Efficient Stereoselective Synthesis of a Key Chiral Aldehyde Intermediate in the Synthesis of Picolinamide Fungicides

Article abstract of DOI:10.1021/acs.oprd.9b00310

A highly stereoselective and efficient synthesis of (4S,5S,6S)-6-(benzyloxy)-5-phenoxy-4-propoxyheptanal, a key intermediate for syntheses of picolinamide fungicides, is described in this report. The synthesis features a scalable allylpropyl ether preparation, an efficient synthesis of the C1-C3 anti,syn-(S,S,S) stereotriad via a highly diastereoselective allylboration, and Cu-catalyzed phenylation of a sterically hindered secondary alcohol with BiPh₃(OAc)₂ followed by highly regioselective hydroformylation with the formation of a linear aldehyde. Excellent overall route efficiency was achieved (six steps and 39% yield) starting from readily available and inexpensive (S)-ethyl lactate.

Full text of DOI:10.1021/acs.oprd.9b00310

Article
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Efficient Stereoselective Synthesis of a Key Chiral Aldehyde
Intermediate in the Synthesis of Picolinamide Fungicides
Fangzheng Li,*,† Steffen Good,† Michael L. Tulchinsky,‡ and Gregory T. Whiteker†
†Process Chemistry, Product Design & Process R&D, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268,
United States
‡Core R&D, Dow Chemical, 1776 Building, Midland, Michigan 48674, United States
S
* Supporting Information
ABSTRACT: A highly stereoselective and efficient synthesis of (4S,5S,6S)-6-(benzyloxy)-5-phenoxy-4-propoxyheptanal, a key
intermediate for syntheses of picolinamide fungicides, is described in this report. The synthesis features a scalable allylpropyl
ether preparation, an efficient synthesis of the C1−C3 anti,syn-(S,S,S) stereotriad via a highly diastereoselective allylboration,
and Cu-catalyzed phenylation of a sterically hindered secondary alcohol with BiPh3(OAc)2 followed by highly regioselective
hydroformylation with the formation of a linear aldehyde. Excellent overall route efficiency was achieved (six steps and 39%
yield) starting from readily available and inexpensive (S)-ethyl lactate.
KEYWORDS: stereoselective allylboration, allyl propyl ether preparation, B-(Z)-γ-(propoxyallyl)diisopinocampheylborane,
phenylation, organobismuth, hydroformylation, picolinamide fungicides
pheyl) was proposed to generate the C2−C4 anti,syn-(S,S,S)
stereotriad of compound 3, presumably via cyclic chairlike
transition state 4.6 We anticipated high stereoselectivity toward
the desired S,S C3 and C4 chiral centers due to the matched
double asymmetric induction of (S)-lactate-derived aldehyde 6
with borane 5 derived from allyl n-propyl ether (7).
INTRODUCTION
■
Fungicides are key agricultural inputs for the control of plant
diseases that can dramatically reduce the yield of crops.1
Several factors necessitate the development of fungicides with
new modes of action. Because of their rapid rate of
reproduction, plant pathogens can develop resistance to
fungicides that limit their utility over time. In addition, many
fungicides have been removed from use by regulatory agencies
because of safety concerns.2 Our efforts to identify new crop
protection products to meet these needs led to the discovery of
a novel class of cyclic and acyclic picolinamide fungicides
(Figure 1).3 During these efforts, (4S,5S,6S)-6-(benzyloxy)-5-
phenoxy-4-propoxyheptanal (1) was proposed as a key
synthetic intermediate. We envisioned that intermediate 1
would enable retrosynthetic approaches to picolinamide
fungicides in which the aldehyde functionality could participate
in Wittig, Horner−Wadsworth−Emmons, Knoevenagel, and
aldol chemistry. Compound 1 has several structural features
that posed synthetic challenges. The presence of three
contiguous stererocenters (C4, C5, and C6) with S,S,S
absolute configuration required efficient control of both the
relative and absolute stereochemistry. In addition, the presence
of two different ether moieties at C4 and C5 required these
alcohols to be differentiated. Finally, the presence of a terminal
aldehyde in 1 required a strategy to install this reactive
functional group at a late stage. In this report, we describe an
efficient and stereoselective route to compound 1.
