1.0, CHCl3); H NMR (400
MHz, CDCl3): δ = 1.24 (s, 3H), 1.26 (s, 3H), 1.64 (br s, 1H), 1.77 (d, J =
2.3 Hz, 3H), 2.46 (s, 3H), 2.69–2.74 (m, 1H), 4.06 (dd, J = 7.8 Hz, Jgem
= 9.6 Hz, 1H), 4.23 (dd, J = 6.0 Hz, Jgem = 9.6 Hz, 1H), 7.33–7.37 (m,
2H), 7.79–7.83 (m, 2H); 13C NMR (100 MHz, CDCl3): δ = 3.5, 21.6, 27.3,
27.4, 44.0, 69.8, 71.3, 75.4, 76.7, 80.9, 128.0, 129.8, 132.9, 144.9; IR
(neat): νmax = 3543, 2984, 2926, 1597, 1331, 1169, 1119, 1096, 951, 816
cm-1; HRMS (ESI): m/z calcd for C15H20O4S [M + Na]+ 319.0980; found:
319.0984.
A suspension of (1R,3R)-nitrile (7; 212 mg, 1.59
mmol) and KOH (256 mg, 6.36 mmol) in
ethyleneglycol (3.0 mL), which was stirred at reflux
for 14 h. The mixture was cooled to 20 – 25 ºC and
was extracted twice with Et2O. Separated ethyleneglycol layer was
acidified using 1M-HCl aq. solution, which was re-extracted twice with
Et2O. The combined organic phase was washed with water, brine, dried
(Na2SO4) and concentrated. The obtained crude oil was purified by SiO2-
gelcolumn chromatography (hexane-Et2O = 10 : 1 – 5 : 1) to give the
desired product (190 mg, 79%).
(S)-3-(2-Hydroxypropan-2-yl)hex-4-ynenitrile (5)
25
A solution of (R)-p-toluenesulfonate (4; 3.49 g, 11.8
white crystal; mp 108 – 110 ºC; [α]D +93.0 (c, CHCl3); 1H NMR (400
mmol) in DMSO (10 mL) was added to stirred
suspension of KCN (2.30 g, 35.4 mmol) and Bu4NBr
(TBAB, 380 mg, 1.2 mmol) in DMSO (25 mL) at 20 – 25
ºC under an Ar atmosphere, followed by being stirred at
MHz, CDCl3): δ = 1.25 (s, 3H), 1.29 (s, 3H), 1.62 (d, J = 5.0 Hz, 1H), 1.80
(d, J = 1.8 Hz, 3H), 1.91–1.93 (m, 1H); 13C NMR (100 MHz, CDCl3): δ =
3.5, 19.1, 23.0, 23.6, 29.7, 34.6, 76.1, 76.4, 177.5; IR (neat): νmax = 2961,
2922, 2610, 1682, 1443, 1333, 1288, 1244, 1202, 1111, 947 cm-1.
60 – 65 ºC for 14 h. The mixture was quenched with sat. NaHCO3 aq.,
which was extracted twice with Et2O. The combined organic phase was
washed with water, brine, dried (Na2SO4) and concentrated. The
obtained crude oil was purified by SiO2-gelcolumn chromatography
(hexane-AcOEt = 9 : 1) to give the desired product (1.43 g, 80%) and 2-
methyl-3-methylenehex-4-yn-2-ol as a by-product (147 mg, 10%).
(1R,3R)-2,2-dimethyl-3-((Z)-prop-1-enyl)cyclopropanecarboxylic acid
(1b)[15]
A suspension of (1R,3R)-carboxylic acid (8; 23 mg,
0.15 mmol), 5% Pd-BaSO4 (16 mg, 7.5 μmol), and
quinoline (116 mg, 0.09 mmol) in hexane (1.5 ml),
equipped with a H2 balloon, was stirred stirred at 20 –
1
5 : pale yellow oil; [α]D25 +89.7 (c, CHCl3); H NMR (400 MHz, CDCl3): δ
= 1.32 (s, 6H), 1.62 (br s, 1H), 1.87 (d, J = 2.3 Hz, 3H), 2.48–2.57 (m,
1H), 2.66–2.76 (m, 2H); 13C NMR (100 MHz, CDCl3): δ = 3.5, 19.2, 26.4,
27.5, 41.3, 71.6, 76.1, 81.6, 118.9; IR (neat): νmax = 3460, 2976, 2922,
2855, 2253, 1732, 1377, 1261, 1148 cm-1; HRMS (ESI): m/z calcd for
C9H13NO [M + Na]+ 174.0896; found: 174.0895.
