Calcium hypophosphite mediated deiodination in water: Mechanistic insights and applications in large scale syntheses of d-quinovose and d-rhamnose

Article abstract of DOI:10.1039/c8gc03851a

The inorganic calcium hypophosphite was found to be a cheap, non-toxic, water-soluble and environmentally friendly reducing reagent for radical deiodination in water. Thorough mechanism studies revealed that calcium hypophosphite was oxidized to water insoluble calcium phosphite which was the major co-product of the deiodination reaction. Based on this observation, a practical synthesis of rare d-quinovose and d-rhamnose from cheap and commercially available materials on a hundred-mmol scale was reported.

Full text of DOI:10.1039/c8gc03851a

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DOI: 10.1039/C8GC03851A
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Calcium Hypophosphite Mediated Deiodination in Water:
Mechanistic Insights and Applications in Large Scale Syntheses of
D-Quinovose and D-Rhamnose†
Received 00th January 20xx,
Accepted 00th January 20xx
Zejin Song#,a Lingkui Meng#,a Ying Xiao,a Xiang Zhao,a Jing Fang,a Jing Zenga and Qian Wan*,a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
The inorganic calcium hypophosphite was found to be a cheap, non- process.3a Many other issues must be considered, such as
toxic, water-soluble and environment-friendly reducing reagent for production yield, the way of work-up and purification processes
radical deiodination in water. Thoroughly mechanism studies etc. In addition, co-solvents, surfactants or phase transfer
revealed that calcium hypophosphite was oxidized to water catalysts (PTC) are often required for “on-water”-based
insoluble calcium phosphite which was the major co-product of the reactions, which also increased the cost for the further
deiodination reaction. Based on this observation, a practical purification and treatment processes of water.6 Most
synthesis of rare D-quinovose and D-rhamnose from cheap and importantly, the work-up and purification processes of the
commercially available materials in hundred-mmol’s scale was reaction with water soluble, especially highly water soluble,
reported.
reactants and products are much more complex than that of
water insoluble or less soluble substrates.7a-b Consequently, this
type of reactions has almost been neglected to date.7c
A survey by the ACS Green Chemical Institute Pharmaceutical
Roundtable indicated that 88% by mass of materials used in the
production of APIs (active pharmaceutical ingredients) were
solvents.1 Solvents are widely used in various chemical
syntheses and purification processes. In general, they are often
essential to facilitate mass and heat transfer. However, solvents
are also account for the major source of wasted mass of
pharmaceutical industry. The negative impact to environment
of waste solvents are constant source of society worry.2
a) Tin free chain carrier (Barton and Jang 1992)
O
P
H
radical
initiator
H
O
R-X
R-H
+
phosphinic acid
or hypophosphite
low water solubility substrates
b) Proposed co-products and their hydrolysis (Murphy 2003)
Since water is readily available, cheap, non-flammable and
non-toxic, it is one of the most ideal solvent from environmental
and economic concerns.3 The Breslow’s pioneering work has
boosted the studies using water as the reaction medium in the
following decades.4 Owing to the “on-water” concept
developed by Sharpless et al., most attentions have been paid
to the reactions with insoluble reactants in an aqueous
suspension.5 Despite these advances, running a reaction in
water instead of conventional organic solvent does not
guarantee to improve the environmental impact of a synthetic
O
O
O
O
hydrolysis
or/and
or/and
HO
H
P
I
I
P
I
H
P
OH
P
OH
H2O
OH
A
OH
B
OH
OH
highly water soluble acid or salts
c) Deiodination of highly water soluble substrate in water (this work)
I
radical initiator
O
O
HO
HO
HO
HO
sole water
Ca(H2PO2)2,
Ca(OH)2
H2O
CaHPO3
+
HO
HO
OMe
OMe
water soluble sugars recovery up to 97%
Scheme 1. Radical reductive deiodination with hypophosphorous acid and its salts.