Known aldehyde 6 was prepared on a 0.5 kg scale from (S)-
ethyl lactate (8) using a modified literature procedure (Scheme
2).5a Reaction of 8 with pyrrolidine in the absence of solvent
afforded amide 9 in high yield with excellent purity. Alkylation
of amide 9 with benzyl chloride under phase-transfer
conditions (Aliquat 3365b and NaOH in toluene) furnished
O-benzyl-protected amide 10 in 88% yield. Finally, Red-Al
reduction of ester 10 proceeded smoothly under mild reaction
conditions without overreduction, giving rise to aldehyde 6,
which was stored under N2 at −5 °C over several weeks
without notable decomposition and erosion of enantiopurity.
In contrast, although direct benzyl protection of 8 and
subsequent DIBAL-H reduction afforded aldehyde 6 on a
small scale, alkylation of 8 was irreproducible, and an erosion
of enantiopurity was observed on scale. Furthermore, the
subsequent reduction of the benzyl ester with DIBAL-H
required cryogenic temperatures and was often accompanied
by overreduction.
Since allyl n-propyl ether 7 had not been commercially
available on a large scale, we developed an efficient synthesis of
this raw material (Scheme 3). Because of the similar boiling
points of 7 and common organic solvents, we focused on
developing solvent-free conditions to avoid the need for
isolation by distillation. After several conditions were screened,
RESULTS AND DISCUSSION
■
Retrosynthetically, we envisioned that compound 1 could be
obtained by hydroformylation of olefin 2, which would result
from late-stage phenylation of alcohol 3 (Scheme 1). Through
methodology developed by Brown,4 allylboration of known
aldehyde 65 with (Z)-di-lIpc-allylborane 5 (Ipc = isopinocam-
Special Issue: Corteva Agriscience
Received: July 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.9b00310
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Figure 1. Compound 1 and structures of cyclic and acyclic picolinamide fungicides.
Scheme 1. Retrosynthetic Analysis toward the Synthesis of 1
Scheme 2. Large-Scale Synthesis of Aldehyde 6
need for distillation. This procedure was successfully
performed on a 2.21 mol scale to yield 222 g of 7.
Scheme 3. Synthesis of Allyl n-Propyl Ether (7)
With the successful scale-up of both starting materials 6 and
7, we investigated the stereoselective formation of the C2−C4
anti,syn-(S,S,S) stereotriad in compound 3. As shown in the
allylation transition state 4 (Scheme 1), the stereoselective
formation of the desired C3,C4-syn relative stereochemical
configuration requires selective generation of (Z)-allylborane,
which was achieved by lithiation of allyl alkyl ethers followed
by transmetalation with an alkyl borate.4Furthermore, in a total
synthesis of oleandrose, Wuts reported stereoselective
formation of the 3-methoxy analogue of 3 in 84% yield as an
80:11:9 mixture of diastereomers from the reaction of
aldehyde 6 with the (Z)-2,3-butanediolboronate of 3-
the neat reaction of allyl bromide (11) with n-propanol (12)
(1.5 equiv) was performed at 35 °C using 1.7 equiv of solid
NaOH as the base. Upon completion of the reaction, excess n-
propanol and salts were removed by successive water washes to
give 7 as a neat liquid. This simple workup procedure afforded
7 with less than 3 mol % residual n-propanol, eliminating the
B
DOI: 10.1021/acs.oprd.9b00310
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Scheme 4. Attempted Allylboration of Aldehyde 6 with Allylpinacolboronate 13
Scheme 5. Allylboration of Aldehyde 6 with 9-BBN-allylborane 14
methoxypropene.7 The major diastereomer, resulting from
Felkin−Anh control, was confirmed to have S,S,S absolute
stereochemistry by NMR characterization of its cyclohexane
acetal derivative. Although these conditions led to reasonable
stereoselectivity, the reaction required 7 days for completion.
Not surprisingly, we found (Z)-allylpinacolboronate 13,
derived from 7, to be less reactive under allylboration
conditions. In this case, after 14 days at ambient temperature,
the desired product 3 was formed in 15% isolated yield with
treated with aldehyde 6 (186 g, 1.13 mol). Upon completion of
the reaction, oxidative workup of the reaction mixture with
H2O2/NaOH cleaved the borinic ester adducts to give a
mixture of alcohol 3 and isopinocampheol, which was removed
by Kugelrohr distillation. Neat alcohol 3 (257 g, 0.97 mol,
86%; Scheme 6) was obtained from the distillation pot with
Scheme 6. Scale-Up of the Allylboration of Aldehyde 6 with
Allylborane 5
1
less than 20% conversion of aldehyde 6 as determined by H
NMR analysis. Attempts to accelerate the reaction with a Lewis
acid (BF3·OEt2) or at elevated temperature led to a complex
reaction mixture as a result of decomposition of aldehyde 6
(Scheme 4).
