Ring current effects of phenyl and naphthyl groups: Internal probes for determining the absolute configuration of chiral azetidin-2-ones by 1H NMR

Article abstract of DOI:10.1016/S0957-4166(98)00048-2

The ring current effects of the phenyl and 1-naphthyl rings are used to determine the absolute configuration of ten chiral azetidinones prepared from the [2+2] cycloaddition of (S)-1-(1-naphthyl)ethyl and (S)-1-phenylethyl isocyanate to vinyl ethers under high pressure. The (S)-1-arylethyl group of the studied azetidinones adopts a preferred conformation that can be distinguished by ¹H NMR spectroscopy. The application of this principle to other azetidinones containing the arylethyl substituent is consistent with the configurations determined by chemical correlation and X-ray diffraction and verifies the reliability of the proposed method.

Full text of DOI:10.1016/S0957-4166(98)00048-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 955–965
Ring current effects of phenyl and naphthyl groups: internal
probes for determining the absolute configuration of chiral
azetidin-2-ones by 1H NMR
Cirilo García-Martínez∗,† Yoichi Taguchi, Akihiro Oishi and Kikuko Hayamizu ∗
National Institute of Materials and Chemical Research, 1-1 Higashi, Tsukuba, Ibaraki 305, Japan
Received 5 January 1998; accepted 30 January 1998
Abstract
The ring current effects of the phenyl and 1-naphthyl rings are used to determine the absolute configuration
of ten chiral azetidinones prepared from the [2+2] cycloaddition of (S)-1-(1-naphthyl)ethyl and (S)-1-phenylethyl
isocyanate to vinyl ethers under high pressure. The (S)-1-arylethyl group of the studied azetidinones adopts a
1
preferred conformation that can be distinguished by H NMR spectroscopy. The application of this principle to
other azetidinones containing the arylethyl substituent is consistent with the configurations determined by chemical
correlation and X-ray diffraction and verifies the reliability of the proposed method. © 1998 Elsevier Science Ltd.
All rights reserved.
1. Introduction
Chiral azetidinones are important intermediates in the synthesis of a variety of biologically active
compounds. They can be used as starting materials for the preparation of β-lactam antibiotics1 and
precursors of the phenylisoserine chain of docetaxel analogs.2 In addition, chiral azetidinones can be
transformed into acyclic α- and β-amino acid derivatives, and other important building blocks for
the synthesis of natural products.3 Besides the development of efficient stereoselective syntheses of
azetidinones, the discovery of simple and reliable methods to determine the absolute configuration in
the liquid state is essential. In most cases, the configuration of chiral azetidinones has been assigned by
X-ray analysis,4 chemical correlation,2,5 or by comparison with the physical and spectroscopic data of
compounds of known configuration.6
∗
†
Corresponding authors. Telefax: 81-298-54-4525; e-mail: hayamizu@nimc.go.jp and gmc@hp9000a1.uam.mx
On leave from Universidad Autónoma Metropolitana, División de CBI, Area de Química, Av. San Pablo 180, Azcapotzalco
02200, México D.F.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00048-2

