Scalable Sn-Catalyzed Regioselective Allylation of 1-Methyl- l -α-rhamnopyranoside

Article abstract of DOI:10.1021/acs.oprd.7b00252

A robust selective allylation of 1-methyl-l-α-rhamnose was developed using di-n-butyltin oxide (n-Bu₂SnO) as the catalyst. Proton sponge was found to be the optimal base for high regioselective control. The optimized condition afforded the 3-O-

Full text of DOI:10.1021/acs.oprd.7b00252

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Full Paper
Scalable Sn-Catalyzed Regioselective
Allylation of 1-Methyl-L-#-Rhamnospyranoside
Xiaoyong Li, and Qiang Yang
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 20 Sep 2017
Downloaded from http://pubs.acs.org on September 20, 2017
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Scalable SnꢀCatalyzed Regioselective Allylation of
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1ꢀMethylꢀ
L
ꢀαꢀRhamnospyranoside
*,
†
Xiaoyong Li, Qiang Yang‡
†Process Development, Dow AgroSciences, Midland, Michigan 48674, United States.
‡Process Chemistry, Dow AgroSciences, 9330 Zionsville Rd., Indianapolis, Indiana 46268,
United States.
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ABSTRACT. A robust selective allylation of 1ꢀmethylꢀ
Lꢀαꢀrhamnose was developed using diꢀnꢀ
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butyltin oxide (nBu2SnO) as the catalyst. Proton sponge was found to be the optimal base for
high regioselective control. The optimized condition afforded the 3ꢀOꢀallylated rhamnose in
excellent regioselectivity (>20 : 1) and 82% isolated yield on 50 g scale. A scalable
isolation/purification process was developed which afforded the desired product in 72% yield
with 1530 ppm of Sn. The residual Sn level can be further reduced to <20 ppm by treatment with
scavengers. This catalytic system also showed outstanding potential in selective benzylation of
the same substrate.
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Keywords: Selctive allylation, diꢀnꢀbutyltin oxide, rhamnose, benzylation, Sn removal
INTRODUCTION
Regioselective manipulation of hydroxyl groups in polyols has been critical to carbohydrate
chemistry due to the frequent need for regiospecific transformation of readily available polyol
containing carbohydrates to ultimately access molecules of relevant biological or medicinal
functions. Among the frequently used protective groups, benzyl ether formation is one of the
most popular strategies serving the need for regioselective manipulation of hydroxyls owing to
its outstanding stability toward acids and bases, large size for steric discrimination, as well as
facial cleavage under unique reducing conditions. As a result, tremendous efforts have been
dedicated to develop efficient selective benzylation of carbohydrates using a variety of reagents.
The allyl group is an excellent orthogonal protecting group that also exhibits a number of
advantages including ease of formation, mild and unique cleaving conditions, and excellent
stability. The allyl group also has a distinct feature as a source of functionalizable C3 carbon
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chain. However, selective allylation of polyols has not enjoyed the same popularity as
benzylation partly due to the smaller size of the allyl group, which creates a challenge for high
regioselectivity. Decades ago, Nashed reported that stannylation of cis vicinal diols in
substituted hexapyranoses using stoichiometric amount of diꢀnꢀbutyltin oxide (nBu2SnO) in
MeOH and subsequent allylation using allyl iodide (4 eq.) in DMF at 100 °C can afford allyl
ether regioselectively at equatorial position. 1 Later, Zhou reported the use of TBAI (1 eq.) and
large excess of allyl bromide (10 eq.) to replace allyl iodide for regioselective allylation of triols
with incomplete reactions and 40−70% yield. 2 The requirement of stoichiometric amount of Sn
reagent, preformation of stannylene acetal, moderate yields, and usually challenging isolation of
isomers promoted us to probe the direct allylation of polyols in the presence of a catalytic
amount of nBu2SnO in a highly regiospecific fashion with less enviromental impact. To the best
of our knowledge, there was only one recent report3a about metal catalyzed allylation of
carbohydrate under neat condition with large excess of allylating reagents. Herein we report an
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efficient and highly regioselective monoꢀallylation of 1ꢀmethylꢀ ꢀαꢀrhamnospyranoside (1) with
L
allyl bromide (1.1−2.0 eq.) in the presence of a catalytic amount of nBu2SnO (0.2−0.5 eq.). This
chemistry was readily scaled up to 50 g to afford 3ꢀO allylated product in 26 : 1 selectivity and
82% isolated yield.
