CD-sensitive Zn-porphyrin tweezer host-guest complexes, part 2: Cis- and trans-3-hydroxy-4-aryl/alkyl-β-lactams. A case study

Article abstract of DOI:10.1002/chir.20718

This article describes an application of the host-guest chiral recognition approach called tweezer methodology for the determination of the absolute configuration of 3-hydroxy-β-lactams. These substrates represent challenging cases due to their chemical reactivity, the presence of multiple stereogenic centers and several functional groups which offer various possibilities of binding to the Zn-porphyrin host. OPLS-2005, the force field used in this work to predict the interporphyrin twist, modeled correctly the host-guest complexation mechanism and revealed conformational details of the bound substrates. The computational study also suggested that in cases where an increase in the magnitude of the stereodifferentiation and an intense experimental CD are observed, the bound conformation of the conjugates are hydrogen bonded. The present investigation provides evidence that when the tweezer method is assisted by the OPLS-2005 based computational approach, it can be successfully applied to the con-figurational and conformational elucidation of multi-functional compounds with multiple stereogenic centers.

Full text of DOI:10.1002/chir.20718

CHIRALITY 22:140–152 (2010)
CD-Sensitive Zn-Porphyrin Tweezer Host-Guest Complexes,
Part 2: Cis- and Trans-3-Hydroxy-4-aryl/alkyl-b-Lactams.
A Case Study
YIHUI CHEN,1 ANA G. PETROVIC,1 MARIN ROJE,1 GENNARO PESCITELLI,2 MARGARET M. KAYSER,3
4
YAN YANG,3 NINA BEROVA,1* AND GLORIA PRONI
*
1Department of Chemistry, Columbia University, New York, NY
2Dipartimento di Chimica e Chimica Industriale, Universita` degli Studi di Pisa, Pisa, Italy
3Department of Physical Sciences, University of New Brunswick, Saint John, New Brunswick, Canada
4John Jay College of Criminal Justice, Science Department, New York, NY
ABSTRACT
This article describes an application of the host-guest chiral recognition
approach called tweezer methodology for the determination of the absolute configura-
tion of 3-hydroxy-b-lactams. These substrates represent challenging cases due to their
chemical reactivity, the presence of multiple stereogenic centers and several functional
groups which offer various possibilities of binding to the Zn-porphyrin host. OPLS-2005,
the force field used in this work to predict the interporphyrin twist, modeled correctly
the host-guest complexation mechanism and revealed conformational details of the
bound substrates. The computational study also suggested that in cases where an
increase in the magnitude of the stereodifferentiation and an intense experimental CD
are observed, the bound conformation of the conjugates are hydrogen bonded. The
present investigation provides evidence that when the tweezer method is assisted by
the OPLS-2005 based computational approach, it can be successfully applied to the con-
figurational and conformational elucidation of multi-functional compounds with multiple
C
VV
stereogenic centers. Chirality 22:140–152, 2010.
2009 Wiley-Liss, Inc.
KEY WORDS: metalloporphyrin tweezer; OPLS-2005; supramolecular complexation;
absolute configuration; 3-hydroxy-b-lactams
INTRODUCTION
coupled24,25-based tweezer methodology assisted by
OPLS-2005 computational analysis is applied for the first
time to b-lactams (see Fig. 1).
b-Lactams are one of the most extensively investigated
heterocyclic ring systems. The interest in these structures
stems from their biological activity as antibiotics1 and their
use as precursors of more complex pharmacologically im-
portant substrates.2 In addition, research directed to the
synthesis of new b-lactam-based antibiotics has increased
in the last decade due to the discovery of a growing num-
ber of b-lactam-resistant bacteria3 and the fact that b-lac-
tams with a defined stereochemistry represent important
synthetic targets. For example, b-amino-a-hydroxy esters
constitute key fragments of many biologically important
natural products such as aminosugars, a-hydroxy-b-amino
acids,4 glycosphingolipids, and peptidic enzyme inhibitors.
Many alkaloids are synthetically related to 3-hydroxy-b-lac-
tams5,6 as is the anticancer drug Taxol.7
These substrates, prepared by Kayser et al.8,26 and for
which the absolute configuration was determined by NMR
spectroscopy,11 and X-ray crystallography,10 pose addi-
tional layers of complexity for the stereodifferentiation pro-
cess which may result into possible formation of com-
plexes with opposite sign of twist and different helicity
(see Fig. 2c). In the case of the b-lactams studied the cor-
responding conjugates (Fig. 2b) not only possess several
Contract grant sponsors: Graduate Research Technology Initiative (GRTI)
(John Jay College Research Assistance Program), Professional Staff Con-
gress-City University of New York (PSC-CUNY), Natural Sciences and
Engineering Research Council of Canada, Medical Research Fund of New
Brunswick (MMK).
Marin Roje is currently at Rudjer Boskovic Institute, Department of Or-
ganic Chemistry and Biochemistry, Bijenicka c. 54, 10002 Zagreb, Croatia
*Correspondence to: Dr. Gloria Proni, John Jay College of Criminal
Justice, Science Department, 445 West 59th Street #4405, 10019 New
York, NY. E-mail: gproni@jjay.cuny.edu or Dr. Nina Berova, Columbia
University, Department of Chemistry, 3000 Broadway, Havemeyer Hall,
MC 3114, New York, NY 10027. E-mail: ndb1@columbia.edu
Received for publication 23 October 2008; Accepted 6 February 2009
DOI: 10.1002/chir.20718
The absolute configurations of many members of the b-
lactam family have been determined previously by several
techniques such as X-ray crystallography,8–10 NMR spec-
troscopy,11 electronic circular dichroism12,13 and vibra-
tional circular dichroism.14
In previous papers,15–23 the tweezer methodology was
successfully applied to substrates with only one stereo-
genic center and only two possible binding sites for com-
plexation to zinc porphyrins. In this article exciton-
C
Published online 22 April 2009 in Wiley InterScience
(www.interscience.wiley.com).