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In our previous paper7 we reported that the high pressure [2+2] cycloaddition of (S)-1-phenylethyl
isocyanate 1a to 2,3-dihydrofuran 2a, produces (1S,5R)-7-[(1S)-1-phenylethyl]- and (1R,5S)-7-[(1S)-1-
phenylethyl]-2-oxa-7-azabicyclo[3.2.0]heptan-6-one, 3a and 30a, respectively. The bicyclic azetidinone
3a was isolated as an oil and 30a as a solid, which did not form crystals suitable for X-ray diffraction;
however, the corresponding absolute configurations were unambiguously determined in solution by
1H NMR spectroscopy using tris[3-(2,2,2-trifluoro-1-hydroxyethylidene)-d-camphorato]europium(III),
Eu(tfc)3, and Pirkle’s alcohols. In the configurational study of 3a, 30a and their pure enantiomers in
solution,7 we found that the preferred conformation of the O_C–N–CH(Me)Ph segment resembles the
generally accepted conformation of the open chain amides of α-branched primary amines.8 Since this
finding may enable the determination of the absolute configuration of analogous azetidinones through
the proper interpretation of the ring current effect of the aromatic ring, we have undertaken the 1H NMR
study of the chiral derivatives of 7-[(1S)-1-(1-naphthyl)ethyl]-2-oxa-7-azabicyclo[3.2.0]heptan-6-one 3b
and 30b, 8-[(1S)-1-phenylethyl]-2-oxa-8-azabicyclo[4.2.0]octan-7-one 3c and 30c, and 4-alkoxy-1-[(1S)-
1-phenylethyl]azetidin-2-one 3d–f and 30d–f in order to determine whether the preferred conformation
of the O_C–N–CH(Me)Ph segment is not an exclusive feature of 3a, 30a and their pure enantiomers.7
The present paper demonstrates how the absolute configuration of these novel chiral azetidinones can be
determined in solution using the ring current effect of the intermolecular (S)-1-phenylethyl and (S)-1-(1-
naphthyl)ethyl groups as probes in 1H NMR spectroscopy.
2. Results
The synthesis of azetidinones 3b–f and 30b–f is shown in Scheme 1. The relevant physical properties
1
of these cycloadducts and the conditions of the H NMR measurements are given in the Experimental
section.
The aliphatic protons of most of the studied azetidinones gave a first order subspectrum, hence the
corresponding signals were assigned through the analysis of the coupling constants and according to the
dihedral angles of the 3D molecular structures obtained by MM2 single-point energy calculations.9 The
aromatic protons of the naphthyl ring of bicyclic azetidinones 3b and 30b also gave a first order spin
system, but the phenyl group of azetidinones 3c–f and 30c–f gave a complex AA0BB0C pattern which
was analyzed by computer simulation. The eight protons of the tetrahydropyran ring of 3c and 30c gave
complex spin patterns and they were partially assigned. The pertinent data are presented in Tables 1 and
2. The assignments of 3c and 30f were corroborated by recording the 1H NMR spectra in the presence of
known amounts of the chiral shift reagent Eu(tfc)3.
2.1. Interpretation of the spectra
1
In order to facilitate the comparison of the H NMR data, we have adopted the particular numbering
system and descriptors of the relative orientation of protons shown by the structures of 3b, 3c and 3d.

C. García-Martínez et al. / Tetrahedron: Asymmetry 9 (1998) 955–965
957
Scheme 1. Synthesis of azetidinones 3a–f and 30a–f from the [2+2] cycloaddition of (a) (S)-1-phenylethyl and (S)-1-(1-naph-
thyl)ethyl isocyanate, 1a and 1b, respectively, to 2,3-dihydrofuran 2a and to 3,4-dihydro-2H-pyran 2b and (b) (S)-1-phenylethyl
isocyanate 1a to ethyl, isobutyl and n-butyl vinyl ether, 2d, 3e, 3f, respectively, at 800 MPa
The three aliphatic protons of the four-membered ring of the monocyclic azetidinones 3d–f and 30d–f,
give an ABX spin system, where X corresponds to the H4 nucleus. In all the spectra of these azetidinones,
the H4 resonance has a JAX=1.3 Hz and JBX=3.8 Hz. From our previous studies7 it is known that a 3J≈3.0
Hz of the protons attached to C3 and C4 of the azetidin-2-one ring, is characteristic of the cis arrangement
and therefore in the present study, the nucleus A is assigned to H3trans and the nucleus B to H3cis. This

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C. García-Martínez et al. / Tetrahedron: Asymmetry 9 (1998) 955–965
Table 1
Chemical shifts (δ) and coupling constants (J) in the 1H NMR spectra (400 MHz) of bicyclic
azetidinones 3b, 30b, 3c and 30c (0.05 M) in chloroform-d at 25°C
interpretation is consistent with the reported data for 4-D-glucofuranosyl azetidinones.10 In the spectra
of azetidinones 3d–f, the H3trans resonance appears as a clear doublet of doublets, but as a broad doublet
in the spectra of 30d–f.
The resonances of the O-alkyl groups were assigned by inspection of the multiplicity. The resonance
of the O-CH2 methylene appears as a quartet in the spectra of 3d and as a triplet in 3f. In the spectra of the
other monocyclic azetidinones, the methylene resonance of the O-CH2 segment appears as a multiplet
that can be described as the AB part of an ABM, ABM2 or an ABM3 spin system.
The aromatic protons of the 1-phenylethyl group can be described as an AA0BB0C system since the
benzylic coupling is less than 1 Hz. In 3d–f, the Hmeta, Hortho and Hpara resonances are centered at 7.361,
7.349 and 7.297 ppm, respectively; and in 30d–f, the Hortho, Hmeta and Hpara resonances are centered at

