Synthesis of β-lactams via ring opening of a serine derived aziridine

Article abstract of DOI:10.1055/s-2001-18090

Serine derived aziridine 15 was successfully ring-opened with amino acid esters to give diaminopropionic acid derivatives in excellent yield and regioselectivity. These compounds were cyclised to form the corresponding β-lactams in good overall yield. One

Full text of DOI:10.1055/s-2001-18090

LETTER
1727
Synthesis of -Lactams via Ring Opening of a Serine Derived Aziridine
Synthesis
o
of -Lactam
s
Leiden Institute of Chemistry, Gorlaeus Laboratories, P. O. Box 9502, 2300 RA Leiden, The Netherlands
Fax +31(71)5274307; E-mail: j.boom@chem.leidenuniv.nl
Received 12 July 2001
modified side chain monomers or as dipeptide isosteres
with enhanced resistance towards proteolytic cleavage. In
addition, their structural motif in repeated form is present
(Figure) in biologically active substrates such as as-
Abstract: Serine derived aziridine 15 was successfully ring-opened
with amino acid esters to give diaminopropionic acid derivatives in
excellent yield and regioselectivity. These compounds were cyc-
lised to form the corresponding -lactams in good overall yield.
One example was fully deprotected to give target compound 1 pergillomarasmine A.5 The synthesis of compounds of
(n = 1, R = Me) in excellent yield.
type 2 has been previously reported albeit as a mixture of
diastereoisomers.6 We here present our investigations into
Key words: Freidinger lactams, Mitsunobu reaction, nitrobenzene-
sulfonamides, aziridine, stereoselective synthesis
the stereoselective synthesis of diaminopropionic acid de-
rivatives 2 (R = H, Me, CH2Ph) and their conversion into
the corresponding -lactams 1 (n = 1).
Over the last twenty years, there has been increasing use
of modified peptides in the rational design and synthesis
of pharmaceuticals. Of the various modifications known,
the employment of conformationally restricted peptide
analogues has received considerable attention especially
concerning the development of enzyme inhibitors and re-
ceptor ligands.1 In this respect, Freidinger lactams2 1 (see
Figure), due to their close resemblance to the parent
dipeptide sequence, have been used as tools to limit the
amount of conformers of biologically active oligopeptides
either in efforts directed towards enhancing potency or for
structure activity relationship (SAR) studies.3 There are
many reports on the syntheses of these compounds,2–4
however, there is a notable lack of stereoselective synthet-
ic routes to Freidinger -lactams (1, n = 1). It occurred to
us that such compounds should be accessible in a stereo-
selective manner by cyclisation of their linear counter-
parts 2. The latter compounds can be considered either as
In the first instance, N-2-nitrobenzenesulfonamide-gly-
cine methyl ester 4 was condensed (Scheme 1) with N-tri-
tyl-L-serine allyl ester7 3 (1.3 equivalents) under
Mitsunobu conditions to give amino acid–amino acid hy-
brid 6 in an unacceptable 34% yield. It was reasoned,
based on related observations concerning the inversion of
sterically congested alcohols with carboxylic acids,8 that
Figure
Scheme 1 Reagents and conditions: (i) Ph3P (1.5 equiv), DEAD
(1.5 equiv), THF, –5 °C to r.t., 16 h, 6: 34%, 7: 68%. (ii) nPrNH2 (10
equiv), DCM, r.t., 5 min., 96%. (iii) Pd(Ph3)Cl2 (cat.), HOBt (2
equiv), Bu3SnH (2 equiv), DCM, r.t., 30 min. (iv) EDC (1.5 equiv),
DIPEA (2 equiv), DCM, r.t., 16 h, 85% (2 steps from 8).
Synlett 2001, No. 11, 26 10 2001. Article Identifier:
1437-2096,E;2001,0,11,1727,1730,ftx,en;G14301ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1728
