Rh2(S-1,2-NTTL)4: A novel Rh2(S-PTTL)4 analog with lower ligand symmetry for asymmetric synthesis of chiral cyclopropylphosphonates

Article abstract of DOI:10.1002/chir.22349

A new series of dirhodium(II) tetracarboxylate was derived from N-1,2-naphthaloyl-(S)-amino acid ligands. In terms of enantioselectivity, Rh₂(S-1,2-NTTL)₄ (3a) derived from N-1,2-naphthaloyl-(S)-tert-leucine, was the best-performing

Full text of DOI:10.1002/chir.22349

CHIRALITY (2014)
Rh2(S-1,2-NTTL)4: A Novel Rh2(S-PTTL)4 Analog With Lower Ligand
Symmetry for Asymmetric Synthesis of Chiral
Cyclopropylphosphonates
*
FRADY G. ADLY, JOHNCARLO MADDALENA, AND ASHRAF GHANEM
Chirality Program, University of Canberra, ACT, Australia
ABSTRACT
A new series of dirhodium(II) tetracarboxylate was derived from N-1,2-
naphthaloyl-(S)-amino acid ligands. In terms of enantioselectivity, Rh2(S-1,2-NTTL)4 (3a)
derived from N-1,2-naphthaloyl-(S)-tert-leucine, was the best-performing catalyst among the
new series in the enantioselective synthesis of cyclopropylphosphonate derivatives (up to
>99% enantiomeric excess). A predictive model was proposed to justify the observed high enan-
tiomeric induction exhibited by Rh2(S-1,2-NTTL)4 with donor-acceptor phosphonate carbenoids.
Chirality 00:000–000, 2014. © 2014 Wiley Periodicals, Inc.
KEY WORDS: dirhodium; cyclopropanation; cyclopropylphosphonate; Rh2(S-PTAD)4; Rh2
(S-NTTL)4; Rh2(S-PTTL)4; metal carbenoids; paddlewheel complexes
INTRODUCTION
and development of new methods utilizing stereoselective
cyclopropanation reactions is highly desirable. Accordingly,
a great deal of effort has been devoted to render the
stereoselective synthesis of substituted cyclopropanes more
appealing to organic chemists.27,28
Remarkable progress in dirhodium(II) complex catalyzed
asymmetric transformations has been achieved in a number
of processes including cyclopropanation and C-H insertion30
and was recently supported by the generation and exploration
of physical and chemical properties of a metastable Rh2-
The chiral cyclopropyl moiety has played an important role
in organic chemistry for decades.1–6 Of particular interest,
cyclopropylphosphonate derivatives have been extensively
studied during the last decade as they display several interesting
biological activities.7 For instance, they have been used as moie-
ties of nucleotides,8 as herbicides or plant growth regulators,9
and as insecticides.10 They were also used as analogs of the an-
tidepressant Milnacipran,11 as mimics of 1-aminocyclopropane
carboxylic acid (ACC) with a high inhibitory activity for ACC-
deaminase and alanine racemase,12,13 as analogs of the
unusual amino acids (–)-allonorcoronamic acid14 and (Z)-2,3-
methanohomoserine15 and as an analog of the GABAB receptor
antagonist phaclophen.16 Furthermore, cyclopropylphoshonates
can act as N-methyl-D-aspartate (NMDA) receptor antagonists.17
They also possess antiproliferation properties,18 and are
virostatics,19 antidiabetics,20 antitumor agents,21 selective anti-
HBV agents,22 cytostatic agents,23 and display antiviral activity.24
Typically, enantiomerically enriched compounds are pro-
duced either by chemical transformation of an enantiomerically
enriched precursor—derived from natural chiral pools or by
the separation of racemic mixtures. However, these approaches
have drawbacks: while the former requires stoichiometric
quantities of a suitable precursor, the latter yields only up to
50% of the desired enantiomer. On the other hand, asymmetric
catalysis, which consists of metal complexes with chiral
ligands, have demonstrated vital possible merits over these
conventional procedures whereby a single molecule of the
chiral catalyst can return many equivalents of molecules of
the chiral product for ending catalyst molecule.25,26
carbenoid intermediate supported by
a donor-acceptor
carbene fragment.31 Efforts in this area have led to the devel-
opment of a family of dirhodium(II) carboxylate complexes
that are derived from N-protected amino acids (Fig. 1). The
development in this family of dirhodium paddlewheel
catalysts mainly focused on modifications of the electronic
and/or the steric properties of the ligands, as different
bridging ligands coordinated to the dirhodium axes can
offer distinct degrees of charges to the metal.25 Conse-
quently, it is possible to control the electronic profile of the
whole catalyst by changing these ligands. For instance, the
Hashimoto and Ikegami group developed a series of N-
phthaloyl protected amino acids as ligands for dirhodium
complexes (Fig. 1),25,32,33 with the tert-leucine derived
catalyst Rh2(S-PTTL)4 giving the highest asymmetric induc-
tion.34–40 This has been further developed by the same group
and others to include many other analogs.25,41–44 Müller et al.
used the same scaffold and emerged with Rh2(S-NTTL)4 as a
catalyst derived from N-1,8-naphthaloyl-(S)-tert-leucine.29,45,46
Rh2(S-PTTL)4 and Rh2(S-NTTL)4 proved to be superior cata-
lysts for the preparation of chiral cyclopropanes; however,
none can be considered as a universal catalyst affording high
enantiomeric induction with different classes of substrates
and under different reaction conditions. This limitation has
During the last decade, new methods for the
stereoselective synthesis of highly functionalized cyclopro-
panes have been extensively developed.27,28 Among these
methods, transition-metal-catalyzed cyclopropanation of
olefins with diazoesters occupies a prominent position in the
field of asymmetric catalysis (Scheme 1). Once this principle
was demonstrated, highly selective catalysts were developed,
mainly based on CuI and RhII associated with appropriate
chiral nonracemic ligands.29 However, to enhance the syn-
thetic potential of cyclopropanes further, the understanding
© 2014 Wiley Periodicals, Inc.
*Correspondence to: A. Ghanem, Building 3, Room D41, University of
Canberra, ACT, 2601, Australia. E-mail: ashraf.ghanem@canberra.edu.au
Received for publication 4 January 2014; Accepted 1 May 2014
DOI: 10.1002/chir.22349
Published online in Wiley Online Library
(wileyonlinelibrary.com).

ADLY ET AL.
Scheme 1. Metal catalyzed decompositions of donor-acceptor diazo
compounds.
Fig. 2. Ligands backbone structure comparison.
Hashimoto catalytic series along with the horizontal naphtha-
lene rings of Müller catalytic series (Fig. 2).
MATERIALS AND METHODS
Chemicals
All starting materials and reagents were purchased from Sigma-Aldrich
(St. Louis,, MO) and Acros Organics (Morris Plains, NJ) and used with-
out any further purification. 1,2-Napthalic anhydride was purchased from
Tokyo Chemical Industry (TCI). All solvents were of high-performance
liquid chromatography (HPLC) grade and dried and distilled immediately
prior to use: dichloromethane over calcium hydride, 2,2-DMB, n-pentane
and toluene over activated 4Å-MS, and chlorobenzene from potassium
hydroxide. All moisture-sensitive reactions were performed using oven-
dried glassware and flame dried under vacuum prior to use. Thin-layer
chromatography (TLC) was performed using Sigma-Aldrich precoated
silica gel 60 F254 aluminum support (20 x 20 cm, layer thickness 0.2 mm)
and spots were visualized using UV light (254 nm). Preparative TLC separa-
tions were performed using Sigma-Aldrich precoated silica gel 60 F254
glass support (20 x 20 cm, layer thickness 0.25 mm). Column chromatogra-
phy was carried out on silica gel 60 (130-270 mesh ASTM, Sigma-Aldrich)
52
53
using the specified eluents. Rh2(S-PTTL)4 and Rh2(S-NTTL)4 were
prepared according the previously published procedures.
