The synthesis of unnatural α-alkyl- And α-aryl-substituted serine derivatives

Article abstract of DOI:10.1039/c9ob02472g

The synthesis of α-aryl- and α-alkyl-substituted serine derivatives via [3,3]-sigmatropic rearrangement of allyl carbamates as a key step is reported. Allyl carbamates were obtained from the corresponding allyl alcohols. The former were prepared through three approaches. Aryl-substituted ones were synthesized via the Stille coupling reaction of aryl iodides with enantiomerically enriched vinyl stannanes. Conversely, alkyl-substituted allyl alcohols were prepared by an analogous strategy involving the Negishi coupling reaction of enantiomerically enriched vinyl iodides or by enzymatic kineric resolution of the corresponding racemic alcohols.

Full text of DOI:10.1039/c9ob02472g

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DOI: 10.1039/C9OB02472G
The synthesis of unnatural α-alkyl- and α-aryl-substituted serine derivatives
Aleksandra Narczyk, Sebastian Stecko*
Institute of Organic Chemistry, Polish Academy of Sciences
Kasprzaka 44/52, 01-224 Warsaw, Poland
e-mail: sebastian.stecko@icho.edu.pl
Graphical abstract
Ar
O
OH
HO
HO
NHR
Stille coupling
Negishi coupling
O-PG
R
OH
sigmatropic
rearrangement
Alk
O
OH
enzymatic kinetic resolution
NHR
Abstract
The synthesis of α-aryl- and α-alkyl-substituted serine derivatives via [3,3]-
sigmatropic rearrangement of allyl carbamates as a key step is reported. Allyl
carbamates were obtained from the corresponding allyl alcohols. The former were
prepared through three approaches. Aryl-substituted ones were synthesized via Stille
coupling reaction of aryl iodides with enantiomerically enriched vinyl stannanes.
Conversely, alkyl-substituted allyl alcohols were prepared by an analogous strategy
involving Negishi coupling reaction of enantiomerically enriched vinyl iodides or by
enzymatic kineric resolution of the corresponding racemic alcohols.
Keywords
allyl alcohols, allylamines, serines, sigmatropic rearrangement, cross-couplings,
enzymatic kinetic resolution
1

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DOI: 10.1039/C9OB02472G
Introduction
Serine, as well as its analogues, derivatives, and isosteres play an important
role in the nature as well as in medicinal chemistry.1 Among them, the α-substituted
serine-type unit is a very common structural motif in natural products, such as
myrocine, conagenin, lactacystine, and others (Figure 1). Serine analogues or
derivatives are also highly important in the design and modification of peptide structure
and biological properties.
Serine based bioactive compounds:
R
OH
OH OH
H
N
O
COOH
OH
NH
O
(
)
5
COOH
OH
OH
O
O
HOH2N
O
R: H; myriocin,
R: OH; sphingofungin E
antibiotic & immunosuppresant
conagenin
antitumor agent
O
omuralide
proteasome inhibitor
O
O
NH
SO2NH2
H
HN
OH
BnHN
O
H
O
O
COOH
OH
NHAc
N
O
NH
O
HO
S
lacosamide
CN
OH
O
epilepsy
SCF3
H
HOOC
H
N
NH2
NHAc
Cl
O
CF3
O
lactacystin
salinosporamide A
altemicidin
acaricidal & antitumor
N
proteasome inhibitor proteasome inhibitor
monepantel (ZolvixTM
)
veterinary
H2N
H2N
H2N
H
OH
N
OH
N
N
OH
n-C8H17
O
n-C8H17
O
N
H
O
O
N
n-C8H17
O
PPI-4621
PPI-4691
VPC44239
potent sphingosine 1-phosphate (S1P) receptor antagonists
H2N
HO
OH
OH
HOOC
H2N
CF3
OR
B
Serine based building blocks:
O
OH
Boc
O
serine isosteres
human arginase I inhibitor
O
H
N
I
OR
PG
O
HN
NH2
OH
COOH
iodo-alanine
derivatives
(S)-Garner's
1
aldehyde ( )
O
2
( )
serine palmitoyl transferase inhibitor
Figure 1. Selected bioactive molecules bearing an α-substituted serine subunit and
serine derived building blocks.
Generaly speaking, unnatural α,α-disubstituted α-amino acids and their
derivatives have attracted great interest due to their notable effect on the biological
2