VV
2009 Wiley-Liss, Inc.

CIS- AND TRANS-3-HYDROXY-4-ARYL/ALKYL-ꢀ-LACTAMS
141
Fig. 1. b-lactam substrates and their absolute configuration.
potential coordination sites to the bis-porphyrin host, but implemented in MacroModel package, with the Molecular
also contain more than one stereogenic center in their Merck force field (MMFFs) revealed limitations of the
structure, each of which may affect the stereodifferentia- MC/MMFFs based approach to complex substrates like
tion. Moreover, the conformation of the free conjugate is b-lactams. In the previous paper, Part 1,27 we describe the
potentially influenced by the presence of several possible MC/OPLS-2005 procedure in details and also report its
intramolecular hydrogen bonds. All these factors makes validation on a reference set of chiral alcohols and amines.
the b-lactams the most challenging substrates ever investi- Here we report the application of MC/OPLS-2005 to the
gated with the bis-porphyrin tweezer method.
structural investigation of tweezer complexes with b-lac-
An initial molecular modeling investigation of the host- tams. The aim of the present effort is to test whether the
guest complexes based on the Monte Carlo algorithm, employment of MC/OPLS-2005 calculations can extend
Fig. 2. (a) Formation of the bifunctional conjugate molecule derived by the b-lactam residues and subsequently of the 1:1 complex between the con-
jugate and the tweezer molecule, Zn-T; (b) Chemical representation of the Zn porphyrin tweezer, Zn-T; (c) Schematic representation of the possible con-
formations of opposite interporphyrin twist in the complex. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.
com.]
Chirality DOI 10.1002/chir

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CHEN ET AL.
Scheme 1. Synthetic procedures tested for preparation of conjugate molecules suitable for complexation studies (according to Kurtan et al.).19
the application of the tweezer methodology to complex
Anhydrous solvents were purchased from Aldrich. Sol-
substrates carrying multiple stereogenic centers and sev- vents for circular dichroism measurements were spectro-
eral diverse functionalities.
scopic grade. Unless otherwise noted, materials were
obtained from Aldrich and were used without further puri-
fication. Column chromatography was performed using
ICN silica gel (36f3 mesh).
MATERIALS AND METHODS
High resolution FABMS was performed on a JMS-110/
110 tandem mass spectrometer (Tokyo, Japan) using a m-
nitrobenzyl alcohol (m-NBA) matrix. 1H NMR spectra
were recorded on a Bruker DPX-300 (300 MHz) spectrom-
Synthesis and Characterization of the Conjugate
Molecules Through Procedure A, B, and C
Synthetic procedures A and B (Scheme 1) and the syn-
eter in CDCl3 or CD3OD. Chemical shifts are reported in thesis of 2-(tert-butoxycarbonyl(3-tert-butoxycarbonylami-
ppm relative to Me4Si (0.0 ppm) or CD2HOD (3.3 ppm). no)propyl)amino)ethanoic acid, 6 are described in Kurtan
Data are reported as follows: singlet (s), doublet (d), tri- et al.20 Synthetic procedure C (see Scheme 2) and
plet (t), multiplet (m); coupling constants in Hz; integra- the preparation of 2-(N-tert-butoxycarbonyl-3-(tert-butyldi-
tion. The CD spectra, recorded on a JASCO-810 spectro- methylsiloxy) propylamino)acetic acid, 7 are described in
photometer as mdeg spectra, were converted into Demax Ishii et al.23
[Lmol21cm21]/k [nm] units. The zinc tetraarylporphyrin
Compounds 1a and 2a were prepared following proce-
tweezer is commercially available from TCI (Portland, OR, dure A while compounds 1c and 1d following procedure
cat. no. P1364). The b-lactam substrates were prepared by B; compounds 1e–5e and 1f–-5f were prepared following
Kayser’s group following published protocols.8,10,26 Both procedure C.
cis and trans compounds presented enantiomeric excesses
(2S, 3R)-2-tert-Butyl-1-(4-methoxyphenyl)-4-oxoa-
1
higher than 98%. The optical rotation values for the com- zetidin-3-yl 2-bromoethanoate, 1a (Procedure A). H
pounds investigated are as follow: (3R,4S)-1 [a]D 5 184 NMR (300 MHz, CDCl3) d 7.31 (d, J 5 9.0 Hz, 2H), 6.91
(c 1.2 in CH2Cl2); (3R, 4R)-2 [a]D 5 1216.57 7(c 1.05 in (d, J 5 9.0 Hz, 2H), 6.19 (d, J 5 5.4 Hz, 1H), 4.30 (d, J 5
CH2Cl2); (3R,4S)-3 [a]D 5 240.7 (c 1.01 in CH2Cl2); (3R, 5.4 Hz, 1H), 3.96 (d, J 5 3.1 Hz, 2H), 3.82 (s, 3H), 1.06 (s,
4R)-4 [a]D 5 1 172.58 (c 1.0 CH2Cl2); (3R,4S)-5 [a]D
243.5 (c 1.02 CH2Cl2).