25 ºC for 20 min. The mixture was filtered through Celite® (No.503) with
glass filter washing by Et2O, and the filtrate was concentrated under
reduced pressure. The residue was diluted with Et2O, which was washed
with 1M-NaOH aq. solution and the separated aqueous phase was
acidified using 1M-HCl aq. solution. The obatained mixture was re-
extracted twice with Et2O. The combined organic phase was washed
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801160
European Journal of Organic Chemistry
FULL PAPER
with water, brine, dried (Na2SO4) and concentrated. The obtained crude
oil was purified by SiO2-gelcolumn chromatography (hexane-Et2O = 40 :
1) to give the desired product (21 mg, 89%).
with water, brine, dried (Na2SO4) and concentrated. The obtained crude
oil was purified by SiO2–column chromatography (hexane/Et2O = 20 : 1)
to give the desired product 11 (212 mg, 86%).
pale yellow oil; [α]D +8.3 (c, CHCl3); 1H NMR (400 MHz, CDCl3): δ =
colorless oil; bp 85 – 92 ºC / 3.4 kPa; 1H NMR (500 MHz, CDCl3): δ =
1.63 (s, 3H), 1.71 (s, 3H), 1.67–1.73 (m, 2H), 2.15 (q, J = 7.5 Hz, 14.3 Hz,
2H), 2.32 (t, J = 7.5 Hz, 2H), 5.01 (t, J = 7.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ = 16.4, 17.8, 25.5, 25.7, 26.8, 119.9, 121.8, 134.1; IR (neat):
νmax = 2932, 2247, 1674, 1450, 1377, 1225, 1109, 986, 853, 731 cm-1.
25
1.17 (s, 3H), 1.25 (br s, 1H), 1.32 (s, 3H), 1.47 (d, 1H, J = 5.5 Hz), 1.71
(dd, J = 1.4 Hz, Jgem = 6.9 Hz, 3H), 2.20 (dd, J = 5.5 Hz, Jgem = 7.8 Hz,
1H), 5.10–5.17 (m, 1H), 5.57–5.65 (m, 1H); 13C NMR (100 MHz, CDCl3):
δ = 13.4, 20.4, 22.2, 29.8, 32.5, 34.6, 126.7, 127.4, 178.3; IR (neat): νmax
= 3024, 2924, 1688, 1449, 1416 cm-1.
6-Methyl-2-[2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl]hept-5-enenitrile
(15)
5-Iodo-2-methylpent-2-ene (9)[39]
Following the reported procedure[39]; MeI (15.0 mL, 0.24
mol) in Et2O (100 mL) was added to
a
stirred
nBuLi (1.63 M in hexane, 88 mL,
143 mmol) was added to stirred
solution of iPr2NH (14.5 g, 143
mmol) in THF/HMPA (5:1, 168
mL) at 0 – 5 ºC under an Ar
suspension of granular Mg (5.84 g, 0.24 mol) and cat. I2
at 20 – 25 ºC under an Ar atmosphere, and the mixture was stirred at 20–
25 oC for 0.5 h. After cooling down to 0 – 5 oC, cyclopropyl methyl
ketone (16.8 g, 0.20 mol) in THF (100 mL) was added to the mixture at
the same temperature. After stirring at 20 – 25oC for 1 h, the mixture was
poured into ice-cooled 30% H2SO4 aq. (100 mL) with vigourously stiiring
for 1 h. The resulting mixture was extracted twice with Et2O and
combined organic phase was washed with water, brine, dried (Na2SO4)
and concentrated. The obtained crude oil was purified by distillation to
give the desired product 9 (35.3 g, 84%).