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activity of biomimetics through enhancement of their bioavailibity, biostability, and
DOI: 10.1039/C9OB02472G
hydrolytic properties of peptidomimetics.2-7 Their incorporation into a peptide structure
can cause conformational disorder and result in a change of its biological properties.3-5
Serine derivatives, as well as their analogues, are also versatile and valuable
building blocks in organic synthesis. An excellent example is Garner’s aldehyde (1), as
well as other serinals, which have found numerous applications in the total synthesis
of enantiopure natural products.8,9 Serine derivatives are also attractive building blocks
for the synthesis of various heterocyclic systems.8,9 The replacement of the hydroxyl
group by an iodine atom results in the formation of iodo-alanine derivatives (2) which
were found to be attractive precursors for the preparation of modified amino acids via
the Negishi coupling reaction.10
Although there is a vast number of strategies for the preparation of non-
proteinogenic amino acids, surprisingly only a few of them are applied in the synthesis
of α-substituted unnatural serines.11-14 α-Aryl serines can be prepared via the Strecker
reaction of the corresponding α-hydroxy ketimine derivatives,15, 16 hydroxymethylation
and subsequent reduction of aryl-substituted nitroacetates,17 palladium-catalyzed
allylic amination,18 or oxidative nucleophilic substitution of oxazolines with
nitroarenes.19 The Strecker reaction,20 as well as α-alkylation of serine enolates via a
Seebach approach21, 22,23 are common methods for the preparation of α-alkyl serines.
Less common methods involve the ring opening of chiral azirines,24 the trapping of
ammonium ylides25 or enzymatic or catalyzed desymmetrization of amino diols26, 27 or
nitro diols.28 Most of the mentioned intermolecular strategies suffer from low efficiency
and stereoselectivity in the formation of the tertiary stereogenic center due to steric
hindrance of the reactants (Scheme 1).
3

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One solution to this issue is the formation of a teriary stereogenic center in an
DOI: 10.1039/C9OB02472G
intramolecular fashion, which is particularly useful in the case of the already mentioned
sterically hindred amino acids and their derivatives. An interesing example is the
synthesis of enantiomeric methyl α-methyl serinates and their homologues via acid-
catalyzed intramolecular cyclization of 2-substituted 2,3-epoxytrichloroacetimidates,
reported by Hatakeyama and co-workers.29 The related strategies of Lewis or Brønsted
acid-mediated cyclization with trichloroacetimidates have also been reported.30-33
Another approach is the thermal or catalytic sigmatropic rearrangement of allyl
trichloroacetimidates. Such an approach was used e.g. by Chida and co-workers in the
total synthesis of sphingofungin E from D-glucose,34 as well as in the synthesis of other
structurally related bioactive molecules.35-39 During our ongoing research program on
the application of sigmatropic rearrangements in the synthesis of bioactive molecules,
we demonstrated that the allyl cyanate to allyl isocyanate rearrangement reaction is a
valuable tool for the preparation of unnatural amino acid derivatives, including
threonine-type amino acids40 and lacosamide, a D-serine-derived antiepileptic drug.41
Recently, we have endeavored to extend the presented approach to the preparation
of α-substituted serine (and threonine) derivatives. Such molecules are particularly
interesting as they can serve as a platform for the formation of morpholine and
piperazine rings, which are privileged heterocyclic scaffolds in medicinal chemistry and
drug discovery. In the past, Ichikawa and co-workers have applied this rearrangement
reaction in the synthesis of methyl α-methyl-L-serinate (Scheme 1) starting from a lactic
acid ester. Its further functionalization allowed for the total synthesis of the antitumor
agent conagenin (see Figure 1). Unfortunatelly, Ichikawa’s strategy was limited to α-
methyl serine, and not suitable for the preparation of its homologues, e.g. higher α-
alkyl or α-aryl serines. This limitation arised from the fact that the proposed method of
4