Since dialkylallylboranes are typically much more reactive
than their allylboronate analogues, we prepared (Z)-9-BBN-
allylborane 14 in situ and subsequently added aldehyde 6 at
−78 °C (Scheme 5). Upon warming to ambient temperature
over 3 h, the desired (S,S,S)-alcohol 3 was isolated in 65%
yield as an 88:12 mixture of two isomers as determined by 1H
NMR analysis.
To further improve the diastereoselectivity while maintain-
ing an acceptable reaction time for scale-up, di-lIpc-allylborane
5 was selected for the allylboration of 3. We envisioned that a
double asymmetric induction by the matched stereochemical
configurations of chiral aldehyde 3 and allylborane 54 would
provide improved diastereoselectivity for allylboration com-
pared with 9-BBN-allylborane 14. Deprotonation of allyl n-
propyl ether 7 (119 g, 1.19 mol) with sec-butyllithium in
cyclohexane (1.4 M, 809 mL, 1.13 mol) at −78 °C followed by
sequential addition of (+)-MeOB(Ipc)2 (358 g, 1.13 mol) and
BF3·OEt2 (144 mL, 1.13 mol) generated 5, which was directly
1
≥95% purity as determined by H NMR analysis without
1
further purification. H NMR analysis of the crude product
showed a single diastereomer of 3. This procedure was
successfully scaled up to provide multiple 300 g batches.
Mosher ester analysis8 of alcohol 3 confirmed the S absolute
configuration of the C3 chiral center, and only a single isomer
was observed on the basis of 1H and 19F NMR analyses of both
(R)- and (S)-MTPA esters of 3, which indicated complete
C
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Scheme 7. SNAr Reaction of Alcohol 3 with 4-Fluorochlorobenzene
diastereoselective control of the allylboration reaction (as
shown in the Supporting Information).
alkenes.14 We selected Xantphos15 and bisphosphite L116 as
ligands to study the hydroformylation of 2 (Scheme 9).
Hydroformylation of olefin 2 with the catalyst prepared in situ
from 1 mol % Rh(CO)2(acac) and 1 mol % Xantphos in THF
at 75 °C under 1000 psi 1:1 H2/CO gave the linear aldehyde 2
in 61% isolated yield after column chromatography. Observa-
tion of a triplet at δ 9.68 (J = 1.6 Hz) in the 1H NMR spectrum
of 2 confirmed the product to be the linear aldehyde
regioisomer. The branched isomer was not observed in the
1H NMR spectrum of the crude product mixture. The high
regioselectivity is presumably due to the significant steric
difference between the terminal C6 and internal C5 of the
olefin.
Hydroformylation of 2 using 0.1 mol % Rh(CO)2(acac) and
0.2 mol % bisphosphite L1 at 70 °C under 100 psi 1:1 H2/CO
gave aldehyde 1 in 90% isolated yield. Bisphosphite L1
provided several significant advantages over Xantphos. Use of
L1 allowed the hydroformylation reaction to be performed at
lower CO pressure, reaction temperature, and Rh loading than
with Xantphos as the ligand. More importantly, the polarity of
the aldehyde product combined with the nonpolar nature of
the Rh−L1 catalyst system facilitated product isolation and
catalyst recovery by nonaqueous biphasic extraction with
subsequent catalyst recycling.17,18 Following hydroformylation
of 2 with Rh−L1 in heptane at 70 °C in the next experiment,
acetonitrile was added, and aldehyde 1 was isolated in 84%
yield (97.2% purity by gas chromatography) by evaporation of
the acetonitrile layer. A small amount of hydrogenation side-
product 20 (1 area % by GC) was observed in the sample. The
heptane layer contained a small amount of the aldehyde
product (5% yield) along with byproduct 20 in a 91:9 ratio.
The combined product yield was 91%. The catalyst was mostly
partitioned into the heptane layer and was recycled for an
additional hydroformylation experiment, which gave 1 in 64%
yield with 95% purity after isolation.
Next, conditions for phenylation of secondary alcohol 3
were explored. We first investigated Batey’s etherification
conditions (PhBF3K/Cu(OAc)2/DMAP/O2).9 Cu- and Pd-
catalyzed cross-coupling conditions reported by Buchwald
were also attempted.10 Unfortunately, no desired product 2
was observed under either of these conditions, presumably
because of the hindered nature of alcohol 3. Subsequently, we
explored the SNAr reaction of 3 with electron-deficient 4-
fluorochlorobenzene with the assumption that the activating p-
Cl group could be removed by hydrogenation at a later stage.