J. J. Turner et al.
LETTER
replacing the 2-nitrobenzenesulfonyl (oNs) group with The required (S)-1-(2-nitrobenzenesulfonyl)-aziridine-2-
the more electron withdrawing 2,4-dinitrobenzenesulfo- carboxylic acid tert-butyl ester 15 was synthesised as
nyl (DNs) group might result in a more efficient reaction. shown in Scheme 2 from commercially available N-Boc-
Accordingly, glycine derivative 5 was reacted with 3 un- O-benzyl-L-serine 11. Thus, protective group manipula-
der the same Mitsunobu conditions to give dipeptide isos- tion of 11 involving simultaneous removal of the Boc
tere 7 in an improved 68% yield. However, the group and tert-butyl ester formation gave O-benzyl-L-
condensation of 3 with more functionalised amino acid serine tert-butyl ester 12 in 65% yield. Hydrogenation of
(e.g. alanine, phenylalanine) esters bearing the DNs group 12 followed by sulfonamide formation under Schotten–
furnished no desired product. Instead, intramolecular cy- Baumann conditions furnished aziridine precursor N-
clisation of 3 was observed giving aziridine 10 typically in (ortho-nitrobenzenesulfonyl)-serine tert-butyl ester 14 in
40% yield.9 Nevertheless, Freidinger -lactam 9 could be 96% yield over the two steps. Ring closure of 14 under
readily obtained in good overall yield via dinitrosulfonyl Mitsunobu conditions provided aziridine 15 in 92%
cleavage of 7 furnishing 8, followed by cleavage10 of the yield.14 Although the synthetic route described above
allyl ester and intramolecular condensation under the could be conducted on a multi gram scale, due to the ob-
agency of EDC.
servation that the target aziridine started to decompose
upon prolonged storage, conversion of 14 to 15 was sub-
sequently performed on a scale equal to immediate re-
quirement.15
The inability to form Freidinger -lactams possessing side
chain functionality on the exocyclic amino acid (e.g. 1,
n = 1, R = Me, CH2Ph) led us to explore the ring opening
of a suitably protected serine derived aziridine with
-
Having aziridine 15 in hand, a test reaction with benzy-
amino acid esters. The ring opening of (S)-1-tosyl-aziri- lamine (2 equivalents) was carried out (Scheme 2) at am-
dine-2-carboxylic acid tert-butyl ester with simple, prima- bient temperature in THF with a catalytic amount of
ry alkyl amines has been shown to proceed with good triethylamine12 resulting in a mixture of 16 and 17 in
regioselectivity and high yield11 but the need for a large favour of ring opening at the less hindered -carbon in an
excess of amine and the harsh conditions required for overall yield of 96%. Ring opening of 15 with both L-ala-
cleavage of the tosyl group are notable disadvantages. nine benzyl ester 18 and L-phenylalanine methyl ester 19,
Furthermore, N-nosyl aziridines are significantly more gave 20 and 22 respectively in excellent yield. In this re-
reactive12 than their tosyl counterparts and the conditions spect it is worthwhile mentioning that the latter products
for the removal of the nosyl group are comparatively were accompanied by only traces of the corresponding -
mild.13
attack products 21 and 23. In contrast to the ring opening
Scheme 2 Reagents and conditions: (i) tBuOAc, HClO4, 65%. (ii) Pd/C, H2, 1 M HCl aq (1 equiv), dioxane/H2O 1/1 (v/v), r.t., 16 h. (iii)
oNsCl (1.2 equiv), Na2CO3 (1.3 equiv), dioxane/H2O 1/1 (v/v), r.t., 3 h, 96% (2 steps from 12). (iv) Ph3P (1.2 equiv), DEAD (1.2 equiv), THF,
–5 °C, 1 h, 92%. (v) Et3N (0.2 equiv), THF, r.t., 16 h, 16: 74%, 17: 22%, 20/21: 94% (17/1), 22/23: 88% (15/1). (vi) TFA, r.t., 30 min. (vii) 1
M HCl aq/dioxane 1/1 (v/v), r.t., 5 min. (viii) EDC (1.5 equiv), DIPEA (2 equiv), DCM, r.t., 16 h, 24: 73% (from 15), 25: 75% (from 15). (ix)
Z-Cl (2 equiv), pyridine (1.5 equiv), DCM, 0 °C, 6 h, 90%. (x) PhSH (5 equiv), DIPEA (4 equiv), DMF, r.t., 4 h, 99%. (xi) Pd/C, H2, AcOH
(1.5 equiv), dioxane/H2O 1/1 (v/v), r.t., 16 h, 100%.
Synlett 2001, No. 11, 1727–1730 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of -Lactams
1729
1993, 36, 2. (c) Marcotte, E. R.; Chugh, A.; Mishra, R. K.;
Johnson, R. L. Peptides 1998, 19, 403.
of 15 with benzylamine, the aforementioned -attack
products observed from the reaction of amino acid esters
18 and 19 with 15 could not be separated from the major
products 20 and 22 by column chromatography.16 None-
theless, treatment of the crude mixtures with trifluoroace-
tic acid (TFA) to cleave the tert-butyl ester, followed by
their transformation to the corresponding HCl salts and
cyclisation under the agency of EDC, gave the -lactams
24 and 25 which could be isolated in a pure form and in
good yield.17
(4) For further examples, see: (a) Robl, J. A.; Cimarusti, M. P.;
Simpkins, L. M.; Weller, H. N.; Pan, Y. Y.; Malley, M.;
DiMarco, J. D. J. Am. Chem. Soc. 1994, 116, 2348.