Instruments
Melting points were measured on a Stuart-SMP10 melting point appara-
tus and are uncorrected. IR was measured on a Perkin-Elmer (Boston,
MA) TravelIR FT-IR spectrometer. Nuclear magnetic resonance (NMR)
spectra were recorded on Varian (Palo Alto, CA) 400-MR spectrometer
at room temperature in the solvents given. Chemical shifts were
expressed in parts per million (ppm) and reported either relative to an
internal tetramethylsilane standard (TMS δ = 0.0 or relative to solvent
peaks (CDCl3 δ = 7.2, HOD δ = 4.8, DMSO-d6 δ = 2.5) for 1H and (CDCl3
δ = 77.0, DMSO-d6 δ; = 39.5) for 13C. Multiplicities are denoted as follows:
s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, ddd =
double double doublet, m = multiplet, br = broad, apt = apparently.
Coupling constants (J) are reported in Hz. Mass spectra were obtained
on Finnigen mat LCQ MS/MS ESI spectrometer and AB MDS Sciex
4800 MALDI-TOF-TOF Mass Analyzer.
Fig. 1. Chiral dirhodium tetracarboxylates derived from N-protected
amino acids.25
led to the development of other promising catalysts belonging
to the same family, Rh2(S-PTAD)4 and Rh2(S-TCPTAD)4,
derived from N-protected adamantylglycine47–49 to access
enantiomerically pure/enriched cyclopropane derivatives.
But, unfortunately, the relatively long synthetic routes of
these catalysts may ruin their overall appeal.50 Therefore,
the development of both synthetically accessible and highly
stereoselective chiral dirhodium catalysis is still highly
desirable.
As a part of our group’s ongoing research and guided by
our previous findings on the nature of the chiral crown cavity
complexes,29,51 we are continuing to pursue variations to the
heterocyclic tether protecting the amine functionality. All
previous reports used to use symmetrical N-protecting
groups in the preparation of the chiral ligands. Herein, the
effect of lowering the symmetry of the N-protecting group
on the enantiomeric induction of the catalyst is the foundation
of this article. A new catalytic series was built derived from
chiral N-protected 1,2-naphthaloyl amino acid ligands at
which the ligands can retain the N-phthaloyl rings of the
Chirality DOI 10.1002/chir
HPLC Analysis
The HPLC analysis was carried out at 25oC using a Prominence
Shimadzu System that consists of LC-20AD solvent delivery unit, SPD-
M20A photodiode-array detector, SIL-20AHT autosampler, and CTO-20A
column oven. For data processing, LabSolutions data managing software,
v. 5.54 SP2 was utilized. Chiralpak AD (0.46mm x 250mm), Chiralcel OJ
(0.46mm x 250mm) and Chiralpak IB (0.46mm x 250mm) were obtained
from Daicel Chemical Company (Tokyo, Japan). HPLC-grade n-hexane,
ethyl acetate and 2-propanol were obtained from Scharlau Chemie
(Barcelona, Spain). Chiral HPLC separation conditions were determined
by obtaining a separation of a racemic sample and by applying previously
reported parameters if any. Refer to supporting information for more details.
Synthesis of Dirhodium Complexes
General procedure for carboxylate ligands preparation. To
a
mixture of 1,2-naphthalic anhydride (1.1 equiv.) and the L-amino acid
(1 equiv.) in anhydrous toluene, triethylamine (0.1 equiv.) was added

ASYMMETRIC SYNTHESIS OF CHIRAL CYCLOPROPYLPHOSPHONATES
and the mixture was heated to reflux for 12 h under nitrogen atmosphere.
J = 8.4 Hz, Ar-H), 8.38 (d, 1H, J = 8.2 Hz, Ar-H), 8.14 (d, 1H, J = 8.2 Hz,
Ar-H), 7.88-7.69 (m, 3H, Ar-H), 6.94 (apt d, 2H, J = 8.5 Hz, Ar-H), 6.51
(apt d, 2H, J = 8.5 Hz, Ar-H), 5.01 (dd, 1H, J = 11.6, 4.8 Hz, NCH), 3.40-
3.25 (m, 3H, CH2, OH); 13C NMR (100 MHz, DMSO-d6): δ 170.3 (COOH),
168.4, 167.5 (2 x CON), 155.8, 136.4, 135.9, 130.3, 130.1, 129.6, 129.2,
129.1, 127.3, 127.0, 125.9, 123.7, 118.4, 115.1 (16 x Ar-C), 53.3 (NCH),
33.2 (CH2); IR (film) ν 3437, 3243, 2943, 1734, 1686, 1387, 1225, 772,
675 cm-1; MS (ESI) m/z: 359.9 (C21H14NO–5; calc. 360.1), 210.2
(C21H14NO–5 - CO2 - C7H6O; calc. 210.1). Re-crystallized from hot MeOH.
The mixture was diluted with ethyl acetate, washed with 0.1M hydrochlo-
ric acid solution, dried over anhydrous Na2SO4, filtered, and concentrated
in vacuo. The residue was then purified on silica gel column chromatog-
raphy using ethyl acetate: n-hexane as an eluent. The amounts of 1,2-
naphthalic anhydride and L-amino acids are presented in that order.
N-(1,2-Naphthaloyl)-(S)-tert-Leucine (S-1,2-NTTL, 1a). 1,2-Naphthalic
anhydride (0.650 g, 3.28 mmol), L-tert-Leucine (0.391 g, 2.98 mmol); Yellow
oil (0.825 g, 89%); Rf =0.38 (1:3 ethyl acetate: n-hexane); 1H NMR (400
MHz, CDCl3): δ 9.47 (br s, 1H, COOH), 8.79 (d, 1H, J=8.1 Hz, Ar-H), 8.03
(d, 1H, J=8.3 Hz, Ar-H), 7.81 (d, 1H, J=8.1 Hz, Ar-H), 7.74 (d, 1H, J=8.2
Hz, Ar-H), 7.58-7.52 (m, 2H, Ar-H), 4.68 (s, 1H, NCH), 1.12 (s, 9H, C(CH3)
3); 13C NMR (100 MHz, CDCl3): δ 172.8 (COOH), 168.0, 167.5 (2 x CON),
135.6, 134.2, 129.8, 128.5, 127.8, 127.6, 126.9, 125.9, 123.9, 117.5 (10 x Ar-C),
58.7 (NCH), 34.6 (C(CH3)3), 26.9 (C(CH3)3); IR (film) ν 3231, 2922, 1751,
1698, 1374, 1104, 1014, 796, 766, 725, 662 cm-1; MS (ESI) m/z: 309.9
(C18H16NO–4; calc. 310.1), 266.0 (C18H16NO–4 - CO2; calc. 266.1), 209.2
(C18H16NO–4 - CO2 - C4H9; calc. 209.1).
General Procedure for Ligand Exchange
A mixture of the carboxylate ligand (6 equiv.) and dirhodium acetate
(1 equiv.) in dry chlorobenzene was refluxed for 24 h under nitrogen
atmosphere using a soxhelt extractor fitted with a thimble containing a
dry mixture of Na2CO3 and sand (1:1) for the removal of acetic acid. After
this, the solvent was evaporated in vacuo and the residue was dissolved in
CH2Cl2, washed with saturated NaHCO3, dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The green residue was then purified
on silica gel column chromatography using ethyl acetate: n-hexane as an
eluent. Products were dried overnight under vacuum at 50oC. The
amounts of carboxylate ligand and dirhodium acetate are presented in
that order.