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preparation of the starting materials involved Wittig or HWE olefination which usually
DOI: 10.1039/C9OB02472G
led to (E/Z)-mixtures. This is a critical point, since complete stereochemical purity of
the starting materials, in this case the allyl alcohol (and thus the carbamate) is crucial
for the enantiomeric purity of the rearrangement product.
O
TBDPSO
Me
H2N
O
Me
CbzHN
HO
COOMe
OTr
COOEt
from D-lactic acid
Scheme 1
Herein, we report the preparation of the mentioned unnatural serine derivatives
through sigmatropic rearrangement of type 3 allyl carbamates. These compounds
could be accessed from readily available type 4 non-racemic propargyl diol derivatives.
Installation of aryl and alkyl substituents was planned to proceed through the
functionalization of a triple bond, as depicted in Scheme 2.
O
introduction of
R group
OH
O-PG
R
R
COOH
OH
rearrangement
H2N
O
*
H2N
O-PG
*
oxidative
cleavage
carbamoylation
*
R: aryl, alkyl
3
4
Scheme 2
Results and discussion
Allyl carbamate 3 precursors required for the preparation of the respective α-
aryl serines were prepared from (S)-3-butyn-2-ol. Initially, the secondary alcohol group
was temporarly silylated and the alkyne treated with a base, followed by the addition
of paraformaldehyde to provide the corresponding propargyl alcohol. Its O-protection
and desilylation afforded non-racemic alcohols 4a and 4b in 78% and 89% yield,
respectively (Scheme 3). Alkynes 4a,b were then subjected to Pd-catalyzed
hydrostannylation, providing vinyl stannanes 5a and 5b in high yield. These β-stannyl
allyl alcohols were accompanied by minor amounts (~10%) of the regioisomeric α-
5

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stannyl alcohols, which could be easily chromatographically separated from the major
DOI: 10.1039/C9OB02472G
products. Surprisingly, the hydrostannylation of type 4 alcohol with an O-silyl protecting
group (R: TBS) led to a complicated mixture of the desired product along with
unidentified side-products. The same problem was observed when less hindered TES
or TMS groups were applied. Hence, it turned out to be impossible to isolate a pure β-
stannyl allyl alcohol containing the TBS group in good yield. Alternatively, vinyl
stannanes 5 can be prepared in racemic form (rac-5) following the reaction sequence
presented in Scheme 3, and then subjected to enzymatic kinetic resolution to provide
(S)-alcohol 5b along with enantiomeric (R)-acetate 5c.
Bu3SnH (1.1 equiv)
Pd(PPh3)2Cl2
(1 mol%)
OH
OR
1) TBDPSCl, Et3N, DMAP, CH2Cl2
2) (CH2O)n, MeLi, THF
OH
OH
SnBu3
THF
0 oC to rt
3) BnBr, TBAB, 50% aq. NaOH
or MOMCl, i-Pr2NEt, CH2Cl2
4) TBAF, THF
OR
(S)-but-3-yn-2-ol
98% ee
5a
; R: Bn, 80%
; R: MOM, 79%
4a
; R: Bn, 78%
; R: MOM, 89%
5b
4b
vinyl acetate
Candida antarctica
OMOM
SnBu3
OMOM
SnBu3
; 46%, 96% ee
OMOM
SnBu3
OH
OH
OR
lipase
+
MS 4A, rt
pentane
rac-5b
5c
R: Ac; ; 47%
5b
aq. K2CO3
MeOH
5b
R: H; ent- ; 99%, 98% ee
Scheme 3
Vinyl stannanes 5a and 5b were then subjected to Stille coupling reaction with
various aryl iodides to provide the corresponding chiral β,β-disubstituted allyl alcohols
6a-x. The coupling reactions proceeded with high yields, regardless of whether
electron-rich or electron-poor aryl iodides were applied, as summarized in Scheme 4.
Only reactions with o-substituted aryl iodides, such as 2-iodoanisole, 2-iodotoluene,
and 2-chloroiodobenzene required longer reaction times (48 h instead of standard 24
h), but the yields were still high.
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DOI: 10.1039/C9OB02472G
ArI (1.3 equiv)
CuI (10 mol%)
Pd(PPh3)4 (3 mol%)
OR
OR
OH
OH
CsF (2 equiv)
THF, 60 o
24 h
C
R2
SnBu3
1
5a
5b
; R : Bn
6
1
; R : MOM
OR
OR
OR
OR
a
a
6aa
6ab
6ac
6ad
; R: Bn, 91%
; R: Bn, 88%
; R: Bn, 73%
; R: Bn, 74%
6ba
6bc
6bd
; R: MOM, 87%
; R: MOM, 86%
; R: MOM, 90%
6bb
; R: MOM, 91%
OR
OR
OR
OR
Bn
MeO
N
F
CF3
Boc
a
6ae
6af
6ag
6ah
; R: Bn, 72%
; R: Bn, 72%
; R: Bn, 77%
; R: Bn, 82%
a
6bf
6bg
6bh
; R: MOM, 77%
; R: MOM, 91%
; R: MOM, 90%
6be
; R: MOM, 81%
OR
OR
OR
OR
Cl
CN
COOMe
a
6ai
6aj
6ak
6al
; R: Bn, 76%
6bl
; R: MOM, 95%
; R: Bn, 79%
; R: Bn, 73%
; R: Bn, 81%
a
6bj
6bk
; R: MOM, 91%
; R: MOM, 95%
6bi
; R: MOM, 83%
OMOM
O
OMOM
OMOM
S
OMOM
N
N
b
b
b
b
6bm
, 84%
6bo
6bp
, 84%
, 81%
6bn
, 79%
a 48 h; b the aryl bromide was used instead of aryl iodide; MOM = methoxymethyl; Bn = benzyl
Scheme 4
Independently, experiments leading to precursors of α-alkyl serines were
conducted. Vinyl stannane 5a was treated with iodine to provide vinyl iodide 7, as
shown in Scheme 5, which was then subjected to Negishi cross-coupling reaction.
Disappointingly, this process was limited to the introduction of simple linear alkyl grups
such as methyl or n-butyl. The yields of the coupling reactions were moderate in the
case of higher primary organozinc reagents, and poor when secondary or tertiary
reagents were applied, due to significant contribution of competing β-hydride
elimination reaction. In the case of secondary alkylzinc reagents, the change of the
7