However, arylation of 3 with 4-fluorochlorobenzene in the
presence of KOtBu in DMF at 45 °C led to an inseparable 4:1
mixture of arylation product 16 and elimination product 17
with 75% conversion. Attempts to optimize this reaction did
not significantly improve the 16:17 product ratio (Scheme 7).
After further investigation, we successfully utilized copper-
(II)-catalyzed phenylation of alcohol 3 with the pentavalent
organobismuth reagent BiPh3(OAc)2 (18) for the synthesis of
2 (Scheme 8). These conditions were previously reported to
Scheme 8. Phenylation of Alcohol 3 with BiPh3(OAc)2 (18)
CONCLUSIONS
■
be effective for arylation of highly functionalized 1,2-diols.11,12
BiPh3(OAc)2 was prepared as a white solid through the
reaction of BiPh3 with AcOOH (32 wt % in acetic acid) in 7:3
CH2Cl2/THF.13 Phenylation of 3 was performed in toluene at
55 °C with 1.3 equiv of BiPh3(OAc)2 in the presence of 5%
mol Cu(OAc)2 and 1.2 equiv of dicyclohexylmethylamine
(NCy2Me) as the base. The phenylation was complete in 4 h
and provided the desired compound 2 in 72% yield after
column chromatography. Notably, elimination byproduct 17
was not detected under the optimized conditions.
A scalable and highly stereoselective route to (4S,5S,6S)-6-
(benzyloxy)-5-phenoxy-4-propoxyheptanal (1), an advanced
intermediate for picolinamide fungicides, was developed. The
key route designs included a matched double asymmetric
allylboration of aldehyde 6 with (Z)-di-lIpc-allylborane 5 to
provide compound 3 containing the synthetically challenging
C2−C4 anti,syn-stereotriad as a single isomer. A mild Cu-
catalyzed arylation of sterically hindered secondary alcohol 3
with BiPh3(OAc)2 and a hydroformylation process to form the
terminal aldehyde with excellent regio- and chemoselectivity
were demonstrated. A practical preparation of allyl n-propyl
ether (7) was also developed. The overall route efficiency for 1
is excellent (six steps and 39% overall yield) starting from (S)-
ethyl lactate. With the exception of the phenylation step, all of
With terminal olefin 2 in hand, Rh-catalyzed hydro-
formylation was explored next. We found several ligands
reported in the literature that exhibited high regio- and
chemoselectivity for linear hydroformylation of terminal
D
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Scheme 9. Preparation of Aldehyde 1 by Rh-Catalyzed Hydroformylation of 2 with Xantphos and L1
the column chromatographic purifications were avoided by
implementing scalable distillation, extraction, and recrystalliza-
tion processes. Moreover, the combination of the Brown
allylboration with Rh-catalyzed regioselective hydroformyla-
tion to a linear aldehyde is a powerful strategy for the synthesis
of complex aliphatic aldehydes with multiple contiguous
stereocenters, as illustrated by a recent example of the cascade
asymmetric synthesis of tetrahydropyran derivatives.19 We
have utilized this strategy extensively for the preparation of
aldehyde intermediates analogous to 1, which were further
derivatized to successfully support our internal discovery field
sample synthesis and structure−activity relationship studies.
We believe that the asymmetric allylboration−hydroformyla-
tion reaction sequence is an effective methodology for
asymmetric synthesis of structurally complex aldehydes.
The reaction mixture was allowed to warm gradually to room
temperature (rt) over 72 h. The reaction mixture was
concentrated under vacuum (1 Torr, 50 °C) to afford (S)-2-
hydroxy-1-(pyrrolidin-1-yl)propan-1-one (9) (550 g, 3.84 mol,
1
97% purity by H NMR, 90% yield). The spectroscopic data
for 9 were consistent with values reported in the literature.5
[α]2D0 −48.7 (c 1.15, CHCl3). 1H NMR (400 MHz, CDCl3): δ
4.23 (q, J = 6.6 Hz, 1H), 3.77 (s, 1H), 3.60−3.44 (m, 1H),
3.44−3.34 (m, 2H), 3.27 (m, J = 10.2, 7.0 Hz, 1H), 2.01−1.87
(m, 2H), 1.87−1.74 (m, 2H), 1.26 (d, J = 6.6 Hz, 3H).
