Synthesis of Fmoc-Protected Amino Alcohols via the Sharpless Asymmetric Aminohydroxylation Reaction Using FmocNHCl as the Nitrogen Source

Article abstract of DOI:10.1021/acs.joc.9b02491

The aminohydroxylation of various alkenes using FmocNHCl as a nitrogen source is reported. In general, in the absence of a ligand, the reaction provided racemic Fmoc-protected amino alcohols with excellent regioselectivity but in low to moderate yields. However, in some instances, the yield of an amino alcohol product and the regioselectivity could be altered by the addition of a catalytic amount of triethylamine (TEA). The Sharpless asymmetric variant of this reaction (Sharpless asymmetric aminohydroxylation (SAAH)), using (DHQD)₂PHAL (DHQD) or (DHQ)₂PHAL (DHQ) as chiral ligands, proceeded more readily and in higher yield compared to the same reaction in the absence of a chiral ligand. The enantiomeric ratios (er) of all but two examples exceeded 90:10 with many examples giving er values of 95:5 or higher, making FmocNHCl a highly practical reagent for preparing chiral amino alcohols. The SAAH reaction using FmocNHCl was used for the preparation of d-threo-β-hydroxyasparagine and d-threo-β-methoxyaspartate, suitably protected for Fmoc solid phase peptide synthesis.

Full text of DOI:10.1021/acs.joc.9b02491

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Synthesis of Fmoc-Protected Amino Alcohols via the Sharpless
Asymmetric Aminohydroxylation Reaction Using FmocNHCl as the
Nitrogen Source
Ryan Moreira, Matthew Diamandas, and Scott D. Taylor*
Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, Canada, N2L 3G1
S
* Supporting Information
ABSTRACT: The aminohydroxylation of various alkenes
using FmocNHCl as a nitrogen source is reported. In general,
in the absence of a ligand, the reaction provided racemic
Fmoc-protected amino alcohols with excellent regioselectivity
but in low to moderate yields. However, in some instances, the
yield of an amino alcohol product and the regioselectivity
could be altered by the addition of a catalytic amount of
triethylamine (TEA). The Sharpless asymmetric variant of this
reaction (Sharpless asymmetric aminohydroxylation (SAAH)),
using (DHQD)2PHAL (DHQD) or (DHQ)2PHAL (DHQ)
as chiral ligands, proceeded more readily and in higher yield
compared to the same reaction in the absence of a chiral
ligand. The enantiomeric ratios (er) of all but two examples
exceeded 90:10 with many examples giving er values of 95:5 or higher, making FmocNHCl a highly practical reagent for
preparing chiral amino alcohols. The SAAH reaction using FmocNHCl was used for the preparation of D-threo-β-
hydroxyasparagine and D-threo-β-methoxyaspartate, suitably protected for Fmoc solid phase peptide synthesis.
used as a nitrogen source for the SAAH reaction under base-
free conditions.3
INTRODUCTION
■
The Sharpless asymmetric aminohydroxylation (SAAH)
reaction is perhaps the most powerful and direct approach
for preparing vicinal amino alcohols in an enantioselective
manner.1 N-Chlorinated derivatives of benzyl (CbzNHCl) and
tert-butyl carbamates (BocNHCl), which are usually generated
in situ from the corresponding carbamates and tert-butylhypo-
chlorite, have been widely used as the nitrogen source in the
SAAH reaction.1 In contrast, until very recently, fluorenyl-
methyl (Fmoc) carbamates, such as FmocNHCl (1, Figure 1),
Recently, we reported that Fmoc-protected amino alcohol 4
could be prepared in good yield and enantioselectivity from
alkene 3 via a SAAH reaction under classic (i.e., basic) SAAH
reaction conditions using 1 as the nitrogen source (Scheme
1).4 We showed that the reaction proceeded much better when
1 was introduced into the reaction mixture as a reagent rather
than being generated in situ from FmocNH2 and tert-
butylhypochlorite. Multigram quantities of reagent 1 were
prepared in a single step and in high yield by reacting
FmocNH2 with trichloroisocyanuric acid, an inexpensive
chlorinating agent, and 1 is a stable, easily handled solid and
is storable at room temperature.4a Compound 4 was used to
achieve concise syntheses of L-threo-β-hydroxyasparagine, L-
threo-β-methoxyaspartate, and L-erythro-β-methoxyaspartate,
suitably protected for Fmoc solid phase peptide synthesis (5,
6a, and 6b, respectively in Scheme 1).4a,b Amino acids 5 and
6b were used to achieve the total synthesis of A54145 factor D,
a complex cyclic lipodepsipeptide antibiotic.4b Overall, these
studies suggested that reagent 1 could be a very useful and
general reagent for SAAH reactions and natural product
synthesis.
Figure 1. Reagents used for introducing Fmoc-protected amines in
the SAAH reaction.
had never been used as a nitrogen source in SAAH reactions.
The reason for this is probably because it had been assumed
that the Fmoc group was too bulky to allow for high
enantioselectivity2 and too base labile to survive the basic
conditions normally employed in the SAAH reaction. The
latter problem was circumvented in 2011 by Harris et al., who
reported that fluorenylmethylcarbamate 2 (Figure 1) could be
Here we report the results of our investigations on the scope
of the SAAH reaction using reagent 1 as the nitrogen source
Received: September 13, 2019
Published: October 31, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b02491
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Article
Scheme 1. Synthesis of Fmoc-Protected Amino Alcohol 4 Using Reagent 1
both in the absence of a chiral ligand and in the presence of the
chiral ligands (DHQD)2PHAL (DHQD) and (DHQ)2PHAL
(DHQ). These studies enabled us to develop an efficient
synthesis of highly enantiomerically enriched ent-5 and ent-6a
(D-threo-β-hydroxyasparagine and D-threo-β-methoxyaspartate,
respectively), which could not be achieved starting from 3.
reduction of the catalyst loading to 2% did not result in an
increase in the yield of ( )-8B even if the reaction time was
doubled (entry 3).
It is well-known that some simple, achiral tertiary amine base
ligands accelerate the osmium catalyzed dihydroxylation
process.6 Therefore, we considered that the addition of a
catalytic amount of achiral amine base ligand could suppress
unwanted hydrolysis by accelerating the osmylation step in the
aminohydroxylation process.6 Only a few reports have
appeared describing the effects of simple, achiral tertiary
amine base ligands on the aminohydroxylation process. The
most notable examples were described by Angelaud et al.7 and
Donohoe et al.8 Angelaud et al.7 reported that the addition of
quinuclidine or DIPEA greatly affected the regioselectivity of
the aminohydroxylation process. Unfortunately, no data on
reaction yield was provided. Donohoe et al. explored the effects
of quinuclidine and DIPEA on the tethered amino-
hydroxylation reaction and found that DIPEA enhanced the
rate of the reaction substantially and increased the yield.8
Interestingly, quinuclidine was found to slow the reaction
down and greatly decreased the reaction yield. The mixed
results observed by Donohoe et al. may be explained by the
fact that the ligand can accelerate the osmylation step but
hinder the rate-controlling hydrolysis step.6 With this in mind,
we screened a series of tertiary amine bases to determine if any
were capable of improving the efficiency of the amino-
hydroxylation reaction on styrene (Table 1).