5
9H); HRFABMS m/z 369.0590 [M 1 H]1, calcd. for
C16H20O4NBr, 369.0576.
Scheme 2. Synthetic procedure to obtain conjugate molecules suitable for host-guest complexation studies (according to Ishii et al.).22
Chirality DOI 10.1002/chir

CIS- AND TRANS-3-HYDROXY-4-ARYL/ALKYL-ꢀ-LACTAMS
143
(2S,3R)-2-(Furan-2-yl)-1-(4-methoxyphenyl)-4-oxoa-
(2R,3R)-2-(Furan-2-yl)-1-(4-methoxyphenyl)-4-oxo-
1
zetidin-3-yl 2-bromoethanoate, 2a (Procedure A). H azetidin-3-yl 2-(3-hydroxypropylamino)ethanoate, 2f
1
NMR (300 MHz, CDCl3) d?7.44 (dd, J 5 1.0, 0.8 Hz, 1H), (Procedure C). H NMR (300 MHz, CD3OD) d 7.57 (d, J
7.29 (dd, J 5 9.1, 2.1 Hz, 2H), 6.83 (dd, J 5 9.1, 2.1 Hz, 5 1.5 Hz, 1H), 7.28 (d, J 5 10 Hz, 2H), 6.86 (d, J 5 10 Hz,
2H), 6.46 (d, J 5 3.4 Hz, 1H), 6.40 (dd, J 5 3.4, 1.8 Hz, 2H), 6.68 (d, J 5 3.3 Hz, 1H), 6.47 (dd, J 5 3.2, 1.8 Hz,
1H), 6.01 (d, J 5 4.7 Hz, 1H), 5.42 (d, J 5 4.7 Hz, 1H), 3.78 1H), 5.92 (m, 1H), 5.33 (d, J 5 1.8 Hz, 1H), 4.50 (m, 2H),
(s, 3H), 3.71 (d, J 5 10.9 Hz, 2H); HRFABMS m/z 4.17 (d, J 5 15.1 Hz, 2H), 3.75 (s, 3H), 3.28 (m, 2H), 2.20
380.0136 [M 1 H]1, calcd. for C16H15O5NBr, 380.0134.
(m, 2H), 1.95 (m, 2H); HRFABMS m/z 375.1564 [M 1
(2S,3R)-2-tert-Butyl-1-(4-methoxyphenyl)-4-oxoazeti- H]1, calcd. for C19H23O6N2, 375.1556.
din-3-yl 2-(tert-butoxycarbonyl(3-(tert-butoxycarbony-
(3R,4R)-1-(4-Methoxyphenyl)-2-oxo-4-(thiophen-2-
1
lamino)propyl)amino)ethanoate, 1c (Procedure B). H yl)azetidin-3-yl 2-(tert-butoxycarbonyl(3-(tert-butyldi-
NMR (300 MHz, CDCl3) d 7.29 (dd, J 5 9.0, 2.1 Hz, 2H), methylsilyloxy)propyl)amino)ethanoate 4e (Proce-
1
6.88 (dd, J 5 9.0, 2.1 Hz, 2H), 6.18 (d, J 5 5.3 Hz, 1H), 4.27 dure C). H NMR (300 MHz, CDCl3) d 7.29 (d, J 5 8.8
(d, J 5 5.3 Hz, 1H), 4.03 (s, 2H), 3.81 (s, 3H), 3.46 (m, 2H), Hz, 2H), 7.10 (bs, 1H), 7.01 (m, 1H), 6.82 (d, J 5 8.8 Hz,
3.35 (m, 2H), 3.19 (m, 2H), 1.70 (m, 2H), 1.46 (s, 18H), 1.03 2H), 6.00 (m, 1H), 5.60 (m, 1H), 4.00 (m, 1H), 3.77 (s,
(s, 9H); HRFABMS m/z 563.3204 [M 1 H]1, calcd. for 3H), 3.50 (m, 3H), 3.10 (m, 2H), 1.55 (m, 2H), 1.45 (s,
C29H45O8N3, 563.3207.
3H), 1.40 (s, 3H), 0.90 (s, 9H), 0.10 (s, 9H).