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catalytic system to Pd(OAc)2/Cphos,42 suitable for secondary alkyl bDroOIm: 10id.10e3s9/C9oOrB02472G
chlorides, did not enhance the efficiency of the coupling reaction significantly.
RMgX or RLi (3 equiv)
ZnCl2 (3 equiv)
Pd(PPh3)2Cl2 (5 mol%)
OBn
R
OBn
OBn
I
OH
OH
OH
I2
SnBu3
CH2Cl2
THF, rt
3-4 h
0 o
C
8
5a
7
, 95%
R: Me, 70%
R: n-Bu, 72%
R: n-Hex, 70%
Scheme 5
Due to the mediocre efficiency and, above all, limited scope of the investigated
C(sp2)-C(sp3) coupling reactions, the synthetic strategy for the preparation of allyl
alcohols 8 was revised. Initially, we focused on their preparation through an
enantioselective reduction of the corresponding enones 9. For this purpose, ethyl
butynoate 10 was subjected to a 1,4-addition reaction of organocopper reagents43 to
provide a series of α,β-unsaturated esters 11 as Z isomers predominantly (Scheme 6).
Then, esters 11 were readily converted into Weinreb amides which, upon trearment
with MeMgBr, gave the corresponding unsaturated ketones 9. As mentioned, the 1,4-
addition step provided mainly Z isomers. A slight contamination with the E isomer was
readily removed through column chromatography of the corresponding Weinreb
amides.
8