In 1992, Barton, Jang and Jaszberenyi reported that H3PO2
(hypophosphorous/phosphinic
acid)
and
its
salts
a. Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation,
School of Pharmacy, Huazhong University of Science and Technology, 13
Hangkong Road, Wuhan, Hubei, 430030, P. R. of China. E-mail:
wanqian@hust.edu.cn
(hypophosphite) were fascinating reducing reagents for the
radical deoxygenation, dehalogenation and deamination
reactions.8 (Scheme 1a) Various hypophosphites (sodium,9a N-
ethylpiperidinium,9b tetraalkylammonium9c and anilinium9d
etc.), dialkyl phosphites,9e diethyl thiophosphite9f and
diethylphosphine oxide,9g were subsequently found to be able
to perform the reduction reactions as well. Later, Jang reported
b. Institute of Brain Research, Huazhong University of Science and Technology, 13
Hangkong Road, Wuhan, Hubei 430030, P. R. of China.
# These authors contributed equally.
† Dedication to the memory of Ronald Charles D. Breslow.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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OH
O
I
I
I
2, PPh3
that a mixture of H3PO2/NaHCO3 could reduce water soluble
organohalides in water.7b Jang also pointed out that the yields
of highly water-soluble substrates were decreased due to the
challenging work-up process. Compared to the conventional
hydrides (tin, aluminium, boron, silicon, etc.),10a the
phosphorous derivatives are non-toxic, cheap, abundant, non-
flammable and environmentally compatible.10b-e However,
phosphorous reagents were usually used in large excess (5-10
equiv.), and the unreacted phosphorus reagents were difficult
to be recovered in these reports. These situations bring
problems in production of more unnecessary wastes. Indeed,
Murphy et al. has already warned this matter in 2003.9g Murphy
also proposed two possible intermediates, mono-iodo-
phosphite A9c,9g and di-iodo-phosphate B9g for the deiodination
reactions with N-ethylpiperidinium hypophosphite (EPHP).
These two iodo-substrates could be hydrolyzed to phosphorous
acid and phosphoric acid (Scheme 1b). However, to our best
knowledge, neither the recovery of the unreacted reagents, nor
the mechanism has been well addressed in these reactions.11
Herein, we wish to report a calcium hypophosphite12
mediated radical deiodination of a highly water soluble
substrate in water. The process was monitored by time-
evolution of 31P NMR and the inorganic precipitates were
isolated and analyzed by X-ray photoelectron spectroscopy
(XPS), X-ray fluorescence (XRF) and power X-ray diffraction
(XRD). Our studies confirmed that the water insoluble calcium
phosphite is major co-product along with the deiodination
(Scheme 1c). Based on these observations, an efficient synthesis
of tetra-O-acetyl-D-quinovose 1, from cheap and readily
available material was developed. More than 110 grams of 1
were prepared in four steps without column chromatography
(Fig. 1).
O
Ac2O/pyridine
O
View Article Online
DOI: 10.1039/ACcO8GC03851A
Imidazole, THF
HO
HO
HO
HO
AcO
AcO
Garegg-Samuelsson
procedure
HO
HO
OMe
OMe
OMe
2
3
4
(84%, two steps)
3 atm
H2
(
)
O
O
AcO
AcO
AcO
AcO
H2SO4, Ac2O
AcOH
Pd/C
5%
(cat.)
OAc
AcO
AcO
EtOAc-H2
O
OMe
5
1
(91%, two steps)
Scheme 2. Ueda’s synthetic approach to 1 from glucose.