(S)-2-(Benzyloxy)-1-(pyrrolidin-1-yl)propan-1-one
(10). A 5 L three-neck round-bottom flask equipped with
overhead stirring, a temperature probe, an addition funnel, and
a N2 inlet was charged with benzyl chloride (282 mL, 2.42
mol), N-methyl-N,N,N-trioctylammonium chloride (37.6 g, 93
mmol), and toluene (2.1 L). The flask was cooled to 0 °C, and
powdered NaOH (269 g, 6.52 mol) was added. Compound 9
(275 g, 97% purity, 1.86 mol) was added over 40 min via
addition funnel while the internal temperature was maintained
at <10 °C. After complete addition, the reaction mixture was
warmed to rt, stirred for 4 h, and then poured into rapidly
stirring cold 2 M HCl. The phases were partitioned, and the
organic layer was washed with saturated NaHCO3, dried over
Na2SO4, filtered, and concentrated. Hexanes (1 L) was added,
and the biphasic mixture (hexanes/crude oil) was stirred at
−78 °C to initiate crystallization. Crystalline (S)-2-(benzyl-
oxy)-1-(pyrrolidin-1-yl)propan-1-one (10) (272 g) was
collected via filtration. The filtrate was purified via flash
column chromatography over silica gel to afford additional 10
(88 g, 360 g combined, 1.54 mol, 98% purity, 81% yield). The
spectroscopic data for 10 were consistent with values reported
in the literature.5 [α]D20 −61.5 (c 1.15, CHCl3). 1H NMR (400
MHz, CDCl3): δ 7.31−7.16 (m, 5H), 4.54 (d, J = 11.8 Hz,
1H), 4.36 (d, J = 11.8 Hz, 1H), 4.12 (q, J = 6.7 Hz, 1H), 3.50−
3.38 (m, 2H), 3.38−3.29 (m, 2H), 1.88−1.78 (m, 2H), 1.78−
1.69 (m, 2H), 1.34 (d, J = 6.7 Hz, 3H).
EXPERIMENTAL SECTION
■
General. All of the reagents were commercially available
and used as purchased without further purification. Unless
otherwise noted, all of the reactions were performed in round-
bottom or jacketed cylindrical flasks under nitrogen. 1H NMR
spectra were recorded on a Bruker Ultrashield 400 NMR
spectrometer or a Varian 400-MR spectrometer. Mass spectra
were obtained using a Waters Micromass ZQ mass
spectrometer. HPLC analysis was performed using an Agilent
1260 chromatograph with a YMC Pack-ODS-AQ column (4.6
mm × 150 mm, 5.0 μm, P/N 0415212347); GC analyses were
performed using an Agilent 7890 chromatograph with samples
prepared by weighing approximately 0.05 g of the material into
a 2 mL glass GC vial and diluting with about 1.5 mL of
acetone. GC results are expressed in area %. GC/MS analyses
were performed on an HP 7890A series GC system with an
RVM Scientific low thermal mass (LTM) 15 m × 250 μM ×
0.25 μM Varian VF-5MS column using a 5795 EI/CI mass-
selective detector in chemical ionization (CI) positive ion
mode.
(S)-2-(Benzyloxy)propanal (6). A 5 L three-neck round-
bottom flask equipped with overhead stirring, a thermocouple,
an addition funnel, and a N2 inlet was charged with 10 (500 g,
2.1 mol) and anhydrous toluene (2.3 L). The flask was cooled
to −12 °C, and a 60 wt % solution of Red-Al in toluene was
added over 30 min via addition funnel. The reaction mixture
(S)-2-Hydroxy-1-(pyrrolidin-1-yl)propan-1-one (9). A
2 L round-bottom flask equipped with a thermocouple and
nitrogen inlet was charged with (S)-ethyl lactate (8) (0.485 L,
4.15 mol). The flask was cooled to −1 °C, and pyrrolidine
(0.520 L, 6.22 mol) was added via addition funnel over 1 h at
such a rate that the internal temperature was kept below 5 °C.
