Stereocontrolled formation of cephams from 1,3-O-ethylidene-L-erythritol

Article abstract of DOI:10.1016/S0957-4166(01)00167-7

[2+2]Cycloaddition of chlorosulfonyl isocyanate to (Z)-1,3-O-ethylidene-2-O-propenyl-4-O-trityl-L-erythiritol proceeds with excellent stereoselectivity to afford the corresponding (R)-4′-alkoxy-azetidin-2-one which can transformed into 5-oxa-cepham by intramolecular alkylation of the β-lactam nitrogen atom. Cepham having the alternative (S) configuration at the bridgehead carbon atom can be achieved by another methodology based on alkylation of the nitrogen atom in 4-vinyloxy-azetidin-2-one by the suitably protected 1,3-ethylidene-L-erythritol followed by intramolecular displacement of the vinyloxy group.

Full text of DOI:10.1016/S0957-4166(01)00167-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 979–981
Stereocontrolled formation of cephams from
1,3-O-ethylidene-
-erythritol†
L
Katarzyna Borsuk,a Kinga Suwin´skab and Marek Chmielewskia,*
aInstitute of Organic Chemistry of the Polish Academy of Sciences, 01-224 Warsaw, Poland
bInstitute of Physical Chemistry of the Polish Academy of Sciences, 01-224 Warsaw, Poland
Received 15 March 2001; accepted 5 April 2001
Abstract—[2+2]Cycloaddition of chlorosulfonyl isocyanate to (Z)-1,3-O-ethylidene-2-O-propenyl-4-O-trityl-L-erythritol proceeds
with excellent stereoselectivity to afford the corresponding (R)-4%-alkoxy-azetidin-2-one which can be transformed into 5-oxa-
cepham by intramolecular alkylation of the b-lactam nitrogen atom. Cepham having the alternative (S) configuration at the
bridgehead carbon atom can be achieved by another methodology based on alkylation of the nitrogen atom in 4-vinyloxy-aze-
tidin-2-one by the suitably protected 1,3-ethylidene-
© 2001 Elsevier Science Ltd. All rights reserved.
L-erythritol followed by intramolecular displacement of the vinyloxy group.
Recently we have shown that [2+2]cycloaddition of
chlorosulfonyl isocyanate (CSI) to 3-O- and 5-O-vinyl
For these model studies we selected 1,3-O-ethylidene-
erythritol 1, which is readily synthesized from -glu-
L-
D
ethers of 1,2-O-isopropylidene-
D
-glycofuranose pro-
cose.8 The terminal hydroxymethyl group in 1 was
protected as a trityl9 or tert-butyldimethylsilyl (TBS)10
ether and the secondary hydroxyl was protected as its
allyl ether. The allyl substituent in compound 3 was
then transformed into the corresponding (Z)-propenyl
ether 6,11 by the standard potassium tert-butoxide iso-
merization.12 In the case of 5, isomerization of the allyl
ether caused concomitant deprotection of the silyl
ether, yielding 7. The hydroxyl group in 7 was mesyl-
ated or tosylated under standard conditions to afford
the corresponding sulfonates 8 and 9.
ceeds in many cases with excellent stereoselectivity and
allows control of the configuration at C-(4) of the
4-alkoxy-azetidin-2-one.1–3 The cycloadducts offer an
entry to 5-oxacephams and clavams via suitable trans-
formation of the sugar auxiliary.4,5 Due to the specific
multifunctional character of the 1,2-O-isopropylidene-
D
-glycofuranose
residue,
previously
presented
syntheses4,5 are of limited practical value.
Herein, we demonstrate that the stereochemical [2+2]-
cycloaddition model proposed by us recently6 has a
general applicability and that alternative strategies for
the formation of 5-dethia-5-oxa-cephams7 offer full
control of the configuration at the bridgehead carbon
atom of the antibiotic, C-(6).
It has been shown that both vinyl and (Z)-propenyl
ethers display the same direction of asymmetric induc-
tion in [2+2]cycloadditions with CSI.12 Since the forma-
tion of vinyl ethers requires acid catalysis, which could
* Corresponding author. Fax: +48-22-6323789; e-mail: chmiel@icho.edu.pl
†
Dedicated to Professor Dr. Joachim Thiem in the year of his 60th birthday.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00167-7