(b) Piscopio, A. D.; Miller, J. F.; Koch, K. Tetrahedron Lett.
1998, 39, 2667.
(5) (a) Mikami, Y.; Suzuki, T. Agric. Biol. Chem. 1983, 47,
2693. (b) Friis, P.; Olsen, C. E.; Møller, B. L. J. Biol. Chem.
1991, 266, 13329; and references cited therein.
(6) Krumme, D.; Tschesche, H. Tetrahedron 1999, 55, 3007.
(7) All new compounds were fully characterised by 1H and 13
C
Although it is possible to deprotect primary nitrobenzene-
sulfonamides,12 the reaction conditions required are po-
tentially detrimental to the integrity of the lactam ring.18
However, the oNs protecting group can be activated for
conventional, mild deprotection by conversion of the pri-
mary sulfonamide to the corresponding urethane protect-
ed nitrobenzenesulfonylimide.12 In order to confirm this,
-lactam 24 was reacted with benzyl chloroformate19 to
give 26. Treatment of 26 with thiophenol (5 equivalents)
in the presence of DIPEA (4 equivalents),20 gave the ben-
zyloxy carbonyl protected Freidinger -lactam 27 in ex-
cellent yield. Deprotection of 27 by palladium assisted
hydrogenation in the presence of acetic acid (1.5 equiva-
lents) afforded 28 in quantitative yield.
NMR spectroscopy as well as mass spectrometry. Data for
selected examples is as follows. (S)-1-(2-Nitro-
benzenesulfonyl)-aziridine-2-carboxylic Acid tert-Butyl
Ester(15): 1H NMR (200 MHz, CDCl3): 8.30–8.25 (m, 1
H, 1
Harom oNs), 7.81–7.74 (m, 3 H, 1 Harom oNs), 3.52
(dd, 1 H, H2, J2,3 = 7.3 Hz, J2.3’ = 4.4 Hz), 3.02 (d, 1 H, H3),
2.72 (d, 1 H, H3’), 1.49 (s, 9 H, CH3 t-Bu); 13C NMR (50
MHz, CDCl3): 164.8 (C1), 147.8 (C-NO2), 134.6, 132.0,
130.6, 124.1 (CHarom oNs), 82.4 (Cq t-Bu), 38.0 (C2), 33.1
(C3), 27.1 (CH3 t-Bu); MS (ESI): m/z (%) = 351.0 [M + Na]+.
(S)-3-Benzylamino-2-(2-nitro-benzenesulfonylamino)-
propionic Acid tert-Butyl Ester(16): 1H NMR (200 MHz,
CDCl3): 8.11–8.08 (m, 1 H, 1 Harom oNs), 7.94–7.90 (m,
1 H, 1
Harom oNs), 7.73–7.68 (m, 2 H, 1 Harom oNs), 7.30
(m, 5 H, Harom Bn), 6.35 (bs, 1 H, NH-oNs), 4.19 (t, 1 H, H2,
J2,3 = 4.8 Hz), 3.82 (AB, 2 H, CH2 Bn), 2.99 (d, 2 H, H3),
1.25 (CH3 t-Bu); 13C NMR (50 MHz, CDCl3): 170.9 (C1),
133.5, 132.8, 130.4 (3 CHarom oNs), 128.4, 128.0, 127.1
(CHarom Bn), 126.5 (Cq Bn), 125.5 (1 CHarom oNs), 82.7 (Cq
t-Bu), 57.0 (C2), 53.1, 50.7 (C3 and CH2 Bn), 27.6 (CH3 t-
Bu); MS (ESI): m/z (%) = 436.2 [M + H]+. (R)-2-
In summary, the Mitsunobu condensation of amino acids
onto the side chain of serine to form dipeptide isosteres of
type 2 could only be realised with glycine derivatives 4
and 5. However, further examples were obtained by ring
opening serine-derived aziridine 15 with -amino acid es-
ters 18 and 19. Compounds of type 2 made in either way
were readily cyclised to form the target Freidinger -lac-
tams (1, n = 1) in good overall yield. Furthermore, the
ability to fully deprotect these compounds was demon-
strated by the conversion of 24 to 28 in excellent yield.
The efficient and facile synthesis of aziridine 15 in con-
junction with its regioselective and high yielding ring
opening with amino acid esters represents an attractive
route to the synthesis of both target compounds 1 (n = 1)
and 2.