RESULTS AND DISCUSSION
■
We first explored the effectiveness of FmocNHCl as a nitrogen
source for the amino hydroxylation on some common olefins
in the absence of chiral ligands. We began this study by
subjecting styrene (7) to 1/NaOH/8% osmate in nPrOH/
H2O (Table 1, entry 1). Although the regioselectivity was
Table 1. Effect of a Catalytic Amount of an Achiral Ligand
on the Yield and Regioselectivity of the
Aminohydroxylation Reaction Using Styrene as a Substrate
mol %
achiral ligand
(6 mol %)
K2OsO4·
time
(h)
% yield
a
b
entry
2H2O
( )-8B
regioselectivity
1
2
3
4
5
6
7
8
9
none
none
none
pyridine
NMM
DABCO
TEA
DIPEA
DBU
8
4
2
4
4
4
4
4
3
3
6
4
4
1
6
4
6
45
56
56
18
30
36
69
61
62
1:19
1:19
1:10
1:10
1:7
1:7
1:10
1:6.2
For its historical significance,6 we first tried pyridine which
we found to inhibit catalytic turnover almost immediately (the
solution quickly turned from green to bright yellow, indicating
that the dioxo osmium(VI) monoazaglycolate species was no
longer present).9 After 4 h, the reaction was worked-up and the
small amount of product that was recovered had a
regioselectivity of 1:10 (entry 4). The same turnover-inhibiting
effect was observed when pyridyl acrylates were subjected to
SAAH with in situ generated CbzNHCl.10 We found that the
N-methylmorpholine (NMM) decreased the reaction yield and
altered the regioselectivity to 1:7 (entry 5). Similar results were
observed with 1,4-diazabicyclo[2.2.2]octane (DABCO),
although the regioselectivity was 1:10 (entry 6). It should be
noted that turnover with DABCO was quickly inhibited, which
may be explained by the formation of an unreactive bridged
DABCO−imidoosmium complex.11 The results observed with
triethylamine (TEA) as a ligand are perplexing (entry 7). We
found TEA to substantially increase the overall yield (76%)
and isolated reaction yield (69%) even though the
regioselectivity decreased to 1:10 and the reaction took twice
as long to reach completion.We initially thought that TEA was
stabilizing the imidoosmium complex, decreasing the reaction
rate and preventing hydrolysis of the imidoosomium complex.
However, closer analysis of the FmocNHCl, FmocNH2, and
4
1:7
a
b
1
Isolated yield of ( )-8B. ( )-8A:( )-8B determined by H NMR
of mixture of ( )-8A and ( )-8B.
excellent in that the ratio of the resulting amino alcohols,
( )-8A:( )-8B, was 1:19, the isolated yield of the major
product, ( )-8B, was only a moderate 45%. We noticed that
this reaction produced significant amounts of FmocNH2,
suggesting that competing hydrolysis of the in situ formed
FmocNOsO3 was having a deleterious effect on reaction
efficiency.5 This prompted us to investigate the stability of
FmocNHCl which we found to spontaneously convert to
FmocNH2 in nPrOH/H2O at 0 °C; however, the conversion is
much faster in the presence of osmate and an alkene (see
Scheme S1). The hydrolysis could be suppressed to an extent
by lowering the catalyst loading to 4% (Scheme S5), which
gave ( )-8B in an isolated yield of 56% (entry 2). Further
B
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Table 2. Aminohydroxylation Reactions Using FmocNHCl
a
b
c
d
e
Ratio of A:B determined using 1H NMR. Isolated yield of major product. NA = not applicable. NR = no reaction. 3:2 MeCN/H2O was used
f
g
1
as a solvent. Yield of major product estimated using H NMR. 6 mol % DIPEA in place of TEA.
( )-8B produced under ligand and ligand-free conditions (see
Table S5) suggests that TEA selectively accelerates the
osmylation process and has little effect on the amount of
carbamate produced. Therefore, the extended reaction time
observed with TEA does not reflect a decrease in reaction rate
but demonstrates that catalytic turnover is still possible at
much lower concentrations of FmocNHCl, compared to the
ligand-free conditions. In addition, this analysis revealed that
TEA seems to have a similar, although less dramatic, effect on
the reaction rate compared to DHQD. Similar effects are
observed with N,N-diisopropylethylamine (DIPEA), although
the observed regioselectivity is lower (1:6.2, entry 8). These
results show that the observed effects on regioselectivity are
not due to small changes in pH since TEA and DIPEA have
the same pKa, and thus the two ligands must be forming a
complex with FmocNOsO3 in solution.12 1,8-Diazabicyclo-
(5.4.0)undec-7-ene (DBU) gave results that are almost
identical to those observed with DIPEA.
Using 4 mol % osmate catalyst, we examined several other
common alkenes as substrates (Table 2). Like styrene, the
regioselectivity of the reaction with alkene 9 was very high and
the yield of the major product, ( )-10B, was a moderate 55%
(entry 3). To our surprise, we found that the addition of TEA
reduced the yield of ( )-10B to 43% (entry 4). Adding DIPEA
in place of TEA gave ( )-10B in a 46% yield and caused no
change in regioselectivity, suggesting that this effect is not due
to sterics alone.
Initial attempts at converting alkene 11 to ( )-12 were
unsuccessful due to the alkene’s poor solubility in the aqueous
alcohol solvent system. When aqueous acetonitrile was used,
11 was converted to ( )-12 in a 47% yield (entry 5). Under
these conditions, the addition of catalytic TEA dramatically
improved the yield of ( )-12 to 84% (entry 6).
The reaction using alkene 13 produced amino alcohols
( )-14A and ( )-14B, which were difficult to separate by
column chromatography and so were characterized as a 1:2
mixture (( )-14A:( )-14B). The yield of the major product,
( )-14B, was estimated using 1H NMR on the isolated
mixture to be only 18% (entry 7). In the presence of catalytic
TEA, the yield of ( )-14B was improved to 33% (entry 8)
although the regioselectivity was not substantially affected
(1:2.4).
The reaction using isopropylcinnamate (15) produced
products ( )-16A and ( )-16B as a 1:1.9 mixture
(( )-16A:( )-16B), entry 9). The regioselectivity of this
entry matched that reported by Harris et al. under base-free
conditions using reagent 2.3,13 These two amino alcohols were
also difficult to separate by column chromatography and so
were characterized as a 1:1.9 mixture. The yield of the major
product, ( )-16B, was estimated using 1H NMR on the
isolated mixture to be 46% (entry 9), which is quite high
compared to the previous entries despite the reaction having to
proceed for 60 h. The yield of ( )-16B was improved to 55%
by the addition of catalytic TEA while the regioselectivity was
C
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Table 3. Asymmetric Aminohydroxylation Reactions Using FmocNHCl
a
b
c
d
e
entry
alkene
7 (R1 = Ph, R2 = H)
7
solvent
ligand
time (h)
major product
product ratio
yield (%)
er
1
2
nPrOH/H2O
nPrOH/H2O
nPrOH/H2O
nPrOH/H2O
nPrOH/H2O
nPrOH/H2O
nPrOH/H2O
nPrOH/H2O
nPrOH/H2O
nPrOH/H2O
nPrOH/H2O
nPrOH/H2O
nPrOH/H2O
MeCN/H2O
nPrOH/H2O
MeCN/H2O
nPrOH/H2O
MeCN/H2O
nPrOH/H2O
DHQD
DHQ
DHQD
DHQ
DHQD
DHQ
DHQD
DHQ
DHQD
DHQ
DHQD
DHQ
DHQD
DHQD
DHQ
3
8B
8B′
18A (1R,2S)
18A′ (1S,2R)
16A
16A′
21A
21A′
14A
14A′
23A
23A′
4A
4A
47:53
49:51
−
45
41
62
73
81
71
67
86
67
46
65
59
70
56
51
25
73
45
73
93:7
18
20
36
3
3
2
2
2.5
3
4
23
3
5
8
18
3
4
89:11
98:2
84:16
98:2
99.5:0.5
97:3
fg
3 ,
cyclohexene (17)
fg
4 ,
17
−
5
6
7
8
15 (R1 = Ph, R2 = CO2iPr)
>20:1
>20.1
15:1
15:1
>20:1
>20.1
20:1
8.4:1
12:1
4:1
ND
ND
15:1
5:1
15:1
15
20 (R1 = Ph, R2 = CO2Me)
20
94:6
95:5
98:2
98:2
>99
95:5
96:4
92:8
9
13 (R1 = 4-MeOPh, R2 = CO2Me)
10
11
12
13
14
15
16
17
18
19
13
22 (R1 = N-tBoc-3-indol, R2 = CO2Me)
22
3 (R1 = BnOCH2, R2 = CO2tBu)
3
3
3
4A′
4A′
25A
25A′
25A′
DHQ
92.5:7.5
89:11
93:7
24 (R1 = 4-MeOBnOCH2, R2 = CO2Me)
24
24
DHQD
DHQD
DHQ
2
96:4
a
b
c
Ratio of nPrOH/H2O or MeCN/H2O was 3:2. 12 mol % ligand used, 8 mol % K2OsO4·2H2O used in all reactions. Product ratio = A:B or
d
e
f
1
A′:B′ determined by H NMR. Isolated yield of major product. er = enantiomeric ratio of major product as determined by chiral HPLC. The
g
general scheme does not apply to this cis alkene. The configuration of the product is indicated under the major product column. Carbon 1 bears
the installed alcohol. Carbon 2 bears the installed carbamate.
almost unaffected (1:2) (entry 10). In this case, TEA also
reduced the reaction time to 48 h.
for the same reaction and ligand but using other nitrogen
sources.3,5,16 The reaction was slower with DHQ, but the yield
of the major product, 18A′, was higher while the er was lower
(entry 4) compared to the corresponding DHQD reaction.