E
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was stirred between −13 and −10 °C for 2.5 h, and the
reaction was quenched with acetone (100 mL). The mixture
was stirred for 10 min and then poured into HCl (6.5 L, 1 N)
at 0 °C. The phases were partitioned, and the aqueous layer
was back-extracted with ethyl acetate (2.5 L). The combined
organic extracts were washed with dilute HCl (0.1 M), dried
over Na2SO4, filtered, and concentrated to afford (S)-2-
(benzyloxy)propanal (6) (326 g, 1.98 mol, 95% purity, 90%
yield) as an oil. The spectroscopic data for 6 were consistent
with values reported in the literature.5 [α]D20 −58.44 (neat). 1H
NMR (400 MHz, CDCl3): δ 9.67 (d, J = 1.8 Hz, 1H), 7.45−
7.28 (m, 5H), 4.94−4.44 (m, 2H), 3.90 (qd, J = 6.9, 1.8 Hz,
1H), 1.34 (d, J = 6.9 Hz, 3H).
(65−70 °C, 0.4−0.6 Torr) to remove isopinocampheol,
affording (2S,3S,4S)-2-(benzyloxy)-4-propoxyhex-5-en-3-ol
(3) (257 g, 0.97 mol, 86%) as an orange oil. H NMR (400
1
MHz, CDCl3): δ 7.37−7.33 (m, 4H), 7.32−7.26 (m, 1H), 5.76
(ddd, J = 17.2, 10.4, 7.5 Hz, 1H), 5.28 (ddd, J = 8.9, 1.8, 0.9
Hz, 1H), 5.28−5.22 (m, 1H), 4.61 (d, J = 11.6 Hz, 1H), 4.48
(d, J = 11.7 Hz, 1H), 3.83 (ddt, J = 7.5, 4.5, 0.9 Hz, 1H), 3.58
(p, J = 6.1 Hz, 1H) 3.53−3.43 (m, 2H), 3.18 (dt, J = 9.61, 6.6
Hz, 1H), 2.42 (d, J = 5.8 Hz, 1H), 1.62−1.45 (m, 2H), 1.27
(d, J = 6.2 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H). 13C NMR (101
MHz, CDCl3): δ 138.6, 135.9, 128.3, 127.8, 127.5, 118.3, 80.2,
76.2, 74.7, 70.7, 70.5, 23.0, 15.3, 10.7. HRMS-ESI (m/z): calcd
for C16H25O3 ([M + H]+), 265.1798; found, 265.1793.
3-Propoxyprop-1-ene (7). A 1 L three-neck round-
bottom flask equipped with overhead stirring, a nitrogen
inlet, a thermocouple, and an addition funnel was charged with
1-propanol (297 mL, 3.97 mol). NaOH (pellets, 180 g, 4.50
mol) was added in one portion, and the internal temperature
rose to 40 °C. The mixture was then heated to 65 °C and
stirred for 20 min. The suspension was cooled to 35 °C, and
allyl bromide (229 mL, 2.65 mol) was added over 1 h via
addition funnel while the internal temperature was maintained
between 35 and 55 °C. After complete addition, the reaction
mixture was stirred for 20 h and then cooled to 0 °C, and water
(500 mL) was added. The biphasic mixture was stirred for 10
min, after which the layers were partitioned and the organic
layer was washed with water (2 × 500 mL) and brine (2 × 500
mL) to afford 3-propoxyprop-1-ene (7) (222 g, 2.21 mol,
(((2S,3S,4S)-2-(Benzyloxy)-4-propoxyhex-5-en-3-yl)-
oxy)benzene (2). A 3 L four-neck round-bottom flask was
charged with 3 (93 g, 0.35 mol), toluene (1.17 L),
BiPh3(OAc)2 (269 g, 0.46 mol), Cu(OAc)2 (3.29 g, 17.6
mmol), and N,N-dicyclohexylmethylamine (91 mL, 0.42 mol).
The reaction mixture was heated to 55 °C and stirred for 4 h.
