6-Methyl δ-lactol derived chiral glycine equivalents for the asymmetric synthesis of protected α-amino amides

Article abstract of DOI:10.1016/j.tetasy.2004.01.026

Two new δ-lactol derived chiral glycine equivalents have been prepared in one-pot processes in good yields from the known 6- methyltetrahydropyran-2-ol. Alkylation proceeds in moderate to good yields and moderate to good selectivities under experimentally simple conditions. The lactol chiral auxiliary is readily removed under mild acidic conditions to give N-Cbz protected alpha-amino amides in good yields.

Full text of DOI:10.1016/j.tetasy.2004.01.026

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 913–916
6-Methyl d-lactol derived chiral glycine equivalents for the
asymmetric synthesis of protected a-amino amides
Darren J. Dixon,a,* Richard A. J. Horana and Nathaniel J. T. Monckb
aCambridge University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK
bVernalis Research Ltd, Oakdene Court, 613 Reading Road, Winnersh, Wokingham RG41 5UA, UK
Received 23 December 2003; accepted 23 January 2004
Abstract—Two new d-lactol derived chiral glycine equivalents have been prepared in one-pot processes in good yields from the
known 6-methyltetrahydropyran-2-ol. Alkylation proceeds in moderate to good yields and moderate to good selectivities under
experimentally simple conditions. The lactol chiral auxiliary is readily removed under mild acidic conditions to give N-Cbz protected
alpha-amino amides in good yields.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
range of analogues. The stereocontrol in the asymmetric
reaction should be acceptable and, where it is moderate,
the diastereoisomers should be easily separable. Finally,
conversion to the N-protected amino carbonyl com-
pounds should be straightforward and efficient using
readily prepared or commercially available organo-
metallic reagents.
The chiral building block has enjoyed a prime position
for the facile synthesis of a wide range of desirable
multifunctional compounds in their enantio-enriched
forms. Amine-containing building blocks have been
designed primarily for the synthesis of a-amino acid
1;2
€
derivatives. The work of Schollkopf et al., Williams
et al.,3–5 Seebach et al.,6–9 Myers and Gleason10 and
Davies et al.,11 as well as many others,12–21 employing
chiral glycine equivalents,22 are notable examples.
Herein we report our preliminary studies on the design,
synthesis and alkylation of a new building block for the
synthesis of N-protected a-amino carbonyl compounds.
Our group has also been interested in the development
of amine-containing building blocks, targeting not just
a-amino acids, but any N-protected a-amino carbonyl
compound. The reasoning for this was based on the idea
of maximising the synthetic potential of the building
block. If suitably protected amino carbonyl compounds
(as well as amino acid derivatives) can be accessed
rapidly from a building block, then their application
towards the synthesis of amino acids, ketones, aldehydes
and alcohols should be straightforward.
2. Results and discussion
We chose to adopt the chiral enolate approach22 owing
to its conceptual simplicity and the availability of
myriad alkyl halide electrophiles. Instead of placing
chirality at the carboxylate end of the glycine derivative,
such as the vast majority of literature examples, we
decided to employ a simple carboxylic acid dimethyl
amide. The enolates of dimethyl amides are readily
prepared in the (Z)-form;23 are highly reactive towards a
range of electrophiles and yet are stable to relatively
high reaction temperatures. Additionally, dimethyl
amides are known to be precursors to aldehydes and
ketones through nucleophilic attack of organometallic
reagents.24;25 Accordingly, the stereodirecting group had
to be located on the N-terminus and be removable under
nonracemising conditions (Fig. 1). We believed that a
solution to the N-protecting/stereodirecting group
Placing these requirements on such a tool leads to a
series of design implications and constraints that must
be addressed. The building block should be available in
both enantiomeric forms and readily synthesised on a
multigram scale. Its chemistry should be general to a
* Corresponding author. Tel.: +44-0-1223-763-965; fax: +44-0-1223-
336-362; e-mail: djd26@cam.ac.uk
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.01.026