The er values using DHQ and reagent 1 are slightly better than
those reported for the same reaction and ligand using other
nitrogen sources.3,5,16
The reaction with alkene ester 15 also proceeded much
faster in the presence of the ligands, and in good yield, with
very high regioselectivity and enantioselectivity with either
ligand (entries 5 and 6). The reaction in the presence of a
ligand favored the formation of 16A and 16A′, while in the
absence of an alkaloid ligand 16B was favored (entries 9 and
10, Table 2).
Substituting the isopropyl group in 15 with a methyl group
(20, entries 7 and 8) resulted in only a small decrease in
regioselectivity, and the enantioselectivity was still excellent.
Ester 20 has been examined by Harris et al. as a substrate in
the SAAH reaction using reagent 2 under base-free conditions
using both DHQD and DHQ as ligands.3 They obtained the
same regioisomers (21A and 21A′) as the major products and
in similar yields and enantioselectivities to those reported here;
however, their regioisomeric ratios were significantly less
(approximately 6:1 for both ligands).3,17
The reaction with cyclohexene (17) gave amino alcohol
( )-18 in a meager 18% yield after 24 h (entry 11). The
addition of catalytic TEA was found to almost completely
inhibit conversion of this starting material (entry 12). Attempts
to convert 19 to its amino alcohol proved unfruitful (entry 13)
even in the presence of achiral bases (TEA) and even chiral
ligands (DHQ)2PHAL or (DHQD)2PHAL.
Next, we explored the reaction in the presence of chiral
ligands (DHQD)2PHAL (DHQD) and (DHQ)2PHAL
(DHQ) (Table 3). With styrene (7), we found that the
presence of either ligand significantly increased the overall
reaction yield, but since little regioselectivity was observed, the
isolated yields of the major products, 8B and 8B′, were
moderate (entries 1 and 2). Poor regioselectivity is often
observed when using styrene and in situ generated CbzNHCl14
or BocNHCl15 in the SAAH reaction. The er values using
reagent 1 are slightly less than those reported for the same
reaction and ligands using in situ generated CbzNHCl14 or
BocNHCl.15
The presence of a chiral ligand dramatically increased the
rate of the reaction with cyclohexene (17) (entries 3 and 4).6
Using DHQD, amino alcohol 18A was obtained in a
reasonable yield and with excellent enantioselectivity (entry
3). The er values using reagent 1 are considerably superior,
while the yield of the major product is similar to those reported
The reaction using the p-methoxyphenyl derivative of 20,
compound 13, and the DHQD ligand proceeded with excellent
regioselectivity and provided amino alcohol 14A as the major
D
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Scheme 2. Synthesis of ent-5
Scheme 3. Synthesis of ent-6a
product in good yield and enantioselectivity (entry 9). The er
obtained with reagent 1 is slightly lower than those reported
for the same reaction using the DHQD ligand and in situ-
generated CbzNHCl.18,19 The reaction using the DHQ ligand
also proceeded with excellent regioselectivity and enantiose-
lectivity; however, the yield of the major regioisomer, 14A′,
was moderate (entry 10).
Using the DHQD ligand, indole alkene 22 afforded 23A as
the major regioisomer in a good yield with excellent
regioselectivity and enantioselectivity (entry 11). Likewise,
the reaction with the DHQ ligand proceeded with high
regioselectivity and excellent enantioselectivity providing 23A′
in a similar yield (entry 12). Although the regioselectivity using
the DHQ ligand is poorer than that previously reported with a
very similar substrate and in situ generated CbzNHCl, the
enantioselectivity using either the DHQD or DHQ ligand and
1 as a nitrogen source is superior.10
We previously reported that the SAAH reaction of alkene 3
with the DHQD ligand proceeded with very good
regioselectivity and provided amino alcohol 4A (compound
4 in Scheme 1) in good yield and enantioselectivity (entry
13).4 Changing the solvent to MeCN/H2O resulted in a
decrease in regioselectivity and yield of 4A, but with almost
identical enantioselectivity (entry 14). To our surprise, the
reaction was slower with the DHQ ligand, and the major
product, 4A′, was produced in lower yield and er compared to
the reaction using DHQD regardless of whether the solvent
was nPrOH/H2O or MeCN/H2O (entries 15 and 16).
Previous work by Janda and McLeod showed that p-
methoxy phenyl ethers are strong directing groups for the
SAAH reaction.20−22 The reaction on the p-OMe analog
(2423) of compound 3 proceeded with better regioselectivity
compared to the reaction using alkene 3, and the yield of the
major products, 25A or 25A′, was also better, regardless of the
ligand used (entries 17 and 19). However, with the DHQD
ligand, the er of 25A was less than that of compound 4A, while
with the DHQ ligand, the er of amino alcohol 25A′ was greater
than that of 4A′. Performing this reaction with the DHQD
ligand in MeCN/H2O resulted in a decrease in regioselectivity
and yield of the major product, though the er did not change
significantly (entry 18).
As part of our work on the synthesis of lipopeptide
antibiotics,4a,b we wished to prepare the enantiomers of
protected amino acids 5 and 6a. For these syntheses, it
would have been preferable to start with compound 4A′ (entry
15, Table 2), which is the enantiomer of 4A (compound 4 in
Scheme 1), as this would have allowed us to use the identical
route that we developed for the syntheses of 5 and 6a (ent-5
and ent-6a, respectively).4 Unfortunately, the er of 4A′ was not
quite high enough for this purpose. Since the er of 25A′ (entry
19, Table 2) was high enough, we decided to develop a
synthesis of ent-5 and ent-6a starting with 25A′.
To prepare ent-5, we first hydrolyzed the methyl ester of
25A′ with aqueous lithium hydroxide in the presence of a high
concentration of calcium chloride (Scheme 2).24 After aqueous
workup, the crude material was amidated using BOP/DIPEA/
NH4Cl25 yielding 26 in a 62% yield over two steps. Silylation
of 26 using TBSCl/imidazole and catalytic DMAP gave 27 in a
74% yield. Attempts to remove the PMB group in 27 using
Bobbitt’s salt were unsuccessful.4 We also tried to remove the
PMB group in 27 using DDQ in aqueous DCM; however,
these conditions provided 28 in low yield due to concomitant
removal of the TBS group.26 However, 28 could be obtained in
an 86% yield using BCl3 with pentamethylbenzene as a
E
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scavenger.27 Oxidation of 28 using TEMPO/NaClO2/NaOCl
provided ent-5 in very high yield, although a stoichiometric
amount of TEMPO was required to prevent chlorination of the
amide nitrogen. The NMR data of ent-5 were identical to
those reported for 5 and possessed an optical rotation equal
and opposite to that reported for 5.4
Analytical samples were prepared by dissolving a small amount of
pure sample in 1 mL of mobile phase. For some samples run on the
normal phase column which were not very soluble in the mobile
phase, the solid was first dissolved in MeCN (50 μL) before being
diluted with 90:10 iPrOH/hexanes. High resolution positive electro-
spray (ESI) mass spectra were obtained using an orbitrap mass
spectrometer. Samples were sprayed from MeOH/1% formic acid in
1
H2O. All spectra were collected in the positive mode. H and 13C
To prepare ent-6a, 25A′ was methylated with MeI/Ag2O to
give 29 in an 88% yield (Scheme 3). We found that the
hydrolysis of the ester in 29 was too slow using aqueous
lithium hydroxide to allow for selective deprotection of the
acid in the presence of the Fmoc group, even at high calcium
concentrations. After trying trimethyl tin hydroxide28 and
AlCl3/DMA,29 we found that efficient deprotection of 29
could be achieved in good yield using LiI in ethyl acetate at 80
°C.30 The free acid 30 was converted to tert-butyl ester 31 in
excellent yield using tert-butyltrichloroacetimidate catalyzed by
BF3·Et2O. However, we found that these results were difficult
to reproduce at larger scales (>1 g) due to concomitant
removal of the PMB group, which yielded a mixture of 31 and
32.34 We saw this as potentially advantageous since 32 could
simply be added to the subsequent oxidation, after the cleavage
was complete, reducing that amount of Bobbit’s salt needed to
afford ent-6a. As suspected, the PMB group of 31 was easily
removed and the resulting in situ generated primary alcohol
was oxidized via a two-stage, one-pot reaction employing 1.1
equiv of Bobbit’s salt followed by treatment with TEMPO/
NaClO2/NaOCl.4 This provided ent-6a in 80% yield. The
NMR data of ent-6a were identical to those reported for 6a
and possessed an optical rotation equal and opposite to that
reported for 6a.4
NMR were collected using a Bruker Avance-300 spectrophotometer.