atmosphere, followed by being stirred for 15 min. The mixture was
cooled down to −78 oC and nitrile 11 (16.0 g, 130 mmol) in THF/HMPA
(5:1, 30 mL) was added to the mixture at the same temperature. After
stirring for 0.5 h, 2-bromoethanol tetrahydropyranyl ether (14; 32.6 g, 156
mmol) in THF/HMPA (5:1, 30 mL) was added to the mixture. The mixture
was stirred at the same temperature for 0.5 h and was allowed to warm
up to 20 – 25 oC, followed by being stirred for 14 h. The mixtre was
poured onto ice-cooled sat. NH4Cl aq. solution, which was extracted
twice with Et2O. The combined organic phase was washed with a large
amounts of water to remove HMPA, brine, dried (Na2SO4), and
concentrated. The obtained crude oil was purified by SiO2–column
chromatography (hexane-AcOEt = 20 : 1) to give the desired product 15
(19.0 g, 58%) with dialkylated byproduct 15’ (9.9 g, 20%).
1
purple coloured oil; bp 50 – 52 ºC / 3.0 kPa; H NMR (500 MHz, CDCl3):
δ = 1.62 (s, 3H), 1.70 (s, 3H), 2.57 (q, J = 7.5 Hz, 14.9 Hz, 2H), 3.11 (t, J
= 7.5 Hz, 2H), 5.07–5.12 (m, 1H); 13C NMR (125 MHz, CDCl3): δ = 6.0,
17.9, 25.6, 32.4, 123.0, 134.3; IR (neat): νmax = 2967, 2913, 1423, 1375,
1248, 1209, 1165, 982, 831 cm-1.
Ethyl 2-cyano-6-methylhept-5-enoate (10)
15: colorless oil; 1H NMR (500 MHz, CDCl3): δ = 1.49–1.90 (m, 10H),
1.64 (s, 3H), 1.70 (s, 3H), 2.14–2.25 (m, 2H), 2.77–2.85 (m, 1H), 3.49–
3.57 (m, 2H), 3.82–3.94 (m, 2H), 4.58–4.62 (m, 1H), 5.07 (t, J = 7.5 Hz,
1H); 13C NMR (75 MHz, CDCl3): δ = 17.8, 19.3, 19.6, 25.4, 25.55, 25.58,
25.7, 27.9, 28.0, 30.5, 30.6, 32.3, 32.4, 62.1, 62.6, 64.1, 64.4, 98.6, 99.4,
122.0, 122.2, 133.57, 133.62; IR (neat): νmax = 2938, 2868, 2237, 1738,
1454, 1377, 1354, 1136, 1123, 1034, 980 cm-1; HRMS (ESI): m/z calcd
for C15H25NO2 [M + Na]+ 274.1783; found: 274.1786.
15’ : 1H NMR (500 MHz, CDCl3): δ = 1.50–1.85 (m, 18H), 1.63 (s, 3H),
1.69 (s, 3H), 1.92–2.01 (m, 4H), 2.15 (q, J = 7.5 Hz, 16.6 Hz, 2H), 3.50–
3.60 (m, 4H), 3.80–3.99 (m, 4H), 4.60 (t, J = 3.4 Hz, 2H), 5.07 (t, J = 7.5
Hz, 1H).
Ethyl cyanoacetate (37.3 g, 0.33 mol) in toluene (80
mL) and iodide 9 (34.6 g, 165 mmol) in toluene (80
mL) were successively added to a stirred solution of
DBU (50.2 g, 0.33 mol) in toluene (165 mL) at 0 – 5
ºC under an Ar atmosphere, followed by being stirred at 80 - 85 oC for 1 h.