914
D. J. Dixon et al. / Tetrahedron: Asymmetry 15 (2004) 913–916
CbzCl in the presence of aqueous Na2CO3 under
NMe2
H2N
biphasic conditions. Any excess CbzCl was scavenged
using glycine and purification by chromatography on
silica gel afforded the desired product 4 as a single dia-
stereoisomer in 71% yield over the three steps (Scheme
2).
O
NMe2
O
OH
O
N
X
O
O
O
R
O
O
R
Figure 1. Building block disconnection.
i
NMe2
O
N
O
OH
problem was the enantiopure tetrahydropyranyl ring,
which could be readily installed through a condensation
reaction26 and removed by mild acid hydrolysis. We
have recently reported that the naked alkoxide anions of
enantiopure tetrahydropyran-2-ols impart very high
levels of stereo- control in oxy-Michael addition reac-
tions.27 It was hoped that this level of control could also
be offered here in enolate alkylation reactions. In the
main text the chiral tetrahydropyranyl group will be
referred to as THP*.
Cbz O
4
1
Scheme 2. Reagents and conditions: (i) (a) H-Gly-NMe2, neat, rt, 3 h;
(b) Cbz-Cl, Na2CO3, Et2O/H2O, 0 °C to rt, 3 h; (c) glycine, rt, 16 h,
71%.
With multigram quantities of 4 in hand, a preliminary
screening of the lithium, sodium and potassium enolates
and their reactions with benzyl bromide in various sol-
vents was performed (Scheme 3, Table 2). The optimal
selectivity was observed when the sodium enolate in
THF, formed by treatment of 4 with NaHMDS
(1.05 equiv), was reacted with benzyl bromide at )78 °C,
then with slow warming to room temperature. In this
case, the separable diastereoisomers 5a and 6a were
formed in the ratio of 10:1 and with a combined yield of
86% (entry h).
Critical to the success of the building block is the chiral
relay effect initiated by the condensation of the d-lactol
with an amine functionality. Preliminary studies to
probe the condensation reaction were carried out using
the known (R)-6-methyl d-lactol 128 and a range of
glycine derivatives. In all cases the reactions were per-
formed by simply mixing equimolar amounts of the
glycine derivatives and the lactol neat at room temper-
ature (Scheme 1, Table 1). Both the ethyl and tert-butyl
ester of glycine condensed efficiently and with high ste-
reoselectivity towards the 2,6-cis-THP* amine products
(entries a and b, 24:1 and 28:1, cis:trans, respectively). A
slightly lower diastereoselectivity was observed with
glycine dimethyl amide but the reaction maintained its
high efficiency (entry c, 7:1, cis:trans).
Ph
i
NMe2
NMe2
O
N
O
N
Cbz O
Cbz O
4
major 5a
+ minor 6a
i
Scheme 3. Reagents and conditions: (i) (a) base, solvent, )78 °C,
30 min; (b) BnBr, )78 °C to rt.
O
NHR
O
NHR
O
OH
1
2a-c
3a-c
Table 2. Screening of conditions for building block alkylation with
benzyl bromide
Scheme 1. Reagents and conditions: (i) RNH2, neat, rt, 1–24 h.
Entry
Base
Solvent
Yield (%)a
Ratio
5a:6ab;c
Table 1. Condensation of d-lactol with amines from Scheme 1
a
b
c
d
e
f
LiHMDS
KHMDS
NaHMDS
KHMDS
NaHMDS
KHMDS
LiHMDS
NaHMDS
KHMDS
LiHMDS
NaHMDS
KHMDS
PhMe
PhMe
Dioxane
Dioxane
Et2O
34
42
30
34
38
57
86
86
30
5
2.2:1
3.1:1
4.8:1
5.4:1
3.6:1
3.5:1
4.3:1
10:1
Entry
RNH2
Ratio 2:3
a
b
c
H-Gly-OEt
H-Gly-OtBu
H-Gly-NMe2
28:1
24:1
7:1
Et2O
THF
g
h
i
THF
THF
These hemiaminal compounds were found to be unsta-
ble to chromatography on silica gel, reverting to starting
materials under acidic conditions. However, using this
key condensation reaction the desired building block 4
could be constructed in three steps and one pot by
treating (R)-6-methyl d-lactol with neat glycine dimethyl
amide (1.2 equiv) at room temperature for 16 h, then
reacting an ethereal solution of the crude product with
6.1:1
1.9:1
3.6:1
4.8:1
j
DME
DME
DME
k
l
26
38
a Isolated yield 5a and 6a after column chromatography.
b From crude 1H NMR.
c Stereochemistry of 6a determined by chemical correlation and com-
parison of specific rotations.