1H NMR chemical shifts (δ) are reported in ppm relative to an
internal standard (trimethylsilane, 0 ppm). 13C{1H} NMR chemical
shifts are reported relative to the residual solvent peak (77.0 ppm for
CDCl3, 49.2 ppm for CD3OD, 39.5 ppm for DMSO-d6). The
configurations of 8B, 14A, 18A, and 23A′ were determined using
Mosher’s ester.31
Improved Procedure for Preparing FmocNHCl. FmocNH2
(12 g, 50.15 mmol, 1 equiv) was dissolved with heating in MeOH
(750 mL). When the reaction mixture had cooled to 35 °C,
pulverized trichloroisocyanuric acid (3.86 g, 16.72 mmol, 1/3 equiv)
was added in a single portion. The reaction was stirred for 14 h at
room temperature in a dark fumehood and then reheated to 35 °C,
and another portion of pulverized trichloroisocyanuric (386 mg, 1.66
mmol, 0.03 equiv) was added. After stirring at room temperature for
an additional 4 h, the reaction mixture was concentrated and the
resulting solid was suspended in hot toluene and then filtered while
hot. Crystals form in the filtrate as the filtrate cools. Pure FmocNHCl
(13.0 g, 95%) was obtained by heating the filtrate until the crystals
redissolved and then allowing the filtrate to cool slowly at which point
pure FmocNHCl crystallized out of solution. The resulting crystals
(FmocNHCl) were obtained by filtration and then dried under high
vacuum. .
General Procedure for Sharpless Aminohydroxylation
Reactions Using FmocNHCl. To a suspension of FmocNHCl
(221 mg, 0.804 mmol, 2.00 equiv) in nPrOH (1.75 mL) cooled in an
ice−water bath was added NaOH (24 mg, 0.60 mmol, 1.5 equiv) in
H2O (3 mL). This was followed by the addition of a solution of
(DHQD)2PHAL, (DHQ)2PHAL (38 mg, 0.048 mmol, 12 mol %), or
triethylamine (6 mol %) fully dissolved in nPrOH (3 mL) and a
solution of alkene (0.402 mmol) in nPrOH (1.5 mL).
K2[OsO2(OH)4] (12 mg, 0.032 mmol, 8 mol %) dissolved in H2O
(1.25 mL, a couple drops of the NaOH solution were added to the
solution of K2[OsO2(OH)4] in H2O) was added to the reaction
mixture, and at this point, the reaction solution was deep-green and
homogeneous. The cooled (ice−water bath) reaction mixture was
stirred until the green color had dissipated or until TLC had indicated
complete conversion of the alkene. The reaction was extracted with
EtOAc (20 mL) twice, and this organic layer was washed with
aqueous sat. NaHCO3 (30 mL) and brine. The organic layer was
dried with Na2SO4 and concentrated. The crude residue was purified
by silica-gel column chromatography.
SUMMARY AND CONCLUSIONS
■
In summary, we have shown that FmocNHCl (1) is an
effective nitrogen source for the SAAH reaction. In the absence
of a ligand, the reaction usually provided Fmoc-protected
amino alcohols in moderate yields but with excellent
regioselectivity. However, in some instances, both the yields
and regioselectivities could be altered by the addition of a
catalytic amount of TEA. In the presence of a chiral ligand, the
reactions proceeded more readily. In general, yields as well as
regio- and enantioselectivities were similar to those reported
using other carbamate nitrogen sources. Remarkably, the
enantioselectivity of all but two examples exceed an er of 90:10
with many examples giving an er of 95:5 or higher. A practical
application of this chemistry was demonstrated by the
synthesis of D-threo-β-hydroxyasparagine and D-threo-β-
methoxyaspartate, suitably protected for Fmoc solid phase
peptide synthesis.
(9H-Fluoren-9-yl)methyl (R)-(2-Hydroxy-2-phenylethyl)-
carbamate (8B) and (9H-Fluoren-9-yl)methyl (S)-(2-Hydroxy-
2-phenylethyl)carbamate (8B′). 8B was prepared from 7 following
the general procedure using (DHQD)2PHAL as a ligand. It was
isolated by silica gel column chromatography (5% EtOAc/95%
CH2Cl2) which yielded 8B as a colorless, crystalline solid (65 mg,
45%). [α]22D = −18.2° (c 0.560, CH2Cl2). Er = 94:6 (see Figure S1).
8B′ was prepared from 7 following the general procedure using
(DHQ)2PHAL as a ligand. It was isolated by silica gel column
chromatography (5% EtOAc/95% CH2Cl2) which yielded 8B′ as a
EXPERIMENTAL SECTION
■
General Experimental Information. All reagents were pur-
chased from commercial suppliers. ACS grade n-propanol (nPrOH)
and toluene were used without further purification. Methylene
chloride (CH2Cl2) and acetonitrile (ACN) were dried by distillation
over calcium hydride under nitrogen. Pyridine was dried by refluxing
over potassium hydroxide followed by fractional distillation.
Tetrahydrofuran (THF) was distilled from sodium metal in the
presence of benzophenone under N2. Chromatography was
performed using 60 Å silica gel. All reported enantiomeric ratios
(er’s) were determined by chiral HPLC. Reversed-phase analytical
chiral HPLC was performed using a CHIRAL PAK AS-RH 5 μm 4.6
mm × 150 mm column with a flow rate of 0.5 mL/min. Normal-phase
analytical chiral HPLC was performed using a CHIRAL PAK OD-H 5
μm 4.6 mm × 250 mm column with a flow rate of 0.4 mL/min.
colorless, crystalline solid (54 mg, 37%). [α]22 = 15.9° (c 0.324,
D
CH2Cl2). Er = 88:11 (see Figure S1). NMR data matched those
previously reported.32 The H NMR spectra of ( )-8B, 8B, and 8B′
1
1
were identical. H NMR (300 MHz, CDCl3): δ 7.68 (2H, d, J = 7.5
Hz), 7.49 (2H, m), 7.34−7.16 (9H, m), 5.14 (1H, m), 4.73 (1H, d, J
= 9.3 Hz), 4.34−4.32 (2H, m), 4.12 (1H, dd, J = 6.9, 6.9 Hz), 3.48−
3.44 (1H, m), 3.25−3.16 (1H, m), 2.78 (1H, br. s). 13C{1H} NMR
(75 MHz, CDCl3): 157.1, 143.8, 141.5, 141.3, 128.5, 127.9, 127.7,
127.0, 125.9, 125.0, 120.0, 73.6, 66.8, 48.5, 47.2. HRMS-ESI+ (m/z):
[M + H]+ calculated for C23H22O3N, 360.1594; found, 360.1594.
F
DOI: 10.1021/acs.joc.9b02491
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(9H-Fluoren-9-yl)methyl (2-hydroxy-3-phenylpropyl)-
carbamate (( )-10B). ( )-10B was prepared from 9 following
the general procedure (no ligand was added). It was isolated by silica
gel column chromatography (5% EtOAc/95% CH2Cl2) which yielded
( )-10B as a colorless, crystalline solid (83 mg, 55%). 1H NMR (300
MHz, CDCl3): δ 7.68 (2H, d, J = 7.8 Hz), 7.51 (2H, m), 7.34−7.11
(9H, m), 4.35 (1H, m), 4.12 (1H, dd, J = 6.3, 6.3 Hz), 3.85 (1H, m),
3.36 (1H, m), 3.03 (1H, m), 2.74−2.57 (2H, m), 2.15 (1H, br. s).
