Practical synthesis of dirhodium(II) tetrakis[N-phthaloyl-(S)- tertleucinate]

Article abstract of DOI:10.1248/cpb.53.1366

An efficient and reliable procedure for the preparation of dirhodium(II) tetrakis[N-phthaloyl-(S)-tert-leucinate], Rh₂(S-PTTL)₄, a universally effective catalyst for a range of enantioselective carbene transformations, is described. The N-phthaloylation of (S)-tert-leucine by the method of Bose with essentially no racemization is a key to this process.

Full text of DOI:10.1248/cpb.53.1366

1366
Notes
Chem. Pharm. Bull. 53(10) 1366—1368 (2005)
Vol. 53, No. 10
Practical Synthesis of Dirhodium(II) Tetrakis[N-phthaloyl-(S)-tert-
leucinate]
Hideyuki TSUTSUI, Takumi ABE, Seiichi NAKAMURA, Masahiro ANADA, and Shunichi HASHIMOTO*
Graduate School of Pharmaceutical Sciences, Hokkaido University; Sapporo 060–0812, Japan.
Received July 15, 2005; accepted July 28, 2005; published online July 29, 2005
An efficient and reliable procedure for the preparation of dirhodium(II) tetrakis[N-phthaloyl-(S)-tert-leuci-
nate], Rh2(S-PTTL)4, a universally effective catalyst for a range of enantioselective carbene transformations, is
described. The N-phthaloylation of (S)-tert-leucine by the method of Bose with essentially no racemization is a
key to this process.
Key words tert-leucine; N-phthaloylation; dirhodium(II) carboxylate; chiral catalyst
Over the past decade, remarkable progress in dirhodi- straightforward (vide infra). The purpose of this paper is to
um(II) complex-catalyzed, asymmetric carbene transforma- describe an improved preparation of N-phthaloyl-(S)-tert-
tions of a-diazo carbonyl compounds has been achieved in a leucine, bridging ligands of Rh2(S-PTTL)4.
number of processes, including cyclopropanation, C–H inser-
Dirhodium(II) carboxylate catalysts 1a—d can be readily
tion, and rearrangement or cycloaddition via ylide genera- prepared from Rh2(OAc)4 by a ligand exchange reaction with
tion.1—4) In this context, a great deal of effort continues to be the corresponding N-phthaloyl-(S)-amino acids.12) Needless
devoted to the design, synthesis and evaluation of chiral to say, the use of optically pure ligands is crucial to the facile
dirhodium(II) catalysts. Unique in their design are chiral access to extremely reliable catalysts. With respect to N-
bridging ligands bound to the dirhodium(II) core, which con- phthaloylation, the most widely used fusion procedure with
stitute one of the most fundamental factors for the high level phthalic anhydride at 145 °C is ideally suited for the prepara-
of reactivity, turnover numbers, regio-, diastereo- and enan- tion of N-phthaloyl-(S)-alanine, -phenylalanine, and -valine,
tioselectivity. Our efforts in this area have led to the develop- in which optically pure products can be obtained in high
ment of dirhodium(II) carboxylate catalysts 1a—d (Fig. 1), yields with one recrystallization.13) However, such is not the
which incorporate N-phthaloyl-(S)-amino acids as bridging case for 2. Even though the N-phthaloylation of (S)-tert-
ligands.5) The presence of phthalimido groups in the bridging leucine (3) under the same conditions proceeded with ca.
ligands has proven to be crucial for a high degree of enan- 10% racemization, repeated recrystallizations were required
tioselection, even though the secondary effect of the alkyl to obtain an optically pure material at the cost of product
substituent of amino acids on enantioselectivities has yet to yield. The tedious operation can be attributed to the fact that
be elucidated. Of these catalysts, dirhodium(II) tetrakis[N- small amounts of racemate (mp 190.0—190.5 °C) crystal-
phthaloyl-(S)-tert-leucinate], Rh2(S-PTTL)4 (1d), has proven lizes out together with the optically pure material (mp
to be the most universally efficient catalyst for a range of 153.5—154.0 °C).
rhodium(II)-carbene transformations of a-diazo carbonyl
Thus, we explored the racemization-free N-phthaloylation
compounds.6—11) The effectiveness of 1d has been particu- of 3 by alternate procedures. Among these, the procedures of
larly well demonstrated in intramolecular C–H insertions,6) Nefkens14) and Casimir,15) which use N-ethoxycarbonylph-
double intramolecular C–H insertions,7) enantiotopically se- thalimide or methyl 2-(succinimidooxycarbonyl)benzoate,
lective aromatic C–H insertions,8) intermolecular 1,3-dipolar respectively, have the potential advantage of allowing the N-
cycloadditions via the generation of ester-carbonyl ylides,9) phthaloylation of free amino acids under mild conditions. In-
and [2,3]-sigmatropic rearrangements via the intramolecular deed, the N-phthaloylation of 3 with N-ethoxycarbonylph-
formation of allylic or propargylic oxonium ylides10,11) with thalimide (Na2CO3, H2O, rt, 10 h) proceeded without racem-
high levels of enantioselectivities up to 98% ee. However, a ization to give optically pure 2, but the isolated yield was
problem associated with the original synthesis of Rh2(S- only 14%.16) Furthermore, the reaction with methyl 2-(suc-
PTTL)4 involves product yield simply because the prepara-
tion of optically pure N-phthaloyl-(S)-tert-leucine (2) is not
Fig. 1. Structure of Chiral Dirhodium(II) Carboxylates Incorporating N-
Chart 1. Preparation of Rh2(S-PTTL)4
Phthaloyl-(S)-amino Acid as Bridging Ligands
∗ To whom correspondence should be addressed. e-mail: hsmt@pharm.hokudai.ac.jp
© 2005 Pharmaceutical Society of Japan