RESULTS AND DISCUSSION
As illustrated in Scheme 1, the hypothesis for selective allylation consists of three key steps.
First, nBu2SnO would preferentially react with the cis 2,3ꢀdiol as opposed to the trans 3,4ꢀdiol of
1 to generate the cyclic dibutylstannylene acetal 2 in situ, This is analogous to the regiospecific
formation of a fiveꢀmembered ring metal complex as described in elegant studies using Sn(IV),3
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Si(IV),4 boronic/borinic acid,5 Cu(CF3COO)2,6 and Mo (V) salt,7 for selective sulfonylation,
benzoylation, or benzylation. Subsequent allylation with allyl halide and an ionic halide additive
would produce an allylated Sn intermediate 3. The halide anion from the ionic halide additive
plays a promoting role by coordinating with Sn and forming the pentacoordinated tin complex
with enhanced nucleophilicity of oxygen atoms in SnꢀO bonds while weakening the SnꢀO bond.8
Finally, the acyclic tin intermediate would react with starting material 1 to release product 4 and
regenerate cyclic dibutylstannylene acetal 2. This step is facilitated by a nonꢀnucleophilic base
which could play a crucial role for securing the catalytic efficiency. The base should be
appropriately selected to minimize the undesired background allylation of low selectivity. It
should be noted that only the monomeric form of dibutylstannylene acetal was depicted in the
proposed mechanism shown in Scheme 1. The participation of dimeric species cannot be
excluded at this point since its population in solution can significantly depend on solvent,
temperature, and additives.3dꢀe, 8b,9
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Scheme 1. Proposed mechanism for the selective allylation catalyzed by nBu2SnO
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Scheme 2. Conformational preference for selective allylation of Sn complexed
carbohydrate
The regioselectivity can be ascribed to an elevated difference in nucleophilicity between
equatorial (3ꢀposition) and axial (2ꢀposition) oxygen in metal complexed cis vicinal diols in
carbohydrates (Scheme 2). Similar conformational preference has been observed for selective
functionalization of carbohydrates.3ꢀ7 Though origin of this conformational preference is not
unambiguously established, stereoelectronic effect could play a critical role.5a, 8b
Based on this hypothesis, initial trials were conducted with 0.2 eq. of nBu2SnO and 1.1 eq. of
allyl bromide. Acetonitrile was chosen as the solvent since it proved to be efficient during
allylation of stoichiometric amount of dibutylstanlene acetal.10 It was discovered that allylation
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proceeded well in the presence of K2CO3 (1.1 eq.) as base and TBAB (0.5 eq.) as additive. H
NMR indicated 72% conversion after 24 h at room temperature with decent selectivity (8: 1)
favoring the 3ꢀOꢀallylation (entry 1). Absence of the tin catalyst, additive, or base led to <5%
conversion at room temperature (entry 2−4). The nonꢀcatalyzed background reaction in the
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absence of nBu2SnO was negligible with K2CO3 (1.1 eq.) at 25 °C (entry 2), strongly suggesting
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that the proposed mechanism in Scheme 1 was operative. At elevated temperature, background
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reaction occurred slowly (entry 5) and a complicated mixture was revealed by H NMR,
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indicating poor selectivity. No conversion to desired product was observed with DBACO (1,4ꢀ
diazabicyclo[2.2.2]octane) or DBU (1,8ꢀDiazabicyclo[5.4.0]undecꢀ7ꢀene) in place of K2CO3. It
should be noted that a nBuSn2O catalyzed protocol for highly selective benzylation in a recent
report3e was attempted for this allylation and moderate selectivity (6 : 1) was observed,
suggesting difficult regiospecific differentiation during allylation of carbohydrates under the
reported conditions.
Table 1. nBu2SnO catalyzed selective allylation of 1-methyl- -α-rhamnospyranoside
L
Entrya
Conv.b
4 : 5e
nBu2SnO
Additive
Base
AllylBr T /°C
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2
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4
5
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8
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0.2 eq.
