Photo-oxidation of Cyclopentadiene Using Continuous Processing: Application to the Synthesis of (1 R,4 S)-4-Hydroxycyclopent-2-en-1-yl Acetate

Article abstract of DOI:10.1021/acs.oprd.0c00066

(1R,4S)-4-Hydroxycyclopent-2-en-1-yl acetate is a chiral small building block that was requested to advance several Pfizer programs into the clinic. Pfizer and Syncom partnered to develop a photo-oxidation process of cyclopentadiene using a flow approach followed by subsequent bis-acetylation of the meso diol and final biocatalytic desymmetrization. This continuous process was demonstrated on a 6 g·h-1 input and is amenable to larger scale. The optimization and scale-up of this sequence is described therein.

Full text of DOI:10.1021/acs.oprd.0c00066

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Communication
Photo-Oxidation of Cyclopentadiene using Continuous Processing:
Application to the Synthesis of (1R,4S)-4-hydroxycyclopent-2-en-1-yl acetate
Elena Herrero-Gomez, Cornelis Herman Michel van der Loo, Lena Huck, Ana
Rioz-Martinez, Nandell Keene, Bryan Li, Kees Pouwer, and Christophe Allais
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00066 • Publication Date (Web): 14 Apr 2020
Downloaded from pubs.acs.org on April 15, 2020
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Photo-Oxidation of Cyclopentadiene using
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Continuous Processing: Application to the Synthesis
of (1R,4S)-4-hydroxycyclopent-2-en-1-yl acetate
Elena Herrero-Gomez,1 Cornelis H. M. van der Loo,1 Lena Huck,1 Ana Rioz-Martínez,1 Nandell
F. Keene,2 Bryan Li,2 Kees Pouwer*1 and Christophe Allais*2
1Syncom B.V., Kadijk 3, 9747 AT Groningen, The Netherlands.
2Chemical Research and Development, Pfizer Worldwide Research and Development, Eastern
Point Road, Groton, Connecticut 06340, United States
Photo-oxidation, flow chemistry, continuous process, cyclopentadiene, meso desymmetrization,
Novozyme.
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ABSTRACT
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(1R,4S)-4-Hydroxycyclopent-2-en-1-yl acetate is a chiral small building block that was
requested to advance several Pfizer programs into the clinic. Pfizer and Syncom partnered to
develop a photo-oxidation process of cyclopentadiene using a flow approach followed by
subsequent bis-acetylation of the meso diol and final biocatalytic desymmetrization. This
continuous process was demonstrated on a 6 g.h-1 input and is amenable to larger scale. The
optimization and scale-up of this sequence is described therein.
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Keywords: flow, photoredox, oxidation, cyclopentadiene, Novozyme, desymmetrization
INTRODUCTION
The increased use of continuous reactors on laboratory scale has allowed “old fashioned”
chemistry to flourish.1 A prime example for this is photochemistry, which was deemed impractical
for large scale application and mostly utilized in academic settings. The use of flow reactors has
changed this completely, bringing this technology back into the spotlight. Flow reactors, having
small irradiation pathways, allow problems associated with the low transmission of light through
reaction mixtures to be overcome. As a result, photochemistry in flow has experienced an outburst
of activity in the recent years.2
However, adoption of flow technologies also comes with challenges. Commercial continuous
reactors are advertised as fit-for-purpose, which can be quite a drawback when not working in a
production environment. For this reason, we custom built our flow reactors for a specific reaction
or series of transformations.3 The advantages of this approach are: 1) reactors are made of
different modules which can be assembled to accommodate different processes; 2) reactors are
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tailor made to the specific needs of the reaction; 3) as the modules employed are normally
inexpensive, this approach is more cost efficient compared to acquiring commercial equipment.
In the course of our investigations, we needed to develop a scalable route towards (1R,4S)-4-
hydroxycyclopent-2-en-1-yl acetate (6), a known building block in the construction of
prostaglandins,4 and a key raw material for one of our API manufacture. Our previous experience
with this compound shed light on the lack of multiple suppliers for this building block on scale.