Benzylamino-3-(2-nitro-benzenesulfonylamino)-
propionic Acid tert-Butyl Ester(17): 1H NMR (300 MHz,
CDCl3): 8.16–8.08 (m, 1 H, 1 Harom oNs), 7.92–7.83 (m,
1 H, 1 Harom oNs), 7.78–7.70 (m, 2 H, 1 Harom oNs),
7.35–7.23 (m, 5 H, Harom Bn), 6.12 (bs, 1 H, NH-oNs), 3.70
(AB, 2 H, CH2 Bn), 3.39–3.27 (m, 2 H, H2 and 1 H3), 3.13–
3.07 (m, 1 H, 1 H3), 1.49 (CH3 t-Bu); 13C NMR (75 MHz,
CDCl3): 171.4 (C1), 148.1 (C-NO2), 139.0 (Cq Bn), 135.1,
132.7, 131.0 (3 CHarom oNs), 128.4, 128.2, 127.3 (CHarom
Bn), 126.5 (Cq Bn), 125.3 (1 CHarom oNs), 82.7 (Cq t-Bu),
59.9 (C2), 52.0 (CH2 Bn), 45.0 (C3), 28.0 (CH3 t-Bu);); MS
(ESI): m/z (%) = 436.2 [M + H]+. (S)-3-((S)-1-
Methoxycarbonyl-2-phenyl-ethylamino)-2-(2-
nitrobenzenesulfonylamino)-propionic Acid tert-Butyl
Ester(22): 1H NMR (300 MHz, CDCl3): 8.08–8.03 (m, 1
H, 1 Harom oNs), 7.94–7.90 (m, 1 H, 1 Harom oNs), 7.75–
Acknowledgement
This work was financially supported by Unilever. The authors
would like to thank Fons Lefeber and Kees Erkelens for recording
NMR spectra, Hans van den Elst for performing the mass spectro-
mic analyses and Nico Meeuwenoord for conducting HPLC analy-
ses.
7.67 (m, 2 H, 1
Harom oNs), 7.31–7.13 (m, 5 H, Harom Ph),
6.46 (bd, 1 H, NH oNs, JNH,2 = 8.7 Hz), 4.12 (m, 1 H, H2),
3.66 (s, 3 H, OMe), 3.46 (m, 1 H, H1’), 3.12 (dd, 1 H, H3a,
J
3a,3b = 12.3 Hz, J3a,2 = 4.4 Hz), 2.92–2.74 (m, 2 H, H2’), 2.72
(dd, 1 H, H3b, J3b,2 = 4.5 Hz), 1.22 (s, 9 H, CH3 t-Bu); 13
C
NMR (75 MHz, CDCl3): 174.2, 168.7 (C1, COOMe), 147.6
(C-NO2), 136.6 (Cq, Ph), 134.5 (C-SO2), 133.4, 132.7, 130.4
(3 CHarom oNs), 129.1, 128.4, 126.7 (CHarom Ph), 125.4
(1 CHarom oNs), 82.6 (Cq, t-Bu), 62.5 (C1’), 57.2 (C2), 51.7
(COOMe), 49.8 (C3), 39.6 (C2’), 27.5 (CH3, t-Bu); MS (ESI):
m/z (%) = 508.3 [M + H]+. (S)-2-[(S)-3-(2-Nitro-
benzenesulfonylamino)-2-oxo-azetidin-1-yl]-propionic
Acid Benzyl Ester(24): 1H NMR (CDCl3): 8.16–8.13 (m,
1 H, 1 Harom oNs), 7.92–7.89 (m, 1 H, 1 Harom oNs),
References and Notes
(1) (a) Giannis, A.; Kolter, T. Angew. Chem. Int. Ed. Engl. 1993,
32, 1244. (b) Liskamp, R. M. J. Recl. Trav. Chim. Pays-Bas
1994, 113, 1.
(2) Freidinger, R. M.; Verber, D. F.; Perlow, D. S. Science 1980,
210, 656.
(3) (a) Sreenivasan, U.; Mishra, R. K.; Johnson, R. L. J. Med.
Chem. 1993, 36, 256; and references cited therein.