N1-(2-((2S,3R)-2-tert-Butyl-1-(4-methoxyphenyl)-4-
(3R,4R)-1-(4-Methoxyphenyl)-2-oxo-4-(thiophen-2-
oxoaze-tidin-3-yloxy)-2-oxoethyl)propane-1,3-diamini- yl)azetidin-3-yl 2-(3-hydroxypropylamino)ethanoate,
um TFA salt, 1d (Procedure B). 1H NMR (300 MHz, 4f (Procedure C). H NMR (300 MHz, CD3OD) d 7.50
1
CD3OD) d 7.42 (dd, J 5 6.8, 1.6 Hz, 2H), 7.04 (dd, J 5 6.8, 1.6 (d, J 5 5 Hz, 1H), 7.34 (dd, J 5 8.0, 1.5 Hz, 2H),
Hz, 2H), two doublets of two different species at 6.39 and 6.32 7.25 (m, 1H), 7.10 (m, 1H), 6.91 (dd, J 5 8.0, 1.5 Hz,
(d, J 5 5.3 Hz, 1H), two doublets of two different species at 4.60 2H), 6.22 (dd, J 5 4.7, 1.5 Hz, 1H), 5.94 (d, J 5 4.7 Hz,
and 4.56 (d, J 5 5.3 Hz, 1H), one singlet 1 one doublet for 1H 1H), 4.48 (m, 2H), 4.18 (d, J 5 18.7 Hz, 1H), 3.79 (s,
at 4.35 (s) and 4.28 (d, J 5 5.9 Hz), 3.89 (s, 3H), 3.59 (m, 2H), 3H), 3.74 (d, J 5 18.7 Hz, 1H), 3.05 (m, 2H), 2.15 (m,
3.36 (m, 2H), 3.19 (m, 2H), 2.20 (m, 2H), (s, 9H);
(2S,3R)-2-tert-Butyl-1-(4-methoxyphenyl)-4-oxoaze-
tidin-3-yl 2-(tert-butoxycarbonyl(3-(tert-butyldimethyl- zetidin-3-yl 2-(tert-butoxycarbonyl(3-(tert-butyldime-
silyloxy)propyl)amino)ethanoate, 1e (Procedure C). H thylsilyloxy)propyl)amino)ethanoate, 3e (Procedure
2H).
(2S,3R)-2-(Furan-2-yl)-1-(4-methoxyphenyl)-4-oxoa-
1
1
NMR (300 MHz, CDCl3) d 7.29 (d, J 5 9.0 Hz, 2H), 6.87 (d, C). H NMR (300 MHz, CDCl3) d 7.30 (m, 1H), 7.28 (d, J
J 5 9.0 Hz, 2H), 6.17 (m, 1H), 4.25 (m, 1H), 4.12 (d, J 5 6.0 5 9.0 Hz, 2H), 7.13 (m, 1H), 7.00 (m, 1H), 6.82 (d, J 5 9.0
Hz, 1H), 4.06 (s, 1H), 3.80 (s, 3H), 3.64 (m, 2H), 3.39 (m, Hz, 2H), 5.53 (d, J 5 19.0 Hz, 1H), 5.21 (d, J 5 19.0 Hz,
2H), 1.75 (m, 2H), 1.47 (s, 3H), 1.44 (s, 3H), 1.02 (s, 9H), 1H), 4.05 (s, 2H), 3.77 (s, 3H), 3.64 (m, 2H), 3.40 (m, 2H),
0.90 (s, 9H), 0.06 (s, 9H); HRFABMS m/z 578.3412 [M 1 1.74 (m, 2H), 1.48 (s, 3H), 1.46 (s, 3H), 0.90 (s, 9H), 0.06
H]1, calcd. for C30H50O7N2Si, 578.3387.
(s, 9H); HRFABMS m/z 588.2899 [M 1 H]1, calcd. for
(2S,3R) 22-tert-Butyl-1-(4-methoxyphenyl)-4-oxoa- C30H43O8N2Si, 588.2895.
zetidin-3-yl 2-(3-hydroxypropylamino)ethanoate, 1f
(Procedure C). H NMR (300 MHz, CD3OD) d 7.37 (d, J zetidin-3-yl 2-(3-hydroxypropylamino)ethanoate, 3f
5 9.0 Hz, 2H), 6.99 (d, J 5 9.0 Hz, 2H), 6.35 (d, J 5 6.2 (Procedure C). H NMR (300 MHz, CD3OD) d 7.57 (d, J
(2S,3R)-2-(Furan-2-yl)-1-(4-methoxyphenyl)-4-oxoa-
1
1
Hz, 1H), 4.55 (m, 2H), 4.32 (d, J 5 3.0 Hz, 1H), 4.26 (d, J 5 1.5 Hz, 1H), 7.28 (d, J 5 10 Hz, 2H), 6.86 (d, J 5 10 Hz,
5 4.0 Hz, 1H), 3.84 (s, 3H), 3.30 (m, 2H), 2.29 (m, 2H), 2H), 6.68 (d, J 5 3.3 Hz, 1H), 6.47 (dd, J 5 3.2, 1.8 Hz,
1.98 (m, 2H), 1.09 (s, 9H); HRFABMS m/z 365.2071 [M 1 1H), 5.92 (m, 1H), 5.33 (d, J 5 1.8 Hz, 1H), 4.50 (m, 2H),
H]1, calcd. for C19H29O5N2, 365.2076.
4.17 (d, J 5 15.1 Hz, 2H), 3.75 (s, 3H), 3.28 (m, 2H), 2.20
Chirality DOI 10.1002/chir

144
CHEN ET AL.
(m, 2H), 1.95 (m, 2H); HRFABMS m/z 375.1557 [M 1 in CH2Cl2 (1.0 mL) was added TFA (10% V/V) and stirred
H]1, calcd. for C19H23O6N2, 375.1556.
for 3 h at room temperature. The salt was neutralized with
(3R,4S)-1-(4-Methoxyphenyl)-2-oxo-4-(thiophen-2- sodium carbonate (10 mg) in methanol (1.0 mL). After re-
yl)azetidin-3-yl 2-(tert-butoxycarbonyl(3-(tert-butyl- moval of the methanol in vacuo, conjugate 8 was used in
dimethylsilyloxy)propyl)amino)ethanoate, 5e (Proce- the complexation with zinc porphyrin tweezer without fur-
dure C) 1H NMR (300 MHz, CDCl3) d 7.42 (d, J 5 6.8 Hz, ther purification.