The resulting mixture was quenched with water, which was extracted
twice with Et2O. The combined organic phase was washed with 1M-HCl
aq., brine, dried (Na2SO4), and concentrated. The obtained crude oil was
purified by SiO2–column chromatography (hexane/AcOEt = 20 : 1) to give
the desired product 10 (25.1 g, 84%).
colorless oil; 1H NMR (500 MHz, CDCl3): δ = 1.33 (t, 3H, J = 6.9 Hz),
1.64 (s, 3H), 1.71 (s, 3H), 1.99 (q, J = 7.5 Hz, 14.9 Hz, 2H), 2.22 (q, J =
7.5 Hz, 14.9 Hz, 2H), 3.49 (t, J = 6.9 Hz, 1H), 4.26 (q, J = 6.9 Hz, 14.3 Hz,
2H), 5.03–5.08 (m, 1H); 13C NMR (125 MHz, CDCl3): δ = 14.0, 17.7, 25.1,
25.7, 29.9, 36.8, 62.7, 116.6, 121.1, 134.8, 166.3; IR (neat): νmax = 2933,
1742, 1447, 1369, 1254, 1192, 1109, 1022, 854 cm-1; HRMS (ESI): m/z
calcd for C11H17NO2 [M + Na]+ 218.1157; found: 218.1167.
4-(3,3-Dimethyloxiran-2-yl)-2-[2-((tetrahydro-2H-pyran-2-
yl)oxy)ethyl]butanenitrile [(±)-17]
mCPBA (4.66 g, 27 mmol) in CH2Cl2 (30 mL) was
added to a stirred solution of nitrile 15 (3.77 g, 15
mmol) in CH2Cl2 (15 mL) at 0 – 5 ºC under an Ar
atmosphere, and the mixture was stirred at 20 – 25
6-Methylhept-5-enenitrile (11)[32]
(i) Krapco decarboxylation method; A suspension of
nitrile 10 (30.0 g, 154 mmol), NaCl (27.0 g, 0.46 mol),
and water (8.33 g, 0.46 mol) in DMSO (300 mL) was
ºC for 14 h. The mixture was quenched with water, which was extracted
twice with CH2Cl2. The combined organic phase was washed with sat.
NaHCO3 aq., brine, dried (Na2SO4) and concentrated. The obtained
crude oil was purified by SiO2–column chromatography (hexane/AcOEt =
8:1 – 2:1) to give the desired product (±)-17 (3.85 g, 96%).
colorless oil; 1H NMR (500 MHz, CDCl3): δ = 1.30 (s, 3H), 1.33 (s, 3H),
1.50–1.63 (m, 5H), 1.68–1.93 (m, 7H), 2.72–2.75 (m, 1H), 2.84–2.94 (m,
1H), 3.50–3.57 (m, 2H), 3.82–3.95 (m, 2H), 4.58–4.62 (m, 1H).
stirred stirred at 150 – 155 ºC for 4 h. The resulting mixture was
quenched with water, which was extracted twice with Et2O. The
combined organic phase was washed with a large amounts of water to
remove DMSO, brine, dried (Na2SO4) and concentrated. The obtained
crude oil was purified by distillation to give the desired product 11 (16.4 g,
86%).
(ii) Negishi cross-coupling method; 3-Cyanopropylzinc bromide (12; 0.5
M solution in THF, 5.6 mL, 2.8 mmol, commercially available) was added
to a stirred suspension of 1-bromo-2-methylprop-1-ene (13; 276 mg, 2.0
mmol) and Pd(PPh3)4 (23 mg, 20 μmol) in THF (4.0 mL) at 20 – 25 ºC
under an Ar atmosphere, and the mixture was stirred at 50 – 55 oC for 3
h. The resulting mixture was quenched with 1M-HCl aq., which was
extracted twice with Et2O. The combined organic phase was washed
4-[(R)-3,3-Dimethyloxiran-2-yl]-2-[2-((tetrahydro-2H-pyran-2-
yl)oxy)ethyl]butanenitrile (17)
Oxone® (10.18 g, 16.6 mmol) in Na2[EDTA] aq. (4.0
× 10–4 M, 78 mL) and K2CO3 (9.62 g, 69.6 mmol) in
water (78 mL) were simultaneously and
proportionally added dropwise to
a
stirred
suspension of nitrile 15 (3.02 g, 12.0 mmol),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801160
European Journal of Organic Chemistry
FULL PAPER
mannitol–derived ketone 16 (930 mg, 3.6 mmol), and Bu4NHSO4 (163
mg, 0.48 mmol) in MeCN (60 mL), dimethoxymethane (120 mL) and
buffer (0.05 M solution of Na2B4O7・10H2O in 4.0 × 10–4 M Na2[EDTA]
aq., 120 mL) at 0 – 5 ºC over a period of 1.5 h under an Ar atmosphere.