ꢀꢀ
TBAB (0.5 eq.)
TBAB (0.5 eq.)
ꢀꢀ
K2CO3 (1.1 eq.)
K2CO3 (1.1 eq.)
K2CO3 (1.1 eq.)
ꢀꢀ
1.1 eq.
1.1 eq.
1.1 eq.
1.1 eq.
1.1 eq.
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25
25
25
50
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50
90
50
72
8:1
< 5%
<5%
<5%
14%
17%
< 5%
38%
56%
ND
0.2 eq.
0.2 eq.
ꢀꢀ
ND
TBAB (0.5 eq.)
TBAB (0.5 eq.)
TBAB (0.5 eq.)
TBAB (0.5 eq.)
TBAB (0.5 eq.)
TBAFꢀ3H2O(1.0
ND
K2CO3 (1.1 eq.)
ND
0.2 eq.
--
Proton Sponge (1.1 eq.) 1.1 eq.
Proton Sponge (1.2 eq.) 1.1 eq.
Proton Sponge (1.2 eq.) 1.1 eq.
Proton Sponge (1.2 eq.) 2.0 eq.
18 : 1
ND
0.2 eq.
0.2 eq.
14 : 1
11 : 1
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c
eq.)
TBAFꢀTHF(0.5 eq.) Proton Sponge (1.2 eq.) 2.0 eq.
TBAB (0.5 eq.) Proton Sponge (1.2 eq.) 2.0 eq.
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0.2 eq.
0.5 eq.
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31%
13:1
88% d
(72%) e
19:1 f
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a
All reactions were run at 1.0 mmol (178 mg) scale in CH3CN (4.0 mL, 0.25 M) for 24 h unless otherwise
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indicated; Conversion was estimated by H NMR (number in bracket was isolated yield) ; 4 Å molecular sieves
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(70%) was added; 48 h; Ratio was estimated by H NMR; ND: not determined; Ratio was estimated by
quantitative 13C NMR.
Separation of the 3ꢀOꢀallyl isomer and 2ꢀOꢀallyl isomer was challenging by silica gel column
chromatograph and suffered from significant yield loss. Consequently, it is highly desirable to
attain much higher regioselectivity. To this end, a nonꢀnucleophilic strong base, proton sponge
[1,8ꢀbis(dimethylamino)naphthalene, pka of conjugated acid = 12.3 in water11] was tested.
Though reaction was slow with 17% conversion at 50 °C after 24 h, excellent isomeric ratio (18 :
1) was achieved with 0.2 eq. of nBu2SnO (entry 6). This could be attributed to the negligible
background reaction in the presence of proton sponge even at 50 °C. Without the Sn catalyst,
no appreciable amount of product was detected. Conversion can be improved to 38% at higher
temperature (90 °C); however, at the expense of erosion on regioselectivity (entry 8). TBAF was
utilized to accelerate the reaction with the notion that a stronger coordination of Fꢀ to
tetracoordinated tin in dibutylstannylene acetal could facilitate dissociation of SnꢀO bond during
allylation. Moderate yet unsatisfactory improvement in conversion was acquired (entry 9−10).
Pleasingly, excellent conversion (88%) and selectivity (19 : 1) were achieved when the loading
of nBu2SnO was increased to 0.5 eq. and temperature was adjusted to 60 °C (entry 11).
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The use of proton sponge as base is decisive to ensure excellent selectivity. Further fine tuning
of the condition was then focused on different loadings of catalyst (0.2 eq. vs. 0.5 eq.) and allyl
bromide (1.1 eq., 1.5 eq., 2.0 eq.) at 60 °C as shown in Table 2. Higher substrate concentration
(0.56 M) was also employed to enhance the reactivity as well as throughput. The reaction was
dramatically accelerated under more concentrated conditions even at 0.2 eq. of catalyst loading
and 68% conversion was achieved after 24 h as compared to 17% conversion in dilute solution
(0.25 M, entry 6 in Table 1). Figure 1 depicted a straightforward comparison of reaction kinetic
profiles in various allylation scenarios. Allylation was consistently faster at higher catalyst
loading (0.5 eq.) reaching 77−88% conversion at 24 h (as compared to 68−82% with 0.2 eq. of
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catalyst) and 93−96% conversion at 62 h (as compared to 84−93% with 0.2 eq. of catalyst).