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959
Table 2
Chemical shifts (δ) and coupling constants (J) in the 1H NMR spectra (400 MHz) of the monocyclic
azetidinones (0.05 M) in chloroform-d at 25°C
7.368, 7.341 and 7.269 ppm, respectively. The methyl group and the methine proton H5 form an apparent
isolated AX3 spin system.
The six protons of the tetrahydrofuran ring of 3b and 30b were assigned by comparison with their
analogs 3a and 30a.7 In a similar way, the seven protons of the 1-naphthyl group were assigned by
comparison with the spectrum of (S)-1-(1-naphthyl)ethylamine.11
The eight protons of the tetrahydropyran ring of 3c and 30c give a complex spin pattern. In the spectrum
of 3c, the H1 resonance appears as a doublet at 5.019 ppm (JH1H6=4.6 Hz) and H6 as an apparent quintet
0
0
0
at 3.075 ppm (JH6H5a =8.4 Hz, JH6H5e =4.1 Hz). The H3a resonance appears as a doublet of doublet of
0
0
0
0
0
doublets at 3.798 ppm (Jgem=11.2 Hz, JH3a H4a =7.1 Hz, JH3a H4e =5.1 Hz) and the H3e as an apparent
0
0
0
0
doublet of triplets at 3.701 ppm (JH3e H4a ≈JH3e H4e =5.9 Hz). The remaining protons appear as multiplet
signals within the range of 2.071 to 1.578 ppm. As can be deduced from the vicinal coupling constants
contained in Table 2, the pattern of the eight protons of the tetrahydropyran ring of 30c is similar to that
0
0
of 3c. However, the chemical shifts of H1, H3a , H3e and H6, are remarkably different between the two
bicyclic cycloadducts.12

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3. Discussion
3.1. Bicyclic azetidinones
The 3JH1H5=3.2 Hz of 3b and 30b, and the 3JH1H6=4.6 Hz of 3c and 30c are similar to the reported values
for bicyclic azetidinones having the cis arrangement7,12 and therefore, the only possible configurations
for the bridgehead carbon atoms of each pair of bicyclic azetidinones are (S,R) and (R,S). Compared
with 30b, the chemical shifts of H1 and H5 in 3b, are shielded by 513 and 156 ppb, respectively, and the
chemical shifts of H3endo, H3exo and H4endo are deshielded by 555, 277 and 92 ppb, respectively. These
differences arise from the anisotropy of the anthryl ring13 and indicate that this aromatic ring adopts a
preferred conformation in solution at 25°C. Accordingly, the anthryl ring is oriented towards the exo side
of the rigid framework of 3b and towards the endo side in 30b. Similar tendencies are observed between
the chemical shifts of the protons H1, H6, H3a and H3e of the homologous azetidinones 3c and 30c.
The consecutive addition of fixed amounts of Eu(tfc)3 to a solution of 3c in chloroform-d, causes the
largest induced shift on H9, as it is depicted in Fig. 1. Since the most important interaction is expected to
occur between the chiral shift reagent and the carbonyl oxygen,14 the large induced shift of H9 indicates
that the methine proton of the 1-phenylethyl group is oriented on the same side of the carbonyl group.
0
0
1
This model is consistent with the observed deshielding of H9 as seen in the H NMR spectrum of the
pure 3c and may be attributed to the anisotropy of the carbonyl group.15 Furthermore, the induced shifts
on the H1 and H6 resonances of 3c, are in agreement with the two-point interaction complex between the
shift reagent and the substrate.
The bicyclic azetidinones 3b, 3c, 30b and 30c were prepared from commercial (S)-1-(1-naphthyl)ethyl-
or (S)-1-phenylethyl isocyanate of 96% ee. The reaction produces exclusively the azetidinones with the
cis arrangement, and therefore we have assumed that it proceeds through a concerted mechanism with
retention of configuration of the stereogenic carbon of the isocyanate. Hence, the configuration of the
exocyclic carbon of the resulting bicyclic azetidinones must be S. Since the resonances of the bridgehead
protons of 3b and 3c are shielded by the ring current effect, these protons and the aryl ring are on the same
side and H9 is syn to the carbonyl group. It follows that the absolute configuration of the two bridgehead
carbons of 3b and 3c must be (1S,5R) and (1S,6R) respectively, as depicted in Fig. 2. By the same
principle, the absolute configurations of the bridgehead carbon atoms of 30b, and 30c are determined as
(1R,5S) and (1R,6S) respectively.16
3.2. Monocyclic azetidinones
The configuration of monocyclic azetidinones 3d–f and 30d–f can also be determined from the
shielding effects induced by the phenyl ring. For instance, compared with the azetidinone 30f, the H4 and
H3cis resonances of 3f are shielded by 151 and 75 ppb, respectively. Therefore these two protons and the
phenyl ring must be on the same side. The deshielding of the methine proton of the 1-phenylethyl group in
the spectrum of 3f, is consistent with the assumption that this proton is oriented syn to the carbonyl group.
The 3D structures of 30f obtained by single point energy MM2 calculations, show restricted rotation about
the σ bond of the O–CH2 segment due to the steric interactions between this methylene with the phenyl
ring. The observed AB spin system of the O–CH2 segment is consistent with the calculated 3D structure:
the doublets of the A and B spins are centered at 3.326 and 3.293 ppm, respectively, with JAB=−8.8 Hz.
Accordingly, in the spectrum of 3f the methylene resonance of the OCH2 segment appears as a triplet
centered at 3.329 ppm. Furthermore, the resonances of the AA0BB0C system in 30f are spread over a
wider spectral width than in 3f.