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O
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DOI: 10.1039/C9OB02472G
RMgX and TMEDA
1) BnBr, NaH, DMF,
2) ClCOOEt, MeLi, THF
BnO
R
or RLi; CuI
O
OEt
THF
OEt
OH
OBn
10
11
; 71%
Yield [%]
Z:E ratioa
R
11a
99
96
90
99
85
95>
95>
95>
90:10
90:10
Me (
Bu (
i-Bu (
i-Pr (
Cy (
)
)
)
)
)
11b
11c
11d
11d
a Determined by 1H NMR
1) MeONHMe.HCl,
i-PrMgCl, THF
NaBH4,
BnO
CeCl3 7H2O
BnO
R
BnO
R
O
OH
O
.
2) MeMgBr, THF
OEt
R
2 steps
CH2Cl2:MeOH
(4:1)
11
9a
9b
rac-8a
rac-8b
; R: Me, 84%
; R: Bu, 78%
; R: Me, 95%
; R: Bu, 88%
; R: i-Bu, 84%
9c
rac-8c
rac-8d
; R: i-Bu, 62%
9d
; R: i-Pr, 64%
9e
; R: i-Pr, 86%
rac-8e
; R: Cy, 66%
; R: Cy, 80%
Scheme 6
In the first attempt, a classical CBS reduction of 9a in the presence of a chiral
oxazaborolidine proceeded in moderate yield and with poor enantioselectivity (65%, er
76:24). Surprisingly, transfer hydrogenation of 9a in the presence of Noyori-type
catalysts44, 45 failed and only starting material was recovered. Similarly, Cu-46 or Zn-
catalyzed47, 48 hydrosilylation reactions, as well as Ni-mediated 1,2-reduction,49 which
we have successfully utilized in the past,50,51 did not work in the case of type 9 starting
materials. This seemed to indicate that these reactions were affected by the presence
of the additional hydroxyl group which could interfere in efficient complexation of the
metal to the carbonyl group. Fortunately, it was not the case for simple reduction of
ketones 9 under Luche conditions, and the resulting racemic allyl alcohols rac-8 were
subjected to an enzymatic kinetic resolution process.
Treatment of the alcohols with vinyl acetate in the presence of lipase from
Candida antarctica provided the corresonding (S)-allyl alcohols 8 with high
enantioselectivity (92–99% ee) along with the corresponding (R)-acetates 12. As
presented in Scheme 7, the resolution proceeded efficiently and with an excellent level
9

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of enantioselectivity, although in the case of substrates bearing bDuOlkI:i1e0.r103a9/lCk9yOlB02472G
substituents e.g. i-propyl or cyclohexyl, the reaction time required to achieve 50%
conversion of the starting material was quite long.
BnO
BnO
R
BnO
R
OH
OAc
OH
OAc
Candida antarctica lipase
R
+
pentane, MS 4A, rt
rac-8
8
12
8a
8b
8c
8d
8e
(S)-alcohol 43%, 99% ee 47%, 97% ee
17 h 16 h
44%, 92% ee
42%, 94% ee
40%, 99% ee
10 days
24 h
8 days
12a
12b
12c
12d
12e
, 41%
(R)-acetate
, 45%
, 48%
, 42%
, 40%
Scheme 7
With both β-alkyl and β-aryl substituted allyl alcohols 6 and 8, their further
conversion to tert-allylamines through the sigmatropic rearrangement reaction
following a previously used protocol was examined.50, 52 First, alcohols 6 and 8 were
converted to carbamates 3 by treatment with phenyl carbamate in the presence of
dibutyltin maleate (DBTM) as a catalyst (Scheme 8).53 Direct carbamoylation of 6 and
8 by the treatment with trichloroacetyl isocyanate followed by a basic hydrolysis
provided the corresponding carbamates 3 in lower yields.
10