The resulting mixture was quenched with water, which was extracted
twice with AcOEt. 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 – 2:1) to
give the desired product 17 (3.08 g, 96%; c.a. 80% ee determined by
derivative 18).
min and 23.46 min and 25.01 min. tR[(6R)–form] = 23.80 min. tR[(6S)–
form] = 25.25 min.
2-[(2S)-2-Isocyano-2-[2-((tetrahydro-2H-pyran-2-
yl)oxy)ethyl)cyclobutyl]propan-2-ol (19), (19’)
(R)–Epoxynitrile 17 (3.58 g, 13.4 mmol) in toluene (30
mL) was added to a stirred solution of LiHMDS (1.0 M
in toluene, 40 mL, 40.2 mmol) in toluene (240 mL) at 20
– 25 ºC under an Ar atmosphere, and the mixture was
stirred at 60 – 65 oC for 0.5 h. After cooling down to 0 –
5
oC, the mixture was quenched with 0.5 M–HCl aq. solution and was
extracted twice 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 = 20 :
1) to give the desired product 19 and 19’(dr 60 : 40, 2.97 g, 83%).
pale yellow oil; 1H NMR (500 MHz, CDCl3): δ = 1.12 (s, 3H x 40/100),
1.13 (s, 3H x 60/100), 1.35 (s, 3H x 40/100), 1.36 (s, 3H x 60/100), 1.51–
1.95 (m, 8H), 2.08–2.41 (m, 5H), 2.69–2.74 (m, 1H), 3.50 (m, 2H), 3.83–
4.05 (m, 2H), 4.61–4.64 (m, 1H); 13C NMR (125 MHz, CDCl3): δ = 18.9,
19.0, 19.27, 19.32, 25.3, 25.4, 27.5, 28.6, 28.8, 28.9, 29.1, 30.4, 30.5,
30.6, 30.8, 36.36, 36.39, 52.8, 62.1, 62.2, 64.6, 64.5, 71.0, 71.1, 98.9,
99.0, 124.1, 124.2; HRMS (ESI): m/z calcd for C15H25NO3 [M + Na]+
290.1732; found: 290.1726.
colorless oil; 1H NMR (500 MHz, CDCl3): δ = 1.30 (s, 3H), 1.33 (s, 3H),
1.50–1.63 (m, 5H), 1.68–1.93 (m, 7H), 2.72–2.75 (m, 1H), 2.84–2.94 (m,
1H), 3.50–3.57 (m, 2H), 3.82–3.95 (m, 2H), 4.58–4.62 (m, 1H); 13C NMR
(125 MHz, CDCl3): δ = 18.70, 18.75, 19.30, 19.34, 19.61, 19.65, 24.7,
25.3, 26.1, 26.2, 26.8, 28.1, 28.2, 28.65, 28.73, 28.9, 29.0, 29.5, 29.6,
30.45, 30.53, 32.3, 32.4, 32.6, 32.7, 58.3, 58.5, 62.1, 62.2, 62.6, 62.7,
63.0, 63.4, 63.5, 63.9, 64.0, 64.3, 98.6, 98.7, 99.41, 99.43, 121.5, 121.6;
IR (neat): νmax = 2941, 2237, 1454, 1200, 1123, 1076, 1033, 978, 870,
813 cm-1; HRMS (ESI): m/z calcd for C15H25NO3 [M + Na]+ 290.1732;
found: 290.1732.