C. García-Martínez et al. / Tetrahedron: Asymmetry 9 (1998) 955–965
961
Fig. 1. Plots of the lanthanide-induced shifts in (1S,6R)-8-[(1S)-1-phenylethyl]-2-oxa-8-azabicyclo[4.2.0]octan-7-one 3c (0.05
M in chloroform-d), as a function of the concentration of the chiral shift reagent to the substrate at 25°C. The lanthanide-induced
0
shifts on H3a and Me are overlapped
Fig. 2. The structures depict the absolute configuration of the bridgehead carbons of azetidinones 3a,7 3b and 3c determined
from the shielding effects, in ppb, of the aryl ring attached to the chiral exocyclic carbon having the S configuration

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Fig. 3. Plots of the lanthanide-induced shifts in (4R)-1-[(1S)-1-phenylethyl]-4-butoxyazetidin-2-one 30f (0.05 M in chloro-
form-d), as a function of the ratio of the concentration of the chiral shift reagent to the substrate at 25°C. The signals that
underwent smaller induced shifts are omitted
The orientation of the 1-phenylethyl group in these monocyclic azetidinones, was inferred from the
spectra of 30f in the presence of fixed amounts of Eu(tfc)3. The corresponding induced shifts plotted in
Fig. 3, suggest that even the coordination to the ether oxygen is significant,17 although the coordination
to the carbonyl oxygen is dominant. The largest induced shift on the methine proton of the 1-phenylethyl
group is similar to the results found for the bicyclic azetidinones 3a–c and 30a–c and therefore the
monocyclic and the bicyclic azetidinones have identical orientations in solution. It should be noted
that the preferred orientation of the methine proton of the 1-phenylethyl group resembles the generally
accepted conformation for open chain amides of α-branched primary amines.8 On this basis, the absolute
configuration of the stereogenic center C4 of 3f and 30f can be assigned as (4S) and (4R), respectively. The
azetidinones 3d and 3e have the configuration assigned to 3f, likewise 30d and 30e have the configuration
assigned to 30f.
Chiral azetidinones having the N-(1-arylethyl) group have been prepared from the Staudinger reaction
by several groups. In most cases, the corresponding absolute configuration has been determined by X-ray
diffraction,4 chemical correlation2,5 or by comparison of the physical properties and the spectroscopic
data with the information on compounds of known configuration.6 We have taken from the literature