Therefore, we decided to develop a custom synthesis of 6. Synthetic methods have been reported
in the literature,5 but of particular interest was the singlet-oxygen mediated oxidation of
cyclopentadiene 2 as a key step,6 followed by acetyl protection and selective deprotection (Scheme
1). The short synthetic sequence and use of inexpensive reagents made this approach attractive,
although the key photochemical step to the meso diol 4 seemed to be a challenge on our way to a
process-friendly procedure towards compound 6. It was clear that this process would benefit
tremendously from being performed in continuous flow, so we decided to assess the reported
chemistry with this technology in mind.7
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Step 1
Step 2
Step 2 quench
heat
O2
reductant
O
O
1
2
3
photooxidation
Step 3
OH
OH
OAc
OH
Step 4
di-acetylation
enzyme
OAc
OAc
desymmetrization
4
5
6
Scheme 1. General synthetic approach to (1R,4S)-4hydroxycyclopent-2-en-yl acetate 6.
RESULTS AND DISCUSSION
Following the strategy described in Scheme 1, we initiated this work with the retro-Diels Alder
reaction of dicyclopentadiene 1. This well-known chemistry proceeded uneventfully via a
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modification of the Moffett procedure.8 It should be noted that cyclopentadiene 2 slowly dimerizes
unless stored at -18 °C as a solution in methanol (100 mg/g). Typically, 30-50 g batches of
cyclopentadiene 2 were freshly prepared and stored for less than 16 h prior to use.
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With decent quantities of cyclopentadiene 2 readily available, we tackled the key step. Batch
photooxidation of cyclopentadiene 2 has been reported using Rose Bengal6a-f and porphyrin
analogues6g as photosensitizers in the presence of oxygen and under light. In situ generation of
singlet oxygen oxidizes cyclopentadiene 2 to epidioxide intermediate 3. This labile intermediate
can be treated with various reductants9 to afford meso diol 4. Encouraged by these previous
reports, we started to explore the adaptation of the photo-oxidation step using continuous flow
processing.
The photoreactor was constructed using commercially available parts, as shown in figure 1. The
setup consists of a HPLC pump connected to PFA10 tubing (6.5 m 1/16”, 9 mL) coiled around a
Drechsel bottle which is used as a cooling system. This unit was fitted into a metal box containing
2 LED chips on each side (530 nm, 8 x 30 W for green and 450 nm for blue). A gas compatible
back pressure regulator was placed at the end of the reactor and was set at 8 bars. It is important
to maintain the system under pressure to ensure good mixing between the liquid and gas phases
and to be able to introduce enough oxygen into the reactor. An inexpensive needle-valve was used
to control the oxygen, which was used in excess. The oxygen is being consumed as it travels
through the tubing and reacts with the substrate, which results in a “flow-gradient” in the reactor.
This makes both the overall flow rate and the residence time extremely challenging to calculate.
Therefore, for ease of interpretation, the flow rates reported thereafter are only taking in
consideration liquid flow rates, which were used to determine corresponding estimated residence
time. The flow was adjusted to ensure that some oxygen remained unconsumed after irradiation.
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From a process safety perspective, it is important to note that pure oxygen was used here and that
the final solution has high levels of oxygen in a flammable solvent. The safety risk is mitigated by
the use of flow technology here, since the reactor volume is very small compared to a batch mode
approach. Also, excess oxygen was purged by a nitrogen stream in the receiver tank. On production
scale, the use of diluted oxygen and in-line degasser at the end of the reactor tube would be strongly
advised.
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Figure 1. Schematic overview and picture of the photochemical reactor with green LED chips.
Our initial efforts focused on the use of tetraphenylporphyrin (TTP) as the photosensitizer in
combination with blue LED chips. Since intermediate 3 was too unstable to subject to analysis,
the mixture was quenched with a solution of thiourea in methanol to generate the diol 4, then
analyzed by GC (Table 1).
Table 1. Photooxidation reaction with TPP/blue LED system.