13C{1H} NMR (75 MHz, CDCl3): 157.0, 143.8, 141.3, 137.4, 129.3,
Hydroxycyclohexyl)carbamate (18A′). 18A was prepared from
17 following the general procedure using (DHQD)2PHAL as a ligand.
It was isolated by silica gel column chromatography (5% EtOAc/95%
CH2Cl2) which yielded 18A as a colorless, crystalline solid (113 mg,
75%). [α]22 = −17.4° (c 0.800, CH2Cl2). Er = 98.5:1.5 (see Figure
D
S4). 18A′ was prepared from 17 following the general procedure
using (DHQ)2PHAL as a ligand. It was isolated by silica gel column
chromatography (5% EtOAc/95% CH2Cl2) which yielded 18A′ as a
colorless, crystalline solid (102 mg, 68%). [α]22 = 15.6° (c 0.904,
D
1
128.7, 127.7, 127.0, 126.7, 125.0, 120.0, 72.0, 66.7, 50.7, 47.2, 46.2,
41.2. HRMS-ESI+ (m/z): [M + H]+ calculated for C24H24O3N,
374.1751; found, 374.1746.
CH2Cl2). Er = 84:16 (see Figure S4). The H NMR spectra of 18A
and 18A′ were identical. 1H NMR (300 MHz, CDCl3): δ 7.66 (2H, d,
J = 7.5 Hz), 7.49 (2H, d, J = 7.5 Hz), 7.30 (2H, dd, J = 7.2, 7.2 Hz),
7.21 (2H, dd, J = 7.2, 7.2 Hz), 5.18 (1H, d, J = 7.5 Hz), 4.30 (2H, m),
4.11 (1H, dd, J = 6.9, 6.9 Hz), 3.55 (1H, m), 2.11 (1H, br. s), 1.65−
1.18 (8H, m). 13C{1H} NMR (75 MHz, CDCl3): 156.1, 143.9, 141.2,
127.6, 127.0, 125.0, 119.9, 68.8, 66.5, 52.5, 47.2, 31.7, 27.2, 23.7, 19.6.
HRMS-ESI+ (m/z): [M + H]+ calculated for C21H24O3N, 338.1751;
found, 338.1748.
(9H-Fluoren-9-yl)methyl (2-Hydroxy-1,2-diphenylethyl)-
carbamate (( )-12). ( )-12 was prepared from 11 following the
general procedure using MeCN in place of nPrOH and triethylamine
as a ligand. It was isolated by silica gel column chromatography (2.5%
EtOAc/97.5% CH2Cl2 to 5% EtOAc/95% CH2Cl2) which yielded
( )-12 as a colorless, crystalline solid (147 mg, 84% yield). 1H NMR
(300 MHz, DMSO-d6): δ7.89−7.66 (5H, m) 7.41−7.17 (14H, m)
5.52 (1H, d, J = 4.8 Hz), 4.79−4.74 (2H, m), 4.20−4.12 (3H, m).
13C{1H} NMR (75 MHz, DMSO-d6): 155.7, 143.9, 143.7, 143.0,
Methyl (2S,3R)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)-
amino)-2-hydroxy-3-phenylpropanoate (21A) and Methyl
(2R,3S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-2-hy-
droxy-3-phenylpropanoate (21A′). 21A was prepared from 19
following the general procedure using (DHQD)2PHAL as a ligand. It
was isolated by silica gel column chromatography (5% EtOAc/95%
CH2Cl2) which yielded 21A as a colorless, crystalline solid (113 mg,
141.5, 140.6, 127.7, 127.6, 127.3, 127.0, 127.0, 126.8, 126.6, 126.6,
125.3, 125.2, 120.0, 75.5, 65.5, 61.3, 46.6. HRMS-ESI+ (m/z): [M +
H]+ calculated for C29H26O3N, 436.1907; found, 436.1910.
Methyl (2S,3R)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)-
amino)-2-hydroxy-3-(4-methoxyphenyl)propanoate (14A)
and Methyl (2R,3S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)-
amino)-2-hydroxy-3-(4-methoxyphenyl)propanoate (14A′).
14A was prepared from 13 following the general procedure using
(DHQD)2PHAL as a ligand. It was isolated by silica gel column
chromatography (25% EtOAc/75% hexanes to 20% EtOAc/80%
hexanes) which yielded 14A as a colorless, crystalline solid (119 mg,
67%). [α]22D = −19.5° (c 0.868, CH2Cl2). Er = 97:3 (see Figure S2).
14A′ was prepared from 13 following the general procedure using
(DHQ)2PHAL as a ligand. It was isolated by silica gel column
chromatography (25% EtOAc/75% hexanes) which yielded 14A′ as a
67%). [α]22 = −9.9° (c 0.728, CHCl3). Er = 97:3 (see Figure S5).
D
21A′ was prepared from 19 following the general procedure using
(DHQ)2PHAL as a ligand. It was isolated by silica gel column
chromatography (5% EtOAc/95% CH2Cl2) which yielded 21A′ as a
colorless, crystalline solid (145 mg, 86%). [α]22 = 10.5° (c 0.852,
D
CHCl3). Er = 94:6 (see Figure S5). NMR spectra matched those
2
1
previously reported. The H NMR spectra of 21A and 21A′ were
1
identical. H NMR (300 MHz, CDCl3): δ 7.67 (2H, d, J = 6.7 Hz),
7.48 (2H, d, J = 7.2 Hz), 7.31−7.10 (9H, m), 5.65 (1H, d, J = 9.0
Hz), 5.19 (1H, d, J = 9.6 Hz), 4.43−4.12 (4H, m), 3.74 (3H, s), 3.18
(1H, br. s). 13C{1H} NMR (75 MHz, CDCl3): δ173.1, 155.6, 143.6,
143.6, 141.2, 138.7, 128.6, 127.8, 127.6, 127.0, 124.9, 118.9, 73.3,
66.9, 56.3, 53.1, 47.0. HRMS-ESI+ (m/z): [M + H]+ calculated for
C25H24O5N, 418.1649; found, 418.1639.
colorless, crystalline solid (83 mg, 46%). [α]22 = 21.3° (c 0.952,
D
CH2Cl2). Er = 99:1 (see Figure S2). The 1H NMR spectra of 14A and
14A′ were identical. 1H NMR (300 MHz, CDCl3): δ 7.67 (2H, d, J =
7.2 Hz), 7.47 (2H, m), 7.33−7.16 (6H, m), 6.79 (2H, d, J = 8.7 Hz),
5.63 (1H, d, J = 9.3 Hz), 5.13 (1H, d, J = 9.6 Hz), 4.39−4.08 (4H,
m), 3.73−3.70 (6H, m), 3.22 (1H, d, J = 4.2 Hz). 13C{1H} NMR (75
MHz, CDCl3): 173.3, 159.2, 155.7, 143.7, 141.2, 130.9, 127.9, 127.7,
127.0, 120.0, 114.0, 73.4, 66.9, 55.9, 55.3, 53.1, 47.1. HRMS-ESI+
(m/z): [M + H]+ calculated for C26H26O6N, 448.1755; found,
448.1746.
(2R,3S)-tert-Butyl 3-(1-((((9H-Fluoren-9-yl)methoxy)-
carbonyl)amino)-2-hydroxy-3-methoxy-3-oxopropyl)-1H-in-
dole-1-carboxylate (23A) and (2R,3S)-tert-Butyl 3-(1-((((9H-
fluoren-9-yl)methoxy)carbonyl)amino)-2-hydroxy-3-me-
thoxy-3-oxopropyl)-1H-indole-1-carboxylate (23A′). 23A was
prepared from 2233 following the general procedure using
(DHQD)2PHAL as a ligand. It was isolated by silica gel column
chromatography (20% EtOAc/80% hexanes) which yielded 23A as a
Isopropyl (2S,3R)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)-
amino)-2-hydroxy-3-phenylpropanoate (16A) and Isopropyl
(2R,3S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-2-hy-
droxy-3-phenylpropanoate (16A′). 16A was prepared from 15
following the general procedure using (DHQD)2PHAL as a ligand. It
was isolated by silica gel column chromatography (10% EtOAc/90%
hexanes to 20% EtOAc/80% hexanes) which yielded 16A as a
colorless, crystalline solid (148 mg, 65%). [α]22 = −17.3° (c 0.808,
D
CH2Cl2). Er = 98:2 (see Figure S6). 23A′ was prepared from 2233
following the general procedure using (DHQ)2PHAL as a ligand. It
was isolated by silica gel column chromatography (20% EtOAc/80%
hexanes) which yielded 23A′ as a colorless, crystalline solid (134 mg,
59%). [α]22 = 20.8 (c 0.903, CH2Cl2). Er = >99.5:0.5 (see Figure
colorless, crystalline solid (145 mg, 81%). [α]22 = −17.2° (c 0.744,
D
D
S6). The 1H NMR spectra of 23A and 23A′ were identical. 1H NMR
(300 MHz, CDCl3): δ 8.15 (1H, d, J = 6.5 Hz), δ 7.80−7.49 (6H, m),
δ 7.43−7.21 (6H, m), δ 5.83−5.40 (2H, m), δ 5.66 (1H, br s), δ
4.50−4.10 (3H, m), δ 3.86 (3H, s), δ 3.52 (1H, br s), δ 1.67 (9H, s).