(1S)-2-(2-Hydroxypropan-2-yl)-1-[2-((tetrahydro-2H-pyran-2-
yl)oxy)ethyl]cyclobutane-1-carbaldehyde (20)
DIBAL (1.0 M in toluene, 38 mL, 38 mmol) was added
to a stirred solution of nitrile 1.2–7 (2.53 g, 9.5 mmol) in
toluene (28 mL) at 0 – 5 ºC under an Ar atmosphere,
and the mixture was stirred for 6 h at 20 – 25oC. The
(6R)-3-Cyano-7-methoxy-7-methyloctane-1,6-diyl dibenzoate (18)
A suspension of (R)–epoxynitrile 17 (134 mg, 0.50
resulting mixture was quenched with sat. sodium
potassium tartaric acid aq. solution (40 mL), which was extracted twice
with AcOEt. The combined organic phase was washed with water, brine,
dried (Na2SO4) and concentrated. The obtained product 20 (1.91 g) was
used without purification for next steps.
mmol) and PPTS (13 mg, 50 μmol) in MeOH (1.0
mL) was stirred at 20 – 25oC for 14 h. The mixture
was quenched with water, which was extracted
twice with AcOEt. The combined organic phase
colorless oil; 1H NMR (500 MHz, CDCl3): δ = 1.12 (s, 3H), 1.25 (s, 3H),
1.35–1.86 (m, 9H), 2.03–2.14 (m, 1H), 2.27–2.38 (m, 2H), 2.41–2.49 (m,
2H), 3.27–3.52 (m, 2H), 3.60–3.91 (m, 2H), 4.44 (s, 1H x 40/100), 4.58 (s,
1H x 60/100), 9.58 (s, 1H x 40/100), 9.61 (s, 1H x 60/100).
was washed with water, brine, dried (Na2SO4) and concentrated. The
obtained crude oil product (115 mg) was used for the next step without
purification.
PhCOCl (211 mg, 1.5 mmol) was added to a stirred solution of the
above crude product (115 mg), pyridine (119 mg, 1.5 mmol), and DMAP
(6 mg, 50 μmol) in CH2Cl2 (1.0 mL) at 0 – 5 ºC under an Ar atmosphere,
followed by being stirred at 20 – 25 ºC for 14 h. The mixture was
quenched with water, which was extracted twice with CH2Cl2. The
combined organic phase was washed with sat. NaHCO3 aq. and brine,
dried (Na2SO4) and concentrated. The obtained crude oil was was
2-[(2R)-2-methyl-2-(2-((tetrahydro-2H-pyran-2-
yl)oxy)ethyl)cyclobutyl]propan-2-ol (21)
H2NNH2•H2O (1.06 g, 21.3 mmol) was added to a
stirred solution of aldehyde 20 (1.91 g) in
diethyleneglycol (21 mL) at 20 – 25 ºC under an Ar
atmosphere. After being stirred at 200 – 205 oC for 0.5
purified by SiO2–gel column chromatography (hexane/AcOEt = 12:1
–
h, KOH (1.27 g, 32.0 mmol) in water (0.90 mL) was added to the mixture.
The mixture was stirred at the same temperature for 3 h. After cooling
down to 20 – 25 oC, the mixture was quenched with water, which was
extracted twice 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
– 5 : 1) to give the desired product 21 (dr 60 : 40, 1.47 g, 60% in 2 steps).
