Synthesis of enantiopure 4-(dihydroxyalkyl)-β-lactams from D-mannitol using Ley's BDA-protected L-glyceraldehyde

Article abstract of DOI:10.1055/s-2007-992375

Enantiomerically pure ethylene glycol derived β-lactams have been synthesized from Ley's BDA-protected L-glyceraldehyde imines via Staudinger reaction followed by deprotection. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-992375

3180
LETTER
Synthesis of Enantiopure 4-(Dihydroxyalkyl)-b-lactams from D-Mannitol
Using Ley’s BDA-Protected L-Glyceraldehyde
S
a
ynthesis of
E
i
nantiop
l
ure 4-
(
a
Dihydroxy
r
alkyl)-
b
-lactam
A
s
reces,*a Esther Carrasco,a Mark E. Light,b Miguel Santos,a Joaquín Plumet*c
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Extremadura, 06071 Badajoz, Spain
Fax +34(924)271149; E-mail: pareces@unex.es; E-mail: esthcar@unex.es
b
c
Department of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, 28040 Madrid, Spain
Fax +34(91)3944100; E-mail: plumety@quim.ucm.es
Received 4 October 2007
Dedicated to Prof. Vicente Gotor, University of Oviedo (Spain)
Staudinger reaction achieved on 3 gave the expected b-
lactams 410 in convenient yields and with diastereomeric
excess between 2.5:1 and 5.5:1 (Table 1).
Abstract: Enantiomerically pure ethylene glycol derived b-lactams
have been synthesized from Ley’s BDA-protected L-glyceralde-
hyde imines via Staudinger reaction followed by deprotection.
Key words: b-lactams, Staudinger reaction, stereoselective synthe-
OMe
sis, chiral auxiliaries, protected glyceraldehydes
H
S
RNH2
R1CH2COCl
Et3N
H
O
O
S
H
O
H
OMe
O
O
MeO
OMe
N
R
Ley’s butane-1,2-diacetal (BDA)-protected L-glycer-
aldehyde11 (Scheme 1) constitutes a convenient alterna-
tive to the well-known analogous glyceraldehyde
acetonides. For instance, this compound can be prepared
on 25-gram scale from D-mannitol,2 being storable for
long periods of time.3
1
3
H
S
H
H
H
H
N
H
S
R1
OH
R1
O
MeO
H+
OMe
O
R
OH
N
O
O
R
To the best of our knowledge, imines derived from 1 have
never been used as chiral building blocks and both the re-
activity and the synthetic applications of these compounds
remain unexplored. In this report we wish to account the
first case concerning the diastereoselective synthesis of
optically pure b-lactams 2 with an ethylene glycol moiety
at position 4 (Scheme 1). It should be pointed out that b-
lactams such as 2 and protected diol derivatives have been
obtained using different synthetic protocols. Some of
these synthetic protocols include: addition of tin(IV) eno-
lates, derived from 2-pyridyl thioesters, to imines,4 osmy-
lation of 4-(2-styryl)-b-lactams in the presence of a chiral
ligand,5 and Staudinger reaction of imines derived from
(R)- and (S)-glyceraldehyde acetonide.6 In this context the
synthesis of bis-b-lactams by Staudinger reaction of bis-
imines derived from optically pure 2,3-O-isopropylidene-
L-tartrate should be mentioned.7 On the other hand, b-lac-
tams such as 2 have been used as intermediates for the
synthesis of a,b-dihydroxy-a-amino acids via ring expan-
sion of the b-lactam nucleus.8
4
2
R = (R)- and (S)-CH(Me)(Ph)
R = CH2Ph
Scheme 1
Table 1 Synthesis of b-Lactams 4
Starting
imine
R1
Overall yield
(%)
Diastereomeric
ratioª
3a
3a
3b
3c
PhO
91
72
66
61
4a/4b = 4:1
4c/4d = 3:1
4e/4f = 5.5:1
4g/4h = 2.5:1
4-ClC6H4O
PhO
PhO
ª Evaluated by 1H NMR (400 MHz).