selective iodination and subsequent deiodination were
investigated (Table 1). When non-polar toluene reaction
medium was replaced by acetonitrile, an optimal condition was
found for conversion of 2 to 3. After removal of TPP and TPPO
by extraction, the resulting crude aqueous phase containing 3
was directly subjected to the subsequent Barton and Jang’s
radical deiodination condition.7b,8a,16 The radical reaction was
initiated by water-soluble radical initiator VA-044 at 70 ˚C, and
different water-soluble reductants were examined (Table 1,
entries 1-4). Among them, the inorganic hypophosphite and
H3PO2/NEt3 provided good reductive capacity, especially, the
reduction with 1.0 equiv. of Ca(H2PO2)2 provided the highest
isolated yield; while sodium phosphite (Na2HPO3) was
inefficient. Hypophosphorous acid is generally sold as aqueous
solution (up to 50%), it is a strong acid which may lead to
potential health hazard. In contrast, sodium and calcium
hypophosphite are cheap, environmentally friendly and almost
neutral or weak acidic, thus are optimal reductants.
Table 1. Initial screening and optimization for deiodination.[a]
2) deiodination[d]
I
OH
O
1) idoination[b],[c] HO
HO
Reductant
O
O
AcO
AcO
HO
HO
HO
3) acetylation[e]
AcO
HO
OMe
OMe
OMe
5
3
2
(crude in water)
(0.5 g)
Entry Reductant (equiv.)
Time
2.0 h
1.5 h
1.5 h
8.0 h
Yield[f]
Precipitate
D-Qui
O
HO
HO
D-Qui
H
O
OH
O
OH
O
1
2
3
4
5
H3PO2/TEA (3.0)
NaH2PO2H2O (1.4)
Ca(H2PO2)2 (1.0)
81%
/
O
H
D-Qui
O
AcO
AcO
O
O
OAc
O
N
HO
O
O
HO
HO
HO
O
AcO
O
O
HO
HO
OH
O
83%
/
D-Qui
HO
O
OH
1
O
(112 grams)
O
HO
89%
0.25 g
/
OH
-amylase inhibitor
albinoside VII
O
Figure 1. Selective examples of important bioactive natural products and drug candidate
incorporating D-6-deoxy glucose (quinovose).
Na2HPO35H2O (2.0)[g]
28%[h]
86%
Ca(H2PO2)2 (0.7)
1.5 h
0.23 g
(85%)[i]
Many attractive natural products and clinic reagents
incorporated rare 6-deoxy sugars. For example, -amylase
inhibitor13a,b and noncytotoxic efflux pump inhibitor albinosides
contained D-quinovose moiety (Fig. 1).13c,d As a starting material
to synthesize these bio-important compounds, an efficient and
practical synthetic approach for large scale synthesis of 1 is
highly demanded. Ueda et al. have reported a well-designed
four-step synthetic route to 1 (Scheme 2).14 Garegg and
Samuelsson’s selective iodination of 6-hydroxyl group15 and
hydro-deiodination were the key steps for the success of the
procedure. Despite significant improvement of the efficiency by
this approach, precious metal, un-favorite pyridine and three
bars hydrogen atmosphere were still required.
6
7
8
9
Ca(H2PO2)2 (0.55)
Ca(H2PO2)2 (0.7)
1.5h
1.5 h
1.5 h
1.5 h
78%
Yes[j]
/
0%[k]
85%
Ca(H2PO2)2/Ca(OH)2 (0.7/0.55)
Ca(H2PO2)2 (0.7)
0.35 g
0.35 g[l]
86%[l]
[a] Unless otherwise stated, the equivalent of additives was calculated based on
the starting material 2 (0.5 g). [b] Iodination condition: I2 (1.3 equiv.), PPh3 (1.5
equiv.), imidazole (2.0 equiv.) in MeCN, 70 ˚C; [c] The reaction mixture was
extracted with DCM or Toluene, and the resulting aqueous phase was used directly
for the next step without further purification. [d] 0.1 equiv of VA-044, 70 ˚C, under
argon. [e] Ac2O (6.0 equiv.), Et3N (6.0 equiv.), DMAP (0.1 equiv.), DCM, r.t. [f]
Isolated yield in three steps after one flash column chromatography purification.