1H), 7.27 (d, J 5 8.9 Hz, 2H), 6.81 (d, J 5 8.9 Hz, 2H), 6.51
1H NMR (300 MHz, CDCl3) d 7.28 (d, J 5 9.0 Hz, 2H),
(m, 1H), 6.39 (m, 1H), 5.80 (dd, J 5 14.0, 1.5 Hz, 1H), 4.98 6.88 (d, J 5 9.0 Hz, 2H), 6.17 (d, J 5 5.4 Hz 1H), 4.24 (d,
(dd, J 5 14.0, 1.5 Hz, 1H), 4.04 (d, J 5 5.0 Hz, 2H), 3.77 (s, J 5 5.4 Hz 1H), 4.07(m, 2H), 3.80 (s, 3H), 2.32 (m, 2H),
3H), 3.65 (m, 2H), 3.35 (m, 2H), 1.75 (m, 2H), 1.46 (s, 1.2–1.8 (m, 6H), 1.01 (s, 9H), final free conjugate,
3H), 1.44 (s, 3H), 0.90 (s, 9H), 0.06 (s, 9H); HRFABMS m/ HRFABMS m/z 364.2112, [M 100%], calcd. for
z 605.2726 [M 1 H]1, calcd. for C30H45O7N2SiS, 605.2717.
(3R,4S)-1-(4-Methoxyphenyl)-2-oxo-4-(thiophen-2-
C20H29NO5, 363.4411.
2-(tert-Butoxycarbonyl(methyl)amino)ethanoic acid,
yl)azetidin-3-yl 2-(3-hydroxypropylamino)ethanoate, 13 Prepared following Scapecchi et al.29
1
5f (Procedure C). H NMR (300 MHz, CD3OD) d 7.48 (d,
(2S,3R)-2-tert-Butyl-1-(4-methoxyphenyl)-4-
oxoazetidin-3-yl 2-(methylamino)ethanoate, 9
J 5 5.5 Hz, 1H), 7.29 (d, J 5 9.0 Hz, 2H), 7.25 (d, J 5 5.5 Hz,
1H), 7.05 (dd, J 5 5.0, 3.5 Hz, 1H), 6.87 (d, J 5 9.0 Hz, 2H),
5.66 (dd, J 5 3.4, 1.6 Hz, 1H), 5.55 (d, J 5 1.6 Hz, 1H), 4.50
(m, 2H), 4.23 (s, 1H), 4.20 (d, J 5 8.2, 1H), 3.75 (s, 3H), 3.27
(m, 2H), 2.22 (m, 1H), 1.95 (m, 1H); HRFABMS m/z
391.1347 [M 1 H]1, calcd. for C19H23O5N2S, 391.1328.
A solution of (3R,4S)-4-tert-butyl-3-hydroxy-1-(4-meth-
oxyphenyl)azetidin-2-one, 3 (100 lg, 0.40 lmol), 2-(tert-
butoxycarbonyl(methyl)amino)ethanoic acid, 13 (1 mg,
5.3 lmol), EDC (1 mg, 5.2 lmol) and DMAP (20 lg)
in anhydrous CH2Cl2 (0.3 ml) was in stirred in a
Wheaton V-Vial (0.5 ml) for 12 h under argon. The so-
lution was then evaporated and the crude of the reac-
tion purified by preparative TLC (SiO2) with n-hexane-
ethyl acetate (1-1) to give the protected conjugate. To a
solution of the protected conjugate in CH2Cl2 (1.0 ml)
was added TFA (10% V/V) and stirred for 3 h at room
temperature. The salt was neutralized with sodium car-
bonate (10 mg) in methanol (1.0 ml). After removal of
the methanol in vacuo, conjugate 9 was used in the
complexation with zinc porphyrin tweezer without fur-
ther purification.
6-(tert-Butyldimethylsilyloxy)hexanoic acid 11
Tert-butyldimethylsilyl
trifluoromethanesulfonate
(TBDMS-triflate) (610 ll , 2.28 mmol) was added dropwise
over 20 min to a solution of 6-hydroxyhexanoic acid (100
mg, 0.76 mmol, 10) and triethylamine (634 ll, 4.5 mmol)
in CH2Cl2 (15 ml) under N2. After stirring for 24 h at RT,
the reaction mixture was poured into cold aqueous
NaHSO3 solution (1N) and extracted with CH2Cl2. The or-
ganic layer was washed with cold aqueous NaHSO3 solu-
tion, dried over Na2SO4, filtered and concentrated to yield
194 mg (92%) of crude trimethylsilyl 6-(trimethylsilyloxy)-
hexanoate. The crude product was dissolved in 10 ml
MeOH and 3 ml 10% aqueous potassium hydroxide. The
resulting mixture was stirred at 458C for 1 h, then cooled
to room temperature, and then concentrated to 4 ml. The
solution was then diluted with 20 ml of brine, and the flask
and its contents were cooled to 08C with stirring. 1 M
aqueous potassium bisulfate was added until pH 4 was
obtained. The resulting mixture was diluted to 50 ml with
ice-cold brine, saturated with solid sodium chloride, and
extracted with ethyl acetate (3 3 50 ml). The combined
extracts were dried over sodium sulfate, and concentrated
in vacuum to give 128 mg of crude compound as an oil. 1H
1HNMR (300 MHz, CDCl3) d 7.35 (d, J 5 9.0 Hz,
2H), 7.00 (d, J 5 9.0 Hz, 2H), 6.30 (d, J 5 5.4 Hz
1H), 4.50 (d, J 5 5.4 Hz 1H), 4.35 (d, 2H), 3.80 (s,
3H), 2.78 (s, 3H), 1.01 (s, 9H), final free conjugate,
HRFABMS m/z 321.1824, [M 100%], calcd. for
C17H24N2O4, 320.1834.