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DOI: 10.1039/C9OB02472G
O
O
O
O
R1O
R2
PhO
DBTM (10 mol%)
PhMe, 90 o
NH2
R1O
R2
O
Sn
O
OH
O
NH2
C
DBTM
6 or 8
3
R1O
R1O
R1O
R1O
1
1
1
1
3aa
3ab
3ac
3ad
; R : Bn, 90%
; R : Bn, 85%
; R : Bn, 75%
; R : Bn, 81%
1
1
1
1
3ba
3bb
3bc
3bd
; R : MOM, 86%
; R : MOM, 91%
; R : MOM, 91%
; R : MOM, 87%
R1O
R1O
R1O
R1O
Bn
N
F3C
OMe
F
Boc
1
1
1
1
3ae
3af
3ag
3ah
; R : Bn, 80%
; R : Bn, 70%
; R : Bn, 89%
; R : Bn, 79%
1
1
1
1
3be
3bf
3bg
3bh
; R : MOM, 78%
; R : MOM, 79%
; R : MOM, 84%
; R : MOM, 93%
R1O
R1O
R1O
R1O
Cl
NC
MeOOC
3ak
1
1
1
1
3ai
3aj
3al
; R : Bn, 85%
; R : Bn, 91%
; R : Bn, 89%
; R : Bn, 74%
1
1
1
1
3bi
3bj
3bk
3bl
; R : MOM, 87%
; R : MOM, 98%
; R : MOM, 83%
; R : MOM, 86%
MOMO
MOMO
MOMO
MOMO
S
O
N
N
3bm
3bn
3bo
3bp
, 65%
, 74%
, 85%
, 67%
BnO
BnO
BnO
BnO
BnO
3am
3an
3ao
3ap
3aq
; 98%
; 99%
; 94%
; 90%
; 95%
MOM = methoxymethyl; Bn = benzyl
Scheme 8
Next, carbamates 3 were treated with TFAA (2 equiv) in the presence of Et3N
(6 equiv) to provide allyl cyanates which spontaneously underwent [3,3]-sigmatropic
rearrangement to afford allyl isocyanates. These, in turn, were directly treated with a
nucleophilic reagent (MeOLi) to provide N-Moc protected allylamines 13 with high
overall yields after 3 steps. The rearrangement proceeded efficiently for alkyl, aryl as
well as heteroaryl substituted carbamates 3. Only in case of pyridine and quinoline
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containing carbamates (3bm, 3bn) the dehydration step was performed under
DOI: 10.1039/C9OB02472G
standard Ichikakawa condtions by using Ph3P/CBr4 instead of TFAA, that interact with
heteroaromatic nitrogen atom and surpressed the desired reaction.
O
1. TFAA, Et3N, THF
0 oC, 30 min
R1O
R2
R1O
NHMoc
O
NH2
2. MeOLi, THF, rt
R2
one-pot
3
13
R1O
NHMoc
R1O
NHMoc
R1O
NHMoc
R1O
NHMoc
1
1
1
1
13aa
; R : Bn, 63%
13ab
13ac
13ad
; R : Bn, 55%
; R : Bn, 71%
; R : Bn, 55%
1
1
1
1
13ba
; R : MOM, 85%
13bb
13bc
13bd
; R : MOM, 74%
; R : MOM, 74%
; R : MOM, 77%
R1O
NHMoc
R1O
NHMoc
R1O
NHMoc
R1O
NHMoc
Bn
N
F3C
13ag
OMe
F
Boc
1
1
1
1
13ae
13af
13ah
; R : Bn, 58%
; R : Bn, 66%
; R : Bn, 75%
; R : Bn, 73%
1
1
1
1
13be
13bf
13bg
13bh
; R : MOM, 76%
; R : MOM, 77%
; R : MOM, 76%
; R : MOM, 71%
R1O
NHMoc
R1O
NHMoc
R1O
NHMoc
R1O
NHMoc
Cl
NC
MeOOC
1
1
1
1
13ai
13aj
13ak
13al
; R : Bn, 66%
; R : Bn, 65%
; R : Bn, 69%
; R : Bn, 64%
1
1
1
1
13bi
13bj
13bk
13bl
; R : MOM, 76%
; R : MOM, 77%
; R : MOM, 73%
; R : MOM, 82%
MOMO
NHMoc
MOMO
NHMoc
MOMO
NHMoc
MOMO
O
NHMoc
S
N
N
a,b
a,b
b
13bm
13bn
13bo
13bp
; 85%
; 78%
; 60%
; 79%
BnO
NHMoc
BnO
NHMoc
; 84%
BnO
NHMoc
BnO
NHMoc
; 75%
BnO
NHMoc
13ap
61%
;
13an
13ao
13am
13aq
; 57%
; 80%
a Dehydration was performed under Ichikawa conditions: 1.6 eq. CBr4, 1.5 eq. PPh3, 2 eq. Et3N in CH2Cl2 (instead of TFAA/Et3N in THF)
b MeOH and n-Bu3SnOMe (10 mol%) were used as a nucleophile instead of MeOLi
Moc = methoxycarbonyl; MOM = methoxymethyl ether; Bn = benzyl
Scheme 9
12