N-(1,2-Naphthaloyl)-(S)-Phenylalanine (S-1,2-NTPA, 1b). 1,2-
Naphthalic anhydride (0.5 g, 2.52 mmol), L-Phenylalanine (0.35 g, 2.10
mmol); Pale yellow solid (0.65 g, 89%); mp 182oC; Rf = 0.20 (1:2 ethyl
1
acetate: n-hexane); H NMR (400 MHz, CDCl3): δ 8.85 (d, 1H, J= 8.3 Hz,
Ar-H), 8.12 (d, 1H, J = 8.2 Hz, Ar-H), 7.92 (d, 1H, J = 8.1 Hz, Ar-H), 7.78 (d,
1H, J = 8.3 Hz, Ar-H), 7.66 (dt, 2H, J= 14.9, 6.9 Hz, Ar-H), 7.38-7.00 (m, 5H,
Ar-H), 5.27 (dd, 1H, J = 9.3, 6.9 Hz, NCH), 3.74-3.52 (m, 2H, CH2); 13C
NMR (100 MHz, CDCl3): δ 174.3 (COOH), 168.6, 167.9 (2 x CON), 136.6,
136.5, 135.1, 130.8, 129.5, 128.8, 128.7, 128.6, 127.9, 126.9, 124.9, 118.5 (16
x Ar-C), 52.9 (NCH), 34.5 (CH2); IR (film) ν 3327, 2943, 1701, 1375, 1287,
769, 700 cm-1; MS (ESI) m/z: 343.9 (C21H14NO–4; calc. 344.0), 299.9
(C21H14NO–4 - CO2; calc. 300.1), 209.1 (C21H14NO–4 - CO2 - C7H7; calc.
209.0). Re-crystallized from hot MeOH.
Dirhodium(II,II) tetrakis[N-(1,2-naphthaloyl)-(S)-tert-Leucinate]
(Rh2(S-1,2-NTTL)4, 3a). Ligand (0.69 g, 2.23 mmol), Rh2(OAc)4
(0.17 g, 0.38 mmol); green solid (0.36 g, 65%); Rf = 0.54 (1:2 ethyl acetate:
n-hexane); 1H NMR (400 MHz, CDCl3): δ 8.84 (br s, 4H, Ar-H), 7.92 (br s,
4H, Ar-H), 7.74 (br s, 8H, Ar-H), 7.52 (br s, 8H, Ar-H), 4.92 (s, 4H, 4 x
NCH), 1.1 (s, 36H, 4 x C(CH3)3); 13C NMR (100 MHz, CDCl3): δ 186.2
(COO), 167.3 (CON), 135.3, 133.5, 130.1, 128.2, 127.3, 126.9, 126.1,
124.3, 117.6 (Ar-C), 60.3 (NCH), 34.8 (C(CH3)3), 27.0 (C(CH3)3); IR (film)
ν 2958, 1707, 1610, 1396, 1366, 1341, 1105, 783, 765 cm-1; HRMS (MALDI-
TOF) m/z: 1661.2025 (C72H61N4O16Rh2 + K+ + 2EtOAc, calc. 1661.4481),
1645.2306 (C72H61N4O16Rh2 + Na+ + 2EtOAc, calc. 1645.3395), 1485.1979
(C72H61N4O16Rh2 + K+, calc. 1485.3433), 1469.2275 (C72H61N4O16Rh2 +
Na+, calc. 1469.2347).
N-(1,2-Naphthaloyl)-(S)-Leucine (S-1,2-NTLU, 1c). 1,2-Naphthalic
anhydride (0.5 g, 2.52 mmol), L-Leucine (0.3 g, 2.29 mmol); Pale yellow
solid (0.64 g, 90%); mp 138-139oC; Rf = 0.22 (1:3 ethyl acetate: n-hexane);
1H NMR (400 MHz, CDCl3): δ 10.94 (br s, 1H, COOH), 8.78 (d, 1H,
J = 8.3 Hz, Ar-H), 8.03 (d, 1H, J = 8.2 Hz, Ar-H), 7.81 (d, 1H, J = 8.1 Hz,
Ar-H), 7.73 (d, 1H, J = 8.2 Hz, Ar-H), 7.56 (dt, 2H, J = 24.8, 7.0 Hz, Ar-H),
4.94 (dd, 1H, J = 11.5, 4.3 Hz, NCH), 2.32 (ddd, 1H, J = 14.8, 11.0, 4.1 Hz,
CH2), 1.89 (ddd, 1H, J = 14.4, 10.2, 4.4 Hz, CH2), 1.52-1.41 (m, 1H, CH
(CH3)2), 0.86 (dd, 6H, J = 13.3, 6.6 Hz, CH(CH3)2); 13C NMR (100 MHz,
CDCl3): δ 175.2 (COOH), 167.8, 167.3 (2 x CON), 135.6, 134.1, 129.9,
128.5, 127.8, 127.6, 126.9, 126.0, 123.9, 117.5 (10 x Ar-C), 49.3 (NCH),
36.1 (CH2), 24.0 (CH(CH3)2), 22.0, 19.9 (2 x CH(CH3)2); IR (film) ν
2968, 1705, 1373, 1276, 764, 655 cm-1; MS (ESI) m/z: 309.9 (C18H16NO4–;
Dirhodium(II,II) tetrakis[N-(1,2-naphthaloyl)-(S)-Phenylalaninate]
(Rh2(S-1,2-NTPA)4, 3b). Ligand (0.5 g, 1.45 mmol), Rh2(OAc)4
(0.11 g, 0.24 mmol); green solid (0.25 g, 63%); Rf = 0.28 (1:1 ethyl ace-
tate: n-hexane); 1H NMR (400 MHz, CDCl3): δ 7.98 (d, 4H, J = 8.1 Hz,
Ar-H), 7.82 (d, 4H, J = 7.4 Hz, Ar-H), 7.71 (d, 4H, J = 8.3 Hz, Ar-H),
7.57 (m, 8H, Ar-H), 7.35-6.99 (m, 24H, Ar-H), 5.37 (dd, 4H, J = 11.4,
4.7 Hz, 4 x NCH), 3.73-3.50 (m, 8H, 4 x CH2); 13C NMR (100 MHz,
CDCl3):
δ 188.5 (COO), 168.4, 167.9 (CON), 137.9, 136.5, 135.0,
131.1, 129.4, 128.6, 128.5, 128.0, 127.2, 126.6, 125.3, 118.8 (Ar-C), 54.6
(NCH), 35.7 (CH2); IR (film) ν 2944, 1734, 1716, 1373, 1229, 770, 697
cm-1; HRMS (ESI-TOF) m/z: 1721.2692 (C84H60N4O16Rh2 + 2Acetone +
Na+, calc. 1721.2536), 1663.2191 (C84H60N4O16Rh2 + Acetone + Na+, calc.
1663.2118), 1646.2117 (C84H60N4O16Rh2 + H2O + 2Na+, calc. 1646.1702),
1606.1798 (C84H60N4O16Rh2 + Na+ + H+, calc. 1606.1777).
calc. 310.1), 266.0 (C18H16NO–4 - CO2; calc. 266.1), 209.2 (C18H16NO–4
CO2 - C4H9; calc. 209.1). Re-crystallized from hot MeOH.