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963
Fig. 4. The shielding effects in ppb of H3 and H4, and the deshielding of the methine proton attached to the chiral exocyclic
carbon of 3d, are consistent with the 1H NMR data reported for the depicted azetidinones 4 and 5. The configurations of 4 and
5 have been determined by chemical correlation5a and X-ray diffraction,17 respectively
1
the H NMR data of the azetidinone 4 (Fig. 4) and its diastereomer obtained from the Staudinger
reaction.5a Applying our method we obtained the reported configurations. Also, from the 1H NMR data
of a diastereomeric pair of 1-(2,6-dichlorophenylethyl)-3-phenoxy-4-phenyl azetidin-2-one (5), we also
obtained the configurations previously determined by X-ray diffraction,4b therefore the method described
herein is very reliable.
In conclusion, we have demonstrated that the absolute configuration of the stereogenic centers
of monocyclic and bicyclic azetidinones derived from (S)-1-(1-naphthyl)ethyl and (S)-1-phenylethyl
1
isocyanates can be unambiguously determined by H NMR in solution using the ring current effects
1
arising from the aryl ring. The analysis of the reported H NMR data for related heterocycles prepared
from the Staudinger reaction, show that our method is applicable to all azetidinones having the (R)- or
(S)-1-arylethyl group attached to the nitrogen atom.
4. Experimental
4.1. General
GC analyses were performed on a Shimadzu GC-14A using a Frontier Lab Ultra Alloy-1 column,
30 meters; injector and detector temperature: 270°C. IR spectra were recorded on a JASCO A-302
spectrophotometer. Specific rotations were measured with a JASCO DIP-100 polarimeter. Mass spectra
were recorded on a Hitachi M-80B spectrometer. Melting points were determined with a Mettler FP 90
apparatus.
1H NMR spectra were recorded on a JEOL GX-400 (399.65 MHz) spectrometer equipped with a 5
mm 1H probe. A weighed amount of the appropriate substrate was dissolved in CDCl3 to give a 0.05 M
1
solution at 25°C. The chemical shifts were referenced to internal TMS. Typical H NMR spectra were
obtained using a pulse width of 2.4 µs (30°), a pulse delay of 10 s, 32 transients and a spectral width of
4000 Hz digitized into 64 K data points, resulting in a digital resolution of 0.12 Hz per point.
The measurements with the chiral shift reagent were carried out after the initial spectrum of the
substrate. 40 µL of a 0.02 M solution of Eu(tfc)3 in CDCl3 was added to the substrate contained in
the NMR tube and the spectrum was recorded. This operation was performed four times to increase the
molar ratio of [Eu(tfc)3]/[substrate]. The molecular structures were calculated by single point energy
MM2.9 The subspectra of the aromatic protons were simulated as an AA0BB0C spin system using the
LAOCN program.