Step 2
Step 2 quench
blue LED
OH
OH
Thiourea
(1 equiv)
O
O
O2
MeOH
TTP (0.02-2%)
DCM, 20 °C
2
3
4
flow
batch
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Entry Feed conc. TPP
Flowrate
Conversion Isolated
(equiv)
yield
(mg/mL)
10
(mL/min)
(GC)
1
2
3
4
5
6
7
8a
0.02
1
100%
100%
100%
100%
100%
100%
100%
92%
-
10
0.002
0.001
0.0002
0.001
0.001
0.001
0.001
1
-
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-
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-
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-
100
100
1
-
10
10%
a Tubing diameter increased to 1/8” from 1/16” to accommodate higher flow rate.
First, we studied the amount of sensitizer needed to reach full conversion keeping all other
parameters constant (Table 1, entries 1-4). In all cases, full conversion was achieved according to
GC analyses. We then turned our attention to the concentration of the substrate solution in order
to maximize the throughput (entries 5-7), and once again full conversion was achieved up to 100
mg/mL, at a constant 1 mL/min flowrate. We then decided to switch to large tubing diameter (from
1/16” to 1/8”) to accommodate higher flow rates. A dichloromethane solution of cyclopentadiene
2 (58 g, 100 mg/mL) was flowed through the reactor at a 10 mL/min flow rate and quenched in
batch mode with a solution of thiourea in methanol (entry 8). Although 92% conversion was
observed by GC, only 10 g of diol 4 (10 g/h, 10% yield) was isolated after distillation. At this
point, it became evident that GC data did not reflect the accurate performance of the reaction and
that further work on the analytical method was required. Secondly, we believe that the heat-
exchange between the cooling and the larger tubing was insufficient, which in turn led to
decomposition of the cyclic peroxide intermediate 3 before thiourea mediated reduction.11 This
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prompted us to revert to 1/16” tubing diameter, and switch to a Rose Bengal/green LEDs system
that was known to generate less heat.
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This second approach was performed using a methanol solution of the substrate in which Rose
Bengal was fully soluble. A more reliable and accurate analytical method for optimization of all
parameters was also established. After quench, the crude diol solution was analyzed by 1H NMR
and the ratio of residual thiourea against diol 4 was used to determine in situ yield. Results of this
study are summarized in Table 2.
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Table 2. Photooxidation reaction with Rose Bengal/green LED system.
Step 2
Step 2 quench
green LED
OH
OH
Thiourea
(1 equiv)
O
O
O2
MeOH
Rose Bengal
(0.1 mol%)
MeOH, T °C
flow
2
3
4
batch
Entry Feed conc.
(mg/mL)
T
(°C)
Flowrate Conversion
(mL/min) (1H NMR)
1
100
100
100
100
100
100
100
50
20
0
3
3
5
3
3
3
3
3
3
3
3
1
25%a
25%a
12%a
N/Ab
33%c
25%d
tracese
50%c
64%c
66%c
66%c
40%c
2
3
20
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20
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5
6
9
55%c
40%c,f
33%c,f
Note: reactor set-up: 1/16” tubing diameter with 9 mL coil volume unless stated otherwise. quench method: receiver tank
a
contained a solution of thiourea (1 equiv) in MeOH at 20 °C and 1H NMR analysis was conducted at the end of the run. bquench
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c
method: in-line thiourea quench attempt resulted in clogging the BPR. quench method: receiver tank contained a solution of
thiourea (1 equiv) in MeOH at 20 °C and 1H NMR analysis was conducted after stirring overnight. dquench method: receiver tank
contained a solution of thiourea (1 equiv) in MeOH at -40 °C and 1H NMR was conducted after stirring overnight at 20 °C. equench
method: receiver tank contained a solution of NaBH4 (0.25 equiv) in MeOH at 20 °C and 1H NMR was conducted at the end of the
run. freactor set-up was changed to 1/8” tubing diameter with a 32 mL coil volume.