[g] 0.2 equiv. of VA-044. [h] Determined by 1H NMR. [i] water taken directly from
the Yangtze River at Wuhan. [j] The precipitate was not collected. [k] without VA-
044, 70 ˚C, under argon. [l] 0.55 equiv. of Ca(OH)2 was added after the reaction was
completed.
In view of the advantages of Ueda’s protocol, we considered
to further optimize the conditions for a more efficient and
greener synthesis of 1 in bulk. Initially, the conditions for
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Interestingly, reducing the amount of Ca(H2PO2)2 to 0.7 2a). White precipitate started to form when the reaction
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˚
DOI: 10.1039/C8GC03851A
equivalent, the reduction efficiency was not affected apparently mixture was heated at 70 C for 20 min. However, at this point,
(Table 1, entry 5). Further decrease the amount to 0.55 equiv it was not found any new signal by 31P NMR measurement (Fig
led to lower isolated yield. It was found that the radical 2b). After 1.5 h heating, the reaction was completed and a new
deiodination was quite robust, even using the water directly doublet peak at 2.51 (J = 616 Hz) was appeared (Fig 2c). This
taken from the Yangtze River still offered 85% yield (Table 1, new doublet peak was attributed to a phosphorous derivative,
entry 5). Interestingly, we found that there was copious white most possibly, phosphorous acid or phosphite. However, when
precipitate formed in the aqueous solution when Ca(H2PO2)2 the reaction mixture was treated with additional Ca(OH)2, the
served as reductant (table 1, entry 3, 5). This precipitate was doublet peak couldn’t be detected any more (Fig 2d). Only the
able to be removed from the reaction mixture by a simple signals of phosphorus of unreacted Ca(H2PO2)2 were observed.
filtration, which simplified the following aqueous work-up These studies indicated that only one major new phosphorus
process.
derivative was generated in the deiodination reaction, and
these species could be precipitated by calcium ion. To clarify the
component of the precipitate, the resulting precipitate and an
authentic sample of CaHPO3 monohydrate was dissolved in 20%
HCl solution respectively and monitored by 31P NMR. It was
found that the spectra of the two samples were identical, which
implied that the phosphorus was precipitate in the form of
CaHPO3 and the hypophosphite was possibly oxidized to
phosphite. Other than CaHPO3, it was not surprising that trace
amount of phosphoric species could be found in the crude
precipitate (Fig 2e and 2f).9g
Figure 2. The reaction of table 1 (entry 5) was monitored by proton-coupled 31P-NMR
spectra (0.5 mL of reaction mixture and 0.1 mL D2O): a) before heating (pH ≈ 9.0); b) 20
min, (pH ≈ 8.0); c) 1.5 h, (pH ≈ 7.0); d) additional Ca(OH)2 (0.55 equiv) was added, and
the precipitate was filtrated; e) the isolated precipitates were dissolved in 0.5 mL of HCl
in 20 wt% H2O and 0.1 mL of D6-DMSO; f) Authentic sample of CaHPO3 was dissolved in
0.5 mL of HCl in 20 wt% H2O and 0.1 mL of D6-DMSO.
It was known that hypophosphorous acid is weaker reducing
agent than its corresponding salts. In addition, the strong acidic
condition may sluggish the phosphorous-centered radical chain
reaction or decompose the acid-labile substrates. We also
noticed that the pH tended to drop during the reaction process
when hypophosphites were used for the deiodination. Thus,
additional bases (Et3N or Ca(OH)2) were added to the reaction
to balance the pH value. Interestingly, the synthetic efficiency
was not affected, while the amount of precipitate was
significant increased (table 1, entry 8, 9). These observations are
not trivial, they might provide clues for understanding the
mechanism.