13C{1H} NMR (75 MHz, CDCl3): δ 176.2, 158.6, 152.5, 146.7, 146.6,
CH2Cl2). Er = 98:2 (see Figure S3). 16A′ was prepared from 15
following the general procedure using (DHQ)2PHAL as a ligand. It
was isolated by silica gel column chromatography (10% EtOAc/90%
hexanes to 20% EtOAc/80% hexanes) which yielded 16A′ as a
colorless, crystalline solid (128 mg, 71%). [α]22 = 21.2° (c 0.712,
D
144.1, 138.4, 131.6, 130.6, 130.0, 128.0, 127.7, 126.9, 125.8, 122.9,
122.2, 121.6, 118.3, 86.9, 75.1, 70.1, 56.2, 52.8, 50.0, 31.1. HRMS-ESI
+ (m/z): [M + H]+ calculated for C32H33O7N2, 557.2282; found,
557.2301.
CH2Cl2). Er = 99:1 (see Figure S3). NMR data matched those
2
1
previously reported. The H NMR spectra of 16A and 16A′ were
1
identical. H NMR (300 MHz, CDCl3): δ 7.67 (2H, d, J = 7.2 Hz),
7.48 (2H, m), 7.34−7.22 (9H, m), 5.64 (1H, d, J = 9.3 Hz), 5.22 (1H,
d, J = 9.0 Hz), 5.07 (1H, sept, J = 6.0 Hz), 4.40−4.09 (4H, m), 3.18
(1H, br. s), 1.23−1.16 (6H, m). 13C{1H} NMR (75 MHz, CDCl3):
172.3, 155.6, 143.9, 143.8, 141.3, 139.0, 128.6, 127.8, 127.7, 127.1,
126.7, 125.0, 120.0, 73.5, 70.9, 67.0, 56.3, 47.2, 21.7, 21.6. HRMS-ESI
+ (m/z): [M + H]+ calculated for C27H28O5N, 446.1962; found,
446.1951.
Methyl (2S,3R)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)-
amino)-2-hydroxy-4-((4-methoxybenzyl)oxy)butanoate
(25A). 25A was prepared from 2423 following the general procedure
using (DHQD)2PHAL as a ligand. It was isolated by silica gel column
chromatography (30% EtOAc/70% hexanes to 40% EtOAc/70%
hexanes) which yielded 25A as a colorless, crystalline solid (144 mg,
73%). [α]22 = +2.4° (c 0.704, CH2Cl2). Er = 91:9 (see Figure S7).
(9H-Fluoren-9-yl)methyl ((1S,2R)-2-Hydroxycyclohexyl)-
carbamate (18A) and (9H-Fluoren-9-yl)methyl ((1R,2S)-2-
D
1
The H NMR spectrum was identical to that of 25A′.
G
DOI: 10.1021/acs.joc.9b02491
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Methyl (2R,3S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)-
amino)-2-hydroxy-4-((4-methoxybenzyl)oxy)butanoate
(25A′). To a cooled (ice bath) slurry of FmocNHCl (8.9 g, 32.5
mmol, 2.0 equiv) in nPrOH (71 mL) was added a solution of sodium
hydroxide (975 mg, 24.4 mmol, 1.5 equiv) in water (121 mL). A
solution of (DHQ)2PHAL (1.52 g, 1.95 mmol, 12 mol %) in nPrOH
(121 mL) and a solution of alkene 2423 (3.84 g, 16.3 mmol, 1.0
equiv) in nPrOH (61 mL) were added immediately afterward. The
reaction mixture was cooled (ice bath), and at this point it was
homogeneous. Then, a solution of potassium osmate (479 mg, 1.30
mmol, 8 mol %) and sodium hydroxide (61 mg, 1.525 mmol, 0.09
equiv) in water (51 mL) was added. The cooled reaction was stirred
for 3 h, at which point TLC had indicated that the reaction was
complete. The mixture was neutralized with 1 N HCl, and the
resulting slurry was filtered. The filter cake was washed several times
with 3:2 nPrOH/H2O. The filtrate was concentrated and then
partitioned between ethyl acetate (EtOAc, 100 mL) and water (100
mL). The aqueous layer was extracted twice, and the combined
organic layer was washed with 1 N HCl (300 mL), sat. NaHCO3 (300
mL), and brine (300 mL). The resulting organic layer was dried with
MgSO4, filtered, and concentrated. The crude oil was suspended in
CH2Cl2, filtered, and concentrated. This process was repeated three
times, and then the crude oil was purified by silica gel column
chromatography (30% EtOAc/70% hexanes to 40% EtOAc/60%
Imidazole (764 mg, 11.2 mmol, 5 equiv) and TBSCl (1.69 g, 11.2
mmol, 5 equiv). After 5 min of stirring, DMAP (27 mg, 0.22 mmol,
0.1 equiv) was added and the suspension was stirred for 3 h. After this
time, the reaction was quenched with 0.2 N HCl (22 mL) while cold.
The aqueous layer was then extracted with CH2Cl2 (22 mL) three
times, and the combined organic layer was washed with sat. NaHCO3
(100 mL) and brine (100 mL), dried over Na2SO4, and concentrated.
The crude residue was subjected to silica gel flash column
chromatography (30% EtOAc/70% hexanes then 50% EtOAc/50%
hexanes) yielding 27 as a colorless oil (979 mg, 74%). 1H NMR (300
MHz, CDCl3): δ 7.65 (2H, d, J = 8.4 Hz), 7.53−7.50 (2H, m), 7.29
(2H, t, J = 7.5 Hz), 7.22−7.12 (6H, m), 6.75 (2H, d, J = 8.4 Hz), 6.32
(1H, br. s), 6.04 (1H, br. s), 5.56 (1H, d, J = 9.3 Hz), 4.36−4.11 (7H,
m), 3.68 (3H, s), 3.50−3.23 (2H, m), 0.830 (9H, s), 0.049−0.031
(6H, m). 13C{1H} NMR (75 MHz, CDCl3): δ175.1, 159.1, 155.8,
143.9, 143.9, 141.2, 129.9, 129.2, 127.6, 127.0, 125.1, 119.9, 113.6,
72.6, 71.3, 67.3, 66.8, 55.2, 53.4, 47.1, 25.6, 17.9, −5.1, −5.4. HRMS-
ESI+ (m/z): [M + H]+ calculated for C33H43O6N2Si, 591.2885;
found, 591.2891.