3:1) to give the desired dibenzoate 18 (100 mg, 47% in 2 steps, dr 53 :
47,)
1
colorless oil; H NMR (500 MHz, CDCl3): δ = 1.20 (s, 3H x 47/100), 1.21
(s, 3H x 53/100), 1.232 (s, 3H x 53/100), 1.238 (s, 3H x 47/100), 1.59–
2.22 (m, 6H), 2.68–3.00 (m, 1H), 3.246 (s, 3H x 47/100), 3.254 (s, 3H x
53/100), 4.36–4.58 (m, 2H), 5.12–5.24 (m, 1H), 7.34–7.48 (m, 4H), 7.50–
7.62 (m, 2H), 7.90–8.12 (m, 4H); 13C NMR (125 MHz, CDCl3): δ = 20.5,
20.6, 22.3, 27.0, 27.1, 28.5, 28.85, 28.91, 29.2, 31.5, 31.8, 49.8, 61.9,
76.1, 76.2, 76.9, 77.6, 121.07, 121,10, 128.4, 128.5, 129.7, 129.8, 133.1,
133.2, 166.20, 166.23, 166.3; HRMS (ESI): m/z calcd for C25H29NO5 [M +
Na]+ 446.1943; found: 446.1949; 81% ee; HPLC analysis (OD–H, flow
rate 1.00 ml/min, solvent: hexane/2–propanol = 30/1) tR(racemic) = 21.92
1
colorless oil; H NMR (500 MHz, CDCl3): δ = 1.09 (s, 3H), 1.13 (s, 3H x
40/100), 1.14 (s, 3H x 60/100), 1.23 (s, 3H x 40/100), 1.24 (s, 3H x
60/100), 1.51–2.18 (m, 14H), 3.34–3.55 (m, 2H), 3.74–3.90 (m, 2H),
4.57–4.60 (m, 1H); 13C NMR (75 MHz, CDCl3): δ = 17.8, 19.5, 19.7, 25.4,
28.2, 28.8, 28.9, 29.0, 29.1, 30.3, 30.58, 30.64, 30.7, 34.2, 41.7, 41.8,
56.1, 56.2, 62.2, 62.4, 64.8, 64.9, 71.9, 72.0, 98.9, 99.1; HRMS (ESI):
m/z calcd for C15H28O3 [M + Na]+ 279.1936; found: 279.1939.
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10.1002/ejoc.201801160
European Journal of Organic Chemistry
FULL PAPER
temperature for 14 h. The solution was diluted with Et2O (0.70 mL) and
CH2Cl2 (1.3 mL). Na2SO4 (180 mg) was added to the stirred mixture,
followed by being stirred at the same temperature for 20 min. The
mixture was filtered and the filtrate was concentrated under reduced
pressure. The obtained crude oil was purified by SiO2–gel column
chromatography (hexane/AcOEt = 15 : 1) to give the desired product 2
(33 mg, 97%).
2-[2-((1R,2S)-1-Methyl-2-(prop-1-en-2-
yl)cyclobutyl)ethoxy]tetrahydro-2H-pyran (22)[29,38]
SOCl2 (293 mg, 2.5 mmol) was added to
a stirred solution of alcohol 21 (548 mg,
2.1 mmol) in pyridine (4.1 mL) at 0 – 5 ºC
under an Ar atmosphere, followed by
being stirred for 2 h. The mixture was
pale yellow oil; [α]D +6.6 (c 1.0, CHCl3) [lit.[20] [α]D +6.9 (c 3, CHCl3)];
1H NMR (500 MHz, CDCl3): δ = 1.18 (s, 3H), 1.42–1.47 (m, 1H), 1.55 (br
s, 1H), 1.56–1.73 (m, 3H), 1.67 (s, 3H), 1.73–1.84 (m, 2H), 1.97 (m, 1H),
2.55 (t, J = 9.2 Hz, 1H), 3.63–3.72 (m, 2H), 4.65 (d, J = 1.2 Hz, 1H), 4.84
(d, J = 1.2 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ = 19.2, 23.2, 28.4,
29.3, 36.9, 41.3, 52.5, 60.0, 109.7, 145.2; IR (neat): νmax = 3331, 2947,
2866, 1645, 1454, 1441, 1375, 1238, 1053, 1047, 1013, 1001, 883 cm-1.
25
25
quenched with water, which was
extracted twice with AcOEt. The combined organic phase was washed
with 1M HCl aq. solution, water, brine, dried (Na2SO4) and concentrated.
The obtained crude oil was purified by SiO2–column chromatography
(hexane/AcOEt = 5 : 1) to give the desired product 22 (383 mg, 75%).