-
N-(1,2-Naphthaloyl)-(S)-Tryptophan (S-1,2-NTTR, 1d). 1,2-Naphthalic
anhydride (0.5 g, 2.52 mmol), L-Tryptophan (0.47 g, 2.29 mmol); Yellow solid
(0.83 g, 85%); mp 238-239oC; Rf =0.51 (1:1 ethyl acetate: n-hexane); 1H NMR
(400 MHz, DMSO-d6): δ 13.3 (br s, 1H, COOH), 10.71 (s, 1H, NH), 8.68 (d,
1H, J=8.3 Hz, Ar-H), 8.34 (d, 1H, J=8.3 Hz, Ar-H), 8.11 (d, 1H, J=8.2 Hz,
Ar-H), 7.81-7.69 (m, 3H, Ar-H), 7.51 (d, 1H, J=7.9 Hz, Ar-H), 7.22 (d, 1H,
J=8.1 Hz, Ar-H), 7.06 (d, 1H, J=2.3 Hz, Ar-H), 6.96 (t, 1H, J=7.5 Hz, Ar-H),
6.87 (t, 1H, J=7.4 Hz, Ar-H), 5.14 (dd, 1H, J= 10.3, 5.6 Hz, NCH), 3.71-3.51
(m, 2H, CH2); 13C NMR (100 MHz, DMSO-d6): δ 170.9 (COOH), 168.9,
168.1 (2 x CON), 136.6, 136.4, 136.2, 130.9, 130.5, 129.6, 129.4, 127.4, 127.4,
126.4, 124.1, 123.8, 121.3, 118.8, 118.3, 111.8, 110.3 (18 x Ar-C), 53.1 (NCH),
24.6 (CH2); IR (film) ν 3458, 3317, 2917, 1700, 1380, 1282, 769, 740 cm-1;
MS (ESI) m/z: 382.9 (C23H15N2O–4; calc. 383.1), 339.2 (C23H15N2O4– - CO2;
calc. 339.1), 210.2 (C23H15N2O4– - CO2 - C9H7N; calc. 210.1). Re-crystallized
from hot MeOH.
Dirhodium(II,II) tetrakis[N-(1,2-naphthaloyl)-(S)-Leucinate] (Rh2
(S-1,2-NTLU)4, 3c). Ligand (0.5 g, 1.60 mmol), Rh2(OAc)4 (0.12 g,
0.27 mmol); green solid (0.166 g, 61 %); Rf = 0.69 (1:2 ethyl acetate: n-
hexane); 1H NMR (400 MHz, CDCl3): δ 8.90 (d, 4H, J = 7.8 Hz, Ar-H),
8.22-7.95 (m, 4H, Ar-H), 7.95-7.73 (m, 8H, Ar-H), 7.73-7.43 (m, 8H, Ar-H),
5.02 (br s, 1H, 4 x NCH), 2.23 (br s, 4H, 2 x CH2), 2.03 (br s, 4H, 2 x
CH2), 1.50 (br s, 4H, 4 x CH(CH3)2), 1.01 (br s, 12H, 2 x CH(CH3)2),
0.93 (br s, 12H, 2 x CH(CH3)2); 13C NMR (100 MHz, CDCl3): δ
188.9 (COO), 168.5, 168.0 (CON), 136.3, 134.5, 131.2, 129.1, 128.5,
128.4, 128.0, 127.9, 127.2, 125.2, 118.7, 118.6 (Ar-C), 51.8 (NCH),
38.2, 38.0 (CH2), 25.1 (CH(CH3)2), 23.4, 21.4, 21.3 (CH(CH3)2); IR
(film) ν 2954, 1734, 1716, 1374, 1229, 770, 675 cm-1; HRMS (MALDI-
TOF) m/z: 1661.2783 (C72H61N4O16Rh2 + K+ + 2EtOAc, calc. 1661.4481),
1645.3109 (C72H61N4O16Rh2 + Na+ + 2EtOAc, calc. 1645.3395), 1485.2178
(C72H61N4O16Rh2 + K+, calc. 1485.3433), 1469.2975 (C72H61N4O16Rh2 +
Na+, calc. 1469.2347).
N-(1,2-Naphthaloyl)-(S)-Tyrosine (S-1,2-NTTY, 1e). 1,2-Naphthalic
anhydride (0.5 g, 2.52 mmol), L-Tyrosine (0.42 g, 2.29 mmol); Yellow
solid (0.74 g, 90%); mp 248-249oC; Rf = 0.25 (1:1 ethyl acetate: n-hexane);
1H NMR (400 MHz, DMSO-d6): δ 9.11 (br s, 1H, COOH), 8.70 (d, 1H,
Chirality DOI 10.1002/chir

ADLY ET AL.
Dirhodium(II,II) tetrakis[N-(1,2-naphthaloyl)-(S)-Tryptophanate]
0.46 cm, 1% 2-propanol in n-hexane (v/v%); 2 mL/min, 220 nm, τ1 = 36
min, τ2 = 42 min).
(Rh2(S-1,2-NTTR)4, 3d). Ligand (0.73 g, 1.90 mmol), Rh2(OAc)4
(0.14 g, 0.32 mmol); green solid (0.30 g, 55 %); Rf = 0.20 (2:1 ethyl acetate:
n-hexane); H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 4H, 4 x NH), 8.50
1
(1S,2R)-Diethyl 1,2-diphenylcyclopropylphosphonate (10)55
. Color-
less oil; Rf = 0.26 (1:1 ethyl acetate: n-hexane); Enantiomer separation by
HPLC (Chiralpak AD column, 25 x 0.46 cm, 0.6% 2-propanol in n-hexane
(v/v%); 0.8 mL/min, 220 nm, τ1 =69 min, τ2 = 76 min). The spectroscopic data
are consistent with previously reported data.55
(m, 4H, Ar-H), 8.31 (br s, 4H, Ar-H), 8.07 (br s, 4H, Ar-H), 7.80-7.41 (m,
12H, Ar-H), 7.25 (d, 4H, J = 7.8 Hz, Ar-H), 7.17-6.69 (m, 16H, Ar-H), 5.27
(br s, 4H, 4 x NCH), 3.57 (br s, 8H, 4 x CH2); IR (film) ν 2970, 1734,
1699, 1374, 1228, 768, 740 cm-1; MS (ESI) m/z: 1760.6 (C92H60N8O16Rh2 +
Na+ - H+, calc. 1760.2), 1376.7 (C92H60N8O16Rh2 + Na+ - C23H16N2O4, calc.
1377.1), 992.7 (C92H60N8O16Rh2 + Na+ - C46H32N4O8, calc. 992.9).
(1S,2R)-Diisopropyl 1,2-diphenylcyclopropylphosphonate (11)55
. Co-
lorless oil; Rf = 0.40 (1:1 ethyl acetate: n-hexane); Enantiomer separation
by HPLC (Chiralpak AD column, 25 x 0.46 cm, 0.6% 2-propanol in n-hexane
(v/v%); 0.8 mL/min, 220 nm, τ1 = 49 min, τ2 = 54 min). The spectroscopic
data are consistent with previously reported data.55
Dirhodium(II,II) tetrakis[N-(1,2-naphthaloyl)-(S)-Tyrosinate] (Rh2
(S-1,2-NTTY)4, 3e). Ligand (0.63g, 1.76 mmol), Rh2(OAc)4 (0.13 g,
0.30 mmol); green solid (0.27 g, 56 %); Rf = 0.23 (2:1 ethyl acetate: n-
hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.43-8.25 (m, 4H, Ar-H),
8.21-8.04 (m, 4H, Ar-H), 7.92-7.25 (m, 16H, Ar-H), 7.04-6.82 (m, 8H,
Ar-H), 6.65-6.34 (m, 8H, Ar-H), 5.18-4.90 (m, 4H, 4 x NCH), 3.50-3.05
(m, 12H, 4 x CH2, 4 x OH); IR (film) ν 3294, 2970, 1734, 1699, 1375,
1217, 770, 742, 685 cm-1.