D. J. Dixon et al. / Tetrahedron: Asymmetry 15 (2004) 913–916
915
Although the selectivity with benzyl bromide was not
outstanding, the high chemical yield and the option to
separate diastereoisomers encouraged us to screen fur-
ther electrophiles to gauge the scope of the methodol-
same facial selectivity as that observed with the aryl
electrophiles.
The absolute stereochemistry of the benzylated and
methylated products was determined by THP* removal
ogy. Accordingly,
a
range of aryl bromomethyl
25
D
derivatives was reacted with the sodium enolate under
the optimal conditions, and the results are given below
(Scheme 4, Table 3, entries a–e).
and comparison of the specific rotation {7 ½aꢀ ¼ )35.0
25
D
CHCl3)} with material prepared from commercial
(c 0.26, CHCl3); 8 (50% ee) ½aꢀ ¼ )6.4 (c 0.405,
25
sources {ent-7 ½aꢀ ¼ +35.4 (c 1.326, CHCl3); ent-8
D
25
D
½aꢀ ¼ +17.8 (c 1.164, CHCl3)} (Scheme 5).
R
i
NMe2
NMe2
O
N
O
N
Ph
O
Ph
Cbz O
Cbz O
i
Cbz
NMe2
NMe2
4
5a-i and diastereoisomers 6a-i
N
H
O
N
Cbz O
Scheme 4. Reagents and conditions: (i) (a) NaHMDS, THF, )78 °C,
30 min; (b) RX, )78 °C to rt.
minor, 6a
7
Table 3. Alkylation of 4
i
Entry
a
RX
Yield (%)a
86
Ratio 5:6b;c
Cbz
NMe2
NMe2
N
H
O
N
Br
10:1
O
Cbz O
Br
6f (50% de)
8 (50%ee)
b
c
80
62
59
51
4.1:1
7.8:1
3.5:1
2.4:1
Scheme 5. Reagents and conditions: (i) TFA/H2O (9:1), rt, 24 h; 7
quant; 8 83%.
Br
Br
Br
Br
d
e
The variation in selectivity with the arylmethyl bromides
and the reversal in facial selectivity with nonaryl alkyl
halides suggested that the N-Cbz group was playing an
active role in determining the stereochemical outcome of
the reactions. In order to probe this possibility further
the N-Boc derivative 9 was prepared in an analogous
manner to 4 above and alkylated with a range of elec-
trophiles using the sodium enolate (Scheme 6, Table 4).
Br
Br
I
f
71
36
29
59
1:4.0
1:2.1
1:2.4
2.1:1
I
g
h
i
I
Br
a Isolated yield 5 and 6 after column chromatography.
b From crude 1H NMR.
c Stereochemistries were assigned by analogy with the benzyl bromide
case and are supported by the relative positions of the 1H NMR
signals for the methine proton of the major and minor diastereoiso-
mers.
As can be seen from the results in Table 4, alkylation
follows a similar pattern to the N-Cbz building block
but with increased selectivity for alkylation of the Re
face. Assuming the (Z)-enolate reacts via a seven ring
chelate to the ring oxygen, the metal cation, with its
associated coordinated solvent molecules, appears to
block the approach to the Si face of the enolate with
Surprisingly, the diastereoselectivities for these alkyl-
ation reactions varied considerably throughout the ser-
ies with the optimal case being for benzyl bromide.
Notable is the series of ortho-, meta- and para-bromo
benzyl bromide derivatives (Table 3, entries c–e) where
the observed selectivities are 7.8:1, 3.5:1 and 2.4:1,
respectively. While there is some steric effect on the
favoured transition states, clearly the diastereoselectivity
of the enolate alkylation is not solely dependent on
steric factors.
More surprises were revealed when nonaryl electrophiles
were reacted with the sodium enolate (entries f–i). With
methyl, ethyl and n-propyl iodides, moderate diastereo-
selectivities were observed. However the stereofacial bias
was reversed and products of attack at the Re face were
found to dominate in the reaction mixtures. On the
other hand, the reaction with allyl bromide gave the
Scheme 6. Reagents and conditions: (i) (a) H-Gly-NMe2, neat, rt, 16 h;
(b) Boc2O, DCM, 0 °C to rt, 24 h, 57% (two steps); (ii) (a) NaHMDS,
THF, )78 °C, 30 min; (b) RX, )78 °C to rt.

916
D. J. Dixon et al. / Tetrahedron: Asymmetry 15 (2004) 913–916
Table 4. Alkylation of 9
Acknowledgements
Entry
a
RX
Yield (%)a
42
Ratio 10:11b;c
We thank Vernalis for a studentship (to RAJH), the
National Mass Spectrometry Service at Swansea for
HRMS and Prof. Steven V. Ley for continued and
valued support.
Br
3.2:1
Br
I
b
c
64
43
22
1:1.3
1:35d
1:7.4
I
d
a Isolated yield 10 and 11 after column chromatography.
b From crude 1H NMR.
References and notes
c Stereochemistries were assigned by analogy with the previous cases
and are supported by the relative positions of the 1H NMR signals for
the methine proton of the major and minor diastereoisomers.
d Stereochemistry determined by X-ray crystallography.
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