1
colorless oil; H NMR (500 MHz, CDCl3): δ = 1.16 (s, 3H x 40/100), 1.18
(s, 3H x 60/100), 1.41–2.02 (m, 12H x 60/100 + 10 H x 40/100), 1.45 (s,
3H x 40/100), 1.67 (s, 3H), 2.39–2.45 (m, 2H x 40/100), 2.54 (t, J = 9.2
Hz, 1H x 60/100), 3.32–3.55 (m, 2H), 3.72–3.91 (m, 2H), 4.53–4.61 (m,
1H), 4.64 (s, 1H x 60/100), 4.83 (s, 1H x 60/100); 13C NMR (75 MHz,
CDCl3): δ = 18.6, 19.1, 19.3, 19.6, 23.2, 23.8, 25.4, 25.8, 26.0, 28.3, 28.4,
28.89, 28.94, 29.05, 29.12, 30.8, 33.3, 39.0, 41.2, 44.6, 52.5, 62.1, 62.26,
62.29, 64.5, 64.6, 65.1, 98.88, 98.92, 109.7, 122.4, 138.62, 138.65,
145.0, 145.1; HRMS (ESI): m/z calcd for C15H26O2 [M + Na]+ 261.1828;
found: 261.1830.
Acknowledgements
This research was partially supported by Grant-in-Aids for
Scientific Research on Basic Areas (B) “18350056”, Priority
Areas (A) “17035087” and “18037068”, (C) 15K05508, and
Exploratory Research “17655045” from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT).
2-[(1R,2S)-1-Methyl-2-(prop-1-en-2-yl)cyclobutyl]ethyl
4–
nitrobenzoate (23)
Dowex 50Wx8 (301 mg) was added to
a stirred solution of mixture of THP
The authors (Y.T.) and (N.M.) offer his warmest congratulations
to Professor Ben L. Feringa (University of Groningen, The
Netherlands) on being awarded the 2016 Nobel Prize in
Chemistry. Dedication to Professor Teruaki Mukaiyama on the
celebration of his 90th birthday (Sotuju). We thanks emeritus
professor Kenji Mori, Dr. Yuichiro Ashida, and Dr. Hidefumi
Nakatsuji for their helpful discussion.
ethers 22 and 23’ (429 mg, 4.2 mmol)
in MeOH (28 mL) at 20 – 25 ºC under
an Ar atmosphere, followed by being
stirred at the same temperature for 14
h. The mixture was filtered through Celite® (No.503) and the filtrate was
concentrated under reduced pressure. The obtained crude (+)–grandisol
(2; 730 mg) was subjected to the following further purification.
4–Nitrobenzoyl chloride (1.31 g, 7.0 mmol) in CH2Cl2 (4.0 mL) was
added to a stirred solution of crude (+)–grandisol (2; 30 mg, 4.7 mmol),
pyridine (743 mg, 9.4 mmol), and DMAP (57 mg, 0.50 mmol) in CH2Cl2
(10 mL) at 20 – 25 ºC under an Ar atmospher, followed by being stirred
for 2 h. The mixture was quenched with water, which was extracted
twice with CH2Cl2. The combined organic phase was washed with 1M
HCl aq. solution, water, brine, dried (Na2SO4) and concentrated. The
obtained crude solid was purified by SiO2–column chromatography
(hexane/AcOEt = 300 : 1) to give the desired product 23 (521 mg, 41% in
2 steps) and the by–product 23’ (369 mg, 29% in 2 steps).
Keywords: Synthetic methods; C-C coupling; Synthetic design;
Norchrysanthemic acid; (+)-Grandisol
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10.1002/ejoc.201801160
European Journal of Organic Chemistry
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Entry for the Table of Contents (Please choose one layout)
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Chiral synthesis
Ring-closing cycloalkane formation
Tetsuya Fujiwara,[a] Tomohito
Okabayashi,[a] Yuji Takahama,[a]
Noritada Matsuo,[a] Yoo Tanabe*[a]
Page No. – Page No.
Chiral syntheses of two distinct small cycloalkanes, (1R,3R)-(1Z)-norchrysanthemic
acid (7 steps, 23% overall yield) and (+)-grandisol (8 steps, 8% overall yield), were
performed by common characteristic ring-closing methodologies using carbanions
at the α-position of nitriles (nitrile α-anions).
Ring-Closing Strategy Utilizing Nitrile
α-Anions: Chiral Synthesis of (+)-
Norchrysanthemic Acid and
Expeditious Asymmetric Total
Synthesis of (+)-Grandisol
*one or two words that highlight the emphasis of the paper or the field of the study
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