Note: the reaction was exothermic and became self-heating,
and the internal temperature was maintained between 55 and
60 °C. The reaction mixture was cooled to rt and filtered
through a pad of Celite. The filtrate was partitioned between
EtOAc (1 L) and 1 M HCl (0.50 L). The organic layer was
separated, and the aqueous layer was back-extracted with
EtOAc (0.50 L). The combined organic extracts were dried
over Na2SO4, filtered, and concentrated. The crude product
was purified via flash column chromatography over silica gel
(0−10% EtOAc/hexanes) to afford (((2S,3S,4S)-2-(benzyl-
oxy)-4-propoxyhex-5-en-3-yl)oxy)benzene (2) (91 g, 0.27 mol,
72%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.40−
7.17 (m, 7H), 7.11−6.99 (m, 2H), 6.96−6.85 (m, 1H), 5.81
(ddd, J = 17.3, 10.3, 7.9 Hz, 1H), 5.31 (ddd, J = 17.3, 1.9, 1.0
Hz, 1H), 5.22 (ddd, J = 10.3, 1.8, 0.8 Hz, 1H), 4.61 (d, J =
11.4 Hz, 1H), 4.49 (d, J = 11.4 Hz, 1H), 4.30 (dd, J = 6.4, 4.0
Hz, 1H), 4.07 (ddt, J = 7.8, 3.9, 0.9 Hz, 1H), 3.97 (p, J = 6.3
Hz, 1H), 3.51 (dt, J = 9.3, 6.7 Hz, 1H), 3.23 (dt, J = 9.3, 6.8
Hz, 1H), 1.59 (h, J = 7.2 Hz, 2H), 1.26 (d, J = 6.3 Hz, 3H),
0.89 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ
160.13, 138.70, 136.32, 129.40, 128.50, 127.87, 127.69, 121.10,
118.42, 116.76, 83.67, 80.90, 74.42, 71.13, 71.11, 23.13, 16.19,
10.89. HRMS-ESI (m/z): calcd for C22H29O3 ([M + H]+),
340.2038; found, 340.2022.
1
84%) as a yellow oil with ≤3 mol % propanol by H NMR
analysis. Note: 7 could be further purified by distillation (bp =
1
91 °C, 760 Torr) if desired. H NMR (400 MHz, CDCl3): δ
5.99−5.80 (m, 1H), 5.25 (dq, J = 17.2, 1.7 Hz, 1H), 5.18−5.11
(m, 1H), 4.07−3.80 (m, 2H), 3.37 (t, J = 6.7 Hz, 2H), 1.70−
1.45 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 135.18, 116.62, 72.14, 71.81, 23.02, 10.62.
(2S,3S,4S)-2-(Benzyloxy)-4-propoxyhex-5-en-3-ol (3).
A 5 L three-neck round-bottom flasked equipped with
overhead stirring, a nitrogen inlet, a thermocouple, and an
addition funnel was charged with 7 (119 g, 1.19 mol) and
anhydrous THF (900 mL). The flask was cooled to −78 °C,
and a solution of sec-butyllithium in cyclohexane (1.4 M, 809
mL, 1.13 mol) was added in three portions over 1.5 h via
addition funnel while the internal temperature was maintained
below −65 °C. The mixture was stirred for 1 h, and then a
solution of (+)-MeOB(Ipc)2 (358 g, 1.13 mol) in anhydrous
THF (200 mL) was added over 1.5 h via addition funnel while
the internal temperature was maintained below −65 °C. The
resultant mixture was stirred for 1.5 h, and then BF3·Et2O (144
mL, 1.13 mol) was added via addition funnel as quickly as
possible while the internal temperature was maintained below
−65 °C. Aldehyde 6 (186 g, 1.13 mol) was added over 1 h via
addition funnel while the internal temperature was maintained
below −65 °C. The reaction mixture was allowed to warm
gradually overnight for 16 h. The flask was cooled to 8 °C, and
NaOH (6 M, 226 mL, 1.36 mol) was added. Then 30%
aqueous H2O2 (454 mL) was added in two portions over 2 h
via addition funnel while the internal temperature was
maintained below 30 °C. The mixture was stirred for 1 h,
after which the layers were partitioned and the aqueous layer
was back-extracted with MTBE (3 × 300 mL). The combined
extracts were washed with saturated NaHSO3 (800 mL) and
brine (800 mL), dried over Na2SO4, filtered, and concentrated.
The resulting crude oil was subjected to Kugelrhor distillation
Synthesis of (4S,5S,6S)-6-(Benzyloxy)-5-phenoxy-4-
propoxyheptanal (1) Using Rh−Xantphos (1 mol %
Rh). Compound 2 (1.95 g, 5.73 mmol) was placed in a 40 mL
Parr reactor. THF (5 mL) was added. Rh(CO)2(acac) (15 mg,
1 mol %) and Xantphos (33 mg, 1 mol %) were added as
solids. The reactor was purged three times with CO,
pressurized to 1000 psi 1:1 H2/CO, and heated to 75 °C for
18 h. After cooling, the reactor was vented, and the contents
were rotary-evaporated to obtain a very dark oil. The crude
product was loaded onto a 5 g silica cartridge using CH2Cl2.