(9H-Fluoren-9-yl)methyl((2S,3R)-4-amino-3-((tert-butyl-
dimethylsilyl)oxy)-1-hydroxy-4-oxobutan-2-yl)carbamate
(28). 27 (1.1 g, 1.9 mmol, 1.0 equiv) and pentamethylbenzene (306
mg, 2.06 mmol, 1.10 equiv) were dissolved in dry CH2Cl2 (20 mL)
under an inert atmosphere. The reaction mixture was cooled to −78
°C, and BCl3 (1 M in CH2Cl2, 5.62 mL, 5.62 mmol, 3.00 equiv) was
added dropwise over 10 min. After the addition, the reaction mixture
was warmed in an ice−water bath. The resulting mixture was stirred
for 1 h and then quenched by the dropwise addition of sat. NaHCO3
(40 mL). After 10 min of stirring, the reaction mixture was brought to
room temperature and the aqueous layer was extracted with EtOAc
(40 mL) twice. The organic layers were combined, washed with brine,
dried with MgSO4, and concentrated. The crude oil was purified by
silica gel column chromatography (50% EtOAc/49% hexanes/1%
AcOH to 60% EtOAc/39% hexanes/1% AcOH) yielding 28 (759 mg,
86%) as a colorless foam. Characterization data matched those
previously reported.3 1H NMR (300 MHz, CDCl3): δ 7.73 (2H, d, J =
7.5 Hz), 7.59 (2H, m), 7.40−7.26 (4H, m), 6.06 (2H, m), 5.86 (1H,
d, J = 9.3 Hz), 4.37−4.35 (2H, m), 4.29 (1H, d, J = 3.6 Hz), 4.20
(1H, dd, J = 6.9, 6.9 Hz), 4.00 (1H, m), 3.79−3.62 (2H, m), 0.93
(9H, s), 0.16−0.12 (6H, m). 13C{1H} NMR (75 MHz, CDCl3): δ
175.9, 156.3, 143.8, 143.8, 141.2, 141.2, 127.6, 126.6, 125.1, 119.8,
71.5, 66.9, 61.0, 55.7, 47.1, 25.6, 17.9, −5.2, −5.4. HRMS-ESI+ (m/
z): [M + H]+ calculated for C25H35O5N2Si, 471.2310; found,
471.2309.
(2R,3R)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-
amino-3-((tert-butyldimethylsilyl)oxy)-4-oxobutanoic Acid
(ent-5). 28 (786 mg, 1.67 mmol, 1 equiv) was dissolved in ACN
(23.4 mL) and cooled in an ice−water bath. TEMPO (392 mg, 2.88
mmol, 1.50 equiv) was added to the stirring reaction mixture. NaClO2
(80% w/w; 529 mg, 4.68 mmol, 2.80 equiv) was dissolved in cold
phosphate buffer (0.67 N, pH = 7; 15.8 mL) and added dropwise to
the stirring reaction mixture. NaOCl (6% bleach; 1.44 mL, 1.17
mmol, 0.70 equiv) was added dropwise over 30 min. Once the
addition was complete, the reaction was stirred for 3 h and then
quenched with sat. Na2SO3 (10 mL) and brought to room
temperature. The reaction mixture was acidified with 12 N HCl
(pH ca. 2), and the aqueous layer was extracted with CH2Cl2 (75 mL)
three times. The combined organic layer was dried with MgSO4 and
filtered. After concentrating, the residue was subjected to silica gel
column chromatography (40% EtOAc/60% hexanes/1% AcOH)
allowing for the isolation of ent-5 (721 mg, 92% yield) as a colorless
solid. (635 mg, 92%). NMR data matched those previously reported
for its enantiomer.3 [α]22D = 16.3° (c 0.744, CH3OH) 1H NMR (300
MHz, CD3OD): δ 7.62−7.40 (4H, m), 7.24−7.12 (4H, m), 6.73 (1H,
d, J = 8.7 Hz), 4.61−4.55 (2H, m), 4.23−4.04 (3H, m), 0.81 (9H, s),
0.00 (6H, m). 13C{1H} NMR (75 MHz, CD3OD): δ 175.9, 172.9,
158.6, 145.3, 142.6, 128.9, 128.3, 126.4, 121.0, 75.4, 68.4, 58.9, 26.4,
19.2, −4.7, −5.0. HRMS-ESI+ (m/z): [M + H]+ calculated for
C25H33O6N2Si, 485.2102; found, 485.2105.
hexanes) yielding 25A′ as a colorless foam (5.53 g, 73% yield). [α]22
D
= −3.0° (c 0.801, CH2Cl2). Er = 96:4 (see Figure S7). 1H NMR (300
MHz, CDCl3): δ 7.76 (2H, d, J = 7.2 Hz), 7.61 (2H, m), 7.43−7.28
(6H, m), 6.88 (2H, d, J = 8.1 Hz), 5.66 (1H, d, J = 9.6 Hz), 4.53−
4.20 (7H, m), 3.89−3.55 (9H, m). 13C{1H} NMR (75 MHz, CDCl3):
173.5, 158.9, 155.8, 143.6, 143.4, 140.9, 129.4, 129.1, 127.3, 126.7,
124.8, 124.7, 119.6, 113.4, 72.5, 69.3, 52.4, 46.7. HRMS-ESI+ (m/z):
[M + H]+ calculated for C28H30O7N, 492.2017; found, 492.2011.
(9H-Fluoren-9-yl)methyl((2S,3R)-4-amino-3-hydroxy-1-((4-
methoxybenzyl)oxy)-4-oxobutan-2-yl)carbamate (26). To a
solution of 25A′ (2.88 g, 5.86 mmol, 1 equiv) in THF (40 mL)
and isopropanol (133 mL) was added pulverized CaCl2 (10.66 g,
96.08 mmol, 16.4 equiv). The resulting suspension was cooled (ice−
water bath), and ice-cold LiOH (0.28 N, 41.8 mL, 2.0 equiv) was
added dropwise. After stirring for 15 min more ice cold LiOH (0.28
N, 33.5 mL, 1.6 equiv) was added dropwise to the suspension.
Cooling was removed, and once it had reached room temperature, the
reaction mixture was stirred for 45 min, at which point it was
extracted with diethyl ether (100 mL). The aqueous layer was
acidified with 1 N HCl (pH ca. 2) and extracted with EtOAc (100
mL) three times. The combined organic layer was washed with 0.1 N
HCl (300 mL) twice, dried over MgSO4, filtered, and concentrated.
The crude residue was dissolved in DMF (117 mL) and reacted with
benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-
phosphate (BOP; 3.89 g, 8.79 mmol, 1.5 equiv) for 5 min at room
temperature. NH4Cl (627 mg, 11.7 mmol, 2.0 equiv) and DIPEA
(3.06 mL, 17.58 mmol, 3 equiv) were then added, and the resulting
suspension was stirred at room temperature for 2 h. The reaction
mixture was then diluted with EtOAc (1200 mL) and washed with 1
N HCl (800 mL), sat. NaHCO3 (800 mL), and brine (800 mL) twice.
The organic layer was dried with Na2SO4, concentrated, and
subjected to silica gel flash column chromatography (80% EtOAc/
19% hexanes/1% AcOH then 98% EtOAc/2% AcOH) yielding 26 as
1
a colorless oil (1.73 g, 62% for two steps). H NMR (300 MHz,
CDCl3): δ 7.60 (2H, d, J = 7.5 Hz), 7.44−7.40 (2H, m), 7.27−7.22
(2H, m), 7.17−7.12 (2H, m), 7.05 (2H, d, J = 8.4 Hz), 6.70 (2H, d, J
= 8.7 Hz), 6.66 (1H, br. s), 6.13 (1H, br. s), 5.81 (1H, d, J = 9.0 Hz),
4.35−3.99 (8H, m), 3.70−3.50 (5H, m). 13C{1H} NMR (75 MHz,
CDCl3): δ 175.3, 159.3, 156.6, 143.8, 143.6, 141.2, 129.4, 129.2,
127.6, 127.0, 125.0, 125.0, 119.9, 113.8, 73.1, 72.3, 70.3, 66.9, 55.1,
52.0, 46.9. HRMS-ESI+ (m/z): [M + H]+ calculated for C27H29O6N2,
477.2020; found, 477.2005.