We started by feeding a solution of Rose Bengal (0.1 mol%) and 2 (100 mg/mL) through the
custom-made photoreactor at a 3 mL/min flowrate at 20 °C. The output solution was quenched
directly into a 20 °C solution of thiourea (1 equiv) in MeOH. Analysis of the thiourea/diol 4 ratio
by 1H NMR at the end of the run suggested a 25% in situ yield (Table 2, entry 1). It is known that
the epidioxide intermediate 3 is unstable at temperatures higher than -30 °C.4b Yet, no difference
in conversion was observed at 0 °C (entry 2), which may be explained by the short residence time
(3 minutes). Increasing the flowrate to 5 mL/min was detrimental to the formation of 4 (entry 3,
12% in situ yield), likely due to a shorter residence time. At this flow rate, oxygen bubbles are still
visible towards the end of the coil. In contrast, at 3 mL/min, oxygen bubbles decreased after
approximately 2/3 of the reactor coil length, suggesting that the conversion is complete (Figure 2).
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Figure 2. Oxygen consumption seen over the length of the coil at a 3 mL/min flow rate.
Next, we turned our attention to the quench method. Adding thiourea (1 equiv) to the feed
solution to implement in-line quenching proved extremely challenging due to precipitation of
elemental sulfur that clogged the BPR after only 5 minutes (entry 4). For this reason, the quench
had to be performed in batch mode and we ensured that no degradation over time was observed in
the collection vessel. We also quickly realized that stirring the quench solution overnight prior to
the 1H NMR analysis slightly increased the yield (33%, entry 5) compared to immediate analysis
(25%, entry 1). Quenching at -40 °C did not improve the in situ yield (entry 6) while serious
degradation was observed when using sodium borohydride as the reductant (entry 7).
Substrate concentration was also studied, and illustrated that in situ yield increased as
concentration decreased (entries 8-11). Optimum concentration was determined to be 33 mg/mL
to balance both in situ yield (64%) and material throughput (entry 9). The effect of changing the
flow rate at that concentration was also investigated. When the flow rate was decreased, and thus
a longer reaction time was maintained, significantly lower conversion was observed (40%, entry
12). A possible explanation for this would be degradation of the epidioxide intermediate 3. When
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the reaction time was decreased by increasing the flowrate to 5 mL/min, the conversion decreased
as well (entry 13), suggesting an optimal flowrate of 3 mL/min. Finally, increasing the tubing
diameter size to 1/8” at higher flowrate was attempted to improve material throughput (entries 13
and 14). While in situ yields were somewhat lower in both instances, these two runs demonstrated
that this chemistry should be amenable to large scale production with some further optimization.
With optimized conditions identified for this flow photooxidation, a scale-up run was performed
on 35 g of cyclopentadiene 2. The total irradiation time was 6 hours, giving a throughput of 6 g of
cyclopentadiene per hour, which correlates to a production of 8.6 g of diol 4 per hour. Since the
resulting diol 4 was found to be highly water soluble, extractive workup and isolation were
challenging. Therefore, the diacetylation step was telescoped, using reported reaction conditions.12
Diacetate 5 was obtained in 44% yield (42 g) over three steps (Scheme 2). This result is
noteworthy, as reported batch experiments were only performed on small scale and needed long
irradiation times (16 hours).5b In addition, the use of the flow process reduced the solvent
consumption by half and minimized formation of by-products, allowing a simple aqueous work-
up to remove most impurities and obtain diacetate 5 in >97% purity.
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Step 3
Step 2
Step 2 quench
green LED
OH
OAc
Ac2O (3.96 equiv)
DMAP (9 mol%)
Thiourea (1 equiv)
O
O
O2
MeOH, 20 °C
overnight
Pyridine
0 °C
Rose Bengal
(0.1 mol%)
MeOH, 20 °C
2
OH
4
not isolated
OAc
5
42 g
97% purity
35 g input
3
44% yield
(3 steps)
flow: 3 mL/min
2
throughput: 6 g/h of
Scheme 2. Scale-up synthesis of diacetate 5 from diene 2.
The final step of the sequence was the desymmetrization towards monoacetate 6 using
Novozyme 435, based on a literature precedent as a starting point.5a And while the reaction
performed quite well under the reported conditions with 98.9% selectivity, some over-hydrolysis
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generating 4 as an impurity was detected (Table 3, entry 1). For this reason, an optimization of
relevant parameters (pH, temperature, reaction time and concentration) was undertaken, with the
aim to achieve a robust and scalable desymmetrization process.
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Table 3. Optimization of the biocatalyzed desymmetrization of diacetate 5.