Flash chromatography on a 40 g Isco Gold column (hexane/
EtOAc gradient) gave 1.30 g of 1 as a colorless liquid (61%
1
yield). H NMR (400 MHz, CDCl3): δ 9.68 (t, J = 1.6 Hz,
1H), 7.38−7.18 (m, 7H), 7.03 (dt, J = 7.9, 1.1 Hz, 2H), 6.97−
6.88 (m, 1H), 4.61 (d, J = 11.6 Hz, 1H), 4.45 (d, J = 11.5 Hz,
1H), 4.35 (t, J = 5.0 Hz, 1H), 3.89 (qd, J = 6.3, 5.1 Hz, 1H),
3.59 (dt, J = 8.3, 4.6 Hz, 1H), 3.45 (ddt, J = 39.1, 8.9, 6.8 Hz,
2H), 2.47 (td, J = 7.2, 1.6 Hz, 2H), 2.01−1.78 (m, 2H), 1.59−
1.42 (m, 2H), 1.29 (d, J = 6.3 Hz, 3H), 0.85 (t, J = 7.4 Hz,
3H). 13C NMR (101 MHz, CDCl3): δ 201.98, 159.57, 138.40,
F
DOI: 10.1021/acs.oprd.9b00310
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Notes
129.42, 128.37, 127.63, 127.58, 121.02, 116.15, 82.25, 78.55,
74.58, 73.22, 70.68, 40.20, 23.94, 23.31, 15.87, 10.62. HRMS-
ESI (m/z): calcd for [C23H30O4]+, 370.2144; found, 370.2145.
Synthesis of 1 Using Rh−L1 (0.2 mol % Rh, L1/Rh = 2)
at 60 °C and 100 psi Syngas. Rh(CO)2acac (12.9 mg; 0.05
mmol) and L1 (83.9 mg; 0.1 mmol) were dissolved in
nitrogen-purged heptane (20 mL) with stirring. A portion of
this solution (10 mL; 0.025 mmol Rh and 0.05 mmol L) was
charged to a syngas-purged Parr reactor by syringe. Then
syngas was charged to the reactor at 60 psi, and the solution
was heated at 70 °C for 30 min with the pressure adjusted to
100 psi. The mixture was cooled to 30 °C, and the syngas was
vented, after which 2 (4.26 g, 12.5 mmol, 96.7% pure by GC)
in heptane (4 mL) was quickly charged via syringe. The reactor
was heated to 60 °C at 100 psi with stirring. After 2 h, GC
analysis revealed reaction completion. The reactor contents
were cooled and diluted to a total volume of 170 mL with
heptane. This solution was mixed with an equal volume of
acetonitrile and shaken in a separatory funnel. The phases were
separated and analyzed. The acetonitrile phase contained
about 97.2 GC area % aldehyde 1 and about 1.0 GC area %
hydrogenated olefin (reaction side product), while the heptane
phase showed 81.8 GC area % aldehyde 1 and 8.8 GC area %
hydrogenated olefin. Solvent evaporation produced 3.87 g of
aldehyde 1 from the acetonitrile phase and 0.325 g of the
remaining product from the heptane phase (total 4.20 g, 11.30
mmol, 91% yield).
Catalyst Recycling Using Rh−L1 (0.5 mol % Rh, L1/Rh
= 2) at 60 °C and 100 psi Syngas. The reaction described
above was repeated using 0.85 g (2.50 mmol) of olefin 2 in 12
mL of heptane, and upon reaction completion the reaction
mixture was extracted with an equal by volume amount of
acetonitrile. After phase separation, the solvent was evaporated
from the acetonitrile phase to give 0.72 g (78% yield) of the
aldehyde product 1 with 97.6% GC purity. The heptane phase,
which mostly contained the catalyst/ligand, was reused in the
next cycle of hydroformylation with the same amount of the
starting olefin 2. Upon reaction completion, the mixture was
treated with an equal by volume amount of acetonitrile, the
phases were separated, and the solvent was evaporated from
the acetonitrile phase to give 0.59 g (64% yield) of the
aldehyde product 1 with 95.1% GC purity.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Peter Borromeo, Jeff Nissen, and Amanda
Jevons for their assistance in the scale-up of intermediates.
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ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge on the
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: Fangzheng.li@corteva.com.
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ORCID
Fangzheng Li: 0000-0002-7570-7938
Gregory T. Whiteker: 0000-0002-9439-6696
Author Contributions
The manuscript was written through contributions of all
authors. All of the authors approved the final version of the
manuscript.
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DOI: 10.1021/acs.oprd.9b00310
Org. Process Res. Dev. XXXX, XXX, XXX−XXX