(9H-Fluoren-9-yl)methyl((2S,3R)-4-amino-3-((tert-butyl-
dimethylsilyl)oxy)-1-((4-methoxybenzyl)oxy)-4-oxobutan-2-
yl)carbamate (27). To a cool (ice bath) solution of 26 (1.069 g,
2.244 mmol, 1.00 equiv) in dry CH2Cl2 (22.5 mL) was added
H
DOI: 10.1021/acs.joc.9b02491
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(2R,3S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-2-
methoxy-4-((4-methoxybenzyl)oxy)butanoate (29). 25A′ (1.70
g, 3.46 mmol, 1.00 equiv) was dissolved in ether (69 mL) at room
temperature. Freshly prepared, dry Ag2O (2.40 g, 10.4 mmol, 3
equiv), followed by MeI (4.31 mL, 69.2 mmol, 20.0 equiv), was added
to the flask. The reaction mixture was vortexed briefly until a
suspension was formed. The reaction mixture was then brought to
reflux and allowed to react for 18 h, with vigorous stirring, under an
inert atmosphere. The reaction mixture was cooled to room
temperature, filtered, and concentrated. The residue was purified by
silica gel column chromatography (20% EtOAc/80% hexanes)
allowing for the isolation of 29 (1.54 g, 88% yield) as a colorless,
vicious oil. 1H NMR (300 MHz, CDCl3): δ 7.74 (2H, d, J = 7.2 Hz),
7.59 (2H, m), 7.41−7.28 (6H, m), 6.88 (2H, d, J = 8.1 Hz), 5.40 (1H,
d, J = 9.6 Hz), 4.53−4.13 (7H, m), 3.76−3.71 (6H, m), 3.55−3.45
(5H, m). 13C{1H} NMR (75 MHz, CDCl3): δ 171.0, 159.0, 155.6,
143.7, 143.5, 141.0, 129.6, 129.1, 127.4, 126.8, 124.9, 124.8, 119.7,
113.5, 77.6, 72.5, 67.3, 66.7, 58.6, 54.9, 52.1, 51.8, 46.8. HRMS-ESI+
(m/z): [M + H]+ calculated for C29H32O7N, 506.2173; found,
506.2172.
(2R,3R)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-
(tert-butoxy)-3-methoxy-4-oxobutanoic Acid (ent-6a). 31 (883
mg, 1.61 mmol, 1.00 equiv) was dissolved in freshly prepared 9:1
ACN/H2O (6.5 mL), and Bobbit’s Salt (532 mg, 1.77 mmol, 1.10
equiv) was added to the stirring solution. The reaction mixture was
sealed and allowed to stir for 18 h at room temperature. The resulting
solution was cooled in an ice−water bath (any recovered 32 was
added at this point, and the amount of primary oxidant was scaled
accordingly) and diluted with a solution of NaClO2 (80% w/w; 547
mg, 4.84 mmol, 3.00 equiv) in phosphate buffer (0.67 M, pH ca. 7;
10.75 mL), and then the mixture was neutralized with 1 N NaOH.
The neutralized mixture was diluted with ACN (9.65 mL) followed
by a dropwise addition of NaOCl (6% bleach; 1.40 mL, 1.13 mmol,
0.70 equiv) over 30 min. Once the addition was complete, the
reaction proceeded to completion in 4 h at which point it was
quenched with saturated aqueous Na2SO3. The organic layer was
separated, and the aqueous layer was acidified slowly with 12 N HCl
(pH ca. 2). The aqueous layer was extracted with CH2Cl2 (50 mL)
three times, and the combined organic layer was dried with MgSO4.
The residue was purified by silica gel column chromatography (40%
EtOAc/59% hexanes/1% AcOH), allowing for the isolation of ent-6a
as a colorless solid (569 mg, 80%). NMR data matched those
Preparation of (2R,3S)-3-((((9H-Fluoren-9-yl)methoxy)-
carbonyl)amino)-2-methoxy-4-((4-methoxybenzyl)oxy)-
butanoic Acid (30). To a solution of 29 (1.03 g, 2.04 mmol, 1.00
equiv) in degassed ethyl acetate (14.6 mL) was added LiI (1.36g, 10.2
mmol, 5.00 equiv) at room temperature. The reaction vessel was then
sealed, brought to 80 °C, and stirred for 18 h. Once the reaction
mixture had cooled to room temperature, it was diluted with ethyl
acetate (50 mL) and washed with 0.1 N HCl (50 mL), dried over
MgSO4, and concentrated. The crude residue was subjected to silica
gel column chromatography (40% EtOAc/59% hexanes/1% AcOH)
previously reported for its enantiomer.3 [α]22 = 14.3° (c 0.628,
D
1
CH3OH). H NMR (300 MHz, CDCl3): δ 11.11 (1H, br. s), 7.73
(2H, d, J = 7.2 Hz), 7.61−7.56 (2H, m), 7.40−7.26 (4H, m), 5.76
(1H, d, J = 10.2 Hz), 4.96 (1H, d, J = 9.9 Hz), 4.35−4.32 (3H, m),
4.20 (1H, dd, J = 7.2 Hz), 3.48 (3H, s), 1.45 (9H, s). 13C{1H}NMR
(75 MHz, CDCl3): δ174.5, 168.0, 156.4, 143.7, 143.6, 141.2, 127.7,
127.1, 125.2, 125.2, 119.9, 83.2, 79.6, 77.4, 67.6, 59.3, 56.4, 46.9, 27.9.
HRMS-ESI+ (m/z): [M + H]+ calculated for C24H28O7N, 442.1860;
found, 442.1852.
1
yielding 30 as a colorless oil (800 mg, 80%). H NMR (300 MHz,
CDCl3): δ 11.0 (1H, br. s), 7.73 (2H, d, J = 7.5 Hz), 7.58 (2H, m),
7.40−7.22 (6H, m), 6.85 (2H, d, J = 8.4 Hz), 4.53−4.26 (5H, m),
4.21−4.12 (2H, m), 3.78 (3H, s), 3.52−3.38 (5H, m). 13C{1H} NMR
(75 MHz, CDCl3): δ 174.5, 159.1, 156.3, 143.9, 143.5, 141.2, 141.1,
129.7, 129.3, 127.6, 127.0, 125.2, 125.1, 119.8, 113.7, 72.6, 67.5, 67.2,
59.0, 55.1, 52.1, 52.1, 46.9. HRMS-ESI+ (m/z): [M + H]+ calculated
for C28H30O7N, 492.2017; found, 492.2027.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b02491.
■
S
NMR spectra for all Fmoc-protected amino alcohols;
chiral HPLC chromatograms for all chiral Fmoc-
protected amino alcohols (PDF)
(2R,3S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-2-
methoxy-4-((4-methoxybenzyl)oxy)butanoic Acid (31). To a
solution of 30 (1.00 g, 2.05 mmol, 1.00 equiv) in CH2Cl2 (26 mL)
cooled in an ice−water bath were added tert-butyl 2,2,2-trichlor-
oacetimidate (1.83 mL, 10.25 mmol, 5.00 equiv) and BF3·Et2O (29
μL, 0.21 mmol, 0.10 equiv). The resulting suspension was stirred for 1
h at room temperature and then concentrated. The crude residue was
dissolved in CH2Cl2 (50 mL) and washed with 1 N NaOH (50 mL),
H2O (50 mL) and brine (50 mL), dried over MgSO4, and
concentrated. The crude residue was purified by silica gel column
chromatography (20% EtOAc/80% hexanes then 40% EtOAc/59%
Hexanes/1% AcOH) yielding 31 as a colorless oil (966 mg, 86%). 1H
NMR (300 MHz, CDCl3): δ 7.75 (2H, d, J = 7.5 Hz), 7.57 (2H, d, J =
7.2 Hz), 7.39 (2H, dd, J = 7.2, 7.2 Hz), 7.32−7.28 (2H, m), 6.91 (2H,
d, J = 6.9 Hz), 5.19 (1H, d, J = 9.3 Hz), 4.54−4.16 (6H, m), 3.99
(1H, br. s), 3.79 (3H, m), 3.50−3.44 (5H, m), 1.44 (9H, s). 13C{1H}
NMR (75 MHz, CDCl3): δ 169.8, 159.2, 155.8, 143.9, 143.7, 141.2,
141.2, 130.0, 129.4, 127.6, 127.0, 125.1, 125.1, 119.9, 113.7, 82.1,
78.0, 72.7, 67.9, 66.9, 58.9, 55.2, 52.3, 47.1, 27.9. HRMS-ESI+ (m/z):
[M + H]+ calculated for C32H38O7N, 548.2643; found, 548.2650.
tert-Butyl (2R,3S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)-
amino)-4-hydroxy-2-methoxybutanoate (32). 32 was recovered
from the silica gel column used to purify 31. This yielded 32 as a
AUTHOR INFORMATION
Corresponding Author
*E-mail: s5taylor@uwaterloo.ca.
ORCID
Scott D. Taylor: 0000-0001-5449-5940
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
■
This work was supported by a Natural Sciences and
Engineering Research Council of Canada (NSERC) Discovery
Grant to S.D.T. (RGPIN-2017-04233). R.M. thanks NSERC
for a postgraduate scholarship.
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DOI: 10.1021/acs.joc.9b02491
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The Journal of Organic Chemistry
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