Figure 3. X-ray photoelectron spectroscopy (XPS) analysis and X-ray fluorescence (XRF)
analysis of precipitates which obtained from table 1 (entry 9): a) XRF analysis. b) XPS
survey spectrum. c) P 2p spectrum of XPS. Wt% = weight%, At% = atom%
Although the 31P NMR provided fruitful information to
understand the process of deiodination reactions in water, an
accurate analysis of the precipitate composition was required
to support the hypothesis. The composition of the precipitate
was first detected by XRF experiment. The Ca/P molar ratio
turned out to be 1.0:1.07, which is very close to that of CaHPO3
(1:1) (Fig. 3a). In addition, a survey XPS of the precipitate
prepared as described in table 1 (entry 9) was shown in Figure
3b. The corresponding Ca, P, and O peaks were observed along
with an unexpected C (1s) peak. The C atom interference may
attribute to the adsorption of certain hydrocarbons.17 The P 2p
spectrum clearly suggests the presence of phosphorus atom
Subsequently, the radical deiodination of crude 3 in water
was monitored by 31P NMR experiments. The proton-coupled
31P NMR spectra of the reaction mixture showed a triplet peak
at 6.94 ppm (J = 517 Hz) which was assigned to Ca(H2PO2)2 (Fig
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(Fig. 3c). The P 2p spectrum has been fitted by considering a TPP and TPPO.19 Consequently, the reaction mixture was
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resolved doublet (with a spin-orbital splitting of 0.9 eV between concentrated in vacuo when the iodDinOaI:ti1o0n.103r9e/aCc8tGioCn038w5a1As
2p3/2 and 2p1/2). The value of 132.77 eV is comparable to the completed, and the removed MeCN which could be used in the
reported value of BaHPO3 (132.60 eV) and the measured value following steps was collected. Then water was added to the
of the authentic CaHPO3 sample (132.89 eV) (See SI, Figure S13). resulting residue with vigorously stirring, white precipitates
Therefore, there is a great possibility that the resulting (TPP and TPPO) were formed. The resulting precipitates were
precipitate is CaHPO3 monohydrate in the reduction of organo- removed by a simple filtration. This manipulation ensured us to
iodide using Ca(H2PO2)2 as reductant.18 Finally, powder XRD recover up to 98% of organophosphorus compounds (Scheme
examination provided substantial proof to confirm that the 4, step 1).
precipitate was exactly CaHPO3 monohydrate (See SI, Fig S15).
These results validate the hypothesis that hypophosphorous
anion was oxidized to phosphorous anion during the
deiodination reaction.
OH
O
I
step 1: iodination
HO
HO
O
imidazole
HI
HO
HO
OPPh3 + PPh3
+
+
imidazole•
i) I2, PPh3 Imidazole, MeCN
ii) water (precipitation)
HO
HO
OMe
OMe
2
98% recovery
(pure TPPO 78%)
3
, 412 mmol
(80.0 grams)
aqueous filtrate
imidazole
Me
O
step 3: acetylation
step 2: deiodination
VA-044, Ca(H2PO2
Ca(OH)2, 70 °C, 1.5 h
HO
Ca(H2PO2
+
CaI2
)
initiation
2
CaHPO3•H2
O
+
HO
O
P
O
P
H
)
i) Ac2O, Et3N, DMAP, MeCNa
2
HO
OMe
phosphinic acid
phosphinate
etc.
ii) water (wash)
H
O
+
init
eq 1
eq 2
H
O
6
97% recovery
54.9 grams
I
aqueous filtrate
iodine atom transfer
Me
O
step 4: acetylation
AcO
AcO
O
O
four steps
no column
chromatography
OAc
O
H
I
AcO
AcO
P
+
+
R
I
R
II
P
AcO
112.0 grams
,
AcO
i) H2SO4, Ac2O, AcOH
ii) recrystalization
H
O
O
O
OMe
I
III
1
5
82% over four steps
hydrogen transfer
O
P
O
water soluble
radical initiator
HO
R
AcO
H
P
H
HO
HO
HO
+
R H
N
+
eq 3
eq 4
H
O
O
HN
O
AcO
II
I
OAc
4 steps
AcO
N
N
2 HCl
OMe
hydrolysis
N
8
35.2 grams
,
7
, 129 mmol
(25.0 grams)
HN
83%b over four steps
VA-044
O
O
H
I
P
H2O
+
OH
+
H
P
I
+
H
O
Scheme 4. Synthesis of rare 6-deoxy sugar 1 and 8. a) the recovered MeCN from step 1
was used directly; b) compound 8 is not in crystal form, a short column chromatography
was required.