General Procedure for the Preparation of
Cyclopropylcarboxylates
To a solution of the alkene (5.0 equiv.) and dirhodium catalyst (0.01
equiv.) in dry and degassed solvent under inert atmosphere, the diazo
compound (1.0 equiv.) dissolved in the same dry and degassed solvent,
was added dropwise over 1 h using a syringe pump. After that, the
reaction was stirred for at least 1 h. When the diazo compound was fully
consumed as indicated by TLC, the reaction solvent was removed in
vacuo. The diastereomeric ratio (dr) of the product was determined by
1H NMR of the crude mixture. The product was purified by means of
preparative TLC (ethyl acetate/n-hexane). The enantiomeric excess (ee %)
of the product was determined by chiral HPLC analysis.
General Procedure for the Preparation of
Cyclopropylphosphonate Derivatives
To a stirred solution of alkene (5 equiv.) and Rh(II) catalyst (0.01
equiv.) in 2,2-DMB (5 mL) heated under reflux (59oC) under nitrogen at-
mosphere, a solution of α-diazobenzylphosphonate (1 equiv.) in 2,2-DMB
(10 mL) was added dropwise via syringe pump over 1 h. After the
addition, the reaction was refluxed until the TLC indicates a complete
consumption of the diazo starting material. The diastereomeric ratio
(dr) of the product was determined by 1H NMR of the crude mixture.
The product was purified by means of preparative TLC (ethyl acetate/
n-hexane) and the enantiomeric excess (ee %) of the product was
determined by chiral HPLC analysis.
Methyl 1,2-diphenylcyclopropanecarboxylate (13)56,57
. White solid;
mp 60-62oC; Rf = 0.30 (1:10 ethyl acetate: n-hexane); Enantiomer separation
by HPLC (Chiralcel OJ column, 25 x 0.46 cm, 0.5% 2-propanol in n-hexane;
1 mL/min. 220 nm, τ1 = 14 min, τ2 = 20 min). The spectroscopic data are
consistent with previously reported data.56,57
(1S,2R)-Dimethyl 1,2-diphenylcyclopropylphosphonate (5)54,55
. Co-
Methyl 2β-phenyl-1β-(2-(Z)-styryl)cyclopropane-1α-carboxylate
lorless oil; Rf = 0.15 (1:1 ethyl acetate: n-hexane); Enantiomer separa-
tion by HPLC (Chiralcel OJ column, 25 x 0.46 cm, 2% 2-propanol in
n-hexane (v/v%); 1 mL/min, 220 nm, τ1 = 18 min, τ2 = 21 min). The
spectroscopic data are consistent with previously reported data.54,55
(15)58
.
White solid; mp 58-61oC; Rf = 0.63 (1:3 ethyl acetate: n-hexane);
Enantiomer separation by HPLC (Chiralcel OJ column, 25 x 0.46 cm, 1.5%
2-propanol in n-hexane; 1 mL/min. 254 nm, τ1 = 15 min, τ2 = 21 min). The
spectroscopic data are consistent with previously reported data.58
(1S,2R)-Dimethyl1-pheny-2-(p-chlorophenyl)-cyclopropylphosphonate
(6)55
. Colorless oil; Rf = 0.11 (1:1 ethyl acetate: n-hexane); Enantiomer
General Procedure for One-Pot Intermolecular
Cyclopropanation of Olefins Using Meldrum’s Acid
separation by HPLC (Chiralcel OJ column, 25 x 0.46 cm, 8% 2-propanol
in n-hexane (v/v%); 1 mL/min, 220 nm, τ1 = 10 min, τ2 = 12 min). The
spectroscopic data are consistent with previously reported data.55
To a stirred mixture of Meldrum’s acid (1 equiv.), PhI(OAc)2 (1.4
equiv.), dirhodium catalyst (0.01 equiv.), Al2O3 (2.3 equiv.) and 4Å
molecular sieves in dry dichloromethane under N2 atmosphere, olefin
(10 equiv.) was added. After allowing the reaction mixture to stir at room
temperature for 4 h, the reaction was terminated by filtration through
celite and concentrated under reduced pressure. The residue was puri-
fied by means of preparative TLC chromatography using ethyl acetate:
n-hexane (1:4) as an eluent to get the desired products. The enantiomeric
ratio of the product was determined by HPLC analysis.
(1S,2R)-Dimethyl 1-pheny-2-(p-methoxyphenyl)-cyclopropylphos-
phonate (7)55
. Colorless oil; Rf = 0.11 (1:1 ethyl acetate: n-hexane);
Enantiomer separation by HPLC (Chiralcel OJ column, 25 x 0.46 cm, 3%
2-propanol in n-hexane (v/v%); 1 mL/min, 220 nm, τ1 =37 min, τ2 =42 min).
The spectroscopic data are consistent with previously reported data.55
(1S,2R)-Dimethyl 1-pheny-2-(p-methylphenyl)-cyclopropylphospho-
nate (8). White solid; Rf = 0.17 (1:1 ethyl acetate: n-hexane); 1H NMR
(400 MHz, CDCl3): δ 7.13-7.10 (m, 3H, Ar-H), 7.07-7.04 (m, 2H, Ar-H), 6.85
(d, 2H, J = 7.8 Hz, Ar-H), 6.61 (d, 2H, J = 8.2 Hz, Ar-H), 3.72 (d, 3H, JHP = 10.6
Hz, OCH3), 3.66 (d, 3H, JHP = 10.6 Hz, OCH3), 2.97 (ddd, 1H, JHP = 16.1,
J = 9.1, 6.6 Hz, CH), 2.19 (s, 3H, CH3), 2.03 (ddd, 1H, JHP = 17.5, J= 9.0, 5.1
Hz, CH2), 1.67 (ddd, 1H, JHP = 12.5, J = 6.6, 5.1 Hz, CH2); Enantiomer
separation by HPLC (Chiralcel OJ column, 25 x 0.46 cm, 3% 2-propanol in
n-hexane (v/v%); 1 mL/min, 220 nm, τ1 = 12 min, τ2 = 15 min).
6,6-dimethyl-1-phenyl-5,7-dioxaspiro[2.5]octane-4,8-dione59
. White
solid; mp 132oC; Rf =0.55 (1:3 ethyl acetate: n-hexane); Enantiomer separation
by HPLC (Chiralpak IB column, 25 x 0.46 cm, 10% ethyl acetate in n-hex-
ane; 1 mL/min. 254 nm, τ1 =10 min, τ2 = 12.9 min). The spectroscopic data
are consistent with previously reported data.59
6,6-dimethyl-1-(4-chlorophenyl)-5,7-dioxaspiro[2.5]octane-4,8-
dione59
.
White solid; mp 157oC; Rf = 0.71 (1:3 ethyl acetate: n-hexane);
Enantiomer separation by HPLC (Chiralpak IB column, 25 x 0.46 cm, 10%
ethyl acetate in n-hexane; 0.5 mL/min. 254 nm, τ1 = 26 min, τ2 = 32 min).