Procedure for the Preparation of Host-Guest Complexes
and CD Measurement; Preparation of the Zinc-Tweezer,
Zn-T Complex of 3f
In a typical experiment a methylcyclohexane (MCH)
NMR (CDCl3, 300 MHz) d 4.09 (m, 2H), 2.38 (m, 2H), 1.2- tweezer solution, Zn-T was prepared by addition of 10 lL
1.8 (m, 6H), 0.91 (s, 4.5H), 0.89 (s, 4.5H), 0.10 (s, 6H). MS aliquot of Zn-T (0.1 mM in anhydrous dichloromethane,
m/z 246.78, M 100% calc. d. for C12H26O3Si, 246.42.
CH2Cl2). The exact concentration of the diluted solution
was determined by UV from the known e value of the
Soret band in CH2Cl2 (e 5 890,000 L mol21 cm21). The
free conjugate 3f, prepared from its TFA salt after addition
(2S,3R)-2-tert-Butyl-1-(4-methoxyphenyl)-4-oxoazetidin-
3-yl-6-hydroxyhexanoate 8
A solution of (3R,4S)-4-tert-butyl-3-hydroxy-1-(4-methoxy- of 0.5 ml of methanol followed by solid Na2CO3 (10 mg).
phenyl)azetidin-2-one, 1 (100 lg, 0.40 lmol), 6-(tert-butyl- The solvent was then dried under a stream of argon fol-
dimethylsilyloxy)hexanoic acid,11, (1 mg, 4 lmol), EDC lowed by placement under high vacuum (0.2 Torr) for 20
(1 mg, 5.2 lmol) and DMAP (20 lg) in anhydrous CH2Cl2 min. Anhydrous CH2Cl2 (1 ml) was then added to yield
(0.3 mL) was in stirred in a Wheaton V-Vial (0.5 mL) for the free conjugate solution. Aliquots of 10 ll of the latter
12 h under argon. The solution was then evaporated and solution were added to the prepared porphyrin tweezer
the crude of the reaction purified by preparative TLC solution 2 to afford the tweezer/conjugate host/guest
(SiO2) with n-hexane-ethyl acetate (1-1) to give the pro- complex. In the UV spectra the red shift of the tweezer
tected conjugate. To a solution of the protected conjugate Soret band indicated that complexation took place. Other
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145
Fig. 3. Possible points of ligation to the zinc-tweezer molecule are squared in red and chemical modifications to conjugate structure to verify the
points of ligation to the Zn-tweezer. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
solvents (dichloromethane, toluene and benzene) have to deduce the preferred sign/value of the projection angle17
been used to test the complexation process; none of these y. A preferential positive value of y is considered a prediction
allowed the formation of the complex.
for an experimental positive CD couplet and vice versa.
RESULTS AND DISCUSSION
Synthesis of Conjugates and Chemical Analysis of the
Binding Sites
Molecular Modeling
The present work involved both Quantum Mechanical
(QM) and Molecular Mechanical (MM) computational
approaches. MacroModel v9.528 is used for MM treatment
of the complex while Jaguar v6.528 for QM treatment of
the free-conjugate. Density Functional Theory (DFT) cal-
culations with B3LYP/6-31G**11 level of theory and
maximum number of minimization steps set to 100 were
used for geometry optimization of the free b-lactams conju-
gates. A detailed computational procedure for the MM
based approach, employing the OPLS-2005 force field, is
described in Part 1.27
3-Hydroxy-b-lactams, carrying a secondary hydroxyl
functionality at position 3, have been treated initially as
members of the secondary alcohol family studied previ-
ously.19,20 In the first instance these substrates were deriv-
atized with carrier molecule 6 (see Fig. 2), a derivative of
diaminopropane, to prepare the bifunctional conjugate that
could bind to the tweezer moiety. Two synthetic proce-
dures, A and B, were first attempted (described in Scheme
1). However, similarly as previously reported for hydroxy-
ketones,23 both methods failed to provide the final ester
amino-conjugates because of the instability of b-lactams in
basic conditions. In particular, the coupling with diamino-
propane in procedure A and the neutralization of the TFA
salt with sodium carbonate to obtain the free amine in pro-
cedure B represent critical steps (see Scheme 1).
The coordination sites for the molecular modeling
calculations were set between Zn-centers of the tweezer
and OH and NH moieties of conjugates. The minimized
conjugate structure was placed between the two Zn-
˚
porphyrins at a distance of 2.2 6 0.2 A between NH and
˚
Zn1, and of 2.4 6 0.2 A between OH and Zn2. Force con-
To overcome the chemical instability of the substrates
and prepare suitable conjugates, 3-hydroxy-b-lactams were
derivatized with carrier molecule 7, previously developed
by Ishii et al.23 for the treatment of a-hydroxy ketones. 2-
(tert-butoxycarbonyl)ethyl)amino)ethanoic acid was used
to functionalize each substrate 1--5 in procedure C
(Scheme 2). The conjugates were subjected to acid hydro-
lysis of the Boc- and Tbs- protecting group to give the TFA
stants (FC) relative to N-Zn and O-Zn distances were set
to 50 as a weak constraint for preliminary calculations and
were next refined by using FC of 100.