OH
III
net reaction (omitting initiator)
O
O
eq 5
+
+
H2O
R
H
+
OH
+
R
I
H
P
H
O
H
P
I
OH
A crystallization in petroleum ether provided 132.7 grams
of pure TPPO (78% recovery). The combined aqueous filtrate
including crude 3, imidazole and HI salts, was submitted to
the radical deiodination conditions directly. The reaction
mixture was heated at 70 oC for 1.5 h, then additional of 0.55
equiv. of Ca(OH)2 was added to precipitate of CaHPO3 (54.9
grams, 97%) (Scheme 4, step 2). The rested mother liquor was
Scheme 3. Postulated mechanism.
A plausible radical chain mechanism was shown in Scheme
3. The radical initiator first abstracts a hydrogen atom from
hypophosphorous acid or hypophosphite to produce a
phosphorus centered radical I (eq 1). Following Barton’s
proposal, the radical I abstracts the iodine atom from iodide
to generate alkyl radical II and iodo-hyphosphosrous anion III
(eq 2). The radical II abstracts one hydrogen atom from
radical chain carrier, H3PO2 or hypophosphite to give desired
deiodided product R-H, and regenerates phosphorus
centered radical I (eq 3). There is no doubt that highly reactive
intermediate III react quickly with water to release
phosphorous acid. This hypothesis well explained why the pH
value become lower during the reaction. Due to the presence
of un-neutralized H3PO3, the following acetylation reaction
required 15 equivalents of Ac2O (see SI, Table S3, Entry 3).
However, when the reaction medium expose to Ca2+, the
water insoluble CaHPO3 was formed and adjusted the
reaction mixture to neutral, thus large excess of Ac2O was not
necessary. In this case, water is not only the reaction medium
but also the reaction reagent and precipitant.
concentrated, to give
a residue including crude 6,
Ca(H2PO2)2,20 etc. The residue was dissolved in the MeCN
which was recovered in the iodination step. The subsequent
acetylation of crude 6 with acetic anhydride, triethyl amine
and DMAP performed excellently to produce methyl tri-O-
acetyl--D-quinovose, 5 (Scheme 4, step 3). At this moment,
the key intermediate 5 is still mixed with many other salts.
Among them, the iodine anion was identified to might inhibit
next acetolysis of 5 (see SI, Table S5). So, the iodine salts, the
excess of imidazole introduced from the beginning and other
salts formed during the reactions were removed by
conventional EtOAc/water extraction. Finally, acetolysis of 5
using Ac2O and H2SO4 in AcOH gave 112.0 grams of the
desired 1 (337.8 mmol) as white crystal (Scheme 4, step 4).
Overall, tetra-O-acetyl-D-quinovose 1 was prepared from
cheap methyl--D-glucopyranoside 2 in a chromatography-
free mode in 82% global yield over four steps. The co-
products triphenyl phosphine oxide and calcium phosphite
monohydrate were isolated as pure forms from reaction
mixture which reduced the environmental impact. With
similar strategy, another rare 6-deoxy sugar, tetra-O-acetyl-D-
rhamnose 8 (35.2 grams, 83% over 4 steps), was prepared
Since the major co-product phosphorous anion was able to
be precipitated by calcium ion in the form of CaHPO3, using
Ca(H2PO2)2 as reductant and Ca(OH)2 as additive would facilitate
the following purification process. Based on these observations,
a water-centred synthetic process to 1 was developed.
However, for a 400 mmol-scale of 6-deoxy sugar synthesis, the
liquid-liquid extraction was no longer to be efficient to separate
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8
(a) D. H. R. Barton, D. O. Jang and J. C. Jaszberenyi,
from commercially available methyl--D-mannopyranoside 7
as well.