Major diastereoisomers of 4 were separated by crystalli-
zation and minor ones by column chromatography. Their
structures were secured by X-ray crystal structure
analysis11 and the configuration of the major compounds
4a, 4e, and 4g was assigned as 3S,4R in all cases, whereas
that of the minor diastereoisomers 4b, 4f and 4h was de-
termined as 3R,4S. Correlation of the spectroscopic data
(1H and 13C NMR of 4c and 4d with 4a and 4b) allowed
us to decide for a similar configurational assignment.
Thus, after formation of imines 3, Staudinger reaction fol-
lowed by deprotection in acidic media should afford b-
lactams 2. Benzyl (R = Bn) and (R)- and (S)-1-phenyleth-
ylamine [R = CH(Me)(Ph)] derivatives of 3 were prepared
in excellent yields as E diastereoisomers using standard
methods.9 No epimerization of 1 was observed. The
SYNLETT 2007, No. 20, pp 3180–3182
x
x
.x
x
.2
0
0
7
Advanced online publication: 21.11.2007
DOI: 10.1055/s-2007-992375; Art ID: G30707ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Enantiopure 4-(Dihydroxyalkyl)-b-lactams
3181
Deprotection reaction of compound 4e12 gave optically
pure b-lactam 2a (61%). In the same way, deprotection of
the mixture of b-lactams 4a and 4b and further column
chromatographic separation of the reaction mixture af-
forded pure b-lactams 2b and 2c13 (81%) (Figure 1).
(7) Jarayaman, M.; Deshmukh, A. R. A. S.; Bhawal, D. M.
J. Org. Chem. 1994, 59, 932.
(8) Palomo, C.; Oiarbide, M.; Landa, A.; Esnal, A.; Linden, A.
J. Org. Chem. 2001, 66, 4180.
(9) General Procedure: A stirred solution of the aldehyde 1
(0.842 mmol) in anhyd Et2O (1.6 mL) at 0 °C was treated
with the corresponding amine (0.681 mmol) and molecular
sieves (Merck 4 Å). After the reaction was complete, the
molecular sieves were filtered and the solvent was
H
S
H
H
H
S
PhO
OH
H
H
R
S
evaporated under vacuum to yield the corresponding imine
3. Compound 3a: R = Bn; reaction time: 25 min, 0 °C, 98%.
Compound 3b: R = (R)-CH(Me)(Ph); reaction time: 15 min,
0 °C, 99%. Compound 3c: R = (S)-CH(Me)(Ph); reaction
time: 15 min, 0 °C, 81%.
OH
4-ClC6H4O
OH
N
R
S
R
OH
Ph
O
Me
N
Ph
O
H
2a
2b
(10) General Procedure: A solution of the imine 3 (0.784 mmol)
in CH2Cl2 (3.9 mL) was treated with Et3N (2.359 mmol)
followed by the dropwise addition of a solution of the
corresponding acyl chloride (1.196 mmol) in CH2Cl2 (2.6
mL) at 0 °C under an argon atmosphere. After the reaction
was completed, the reaction mixture was poured into H2O
(6.6 mL), stirred for 15 min, and then extracted with CH2Cl2
(3 × 6.6 mL). The combined organic layers were washed
with 5% NaHCO3 (2 × 2.6 mL), dried with MgSO4 and
concentrated in vacuum affording a mixture of the
H
S
H
H
4-ClC6H4O
OH
R
S
OH
Ph
N
O
2c
Figure 1 Optically pure b-lactams
corresponding b-lactams 4. The major diastereoisomer was
obtained by direct crystallization from the reaction mixture
and purified by recrystallization from hexane–EtOAc. The
minor isomer was isolated from the mother liquors by
column chromatography (silica gel, hexane–EtOAc, 6:1)
and further HPLC separation when it was necessary
(semipreparative system, Zorbax RX-SIL column, hexane–
EtOAc, 60:40; 3 mL/min). Compounds 4a,b: R = Bn, R1 =
PhO; reaction time: 25 min, 0 °C, 91%. Compounds 4c,d:
R = Bn, R1 = p-ClC6H4O; reaction time: 25 min, 0 °C, 72%.
Compounds 4e,f: R = (R)-CH(Me)(Ph), R1 = PhO; reaction
time: 15 min, r.t., 66%. Compounds 4g,h: R = (S)-
In summary, in this paper the first application of Ley’s
BDA-protected glyceraldehyde imines to the synthesis of
enantiopure 4-(dihydroxyalkyl)-b-lactams has been re-
ported. The syntheses of b-lactams were carried out in
convenient yields and moderate diastereoisomeric excess.