Step 4
OAc
OH
Novozyme 435
(2 x 2.6 %wt)
pH 6 buffer
4 °C
OAc
OAc
6
5
Entry Substrate
5 conc.
T (h) T (°C) pH
6 by GC 6 ee% 4 by GC
(area%) (GC)
(area%)
10%
ND
86%
99%
98%
97%
99%
98%
99%
99%
99%
99%
99%
1
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.5 M
1.0 M
18
5
25
25
15
4
8.5
8.5
8.5
8.5
6
98.9%
97.2%
97.3%
97.3%
99.4%
98.7%
98.2%
98.9%
99.1%
98.9%
98.9%
2
ND
3
5
ND
4
5
ND
5
4
25
25
25
15
4
ND
6
4
7
ND
7
4
9.2a
6
ND
8
5
ND
9
5
6
ND
10
11
27
27
4
6
ND
4
6
Conditions: scale: 1mmol of substrate. Buffer (K2HPO4/KH2PO4; 0.1 M), aBuffer (Na2CO3/NaHCO3; 0.1 M); ND: not detected.
As shown in Table 3, decreasing the temperature did not have a huge impact on the outcome of
the reaction (entries 2, 3 and 4). In contrast, a change in pH (entries 5-7) led to dramatically
different reaction profiles. At pH 6, optical purity achieved 99.4%, and most importantly over-
hydrolysis was shut down under these conditions (entry 5).
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As pH 6.0 seemed to eliminate over-hydrolysis, the reaction was performed at this pH at 15 °C
and 4 °C (entries 8 and 9). Performing the hydrolysis at 4 °C and pH 6.0 afforded monoacetate 6
in the highest selectivity and yield. To further improve the scalability of this process, the
concentration of the substrate was increased using optimized conditions (entries 10 and 11). In
both cases only traces of starting material were observed after 27 hours. The product was obtained
with very good selectivity in both cases (98.9% ee) and therefore the substrate could be utilized at
a remarkable 1 M concentration. The reaction was scaled up seamlessly allowing the conversion
of 38 g of diacetate 5. Compound 6 was isolated in 76% yield (22.3 g) and 99.0% ee. The final
product 6 could be recrystallized to increase enantiomeric excess to 99.8%, although this final re-
work was not fully optimized.
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Step 2
Step 2 quench
Step 3
Step 4
O2
Rose Bengal
(0.1 mol%)
green LED
OH
OAc
OH
Ac2O (3.96 equiv)
DMAP (9 mol%)
Novozyme 435
(2 x 2.6 %wt)
Thiourea (1 equiv)
O
O
MeOH (30 mL/g)
19 °C
MeOH (25 mL/g)
20 °C, 12 h
Pyridine (7.7 mL/g)
0 °C, 2 h
pH 6 buffer (5.4 mL/g)
150 rpm, 4 °C, 18 h
2
OH
OAc
5
42 g
97% purity
OAc
6
3 mL/min
35 g input
3
44% yield
(3 steps)
76% yield
22.3 g (from 38 g of 5)
4
throughput: 6 g/h
96% purity
99.0% ee
Scheme 3. Full optimized sequence from cyclopentadiene 2 to key building block 6.
In conclusion, we have developed a straightforward process to produce (1R,4S)-4-
hydroxycyclopent-2-en-1-yl acetate in multigram scale. One of the key improvements of this route
relies in the use of flow chemistry during the photochemical step. This technology clearly
enhanced the overall reaction profile, output of material (up to 8.6 g of 4 per hour) while reducing
by half solvent consumption compared to batch. The flow reactor was constructed from
inexpensive and widely available components, and is clearly capable of supporting larger scale
production. Increasing the coil length by only 5x with additional lamp power would lead to an
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output of at least 1 Kg/day of diol 4. The enzymatic desymmetrization step was also further
optimized, revealing that pH plays a crucial role during this transformation. Indeed, lowering the
pH to 6 led to full conversion with undetectable amount of over-hydrolyzed product and with
>99% enantiomeric purity. We expect this process would be easily adapted for large-scale
synthesis and could supply the synthetic chemistry community with this particularly useful
building block.