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The broad reactivity of isocyanates with various nucleophilic agentDsOIo: 1p0.e10n39s/Ca9OnB02472G
access to various allylamine derivatives bearing different N-protecting groups,
including the commonly utilized Cbz and Boc ones (Scheme 10). Moreover, the ease
of the removal of such protecting groups makes it possible to use these allylamines in
further organic synthesis as building blocks. As we demonstrated in the past, direct
functionalization of the isocyanate intermediates is not limited to their reactions with
alcohols or alkoxides. Such reactions procceded smoothly also with nitrogen, sulfur, or
carbon nucleophiles or hydrides to provide urea derivatives, amides, or free
allylamines.40, 50, 52,54,55, 56
1. TFAA, Et3N, THF
0 oC, 30 min
OR3
NH
O
R1O
R2
O
R1O
O
NH2
2. R3OLi, THF
R2
one-pot
3
13
R1
13ar
R2
R3
Yield [%]
Bn (
)
)
)
)
Me
Me
Ph
Ph
t-Bu
Bn
t-Bu
t-Bu
75
87
77
68
13as
Bn (
MOM (
Bn (
13bq
13at
Scheme 10
Finally, ozonolysis of allylamines 13 followed by Pinnick−Lindgren oxidation
furnished α-substituted serine derivatives 14 which were isolated as methyl esters
upon treatment of the crude carboxylic acid with trimethylsilyldiazomethane. The
corresponding esters 14 were obtained in good overall yields after 3 steps (Scheme
11). Disappointingly, this final transformation failed for heteroaryl containing systems
13bm-bp, providing complicated reaction mixtures. The further studies will be
performed to address this isuee.
13

Organic & Biomolecular Chemistry
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1) O3, CH2Cl2
DOI: 10.1039/C9OB02472G
2) 2-methyl-2-butene, NaH2PO4,
R1O
NHCOOMe
R1O
NHCOOMe
NaClO2, t-BuOH/H2O
R2 COOMe
R2
3) TMSCHN2, MeOH
13
14
R1 = MOM or Bn; R2 = Alkyl or Aryl
MOMO
NHMoc
MOMO
NHMoc
MOMO
NHMoc
MOMO
NHMoc
COOMe
COOMe
COOMe
COOMe
14a
14b
14c
14d
; 90%
; 85%
; 71%
; 71%
MOMO
NHMoc
MOMO
NHMoc
MOMO
NHMoc
MOMO
NHMoc
COOMe
COOMe
COOMe
COOMe
Bn
N
F3C
OMe
F
Boc
14e
14f
14g
14h
; 91%
; 78%
; 79%
; 86%
MOMO
NHMoc
MOMO
NHMoc
COOMe
MOMO
NHMoc
MOMO
NHMoc
COOMe
COOMe
COOMe
Cl
NC
MeOOC
14i
14j
14k
14l
; 61%
; 87%
; 78%
; 81%
BnO
NHMoc
BnO
NHMoc
COOMe
BnO
NHMoc
BnO
NHMoc
COOMe
BnO
NHMoc
COOMe
COOMe
COOMe
14m
14n
14o
14p
14q
; 71%
; 90%
; 82%
; 65%
; 66%
Moc = methoxycarbonyl; MOM = methoxymethyl ether; Bn = benzyl
Scheme 11
Preseted above transformations, that lead to α,α-disubstituted serine
derivatives, proceeded efficiently not only in a small (< 1 mmol) but also in a larger
scale (> 1 mmol). For example, staring from 7 mmol of vinyl stannane 5b a large scale
synthesis of amino acid derivative 15 was performed in overall yield 52% (Scheme 12).
It is worth to mentioned, that at such reaction scale the final amino acid 15 was isolated
by an extraction and no other purification was not required.
14