Acknowledgment
This work was supported by the Ministerio de Educacion y Ciencia,
Spain (Grants BQU 2003-04967-C01 and CTQ2005-07676). E.C.
thanks Ministerio de Educacion y Ciencia, Spain, for a predoctoral
fellowship, and M.S. thanks for a fellowship from Leonardo da Vin-
ci Programme.
CH(Me)(Ph), R1 = PhO; reaction time: 15 min, r.t., 61%.
(11) Crystal structure analysis for 4a: mp 138–139 °C.
C24H29NO6, Mr = 427.48 g mol–1. Crystallographic data
(excluding structure factors) for compound 4a have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 661975.
Crystal structure analysis for 4e: mp 136–137 °C.
References and Notes
(1) For selected reviews on the use of 1,2-diacetals as chiral
building blocks in organic synthesis, see: (a) Ley, S. V.;
Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.; Ince, S. J.;
Priepke, H. W. M.; Reynolds, D. J. Chem. Rev. 2001, 101,
53. (b) Ley, S. V.; Baxendale, I. R.; Grice, P. NATO Science
Series (II, Mathematics, Physics and Chemistry), Vol. 129;
Schneider, M., Ed.; Kluwer Academic Publishers:
Netherlands, 2003, 235. (c) Ley, S. V.; Polara, A. J. Org.
Chem. 2007, 72, 5943.
C25H31NO6, Mr = 441.51 g mol–1. Crystallographic data
(excluding structure factors) for compound 4e have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 661977.
Crystal structure analysis for 4g: mp 185–186 °C.
C25H31NO6, Mr = 441.51 g mol–1. Crystallographic data
(excluding structure factors) for compound 4g have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 661976.
(12) A solution of the diastereomerically pure b-lactam 4e (0.165
mmol) in a mixture of TFA–H2O (9:1, 1.18 mL) was stirred
at r.t. for 5 min. Then the reaction mixture was evaporated
under vacuum and the resulting oil was purified by column
chromatography (silica gel, hexane–EtOAc, 1:2), yielding
2a as a white solid (33 mg, 61%), which was recrystallized
from hexane–CH2Cl2; [a]D –119.0, [a]578 –124.5, [a]546
–142.8, [a]436 –257.3, [a]546 –434.9 (c = 0.53, CH2Cl2, 25
°C). 1H NMR (400 MHz, CDCl3): d = 7.45 (d, J = 7.2 Hz, 2
H, Ph), 7.39 (t, J = 7.2 Hz, 2 H, Ph), 7.27–7.33 (m, 3 H, Ph),
7.12 (d, J = 8.0 Hz, 2 H, Ph), 7.04 (t, J = 7.2 Hz, 1 H, Ph),
5.24 (d, J3,4 = 5.2 Hz, 1 H, H-3), 4.82 (q, J1¢¢,Me = 7.2 Hz, 1 H,
H-1¢¢), 3.96–4.01 (m, 1 H, H-1¢), 3.88 (t, J4,1¢ = J4,3 = 5.2 Hz,
1 H, H-4), 3.66 (dd, J2¢a,2¢b = 11.2 Hz, J1¢,2¢a = 4.0 Hz, 1 H, H-
2¢a), 3.57 (dd, J2¢b,1¢ = 6.4 Hz, J2¢a,2¢b = 11.2 Hz, 1 H, H-2¢b),
(2) Ley, S. V.; Michel, P. Synthesis 2004, 147.
(3) Both enantiomers of glyceraldehyde acetonide are prone to
racemization and rapid polymerization. See:
(a) Hubschwerlen, J.; Specklin, L.; Higelin, J. Org. Synth
1995, 72, 1. (b) Schmid, C. R.; Bryant, J. D. Org. Synth.
1995, 72, 6.
(4) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.;
Raimondi, L. Tetrahedron 1994, 50, 5821.
(5) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.;
Ponzini, F. Bioorg. Med. Chem. Lett. 1993, 3, 2397.
(6) See for instance: (a) Hubschwerlen, C.; Schmid, G. Helv.