The spectroscopic data are consistent with previously reported data.59
(1S,2R)-Dimethyl 1-pheny-2-(1-naphthyl)-cyclopropylphosphonate
(9). Colorless oil; Rf = 0.14 (1:1 ethyl acetate: n-hexane); 1H NMR (400
MHz, CDCl3): δ 7.72-7.53 (m, 2H, Ar-H), 7.50 (d, 1H, J = 7.50 Hz, Ar-H),
7.35 (m, 2H, Ar-H), 7.29 (s, 1H, Ar-H), 7.07 (m, 4H, Ar-H), 6.76 (dd, 1H,
6,6-dimethyl-1-(4-bromophenyl)-5,7-dioxaspiro[2.5]octane-4,8-
dione. White solid; mp 144oC; Rf = 0.40 (1:3 ethyl acetate: n-hexane);
1H NMR (400 MHz, CDCl3): δ 7.34 (dd, 4H, J = 8.5 Hz, Ar-H), 3.39
(apt t, 1H, J = 9.4 Hz, CH), 2.63 (dd, 1H, J = 9.3, 4.8 Hz, CH2), 2.54 (dd, 1H,
J = 9.5, 4.8 Hz, CH2), 1.74 (s, 3H, CH3), 1.71 (s, 3H, CH3); Enantiomer
J = 8.5, 1.8 Hz, Ar-H), 3.75 (d, 3H, JHP = 10.6 Hz, OCH3), 3.70 (d, 3H, JHP
=
10.6 Hz, OCH3), 3.16 (ddd, 1H, JHP = 16.1, J = 9.1, 6.6 Hz, CH), 2.14 (ddd,
1H, JHP = 17.5, J = 9.0, 5.3 Hz, CH2), 1.85 (ddd, 1H, JHP = 12.5, J = 6.6, 5.1
Hz, CH2); Enantiomer separation by HPLC (Chiralpak AD column, 25 x
Chirality DOI 10.1002/chir

ASYMMETRIC SYNTHESIS OF CHIRAL CYCLOPROPYLPHOSPHONATES
separation by HPLC (Chiralpak IB column, 25 x 0.46 cm, 10% ethyl acetate
in n-hexane; 0.5 mL/min. 254 nm, τ1 = 31 min, τ2 = 39 min).
6,6-dimethyl-1-(4-methylphenyl)-5,7-dioxaspiro[2.5]octane-4,8-
dione59
.
White Solid; mp 137oC; Rf = 0.33 (1:3 ethyl acetate: n-hexane);
Enantiomer separation by HPLC (Chiralpak IB column, 25 x 0.46 cm, 10%
ethyl acetate in n-hexane; 0.5 mL/min. 254 nm, τ1 = 26 min, τ2 = 31 min).
The spectroscopic data are consistent with previously reported data.59
6,6-dimethyl-1-naphthyl-5,7-dioxaspiro[2.5]octane-4,8-dione59
. Yellow-
ish solid; mp 120oC; Rf = 0.68 (1:3 ethyl acetate: n-hexane); Enantiomer
separation by HPLC (Chiralpak IB column, 25 x 0.46 cm, 10% ethyl
acetate in n-hexane; 0.5 mL/min. 254 nm, τ1 = 46 min, τ2 = 56 min).
The spectroscopic data are consistent with previously reported data.59
RESULTS AND DISCUSSION
Synthesis of Dirhodium (II) Tetracarboxylate
Catalytic Series
Unlike the previously reported trends used in the develop-
ment of chiral dirhodium(II) catalysts where the modifica-
tions in the dirhodium paddlewheel catalysts mostly focused
on the use of symmetrical N-protecting group (Fig. 1), we
are introducing ligands with a lower symmetry N-protecting
group. As a starting point, we thought about a protecting
group that can retain the N-phthaloyl rings of Hashimoto’s
catalytic series along with the horizontal naphthalene rings
of Müller’s catalytic series (Fig. 2) for intermolecular
cyclopropanation reactions. Thus, chiral carboxylate ligands
derived from N-1,2-naphthaloyl-(S)-amino acids were synthe-
sized. The ligands 1a–e were prepared via the condensation
of 1,2-naphthalic anhydride and (S)-amino acids in toluene/
TEA solvent mixture (Scheme 2). The structures elucidation
of the prepared ligands was confirmed on the basis of their
1D-, 2D-NMR, and MS spectral data. The HMBC spectra for
1a, 1b, 1c, and 1d revealed a long-range chemical shift corre-
lation between the chiral hydrogen and both carbonyl carbons
Scheme 2. Preparation of chiral ligands.
1
of the imide. This long-range H-13C correlation provided evi-
dence for the formation of the cyclic imide structures (1a–e)
and not the open chain amides 2a–b (Scheme 2).
High-temperature ligand exchange was then carried out
using the prepared chiral carboxylic acid ligands and rho-
dium acetate (Rh2(OAc)4).60 Ligand exchange proceeded
successfully, affording the corresponding dirhodium(II,II)
tetrakis[N-(1,2-naphthoyl)-(S)-amino acid] complexes (3a–e)
(Scheme 3). Their structures were confirmed on the basis
1
of their H and 13C NMR spectra.
Screening for Asymmetric Cyclopropanation With
Donor-Acceptor Diazophoshonate Substrates
With the new catalytic series in hand (3a–e), their efficiencies
were evaluated in standard donor-acceptor cyclopropanation
reactions using dimethyl α-diazobenzylphosphonate 4 (as
carbene precursor) and styrene (as olefin substrate) in 2,2-
dimethylbutane (2,2-DMB) as reaction solvent. The previously
reported Rh2(S-PTTL)4 and Rh2(S-NTTL)4 catalysts (Fig. 1)
were included in the screening as well-established cata-
lysts in the enantioselective cyclopropanation reactions
(Table 1). All catalysts revealed high levels of diastereo-
selectivities where the diastereomeric ratios (dr) >20:1
for the resulted cyclopropane products.
Scheme 3. Preparation and structure of new catalysts.
catalyst bearing the bulky tert-butyl group (3a) was the best
catalyst among the series. This was followed by those bearing
the iso-butyl (3c) and benzyl (3b) groups and finally those
carrying the (3-indolyl)methyl (3d) and the 4-hydroxyl-
benzyl (3e) groups. The cyclopropanation reaction catalyzed
by Rh2(S-1,2-NTTL)4 (3a) generated the cyclopropane
product in 92% ee (Fig. 3), which is similar to the same reac-
tion catalyzed by Rh2(S-PTTL)4 and slightly better than the
one catalyzed by Rh2(S-NTTL)4 (90% ee).
The results in Table 1 were in agreement with the previ-
ously reported trend by Hashimoto in regard to the steric
bulk at the α-position and the selectivity of the catalyst.41,61
From the illustrated results, it can be concluded that the
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ADLY ET AL.
TABLE 1. Asymmetric cyclopropanation with dimethyl
α-diazobenzylphosphonate (donor-acceptor substrate)
TABLE 2. Scope of Rh2(S-1,2-NTTL)4 (3a) with respect to the
alkene
Entry
1
R group
Product
Yield (%)
92
ee (%)
Entry
Catalyst
Code
Reaction
Time (h)
Yield
(%)
ee
(%)
6
7
8
9
94
47
1
2
3
4
5
6
7
8
Rh2(S-PTAD)4
Rh2(S-PTTL)4
Rh2(S-NTTL)4
Rh2(S-1,2-NTTL)4
Rh2(S-1,2-NTPA)4
Rh2(S-1,2-NTLU)4
Rh2(S-1,2-NTTR)4
Rh2(S-1,2-NTTY)4
-
-
-
8
10
5
5
5
5
20
20
86
83
91
93
91
94
76
80
99
92
90
92
34
64
22
26
3a
3b
3c
3d
3e
2
3
4
93
90
86
>99
95
Diastereomeric ratios (dr) were determined by 1H NMR of the crude mixture.