Page 15 of 18
Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB02472G
PhI (1.3 equiv)
O
O
CuI (10 mol%)
Pd(PPh3)4 (3 mol%)
CsF (2 equiv)
OMOM
PhO
NH2
MOMO
MOMO
Bu3Sn
OH
O
NH2
OH
DBTM (10 mol%)
THF, 60 o
24 h
C
PhMe, 90 o
10 h
C
6ba
5b
3.04 g (7 mmol)
3ba
1.39 g (6.24 mmol)
yield 89%
1.39 g (5.24 mmol)
yield 84%
1) O3, CH2Cl2, _78 o
C
1. TFAA, Et3N, THF
_10 oC, 30 min
2) 2-methyl-2-butene, NaH2PO4,
MOMO
NHCOOMe
MOMO
NHCOOMe
COOH
NaClO2, t-BuOH/H2O
2. MeOLi, THF, rt
one-pot
13b
15
1.22 g (4.35 mmol)
yield 83%
1.02 g (3.61 mmol)
yield 83%
5b
Total yield 52% (from
)
Scheme 12
As already mentioned many times, serine and its derivatives are highly valuable
building blocks in the organic synthesis, since it bears three differnet functionalities,
hydroxyl, amine and carboxylic acid group that enable vast number of possible further
transformations. With this feature in the mind, carboxylic acid 16, free alcohol 17, free
amine 18, as well as compound 19 and amino alcohol 20 were prepared to
demonstrate an independ access to those three functional groups (Scheme 13).
HO
NHBoc
1) TMSCH2N2, MeOH
2) H2 (1 bar), 10% Pd/C,
MeOH, rt
COOMe
17
88%
.
NH2 HCl
BnO
1) TMSCH2N2, MeOH
2) 4M HCl, 1,4-dioxane
COOMe
1) O3, CH2Cl2, _78 o
C
2) 2-methyl-2-butene, NaH2PO4,
18
88%
BnO
NHBoc
BnO
NHBoc
NaClO2, t-BuOH/H2O, rt
COOH
1) H2 (1 bar), 10% Pd/C,
MeOH, rt
.
HO
NH2 HCl
COOH
one-pot protocol
13at
2) 4M HCl, 1,4-dioxane
16
80%*
19
80%
1) H2 (1 bar), 10% Pd/C,
MeOH, rt
.
HO
NH2 HCl
COOMe
17
* yield of isolated free carboxylic acid. In case of synthesis of
18
16
was not isolated but directly diazonated.
and
carboxylic acid
2) 4M HCl, 1,4-dioxane
20
87%
Scheme 13
15

Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB02472G
Conclusions
An approach to α-aryl- and α-alkyl-substituted serine derivatives was
developed. The presented strategy is based on highly efficient enantiospecific
sigmatropic rearrangement of allyl carbamates. The former ones were obtained from
the corresponding allyl alcohols and three strategies for their preparation has been
reported. 3-Aryl substituted allyl alcohols were readily prepared via Sille coupling of
aryl iodides with enantiomerically enriched vinyl stannanes. An analogous approach
for 3-alkyl-substituted allyl alcohols via Negishi reaction was less efficient and was
essentially limited to the introduction of primary alkyl groups. Thus, a series of 3-alkyl-
substituted allyl alcohols was prepared via a combination of Cu-mediated 1,4-addition
and enzymatic kinetic resolution of racemic alcohols. In addition, it was demonstrated
that the presented stategy is scalable and works well not only in a small (<1 mmol) but
also in a larger (> 1 mmol of final serine derivative) scale. Moreover, as demonstrated,
the proper choice of transformations, allows for preparation of serine derivative either
with carboxylic acid, hydroxyl or amine free group.
Aknowledgements
Authors are grateful to National Science Center of Poland for financial support of the
project (research grant OPUS 2014/15/B/ST5/04398 and PREUDIUM No.
2018/29/N/ST5/01388). A. Narczyk is grateful to National Science Center of Poland for
ETIUDA Ph.D. student scholarship (No. 2018/28/T/ST5/00267).
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