Chim. Acta 1983, 66, 2206. (b) Bose, A. K.; Hedge, V. R.;
Wagle, D. R.; Bari, S. S.; Manhas, M. S. J. Chem. Soc.,
Chem. Commun. 1986, 161. (c) Thomas, R. C. Tetrahedron
Lett. 1989, 30, 5239. (d) Alcaide, B.; Polanco, C.; Sierra, M.
A. J. Org. Chem. 1998, 63, 6786. (e) Grigg, R.; Thornton-
Pett, M.; Xu, J.; Xu, L. H. Tetrahedron 1999, 55, 13841.
Synlett 2007, No. 20, 3180–3182 © Thieme Stuttgart · New York

3182
P. Areces et al.
LETTER
2.39 (1 H, OH), 1.78 (d, JMe,1¢¢ = 7.2 Hz, 3 H, Me). 13C NMR
(100 MHz, CDCl3): d = 166.1 (CO), 157.4 (Ph), 141.0 (Ph),
129.7, 128.9, 127.8, 127.0 (Ph), 122.7 (Ph), 115.9 (Ph), 79.5
(C-3), 71.2 (C-1¢), 63.6 (C-2¢), 59.5 (C-1¢¢), 54.7 (C-4), 20.3
(Me).
129.6, 129.0, 128.4, 127.9 (Ph), 117.3 (Ph), 80.6 (C-3), 71.3
(C-1¢), 63.8 (C-2¢), 57.9 (C-4), 45.9 (Me). 2c: [a]D +82.1,
[a]578 +86.0, [a]546 +98.7, [a]436 +177.0, [a]546 +299.6 (c =
0.53, CH2Cl2, 25 °C). 1H NMR (400 MHz, CDCl3): d =
7.27–7.40 (m, 7 H, Ph), 7.11 (d, J = 8.8 Hz, 2 H, Ph), 5.25
(d, J3,4 = 5.2 Hz, 1 H, H-3), 4.77 (d, J1¢¢a,1¢¢b = 14.8 Hz, 1 H,
H-1¢¢a), 4.22 (d, J1¢¢a,1¢¢b = 14.8 Hz, 1 H, H-1¢¢b), 4.05–4.09 (m,
1 H, H-1¢), 3.92 (t, J4,1¢ = J4,3 = 5.2 Hz, 1 H, H-4), 3.81 (dd,
(13) 2b: [a]D –88.2, [a]578 –92.8, [a]546 –105.8, [a]436 –189.8,
[a]546 –322.9 (c = 0.42, CH2Cl2, 25 °C). 1H NMR (400 MHz,
CDCl3): d = 7.26–7.38 (m, 7 H, Ph), 7.08 (d, J = 8.8 Hz, 2 H,
Ph), 5.17 (d, J3,4 = 5.2 Hz, 1 H, H-3), 4.81 (d, J1¢¢a,1¢¢b = 14.8
Hz, 1 H, H-1¢¢a), 4.41 (d, J1¢¢a,1¢¢b = 14.8 Hz, 1 H, H-1¢¢b), 4.09–
4.13 (m, 1 H, H-1¢), 3.84 (t, J4,1¢ = J4,3 = 5.2 Hz, 1 H, H-4),
3.74 (dd, J2¢a,2¢b = 11.2 Hz, J1¢,2¢a = 3.6 Hz, 1 H, H-2¢a), 3.63
(dd, J2¢a,2¢b = 11.2 Hz, J1¢,2¢b = 6.4 Hz, 1 H, H-2¢b). 13C NMR
(100 MHz, CDCl3): d = 165.9 (CO), 155.9 (Ph), 135.5 (Ph),
J
2¢a,1¢ = 3.1 Hz, J2¢a,2¢b = 11.6 Hz, 1 H, H-2¢a), 3.65 (dd, J2¢b,1¢ =
6.4 Hz, J2¢a,2¢b = 11.6 Hz, 1 H, H-2¢b). 13C NMR (100 MHz,
CDCl3): d = 165.8 (CO), 155.6 (Ph), 134.9 (Ph), 129.6,
129.0, 128.3, 128.2 (Ph), 117.4 (Ph), 81.4 (C-3), 70.8 (C-1¢),
63.9 (C-2¢), 57.4 (C-4), 45.5 (C-1¢¢).
Synlett 2007, No. 20, 3180–3182 © Thieme Stuttgart · New York

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