Enantiomeric excess (ee %) were determined by chiral HPLC using Chiralcel
OJ column, 2% 2-propanol in n-hexane (v/v%), 1 mL/min., 220 nm, τ1 = 18 min.,
τ2 = 21 min. See Materials and Methods section for more details.
>98
Diastereomeric ratios (dr) were determined by 1H NMR of the crude mixture.
Enantiomeric excess (ee %) were determined by chiral HPLC. See Materials
and Methods section for more details.
The scope of the Rh2(S-1,2-NTTL)4 catalyst was further
investigated with respect to the alkene (Table 2). The
reactions proceeded smoothly, resulting in the formation
of cyclopropylphosphonate products with very high yields
(86–93%), diasteroselectivity (>20:1 dr), and enantioselectivity
(94-> 99% ee).
The effect of diazophosphonate ester size on the
enantioselectivity of the Rh2(S-1,2-NTTL)4 - catalyzed reaction
was next examined (Table 3). The diastereoselectivity is
independent on the size of the phosphonate group and not
greatly influenced by the ester size. However, both yield
and enantioselectivity were decreasing with increasing the
ester group size and the highest levels of enantioselectivity
were observed with dimethyl phenyldiazophosphonate
(Entry 1, Table 3).
Fig. 3. Chiral HPLC trace of (1S,2R)-Dimethyl 1,2-diphenylcyclopro-
pylphosphonate (5) (a) prepared using Rh2(OAc)4 (Racemic sample) (b)
prepared using Rh2(S-1,2-NTTL)4. Chromatographic conditions: Chiralcel OJ
column, 2% 2-propanol in n-hexane (v/v%), 1 mL/min., 220 nm.
Screening for Asymmetric Cyclopropanations With Other
Donor-Acceptor Substrates
Encouraged by the cyclopropanation results illustrated in
Tables 1–3, the scope of the new catalysts was further investi-
gated by looking into more donor-acceptor carbenoid
cyclopropanations. To study the influence of replacing the
phosphonate ester group of the carbenoid with a carboxylate
ester group on the catalyst enantioselectivity, the next series
of experiments were carried out using methyl α-
phenyldiazoacetate 12 (Table 4).
As illustrated in Table 4, all catalysts afforded the cyclopro-
pane product 13 in excellent to good yields (89–65%) with
high diastereoselectivity (>18:1 dr). However, the asymmet-
ric induction deteriorated dramatically with the replacement
The yields of the cyclopropane product 5 were generally
high for all catalysts, ranging from 76% to 93%. The observed
yield of the product resulting from the reaction catalyzed by
Rh2(S-1,2-NTTL)4 was slightly higher than those resulting
from reactions catalyzed by Rh2(S-PTTL)4 and Rh2(S-NTTL)4
(Table 1). This can be rationalized to the ligand’s larger
aromatic moiety, which offers a relatively higher solubility of
Rh2(S-1,2-NTTL)4 in nonpolar solvents. Its better solubility also
offered a quicker conversion into products resulting in a
shorter reaction time when compared to Rh2(S-PTTL)4.
Chirality DOI 10.1002/chir

ASYMMETRIC SYNTHESIS OF CHIRAL CYCLOPROPYLPHOSPHONATES
TABLE 3. Effect of the ester group size on the enantiomeric
induction of Rh2(S-1,2-NTTL)4
TABLE 5. Effect of solvent and temperature on the
stereoselectivity of Rh2(S-1,2-NTTL)4 with methyl
α-diazophenylacetate substrate
Entry
R group
Product
Yield (%)
ee (%)
1
2
3
Me
Et
i-Pr
5
10
11
93
69
43
92
60
Entry
Solvent
Temperature (oC)
Yield (%)
ee (%)
68a
1
2
3
4
5
2,2-DMB
2,2-DMB
Toluene
CH2CL2
Pentane
23
-20
23
23
23
89
82
88
90
87
30
28
-2
26
18
aAfter reflux for 3 days. Diastereomeric ratios (dr) were determined by 1H
NMR of the crude mixture. Enantiomeric excess percents (ee %) were deter-
mined by chiral HPLC. See Materials and Methods section for more details.
Diastereomeric ratios (dr) were determined by 1H NMR of the crude mixture.
Enantiomeric excess (ee %) were determined by chiral HPLC using Chiralcel®
OJ column, 0.5% 2-propanol in n-hexane (v/v%), 1 mL/min., 220 nm, τ1 = 14
min., τ2 = 20 min. See Materials and Methods section for more details.
TABLE 4. Asymmetric cyclopropanation with methyl
α-diazophenylacetate (donor-acceptor substrate)
TABLE 6. Asymmetric cyclopropanation with methyl α-
diazostyrylacetate (donor-acceptor substrate)
Entry
Catalyst
Code
Yield (%)
ee (%)
87a
87
88
89
86
86
63
65
21a
20
8
30
18
14
20
16
57
1
2
3
4
5
6
7
8
Rh2(S-PTAD)4
Rh2(S-PTTL)4
Rh2(S-NTTL)4
-
-
-
Rh2(S-1,2-NTTL)4
Rh2(S-1,2-NTPA)4
Rh2(S-1,2-NTLU)4
Rh2(S-1,2-NTTR)4
Rh2(S-1,2-NTTY)4
3a
3b
3c
3d
3e
Entry
Catalyst
Code
Solvent
Yield (%) ee (%)
1
2
3
4
5
6
7
8
Rh2(S-PTTL)4
Rh2(S-NTTL)4
-
-
CH2Cl2
CH2Cl2
CH2Cl2
Pentane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
83
82
88
87
82
89
65
67
40
16
10
10
18
23
20
20
Rh2(S-1,2-NTTL)4
Rh2(S-1,2-NTTL)4
Rh2(S-1,2-NTPA)4
Rh2(S-1,2-NTLU)4
Rh2(S-1,2-NTTR)4
Rh2(S-1,2-NTTY)4
3a
3a
3b
3c
3d
3e
aIn toluene. Diastereomeric ratios (dr) were determined by 1H NMR of the
crude mixture. Enantiomeric excess (ee %) were determined by chiral HPLC
using Chiralcel® OJ column, 0.5% 2-propanol in n-hexane (v/v%), 1 mL/min.,
220 nm, τ1 = 14 min., τ2 = 20 min. See Materials and Methods section for
more details.
of the phosphonate ester group with a carboxylate ester
group. The enantiomeric induction of the catalysts did not
exceed 30% ee, which was exhibited by Rh2(S-1,2-NTTL)4
(3a) (Entry 4, Table 4). Although the enantiomeric induction
of Rh2(S-1,2-NTTL)4 was not significantly high, it was still
considerably higher than those exhibited by Rh2(S-PTAD)4,
Rh2(S-NTTL)4, and Rh2(S-PTTL)4 for the same reaction
(Entries 1, 2, and 3, Table 4).
As an attempt to enhance the enantioselectivity of Rh2(S-
1,2-NTTL)4 catalyst, the effects of changing the reaction
conditions (e.g., solvent and temperature) were investigated
(Table 5). Using methylene chloride as a reaction solvent
rather than 2,2-DMB resulted in slight decrease in
enantioselectivity of Rh2(S-1,2-NTTL)4 (Entry 4, Table 5).
The enantioselectivity decreased dramatically when toluene
or pentane was used (Entries 3 and 5, Table 5). Furthermore,
the variation of temperature had a little influence on the
Diastereomeric ratios (dr) were determined by 1H NMR of the crude mixture.