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4.2. Materials
4.2.1. (1S,5R)-7-[(1S)-1-(1-Naphthyl)ethyl]-2-oxa-7-azabicyclo[3.2.0]heptan-6-one 3b and (1R,5S)-7-
[(1S)-1-(1-naphthyl)ethyl]-2-oxa-7-azabicyclo[3.2.0]heptan-6-one 30b
A homogeneous mixture of (S)-1-(1-naphthyl)ethyl isocyanate (395 mg, 2 mmol) and 2,3-
dihydrofuran (701 mg, 10 mmol) was sealed in a Teflon® tube and placed in a high-pressure apparatus.
The apparatus was compressed to 800 MPa and heated to 100°C for 20 h. After releasing the pressure
and cooling to room temperature, the excess of 2,3-dihydrofuran was removed under reduced pressure.
The yield determined by GC was 94%. The residual crude product was chromatographed on silica
gel using a mixture of hexane:ethyl acetate (2:1 v/v), to give 262 mg (49%) of a colorless oil, which
solidifies on standing (mp 68–70°C). MS (EI) m/z 267.1245 M+ (calcd for C17H17NO2, 267.1258); IR
(neat) 1750 cm−1; [α]D26=−6.6 (c=0.58, chloroform). Further elution gave 240 mg (45%) of colorless
oil. MS (EI) m/z 267.1233 M+ (calcd for C17H17NO2, 267.1258); IR (neat) 1750 cm−1; [α]D24=+6.9
(c=0.47, chloroform). From these data and the results in the present study, the structures of the solid and
the oil were unambiguously assigned to 3b and 30b, respectively.
From this general method were prepared the following cycloadducts.
4.2.2. (1S,6R)-8-[(S)-1-Phenylethyl]-2-oxa-8-azabicyclo[4.2.0]octan-7-one 3c
Colorless oil which solidifies on standing (mp 41–43°C, 24% yield). MS (EI) m/z 231.1268 M+ (calcd
for C14H17NO2, 231.1258); IR (neat) 1753 cm−1; [α]D26=−104 (c=0.85, chloroform).
4.2.3. (1R,6S)-8-[(S)-1-Phenylethyl]-2-oxa-8-azabicyclo[4.2.0]octan-7-one 30c
Colorless oil (22% yield). MS (EI) m/z 232.1358 M++1 (calcd for C14H18NO2, 232.1336); IR (neat)
1753 cm−1; [α]D26=+15.6 (c=0.64, chloroform).
4.2.4. (4S)-1-[(S)-1-Phenylethyl]-4-ethoxyazetidin-2-one 3d
Colorless oil (42% yield). MS (EI) m/z 219.1267 M+ (calcd for C13H17NO2, 219.1258); IR (neat) 1759
cm−1; [α]D27=−26.5 (c=0.91, chloroform).
4.2.5. (4R)-1-[(S)-1-Phenylethyl]-4-ethoxyazetidin-2-one 30d
Colorless oil (44% yield). MS (EI) m/z 219.1265 M+ (calcd for C13H17NO2, 219.1258); IR (neat) 1759
cm−1; [α]D23=−17.3 (c=0.91, chloroform).
4.2.6. (4S)-1-[(S)-1-Phenylethyl]-4-isobutyloxyazetidin-2-one 3e
Colorless oil (32% yield). MS (EI) m/z 247.1585 M+ (calcd for C15H21NO2, 247.1571); IR (neat) 1761
cm−1; [α]D27=−30.1 (c=1.05, chloroform).
4.2.7. (4R)-1-[(S)-1-Phenylethyl]-4-isobutyloxyazetidin-2-one 30e
Colorless oil (36% yield). MS (EI) m/z 247.1550 M+ (calcd for C15H21NO2, 247.1571); IR (neat) 1761
cm−1; [α]D25=−8.3 (c=0.93, chloroform).
4.2.8. (4S)-1-[(S)-1-Phenylethyl]-4-butyloxyazetidin-2-one 3f
Colorless oil (20% yield). MS (EI) m/z 247.1570 M+ (calcd for C15H21NO2, 247.1571); IR (neat) 1761
cm−1; [α]D25=−27.4 (c=0.92, chloroform).

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965
4.2.9. (4R)-1-[(S)-1-Phenylethyl]-4-butyloxyazetidin-2-one 30f
Colorless oil (25% yield). MS (EI) m/z 247.1558 M+ (calcd for C15H21NO2, 247.1571); IR (neat) 1761
cm−1; [α]D22=+1.5 (c=1.07, chloroform).
Eu(tfc)3 was obtained from Aldrich Chemicals and was used without further purification.
Acknowledgements
C. G. M. is indebted to the AIST for a fellowship supporting this work and to the CONACYT-Mexico
for a partial research fellowship. Professor Yukihiko Hashimoto of the University of Tokyo is thanked
for supplying copies of the 1H NMR data of azetidinones prepared in his laboratory.
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ring in the liquid state differs from that found in the solid state, see Urbanczyk-Lipkowska, Z.; Suwinska, K.; Luboradzki,
R.; Mostowicz, D.; Kaluza, Z.; Grodner, J.; Chmielewski, M. Carbohydr. Res., 1994, 256, 1–11.
13. Haigh, C. W.; Mallion, R. B. Prog. NMR Spectrosc., 1980, 13, 303–344.
14. Belleney, J.; Bui, C.; Carrière, F. J. Magn. Reson. Chem., 1990, 28, 606–611.
15. Barrow, K. D.; Spotswood, T. M.; Tetrahedron Lett., 1965, 37, 3325–3335.
16. See Ref. 7 for a complete description of the shielding effects in bicyclic azetidinones.
17. The determination of the absolute configuration of azetidinones 3d–f and 30d–f using pure Pirkle’s alcohols is not
recommended. We have observed that the addition of three-fold excess of (R)-1-(9-anthryl)-2,2,2-trifluoroethanol to 30f
causes upfield shifts of similar magnitudes to those caused by the enantiomer S.