Increasing the allyl bromide loading from 1.1 eq. to 1.5 eq. significantly boosted reaction rate
and further increase to 2.0 eq. led to slight improvement. The regioselectivity with 0.5 eq. of
nBu2SnO catalyst was appreciably higher (22 : 1) than the allylation at lower catalyst loading (17
: 1) and was not compromised at all while raising the loading of allylating reagent (Figure 2).
Using a mixed solvent (10:1 CH3CN/DMF) was not beneficial for the reactivity while the
selectivity degraded slightly from 22 : 1 to 19 : 1.
Table 2. nBu2SnO catalyzed selective alkylation in the presence of proton sponge
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nBu2SnO
Ratio
4 : 5
Conv.b/Yield
Entrya Scale (g)
RBr (eq.)
Time (h)
(eq.)
0.2
0.2
0.5
0.5
0.5
0.5
0.5
0.5
0.2
1
2
3
4
5
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1.0
1.0
1.0
1.0
1.0
10
AllBr (1.1) 62
AllBr (2.0) 62
AllBr (1.1) 62
AllBr (1.5) 62
AllBr (2.0) 48
AllBr (2.0) 62
AllBr (2.0) 62
BnBr (2.0) 62
BnBr (2.0) 62
83.8%/ND
92.9%/ND
92.7%/ND
94.2%/ND
ND/82%
17:1c
17:1c
23:1c
22:1c
22:1c
24:1c
26:1c
30:1d
34:1d
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96.1%/87%
95.8%/82%
ND/85%
50
1.0
1.0
ND/81%
a
b
Reaction conditions: Substrate (1.0 eq.), Proton Sponge (1.2 eq.), TBAB (0.5 eq.), CH3CN (0.56 M), 60 °C;
Conversion was measured by GC; c ratio by GC; d ratio by HPLC; ND: not determined.
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0
0.5 eq Bu2SnO, 2.0 eq AllBr
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0.5 eq Bu2SnO, 2.0 eq AllBr (50 g)
0.5 eq Bu2SnO, 1.5 eq AllBr
0.2 eq Bu2SnO, 2.0 eq AllBr
0.5 eq Bu2SnO, 1.1 eq AllBr
0.2 eq Bu2SnO, 1.1 eq AllBr
0
10
20
30
40
50
60
Time / h
Figure 1. Kinetic profiles of allylation at different loadings of catalyst and allyl bromide
100
99
98
97
0.5 eq Bu2SnO, 2.0 eq AllBr
96
0.5 eq Bu2SnO, 2.0 eq AllBr (50 g)
95
0.5 eq Bu2SnO, 1.5 eq AllBr
94
0.5 eq Bu2SnO, 1.1 eq AllBr
93
0.2 eq Bu2SnO, 2.0 eq AllBr
92
91
90
0.2 eq Bu2SnO, 1.1 eq AllBr
18
28
38
48
58
Time / h
Figure 2. Isomeric ratio of allylation over time at different loadings of catalyst and allyl
bromide
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Using the optimal condition (0.5 eq. of nBu2SnO, 2.0 eq. of allyl bromide, 1.2 eq. of proton
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sponge, 0.5 eq. of TBAB, 60 °C, 0.56 M ), the allylation of 1ꢀmethylꢀ ꢀαꢀrahamnospyranoside
L
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was smoothly demonstrated on 50 g scale. The reaction reached 87% conversion at 24 h and
96% conversion at 62 h, furnishing 50.2 g of product in 82% isolated yield with 26 : 1 selectivity
favoring the 3ꢀOꢀallyl isomer.
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In addition to the allylation reaction, preliminary study also demonstrated that benzylation of 1ꢀ
methylꢀ ꢀαꢀrahamnospyranoside with current protocol performed very well rendering the 3ꢀOꢀ
L
benzyl isomer in 81−84% yield and outstanding selectivity (30−34 : 1) (entry 8, 9 in Table 2).