Two independent models of the complex were initially
generated, with opposite pre-set positive interporphyrin
twists. The conformational space of the host/guest com-
plex was then sampled by means of the Metropolis Monte
Carlo (MC) algorithm. The MC/OPLS2005 search was
performed using the conditions and the convergence crite- salts which were next neutralized with sodium carbonate.
ria described in the proceeding paper.27 In all cases inves-
The conjugate molecules formed by the 3-hydroxy-b-lac-
tigated a number of energy minima were found within 10 tams substrates 1–5 present several possible binding sites
kJ/mol, which were analyzed taking into account angle y (indicated in red on Fig. 3) to the Zn ions of the bis-por-
that defines the sign of the twist between the effective20 phyrin tweezer host. At first sight, it was expected that the
transition dipole moments of the two porphyrins (5–15 binding would involve the primary alcohol and the second-
directions). Distribution graphs of y values against Boltz- ary amine functionalities of the carrier, as observed with
mann population of the respective structures were plotted the related a-hydroxyketone conjugates.23 However, bind-
Chirality DOI 10.1002/chir

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CHEN ET AL.
Fig. 4. UV-Vis and CD spectra in MCH of tweezer complexes formed via coordination of cis-2f and of trans-3f with Zn-T. ACD designates amplitude
of the CD couplet.
ing to carbonyl moieties in other types of conjugates had Vis and CD spectroscopy (see Fig. 4). A red-shift of the
been found with carboxylic acids derivatives.21,22 In Part maximum of absorbance of the Soret band is observed
1,27 moreover, previously unsuspected binding to carbonyl from 416 nm to 419–421 nm (depending on the solvent
groups, on the basis of MC/OPLS-2005 prediction, has used for the experiments) once around 40 eq. of the conju-
also been established to occur for secondary amine deriva- gate molecule are added to Zn-T solution. Moreover, while
tives.
no CD signal is observed for the Zn-porphyrin tweezer
Because of the simultaneous presence of at least four solution, an extremely intense bisignate signal (negative
different electron donor functionalities as potential binding couplets) is observed when conjugates 1f–5f are added to
sites for the Zn-complexation on the conjugate molecules, Zn-T (Table 1). Figure 4 illustrates the observed CD spec-
the problem of determining the effective ligation sites was tra within the porphyrin Soret band of the host-guest com-
tackled with a strategy based on chemical synthesis. Thus, plexes cis-2f and trans-3f, where a very large difference in
purposely selected conjugates 8 and 9 (see Fig. 3) were exciton couplet amplitudes ACD (peak-to-trough distances)
prepared and the UV-Vis and CD profiles of their tweezer between the two compounds is very noticeable.
complexes investigated. The synthetic scheme to prepare
Obviously, the presence of additional stereogenic cen-
compound 8 and 9 is presented in Material and Methods. ters on the substrates has only a secondary effect on the
In compound 8 the secondary amine functionality has complexation: the sign of the interporphyrin twist remains
been replaced by a methylene moiety, while in compound unchanged for both the cis- and trans- substrates having
9 the primary alcohol functionality has been eliminated: the same configuration at 3-C. Therefore the configuration
for both molecules we expected no binding to the tweezer of the stereogenic center in position 3 to which the linker
host. In fact, upon mixing both compounds with Zn-T is appended is the only sign’s determining factor.
host, no UV-Vis shift of the Soret absorption maximum
However, the configuration of 4-C affects profoundly the
was observed, and no circular dichroic signal could be intensity of the CD couplet: cis-isomers 2f and 4f exhibit
detected. These results clearly indicate that both the pri- several fold stronger couplets than the corresponding
mary alcohol and the secondary amine functionalities are trans-isomers 3f and 5f (Table 1 and Fig. 4). An explana-
essential for binding the dimeric porphyrin host.
tion of this phenomenon that reflects the differences in rel-
ative configurations is presented in the computational sec-
tion. Interestingly, the intensities of the CD couplets
observed for all the cis-compounds (absolute ACD > 1000
M21 cm21) are some of the highest ever observed for
CD and Computational Analysis of Conjugates 3f-7f
Formation of the complex between conjugates 3f-7f and
the zinc bis-porphyrin host (Zn-T) was confirmed by UV-
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147
TABLE 1. UV-Vis and CD data measured in MCH for b-lactam conjugates complexed with Zn-T
e / 106 (L mol21
cm21 a
CD couplet predicted
by OPLS-2005
k (nm)b
De (L mol21 cm21 c
)
ACD
d
Conjugates
)
0.48
431
420
2582
458
21040
negative
0.49
431
420
2764
620
21384
negative
0.85
0.40
0.72
431
420
2218
201
2419
21142
2202
negative
negative
negative
431
420
2627
515
431
420
2103
99
aUV-Vis extinction coefficients at 421 nm.
bWavelengths of positive and negative contributions to the bisignate Cotton effects.
cIntensity of bisignate cotton effects.
dAmplitude of the CD exciton couplet.
host-guest complexes of this type. This demonstrates determine the most probable solution structure of
that the bis-porphyrin tweezer method is very well- the complex, including the preferred conjugate confor-
suited to substituted 3-hydroxy-b-lactams, because CD mation.