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EXPERIMENTAL SECTION
Cyclopenta-1,3-diene (2). In a distillation setup, dicyclopentadiene (DCPD) (approximately
150 mL, 1.84 mol) was loaded into a 250 mL 3-neck flask (equipped with thermometer) and was
heated to reflux temperature (167 °C) (heater set: 210 °C). When the collection flask (placed in an
ice batch) was filled until half (~ 4 hours), distillation was stopped, and the colorless oil analyzed
by 1H-NMR. The collected clear oil (35 g, 0.53 mol) was diluted with methanol (530 mL) to
provide a 1M solution. The solution was stored at -18 °C overnight. 1H NMR (300 MHz, CDCl3)
δ 6.63 – 6.53 (m, 2H), 6.52 – 6.43 (m, 2H), 2.99 (s, 2H).
Photo-flow reactor setup: 6.5 m PFA (Perfluoroalkoxy) tube (1/16” OD) with the
correspondent fittings was coiled around a Drechsel bottle used as cooling system to make the 9
ml reactor and placed in the middle of the closed irradiation system. The used light source is green
LED (525 nm). The income of the coil was connected to a T-piece, one side of the T-piece was
connected to the HPLC pump and the other side to the O2 cylinder with a needle valve. At the
outcome of the coil a Zaiput back pressure regulator (BPR) was connected to maintain the system
under 8 bar pressure. A thermometer was attached to the coil, in order to study the increase of the
temperature during the reaction (see set up in Figure SX of the supporting information).
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Process Safety note: since O2 is used in excess and expected in the effluent, a N2 sweep was used
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Cyclopent-4-ene-1,3-diol (4). The flow system was washed with methanol at 3 mL/min for 10
min, the O2 cylinder was opened and the system is setup for a ratio O2/solvent 3/2 under 8 bar
pressure (Zaiput BPR was used). Thiourea (40.3 g, 1 equiv, 0.53 mol) was dissolved in methanol
(1 L) in a 3 L flask equipped with a stirrer, placed in an ice-bath and covered with aluminum foil.
Cyclopenta-1,3-diene 2 (1 M solution in MeOH, 35 g, 0.53 mol) was diluted with methanol (530
mL) in an Erlenmeyer. Rose Bengal (539 mg, 0.1 mol%, 0.53 mmol) was added to the solution
and the Erlenmeyer was placed in an ice-bath. The cooling system of the photoreactor and the light
was switched on. The temperature was constant at 19 °C during the run. The solution of starting
material (1.06 L) was pumped through the photoreactor (9 mL coil) at 3 ml/min (reaction time, Rt
= 3 min) and the outcome collected in the quenching flask at 20 °C. The solution was stirred
overnight, then the solvent was concentrated to 150 mL and filtered through diatomaceous earth.
The filtrate was concentrated to give 87 g of crude material used as is in the next step (160 % crude
yield). 1H NMR (300 MHz, d6-DMSO) δ 5.78 (s, 2H), 4.81 (d, J = 6.1 Hz, 2H), 4.40 (dt, J = 7.3,
6.0 Hz, 2H), 2.61 – 2.49 (m, 1H), 1.24 (dt, J = 12.9, 5.9 Hz, 1H). Selected signals of the desired
product from the crude 1H NMR.
Cyclopent-4-ene-1,3-diyldiacetate (5). Cyclopent-4-ene-1,3-diol (52.2 g, 1 equiv, 0.52 mol)
was dissolved in pyridine (400 mL) at 0 °C under inert atmosphere. N,N-4-Dimethylaminopyridine
(5.7 g, 0.09 equiv, 46.9 mmol) was added and acetic anhydride (195 mL, 3.96 equiv, 2.06 mol)
was added dropwise over two hours, keeping the temperature below 7 °C. Upon completion, the
mixture was poured into 750 mL ice water with caution and extracted with Et2O (3 × 250 mL).
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The organic phases were combined and washed with 1M HCl (3 × 250 ml), NaHCO3 (5% aq.) (2
× 250 ml) and brine (1 × 250 ml). The organic layer was dried over Na2SO4, filtered and the solvent
was evaporated under vacuum to give the desired diacetate 5 (42.1 g, 44 % yield over three steps).