While column chromatography purification successfully afforded the desired product in 82%
yield with nonꢀdetectable residual Sn on a 50 g scale reaction, it is desirable to develop a scalable
isolation/purification process that circumvents the need for column chromatograhpy purification
on large scale. Over the years many research groups have reported methods for the removal of
residual organotin;12ꢀ16 however, most of them still require the use of column chromatography
purification. During our research we opted to take advantage of the solubility difference between
the desired product and other components, including organotin species, in the reaction matirx.
Thus, upon reaction completion the reaction mixture was allowed to cool to ambient and filtered.
The filtrate was concentrated and the residue was suspended in methyl tꢀbutyl ether (MTBE) to
precipitate out additional byproducts. After filtration, the MTBE solution was treated with 1 N
aqueous HCl solution to extract the product into the aqueous layer, while leaving the organotin
species in the MTBE layer. The desired product was then isolated from the aqueous layer by
extraction with EtOAc in 72% yield with 1530 ppm of residual Sn (by ICP analysis). Attempts to
improve extraction efficiency by increasing the ionic strength of aqueous layer with NaCl (5
wt%) resulted in elevated level of residual TBAB in the isolated product. It was observed that the
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isomeric ratio marginally decreased from 24 : 1 to 19 : 1 after the isolation, probably caused by
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different partition preference of the desired product and the 2ꢀOꢀallyl isomer in the two layers.
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Two scavengers, SiliaMetS Cysteine (0.42 mmol/g) and SiliaMetS TAAcONa (0.45 mmol/g)17
were also evaluated for the removal of residual Sn (Table 3). In both cases a solution of the
product (containing 1530 ppm of residual Sn) in EtOAc (2 mL/g of product) was treated with the
respective scavenger for 6 h, and filtered. The level of residual Sn was reduced to 273 ppm by
one treatment with SiliaMetS Cysteine (Entry 2), and 267 ppm by one treatment with SiliaMetS
TAAcONa (Entry 4). A second scavenger treatment successfully reduced the residual Sn to 31.9
ppm with SiliaMetS Cysteine (Entry 3) and 19.5 ppm with SiliaMetS TAAcONa (Entry 5),
respectively. Isomeric purity remained unchanged after the scavenger treatment.
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Table 3. Removal of Residual Sn
Residual Sn (ppm)
Entry
Procedure
Recovery (%)
Starting level End level
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5
Extractive work up
NDb
1530
273
1530
273
72%a
92%
93%
91%
95%
1st Treatment with 20 wt% SiliaMetS Cysteine
2nd Treatment with 20 wt% SiliaMetS Cysteine
31.9
267
1st Treatment with 20 wt% SiliaMetS TAAcONa 1530
2nd Treatment with 20 wt% SiliaMetS TAAcONa 267
19.5
a Yield of reaction; b ND: not determined.
CONCLUSIONS
A highly selective allylation reaction of 1ꢀmethylꢀ ꢀαꢀrhamnose was developed using nBu2SnO
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as catalyst and proton sponge as base. This process proved to be robust and afforded the desired
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product in excellent regioselectivity (>20 : 1) and isolated yield (up to 87%). A scalable columnꢀ
free isolation/purification process was developed which successfully afforded the desired product
in 72% yield with 1530 ppm of residual Sn. The isomeric ratio was only slightly decreased
during work up and the treatment. The level of residual Sn was further reduced to <20 ppm by
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treatment with scavengers. Though only 1ꢀmethylꢀ ꢀαꢀrhamnose was disclosed in this study, it is
L
envisioned that this catalytic system could be generally applicable to selective allylation of other
carbohydrates containing cis vicinal diols, which are frequently encountered molecular motifs in
organic synthesis. The intrinsic conformational preference for selective functionalization with
this protocol is expected to persist in other carbohydrates for desirable regioselective control in
alkylative transformations.