980
K. Borsuk et al. / Tetrahedron: Asymmetry 12 (2001) 979–981
have effected migration or rearrangement of the ethyli-
dene fragment in 2–5, we decided to use propenyl ethers
in this study. The [2+2]cycloaddition of CSI to 6,
followed by reduction of the N-chlorosulfonyl group
with Red-Al,1–6,13 afforded the b-lactam 10 as a single
cis-diastereomer in 82% yield.11 The trityl protecting
group of 10 was then removed cleanly by treatment
with sodium in liquid ammonia to give 11 in 74% yield
and the hydroxy group was subsequently tosylated
under standard conditions. The intramolecular alkyla-
tion of the b-lactam nitrogen in 12 using a two-phase
components, which were independently subjected to
cyclization to afford 16 and 17. The structure and (6S)
configuration of 1711 was again established by X-ray
crystallography (Fig. 1).14
The results of the cycloadditions indicate an s-trans
conformation of the olefin6 in the transition state and
steric control of the reaction. The bulky trityl group
blocks the approach of CSI to the re-face, whereas
substituents smaller than trityl (i.e. tosyl or mesyl)
allow access of CSI to either side of the olefin.
system
(anhydrous
potassium
carbonate/tetra-
butylammonium bromide) in acetonitrile led1,2 to for-
mation of 5-oxacepham 1611 in 60% yield. The structure
and (6R) configuration of 16 was confirmed by X-ray
crystallography (Fig. 1).14
Stereocontrolled formation of the (6S) configuration in
cepham 23 of the same tricyclic skeleton as 16 and 17
can be achieved by a different methodology.7,15 The
crucial substrate for the synthesis of compound 23 was
obtained from 4 by a standard reaction sequence
involving protection of 4 as its p-methoxybenzyl ether,
removal of the silyl protecting group of 18 and forma-
tion of the corresponding triflate 20. Alkylation of the
b-lactam nitrogen atom in 21 with 20 in the presence of
tetrabutylammonium hydrogen sulfate/n-BuLi in
THF15 afforded a mixture of diastereoisomers 22, that
could be easily separated by chromatography. Subse-
quently, BF3–etherate-catalysed transformation of each
stereoisomer of 22 afforded the same (6S)-cepham 23
from either compound.16 The (6S) configuration of 23
was established by X-ray crystallography (Fig. 1).
The cycloaddition performed on 8 and 9 afforded two
corresponding cis azetidin-2-ones in each case: 13 and
14 in a ratio of 2:1, respectively, in 69% yield and 12
and 15 in a ratio of 3:1, respectively, in 52% yield. The
13/14 and 12/15 mixtures were separated into pure
Figure 1. X-Ray structures of cephams 16, 17 and 23 with crystallographic numbering scheme.

K. Borsuk et al. / Tetrahedron: Asymmetry 12 (2001) 979–981
981
Thus, it was demonstrated that the configuration at
C-(6), which is crucial for biological activity of b-lac-
tam antibiotics, can be controlled by selection of the
strategy for cepham formation. The trans fused ring
system provides a rigid template which could induce an
alteration of geometry of the b-lactam nitrogen atom in
isomers 16 and 17. The crystal structures displayed in
Fig. 1 show that there are some changes in geometry of
the ‘decalin’ system between 16 and 17/23, but irrespec-
tive of the relative configuration at C-(3), C-(4) and
C-(6) the environment of the nitrogen atom is only
slightly pyramidal in all cephams obtained. The dis-
tance of the nitrogen atom from the plane formed by
C-(2), C-(6) and C-(8) carbon atoms amounts to only
10. Marusawa, H.; Setoi, H.; Kuroda, A.; Sewada, A.; Seki,
J.; Motoyama, Y.; Tanaka, H. Bioorg. Med. Chem. 1999,
7, 2635–2645.
11. All new compounds were fully characterized by spectral
and analytical data. Selected data of representative com-
pounds 6, 10, 16, 17 and 23 are given below:
6: mp 59–61°C; [h]D=−3.1 (c 0.4, CH2Cl2); IR (CHCl3)
1
1669 cm−1; H NMR (CDCl3) l 5.85 (dq, 1H, J=1.7, 6.1
Hz, H-1%), 4.71 (q, 1H, J=5.0 Hz, H-1%%), 4.21 (dq, 1H,
J=6.1, 6.8 Hz, H-2%). HRMS (ESI) m/z (M+Na)+ found:
453.2048, calcd for C28H30O4Na: 453.2036.
10: mp 136–138°C; [h]D=−19.2 (c 0.4, CH2Cl2); IR (film)
1
1774 cm−1; H NMR (CDCl3) l 4.84 (d, 1H, J=4.5 Hz,
H-4%), 4.72 (q, 1H, J=5.0 Hz, H-1%%), 2.88 (qdd, 1H,
J=2.5, 4.5, 7.5 Hz, H-3%), 1.44 (d, 3H, J=5.0 Hz, CH%3%),
0.85 (d, 3H, J=7.5 Hz, CH%3). HRMS (EI) m/z M+
found: 473.2206, calcd for C29H31O5N: 473.2202.
,
0.250 (2), 0.260 (3) and 0.256 (2) A, respectively.
Acknowledgements
16: mp 59–61°C; [h]D=+111.5 (c 0.6, CH2Cl2); IR (film)
1769 cm−1 1H NMR (C6D6) l 4.54 (d, 1H, J=3.3 Hz,
;
H-6), 2.70 (qdd, 1H, J=1.8, 3.3, 7.6 Hz, H-7), 1.22 (d,
3H, J=5.1 Hz, CH3), 0.92 (d, 3H, J=7.6 Hz, CH3).
HRMS (ESI) m/z (M+Na)+ found: 236.0891, calcd for
C10H15NO4Na: 236.0893.
The authors wish to thank the State Committee for
scientific Research Grant No T 09/PBZ.06.04 for sup-
port of this work.
17: mp 68–71°C; [h]D=−16.0 (c 0.5, CH2Cl2); IR (film)
1769 cm−1 1H NMR (C6D6) l 4.17 (d, 1H, J=3.8 Hz,
;
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HRMS (ESI) m/z (M+Na)+ found: 236.0886, calcd for
C10H15NO4Na: 236.0893.
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