1H NMR (300 MHz, CDCl3) δ 6.09 (s, 2H), 5.53-5.56 (m, 2H), 2.87 (dt, J = 15.0, 7.6 Hz, 1H),
2.06 (s, 6H), 1.74 (dt, J = 15.0, 3.8 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 170.6 (2C), 134.5 (2C),
76.5 (2C), 37.0, 21.0 (2C).
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(1R,4S)-4-hydroxycyclopent-2-en-1-ylacetate (6). To a 4 °C suspension of cyclopent-4-ene-
1,3-diyl diacetate 5 (38.0 g, 1 equiv, 206.5 mmol) in potassium phosphate buffer (pH 6, 206.5 mL)
was charged Novozyme 435 (987.2 mg) and the mixture was stirred at 150 rpm. The reaction was
monitored following this sampling procedure: a 200 µL sample was extracted with DCM (2 × 500
µL), dried over Na2SO4, filtered and analyzed by gas chromatography (GC). After six hours, a
second charge of Novozyme 435 (987.2 mg) was added and stirring was pursued overnight. The
reaction was then filtered, extracted with DCM (4 × 200 mL) and the combined organic layers
were washed with water (1 × 200 mL). The organic layer was dried over Na2SO4, filtered and
evaporated under vacuum. The crude product was isolated as a yellow liquid, 22.3 g (76% yield,
96% purity, 99.0% ee).
An analytical sample was obtained as a pale brown solid by unoptimized crystallization in
diethyl ether / pentane (2:1 v/v) at -20 °C, increasing ee to 99.8%. 1H NMR (300 MHz, CDCl3) δ
6.11 (ddd, J = 5.6, 2.1, 1.2 Hz, 1H), 5.98 (ddd, J = 5.6, 2.1, 1.1 Hz, 1H), 5.55 – 5.43 (m, 1H), 4.71
(s, 1H), 2.80 (dt, J = 14.7, 7.4 Hz, 1H), 2.04 (s, 3H), 1.65 (dt, J = 14.6, 3.8 Hz, 1H). 13C NMR (75
MHz, CDCl3) δ 170.9, 138.5, 132.3, 77. 1, 74.5, 40.4, 21.2.
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AUTHOR INFORMATION
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Corresponding Author
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Email: christophe.allais@pfizer.com
ORCID: 0000-0002-3443-9391
Email: k.pouwer@syncom.nl
ORCID: 0000-0002-5304-1776
Author Contributions
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The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
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7 As we were developing this piece of work, Wu et al. reported on a photoflow approach similar
(see ref 6g) to the one described herein. They nicely demonstrated that use of scCO2 as the solvent
of the reaction cleanly delivered the diol 4 in high yield. However, use of high pressure, limit in
the overall flow rate due to blockages in the system and lower material input still make our
contribution relevant for the community targeting large scale synthesis.
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8 R. B. Moffett, Cyclopentadiene and 3-Chlorocyclopentene, Org. Synth. 1952, 32, 41–44.
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Endoperoxides, Chem. Commun., 2005, 4426–4428; for example of use of triphenylphosphine,
see: b) I. Erden, C. Gärtner, M. S. Azimi, Triphenylphosphine Reduction of Saturated
Endoperoxides, Org. Lett. 2009, 11, 3986–3989; For example of use of sodium borohydride, see
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Reductive Cleavage of 1,2-Dioxolanes. Application to the Synthesis of (±)-Yashabushitriol,
Tetrahedron Lett. 1989, 30, 6985–6988.
10 PerFluoroAlkoxy polymer
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Instability of intermediate 3 has been reported before, see D. Holland, J. F. Stoddart,
Regioselective and Stereoselective Methods for the Synthesis of the Pentitols, J. Chem . Soc.,
Perkin Trans. 1, 1983, 1553–1571.
12 S. Busato, O. Tinembart, Z.-D. Zhang, R. Scheffold, Vitamin B129 a Catalyst in the Synthesis
of Prostaglandins, Tetrahedron 1990, 46, 3155–3166.
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