detection and consequently the configurational assign-
ment of the complexes may occur down to nanomolar to: a) demonstrate the applicability of the bis-porphyrin
concentrations. tweezer method to the assignment of absolute configura-
In this article, molecular modeling calculations aimed
In Part 1,27 we have shown that use of MC/OPLS-2005 tion of 3-hydroxy-b-lactams; b) unveil structural features
molcular modeling allows one to predict the interpor- that provide basis for the observed trend of CD sign/am-
phyrin twist preferentially adopted by the tweezer host- plitude in the family of b-lactams derivatives. As men-
guest complex. This computational approach helps to tioned previously, all of the trans-forms provide relatively
assign the absolute configuration at the stereogenic cen- low-amplitude CD signals, while all of the cis-forms show
ter directly attached to the bidentate carrier and to relatively high-amplitude ones. The sign of the exciton CD
Chirality DOI 10.1002/chir

148
CHEN ET AL.
Fig. 5. Lowest-energy MC/OPLS structure of host/guest complex of cis-1f and trans-3f with Zn-T. Left panel is a front view and right panel is a side
view of the complex. P indicates porphyrin. Dark purple P coordinates with the hydroxyl group, whereas light purple P coordinates with the secondary
amine moiety of the conjugate. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
couplets is preserved between cis-and trans-forms with the energy complexes. Angle y defines the dihedral between the
same configuration at 3-C.
effective transition dipole moments of the two porphyrins.20
Figure 5 shows the representative lowest-energy struc- A positive twist is responsible for a positive couplet in the
ture calculated for the complex between b-lactam cis-conju- Soret region, and vice-versa.15,16,20 As shown in Figure 6, all
gate 1f, which displays H-bonding, and trans-3f with no H- investigated compounds with the (3R) configuration have a
bonding with bis-porphyrin tweezer Zn-T. Figure 6 presents prevalent negative twist angle in agreement with observed
distribution graphs of the twist angle y calculated for the low- CD spectra. Thus, the tweezer method in association with
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CIS- AND TRANS-3-HYDROXY-4-ARYL/ALKYL-ꢀ-LACTAMS
149
Fig. 6. Left panel displays predominant conformation of bound conjugates within Zn-T complex. The total population (%) of H-bonded or non H-bonded
bond conjugates is provided. Amplitude of the CD exciton couplet (ACD) is indicated as measured in MCH. Arrows indicate binding sites to the tweezer. Right
panel displays distribution of dihedral angle y for MC/OPLS converged conformers within 10 KJ/mol. [Color figure can be viewed in the online issue, which
is available at www.interscience.wiley.com.]
MC/OPLS calculations is able to correctly assign the abso- 308) with respect to the trans-ligands (y < 308). Because the
lute configuration of 3-hydroxy-b-lactams.
amplitude of a CD couplet is expected to increase when the
Moreover, in Figure 6 all of the cis-ligands display a distri- dihedral angle between the two coupled transition moments
bution of y values with a larger interporphyrin twist (y > increases from 08 to about 708,24,25 the larger twists associ-
Chirality DOI 10.1002/chir

150
CHEN ET AL.
Fig. 7. DFT B3LYP/6-31G**11 derived energy differences between hydrogen bonded and open conformations of conjugates cis-1f, cis-2f, cis-4f
and trans-3f, trans-5f. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
ated with the cis-ligands parallel the larger magnitude of the 21140 and its Boltzmann-weighted average value of y is
CD signals of their complexes, with respect to their trans- 2398. On the other hand, 5f, the trans-isomer of the ligand,
analogues. For example, cis-compound 4f exhibits ACD
5
exhibits ACD 5 2200 and its average y is 2128. A similar
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CIS- AND TRANS-3-HYDROXY-4-ARYL/ALKYL-ꢀ-LACTAMS
151
trend between cis- and trans-forms is exhibited by cis- and organic compound, the number of functional groups and/
trans-ligands 2f and 3f, respectively.
or stereogenic centers in its structure.
The prevalent bound conformations for all the cis-conju-
gates are folded due to intramolecular hydrogen bonding
between the terminal hydroxyl and the amide carbonyl on
the lactam ring: i.e. cis-compounds 1f, 2f, and 4f (see Fig.
6) which are 100%, 99%, and 59%, respectively, in this con-
formation. For the trans-isomers, on the other hand, the
dominant conformations mostly lack any intramolecular
hydrogen bonding: 5f ligand possesses no clear hydrogen
bonding, while 3f exhibits hydrogen bonding only for con-
formers with high degrees of twist, with 30% total additive
Boltzmann population. It can be concluded that the addi-
tional stereogenic center in b-lactam moiety is responsible
for the difference conformations of the cis- and trans-deriv-
atives and consequently for the hydrogen-bonded versus
non hydrogen-bonded structures on the complexed conju-
gates. Complexes with larger twist angles are generated
for cis-compounds which provide, as a consequence, more
intense CD couplets.
To confirm the trend observed in the molecular model-
ing study of the complexes regarding the possibility of
conjugates 1f to 5f forming a hydrogen bonded conforma-
tion when bound to the tweezer, DFT calculations on the
free conjugates were performed. DFT data provided infor-
mation regarding relative stability between open and
folded conformational forms and more importantly gave
insight into why, when complexed with the tweezer, cis-
isomers are more likely to preserve hydrogen-bonding
than their trans-counterparts.
ACKNOWLEDGMENTS
The authors are grateful to Dr. George Ellestad for his
helpful discussion.
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