EXPERIMENTAL SECTION
General: All reagents were commercially available and used as purchased without further
purification. NMR analysis was conducted on a Bruker 400 MHz NMR spectrometer equipped
with a BꢀACS 60 autochanger and a 5 mm PABBO broadband probe with Zꢀgradients. The
chemical shift data are reported as δ (ppm) downfield from tetramethylsilane which is used as an
internal standard; coupling constants (J) are reported in hertz and refer to apparent peak
multiplicities. GC analysis was performed on an Agilent 6850 equipped with Agilent DBꢀWAX
column (30 m × 320 ꢀm × 0.5 ꢀm, P/N 123−7033). ); Inlet 250 °C; FID, 250 °C; Helium
constant flow: 3 mL/min; hydrogen flow: 40 mL/min; air flow: 450 mL/min; Nitrogen makeup:
30 mL/min; injection volume: 1 ꢀL; split ratio: 25; temperature programming: 50 °C: 0 min,
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30°C/min to 200 °C then 5 °C/min to 250 °C, hold 2 min; maximum column temperature: 250
°C. HPLC analysis was performed using a Waters XBridge C8 column (150 mm × 4.6 mm, 3.5
µm, S/N 01133217713808, P/N 186003055) with a mobile phase A (water + 0.1% TFA) and B
(acetonitrile + 0.1% TFA) and detection at 254 nm; flow: 1.0 mL/min; temp. 25 °C; and
gradient: 0 min: A = 95%, B = 5%; 18 min: A = 5%, B = 95%; 22 min: A = 5%, B = 95%; 22.2
min: A = 95%, B = 5%; and 25 min: A = 95%, B = 5%.
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Allylation of 1-methyl-L-α-rhamnose with catalytic amount of di-n-butyltin oxide with column
chromatographic purification: To a 1000 mL, 3ꢀneck round bottom flask was charged
(2R,3R,4R,5R,6S)ꢀ2ꢀmethoxyꢀ6ꢀmethyltetrahydroꢀ2Hꢀpyranꢀ3,4,5ꢀtriol (50 g, 281 mmol), diꢀnꢀ
butyltin oxide (34.9 g, 140 mmol), TBAB (45.2 g, 140 mmol), proton sponge (72.2 g, 337
mmol), and acetonitrile (500 mL). Allyl bromide (48.5 mL, 561 mmol) was added, and the
reaction was stirred at 60 °C until GC analysis indicated that the reaction was complete. The
reaction was cooled to 20 °C, filtered, and the filtrate was concentrated to dryness. The residue
was dissolved in DCM (20 mL) and purified by silica gel column (750 g silica, 0−80%
EtOAc/hexanes over 5 column volumes, hold for 5 column volumes). The product containing
fractions were concentrated to dryness and the resulting oil was further dried under vacuum to
afford the desired product as a yellow oil (50.2 g, 82% yield). GC showed 26 : 1 ratio favoring
the 3ꢀOꢀallyl isomer.
3ꢀOꢀallyl isomer: 1H NMR (400 MHz, CDCl3) δ 6.02 – 5.87 (m, 1H), 5.33 (dt, J = 17.2, 1.4 Hz,
1H), 5.23 (dt, J = 10.4, 1.4 Hz, 1H), 4.71 (d, J = 1.6 Hz, 1H), 4.17 (dd, J = 5.7, 1.4 Hz, 1H), 4.07
(dd, 1H), 4.02 – 3.96 (m, 1H), 3.71 – 3.60 (m, 1H), 3.58 – 3.47 (m, 2H), 3.37 (d, J = 1.1 Hz, 3H),
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2.47 (s, 1H), 2.42 (s, 1H), 1.33 (dd, J = 6.1, 1.1 Hz, 3H). 13C NMR (101 MHz, DMSOꢀd6) δ
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136.02, 115.92, 101.15, 78.50, 70.76, 69.57, 68.37, 67.15, 53.98, 17.87.