Enantiomeric excess percents (ee %) were determined by chiral HPLC using
Chiralcel OJ column, 1.5% 2-propanol in n-hexane (v/v%), 1 mL/min., 254 nm,
τ1 = 15 min., τ2 = 21 min. See Materials and Methods section for more details.
enantioselectivity of Rh2(S-1,2-NTTL)4 over a reaction tem-
perature range from 23oC to –20oC (Entries 1 and 2, Table 5).
The final series of experiments were carried out using
methyl α-styryldiazoacetate 14 with the phenylvinyl function-
ality as an attempt to enhance the enantioinduction of the
catalysts with diazocarboxylates. The reactions were carried
out at room temperature using methylene chloride as
reaction solvent (Table 6). The desired cyclopropane product
15 was obtained in yield range from 65% to 89% with high
levels of diastereoselectivity (>20:1 dr). However, the
enantiomeric induction did not exceed 23% ee when using
Rh2(S-1,2-NTLU)4 (Entry 6, Table 6). Although the
Chirality DOI 10.1002/chir

ADLY ET AL.
enantioselectivity of Rh2(S-PTTL)4 was the highest (40% ee),
of the resulting cyclopropane derivatives, Rh2(S-1,2-NTTL)4 (3a)
was the best among the series (30-20% ee) and it revealed similar
enantiomeric induction to Rh2(S-NTTL)4 (32-17% ee) but both
were lower than Rh2(S-PTTL)4 (37-27% ee).
the enantioselectivity exhibited by Rh2(S-1,2-NTLU)4 (3c),
Rh2(S-1,2-NTTR)4 (3d), Rh2(S-1,2-NTTY)4 (3e), and Rh2(S-
1,2-NTPA)4 (3b) were higher than that observed when using
Rh2(S-NTTL)4. Altering the reaction solvent from methylene
chloride to pentane did not affect the degree of
enantioselectivity (Entries 3 and 4, Table 6).
Predictive Model for Asymmetric Induction
There are some uncertainties about the arrangement of
ligands in solution for this family of catalysts which led to
some uncertainties about their mode of asymmetric induction
during carbenoid transformations. As a consequence, a
number of predictive models have appeared to justify the
stereoselection in dirhodium(II)-catalyzed reactions.
The first predictive model was proposed by Hashimoto and
it was based on the x-ray crystal structure of Rh2(S-PTPA)4. In
this model, it was proposed that dirhodium(II) carboxylates
derived from N-phthalimido amino acid ligands preferentially
exist in C2-symmetric conformation, at which two adjacent N-
phthalimido groups are positioned on the top face of the
complex and the other two are positioned on the bottom
face.36,61,64 Hashimoto’s model was used to successfully
predict the stereochemical outcome of asymmetric C-H
insertion reactions catalyzed by Rh2(S-PTAD)4.65
Screening for Asymmetric Cyclopropanation With
Diacceptor Substrates
In order to probe the enantiomeric induction of the pre-
pared catalytic series with diacceptor carbenoid intermedi-
ates, the enantioselective cyclopropanation of Meldrum’s
acid with a variety of alkenes was examined. To facilitate
the screening, a previously developed user-friendly one-pot
cyclopropanation procedure was used, wherein the
phenylidonium ylides are generated and decomposed in
situ.53,60,62,63. All the reactions were carried out at room
temperature in methylene chloride as reaction solvent and
the data are summarized in Table 7.
All catalysts revealed moderate isolated yields, except for
Rh2(S-1,2-NTTR)4 (3d) and Rh2(S-1,2-NTTY)4 (3e). The
asymmetric induction exhibited by the prepared catalysts ranged
from moderate to low (30–7% ee) for all substrates. In terms of ee
Later on, Fox and colleagues reported that the Rh2(S-
PTTL)4 had C4-symmetry “all-up” in solid state through its
TABLE 7. Asymmetric cyclopropanation with Meldrum’s acid (diacceptor substrate)
Rh2(S-1,2-
NTTL)4 (3a)
Rh2(S-1,2-
NTPA)4 (3b)
Rh2(S-1,2-
NTLU)4 (3c)
Rh2(S-1,2-
NTTR)4 (3d)
Rh2(S-1,2-
NTTY)4 (3e)
Rh2(S-PTTL)4
Rh2(S-NTTL)4
Yield
(%)
ee
Yield
(%)
ee
Yield
(%)
ee
Yield
(%)
ee
Yield
(%)
ee
Yield
(%)
ee
Yield
(%)
ee
R-group
(%)a
(%)a
(%)a
(%)a
(%)a
(%)a
(%)a
45%
52%
37%
36%
38%
40%
32%
60%
57%
30%
47%
51%
12%b
9%b
54%
59%
16%
18%
20%
18%
18%
14%
16%
13%
31%b
28%b
15%b
14%b
42%
33%
53%
35%
29%
27%
63%
36%
28%
20%
23%
46%
32%
44%
27%
22%
20%
41%
30%
38%
11%
8%
55%
47%
46%
12%
8%
11%
13%
12%
17%
17%
13%
14%
13%
15%
9%
12%
7%
17%b
8%b
9%b
aThe R-enantiomer is the major product. bAnalyzed as crude mixture. Enantiomeric excesses (ee %) were determined by chiral HPLC. See Materials and Methods
section for more details.
Chirality DOI 10.1002/chir

ASYMMETRIC SYNTHESIS OF CHIRAL CYCLOPROPYLPHOSPHONATES
derived from N-protected amino acid ligands. The efficiency
and selectivity of this catalyst has been demonstrated in a
variety of diastereo- and enantioselective reactions of donor-
acceptor and diacceptor carbenoids.
It was demonstrated that Rh2(S-1,2-NTTL)4 (3a) is a
promising backup catalyst for the cyclopropanation reaction
involving donor-acceptor phosphonate carbenoids. However,
the results did not provide a clear advantage for the “lower
symmetry” approach. Further investigations related to this
point are in progress and the results will be reported in due
course.
The results also revealed that the nature of the acceptor
group in the donor-acceptor carbenoid strongly affects
the asymmetric induction imparted by Rh2(S-1,2-NTTL)4.
This can provide a guideline for choosing the optimal
dirhodium(II) catalyst before attempting an asymmetric
cyclopropanation and broadens the range of available cata-
lysts for the synthesis of chiral cyclopropylphosphonate deriv-
atives. Hashimoto’s stereochemical model proved to be an
excellent model to justify the observed selectivity of the new
Rh2(S-1,2-NTTL)4 catalyst. This predictive model raised the
importance of considering the conformational mobility of
the ligands in solution once the carbene binds to the catalyst.
Fig. 4. Model for asymmetric cyclopropanation catalyzed by Rh2(S-1,2-
NTTL)4.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the W.J. Weeden
scholarship program at the University of Canberra, Australia,
for the PhD scholarship offered to Mr. Frady Gamal Adly
Gouany. Dedicated to Professor Paul Müller on the occasion
of his 75th birthday.
x-ray crystal structure, with the four N-phthalimido groups on
one face of the complex creating a chiral crown cavity.66,67
Also, other research groups have reported x-ray structures
of other catalysts that belong to the same family and all these
catalysts were adopting an “all-up” C4 conformation.29,51,68–70
According to the Fox model, the bulky tert-butyl groups
are necessary to limit reactivity to only one of the catalyst
faces, whereas the distorted C4-symmetric chiral crown-like
ligand arrangement guides the facial selectivity at the open
Rh-face.50
SUPPORTING INFORMATION
Additional supporting information may be found in the
online version of this article at the publisher’s web-site.
LITERATURE CITED
Based on the x-ray structure of Rh2(S-1,2-NTPA)4 (3b), that
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phosphonate group (tetrahedral geometry) orients itself away
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can occupy both positions shown in Figure 4b,c. The alkene
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