Tetrahedron Lett., 1992, 33, 5709-5712; (b) H.VYieowrAimrticitlesOun,liHne.
DOI: 10.1039/C8GC03851A
Shinokubo and K. Oshima, Bull. Chem. Soc. Jpn., 2001, 74, 225-
235; (c) A. Visa, B. Maranescu and G. Ilia, Hypophosphorous
Acid and Its Salts as Reagents in Organophosphorus
Chemistry, ed. P. Tundo, L.-N. He, E. Lokteva and C. Mota,
Springer, Cham, 2016, Chemistry Beyond Chlorine, 137-168;
(d) V. V. Popik, A. G. Wright, T. A. Khan, J. A. Murphy, F. Gelat,
J.-L. Montchamp, Hypophosphorous Acid, ed. L. A. Paquette,
Wiley, Hoboken, 2014, e-EROS Encyclopedia of Reagents for
Organic Synthesis, 1-11.
(a) A. E. Graham, A. V. Thomas and R. Yang, J. Org. Chem.,
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Conclusions
Overall, a convenient synthetic process to D-quinovose 1 and D-
rhamnose 8 in dozens to hundreds of grams scales from cheap
and commercially available materials was reported. In the key
calcium hypophosphite mediated radical deiodination
reactions, 31P NMR, XPS, XRF and powder XRD experiments
revealed that the reductant was oxidized to water insoluble
calcium phosphite. Water played vital roles through the whole
process. It precipitated the organophosphorus compounds and
inorganic calcium phosphite in present of highly water-soluble
sugar. Water was also used as the reaction medium and reagent
for the radical deiodination. After acetylation, water was
further used to remove most of salts and imidazole by simple
washing. In some extent, the key to success was differentiated
the solubility of various substrates in water which streamlined
the purification process. We expected that this efficient,
economical and environment-friendly process would be applied
widely in deoxy sugars and other high-value chemicals
synthesis.
9
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Ca(H2PO)2 is an odorless white solid, it appears non-
hydroscopic in the warm, humid Wuhan summer. It has been
used as a source of phosphorous and calcium in veterinary
and human medicine.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Financial support from National Natural Science Foundation of
China (21472054, 21761132014, 21702068, 21772050), the
State Key Laboratory of Bio-organic and Natural Products
Chemistry (SKLBNPC13425), Wuhan Creative Talent
Development Fund and Huazhong University of Science and
Technology are greatly appreciated. We thank Prof. Ye Yuan
(Wuhan University of Technology) for help on 31P NMR studies.
Notes and references
1
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2
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J. Name., 2013, 00, 1-3 | 5
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Green Chemistry
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Journal Name
COMMUNICATION
18 Based on this observation, the reaction co-product CaHPO3
monohydrate can be isolated from reaction mixture in almost
quantitative yield (table 1 entry 8 and 9).
View Article Online
DOI: 10.1039/C8GC03851A
19 Selected TPPO separation works: D. C. Batesky, M. J. Goldfogel
and D. J. Weix, J. Org. Chem., 2017, 82, 9931-9936.
20 The unreacted Ca(H2PO2)2 along with CaI2 can be precipitated
by addition of EtOH. The recycled solid can used directly for
the deiodination without further purification, See SI, Table S4.
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Page 7 of 7
Green Chemistry
A practical and green synthesis of D-quinovose and D-rhamnose were achieved basedView Article Online
DOI: 10.1039/C8GC03851A
on the mechanistic studies of hypophosphite mediated deiodination.
step 2
step 3, 4
step 1
iodination
OH
O
O
AcO
AcO
deiodination acetylations
OAc
HO
HO
AcO
H2O
HO
OMe
112 grams
82% over 4 steps
no column
Ca(H2PO2)2
CaHPO3• H2O
Ca(H2PO2)2 mediated deiodination in water
water-centered synthetic process
chromatography