(b) Williams, B. J.; Curtis, N. R.; McKnight, A. T.; Maguire,
J. J.; Young, S. C.; Veber, D. F.; Baker, R. J. Med. Chem.
7.78–7.72 (m, 2 H, 1
Harom oNs), 7.41–7.32 (m, 5 H, Harom
Bn), 6.28 (bs, 1 H, NH), 5.17 (s, 2 H, CH2 Bn), 4.70 (dd, 1
H, H3’ ser, J3’,4a’ = 5.2 Hz, J3’,4b’ = 2.5 Hz), 4.45 (q, 1 H, H2
ala, J2,3 = 7.4 Hz), 3.65 (app. t, 1 H, H4a’ ser), 3.42 (dd, 1 H,
Synlett 2001, No. 11, 1727–1730 ISSN 0936-5214 © Thieme Stuttgart · New York

1730
J. J. Turner et al.
LETTER
was maintained at low temperature for a further 30 min
whereupon the reaction mixture was diluted with toluene (10
mL/mmol) and concentrated in vacuo at 30 °C to give an
orange oil. The residue was purified by column
chromatography on silica gel (toluene/acetone) to give 15 as
a colourless oil in 92% yield.
H4b’ ser, J4b’,4a’ = 5.9 Hz), 1.41 (d, 3 H, H3). 13C NMR
(CDCl3): 170.2, 164.7 (2 C=O), 147.8 (C-NO2), 135.0
(Cq Bn), 134.0, 133.0, 130.9 (3 CHarom oNs), 128.7, 128.7,
128.3 (CHarom Bn), 125.6 (1 CHarom oNs), 67.5 (CH2 Bn),
58.6 (C3’), 49.7 (C2), 47.0 (C4’), 15.0 (C3); MS (ESI): m/z (%)
= 434.0 [M + H]+, 456.1 [M + Na]+. (S)-2-((S)-3-Amino-2-
oxo-azetidin-1-yl)-propionic Acid(28): 1H NMR (600
MHz, D2O): 4.26 (dd, 1 H, H3’, J3’,4a’ = 5.0 Hz, J3’,
4b’ = 10.0 Hz), 4.01 (q, 1 H, H2, J2,3 = 7.2 Hz), 3.79 (dd, 1 H,
(15) It should be noted that aziridine 15 had to be purified
directly, to prevent its decomposition presumably by attack
from byproducts of the Mitsunobu reaction.
H
4a’, J4a’,4b’ = 13.1 Hz), 3.30 (dd, 1 H, H4b’), 1.52 (d, 3 H, H3);
(16) The ratios of 20:21 and 22:23 were obtained by NMR
spectroscopy and further confirmed with reverse phase
LCMS where the products were clearly separable.
(17) The enantiomer of aziridine 15 was subjected to ring
opening with 18 and cyclised to the -lactam. Comparison of
this compound to 24 as well as comparing the major ring
opened product to 20 (1H NMR) showed that the reaction
sequence proceeds without detectable racemisation (> 95%
diastereomeric purity).
(18) At the time of submission, a milder deprotection strategy for
primary 2-nitrobenzenesulfonamides was reported by:
Nihei, K.-I.; Kato, M. J.; Yamane, T.; Palma, M. S.; Konno,
K. Synlett 2001, 1167.
MS (ESI): m/z (%) = 158.9 [M + H]+.
(8) Saïah, M.; Bessodes, M.; Antonakis, K. Tetrahedron Lett.
1992, 33, 4317; and references cited therein.
(9) Cherney, R. J.; Wang, L. J. Org. Chem. 1996, 61, 2544.
(10) The replacement of acetic acid in the standard allyl ester
deprotectionconditions withN-hydroxybenzotriazole serves
to avoid possible acetylation of the amino groups in the
following cyclisation step (89) see: Loffet, A.; Zhang, H. X.
Int. J. Peptide. Protein. Res. 1993, 42, 346.
(11) Solomon, M. E.; Lynch, C. L.; Rich, D. H. Tetrahedron Lett.
1995, 36, 4955.
(12) Maligres, P. E.; See, M. M.; Askin, D.; Reider, P. J.
Tetrahedron Lett. 1997, 38, 5253.
(19) Branch, C. L.; Pearson, M. J.; Smale, T. C. J. Chem. Soc.,
Perkin Trans. 1 1988, 2865.
(13) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373.
(20) (a) Turner, J. J.; Wilschut, N.; Overkleeft, H. S.; Klaffke,
W.; Van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett.
1999, 40, 7039. (b) Turner, J. J.; Filippov, D. V.; Overhand,
M.; van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett.
2001, 42, 5763.
(14) N-(2-Nitrobenzenesulfonyl)-l-serine tert-Butyl Ester 14
was coevaporated with 1,2-dichloroethane (3 10 mL),
dissolved in THF (10 mL/mmol), cooled to –5 °C and PPh3
(1.2 eq) was added. After stirring for 5 min, DEAD (1.2 eq)
was added dropwise over a period of 30 min and the reaction
Synlett 2001, No. 11, 1727–1730 ISSN 0936-5214 © Thieme Stuttgart · New York