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2ꢀOꢀallyl isomer: H NMR (400 MHz, CDCl3): δ 5.87−5.96 (m, 1H), 5.28−5.33 (m, 1H),
5.21−5.25 (m, 1H), 4.72 (d, J = 2.0 Hz, 2H), 4.17−4.22 (m, 1H), 4.00−4.06 (m, 1H), 3.66−3.71
(m, 1H), 3.62−3.63 (dd, J = 4.0, 2.0 Hz, 1H), 3.57−3.60 (m, 1H), 3.36 (s, 3H), 2.24−2.28 (br,
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2H), 1.33 (d, 3H, J = 8.0 Hz). C NMR (101 MHz, DMSOꢀd6) δ 135.74, 116.13, 98.64, 78.13,
72.21, 71.48, 70.57, 68.30, 54.04, 17.86
Allylation of 1-methyl-L-α-rhamnose with catalytic amount of di-n-butyltin oxide with
column-free purification: To a 1000 mL, 3ꢀneck round bottom flask was charged
(2R,3R,4R,5R,6S)ꢀ2ꢀmethoxyꢀ6ꢀmethyltetrahydroꢀ2Hꢀpyranꢀ3,4,5ꢀtriol (20 g, 112.2 mmol), diꢀnꢀ
butyltin oxide (13.97 g, 56.1 mmol), TBAB (18.09 g, 56.1 mmol), proton sponge (28.9 g, 134.7
mmol), and acetonitrile (200 mL). Allyl bromide (19.40 mL, 224.5 mmol) was added, and the
reaction was stirred at 60 °C until GC analysis indicated that the reaction was complete with an
isomeric ratio of 24 : 1 favoring the 3ꢀOꢀallyl isomer. The reaction was cooled to 20 °C, stirred
for 2 h, and filtered. The filter cake was rinsed with MTBE (2 × 50 mL), and the filtrate was
concentrated to dryness. The residue was suspended in MTBE (200 mL) and stirred for 2 h. The
resulting suspension was filtered and the filter cake was rinsed with MTBE (2 × 50 mL). The
filtrate was diluted with 1 N HCl until pH < 2 (~150 mL) and stirred for 1 h. The layers were
separated and the aqueous layer was extracted with MTBE (100 mL). The aquesous layer was
extracted with EtOAc (4 × 200 mL), and the combined organic layers were concentrated to
dryness to afford a pale yellow oil (17.6 g, 72% yield). Proton NMR was consistent with that of
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previously obtained product, with ~2.7 mol% of TBAB. GC showed 19 : 1 ratio favoring the 3ꢀ
5
6
Oꢀallyl isomer. ICP indicated 1530 ppm of residual Sn.
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Removal of residual Sn: To a solution of (2R,3R,4R,5S,6S)ꢀ4ꢀ(allyloxy)ꢀ2ꢀmethoxyꢀ6ꢀ
methyltetrahydroꢀ2Hꢀpyranꢀ3,5ꢀdiol (5.0 g, containing 1530 ppm Sn) in EtOAc (10 mL) was
charged SiliaMetS TAAcONa (1.0 g, 20 wt%) and the mixture was stirred for 6 h. The
suspension was filtered and the solid was rinsed with EtOAc (5 mL). The filtrates were
concentrated to afford a light yellow oil (4.57 g, 91% recovery). Residual Sn: 267 ppm. The
recovered material was resubmitted to the above conditions to afford the desired product as a
light yellow oil in 95% recovery with 19.5 ppm of residual Sn.
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ASSOCIATED CONTENT
Supporting Information. The supporting information is available free of charge on the ACS
Publications website. 1H NMR and 13C NMR spectra for compounds 4 and 5. 1H NMR for 3ꢀOꢀ
benzylated product. GC and HPLC traces of allylation and benzylation products.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: XLi8@dow.com
Notes
The authors declare no competing financial interest.
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REFERENCES
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9. Kong, X.; Grindley, T. B. Can. J. Chem. 1994, 72, 2405. b) Luchinat, C.; Roelens, S. J.
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10. Dibutylstannylene acetal of 1ꢀmethylꢀLꢀαꢀrhamnose was prepared from nBu2SnO in
MeOH or toluene and isolated as white crystalline solid. Allylation of this compound
with allyl bromide and additive (TBAB or KI) in CH3CN at 60 °C revealed >20 : 1
selectivity favoring 3ꢀOꢀallyl isomer in >75% yield.
11. Alder, R.W.; Bowman, P.S.; Steele, W.R.; Winterman, D.R. Chem. Commun. 1968, 723.
12. Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 7200.
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16. Nishida, T.; Matsuda, D.; Kasuga, I.; Orita, A.; Otera, J. Chem. Lett. 2016, 45, 1280.
17. SiliaMetS Cysteine (Product No.: R80530B, 0.42 mmol/g) and SiliaMetS TAAcONa
(Product No.: R69230B, 0.45 mmol/g) were purchased from SiliCycle Inc.
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