October 2005
1367
(S), 12.4 min (R)].
cinimidooxycarbonyl)benzoate (Na2CO3, aq. CH3CN, rt, 8 h)
gave none of the desired product.17) It is clear that an excep-
tionally bulky tert-butyl group of 3 would have an effect, be-
cause of the severe steric hindrance imposed. After some ex-
Dirhodium(II) Tetrakis[(S)-tert-leucinate] (1d) Bis(ethyl acetate)
Adduct A 100-ml round-bottom flask was equipped with a stirring bar and
charged with Rh2(OAc)4·2MeOH (1.67 g, 3.30 mmol), 1 (4.31 g, 16.5 mmol)
and chlorobenzene (50 ml). The mixture was heated to reflux, while the sol-
perimentation, we found that this goal could be readily vent was distilled off at a rate such that ca. 7 ml of the solvent was removed
achieved by employing the method of Bose.18,19) Thus, the
condensation of 3 with phthalic anhydride in the presence of
triethylamine was conducted in toluene at reflux for 0.5 h,
per hour. After 3 h, the remaining solvent was removed in vacuo, the residue
was dissolved in EtOAc (80 ml). The resulting solution was washed with sat-
urated aqueous NaHCO3 (2ꢃ20 ml) and brine (20 ml), and dried over anhy-
drous Na2SO4. Filtration and evaporation in vacuo furnished a green solid
while the water formed was distilled off. An aliquot of the
crude product thus obtained was transformed into the methyl
ester to check the extent of racemization in this process. The
enantiopurity of the methyl ester was determined to be
ꢀ99% ee by HPLC using a Daicel Chiralcel OJ column.
This result suggests that N-phthaloylation of 3 under Bose’s
conditions proceeds with essentially no racemization, al-
though triethylamine is present as a base. As expected, one
recrystallization of the crude product from ethyl acetate-
hexane provided completely optically pure 2, mp 153.5—
154.0 °C, [a]D24 ꢁ60.6° (cꢂ1.60, EtOH), in 86% yield.
The present N-phthaloylation protocol based on the
method of Bose has the advantages of operational simplicity
as well as reproducibility, thus providing facile and reliable
access to high quality Rh2(S-PTTL)4.
(5.6 g), which was purified by column chromatography on silica gel (60 g,
1 : 1→1 : 2 hexane/EtOAc) to provide a green solid (5.0 g). This material was
recrystallized by dissolving the solid in 20 ml of EtOAc and then adding
30 ml of hexane. The green needles that formed at room temperature after
standing overnight, were collected by suction, washed with 3 ml of
hexane/EtOAc (3 : 1) and dried in vacuo to yield bis(ethyl acetate) adduct of
1d (4.42 g, 93%). TLC Rf 0.26 (1 : 1 hexane/EtOAc). mp ꢀ280 °C. [a]D22
ꢄ102.2° (cꢂ0.0481, CHCl3). IR (KBr) cmꢁ1: 3476, 2963, 1777, 1717,
1611, 1383. 1H-NMR (400 MHz, CDCl3) d: 1.07 (36H, s, t-Bu), 1.20 (6H, t,
Jꢂ6.4 Hz, AcOCH2CH3), 2.01 (6H, s, CH3COEt), 4.09 (4H, q, Jꢂ6.4 Hz,
AcOCH2CH3), 4.87 (4H, s, CH), 7.63—7.65 (8H, m, ArH), 7.78—7.80 (8H,
m, ArH). 13C-NMR (100 MHz, CDCl3) d: 14.1 (CH3), 21.0 (CH3), 28.0
(CH3), 35.6 (C), 60.9 (CH2), 61.3 (CH), 123.1 (CH), 131.8 (CH), 133.6 (C),
167.6 (CꢂO), 172.8 (CꢂO), 186.8 (CꢂO). FAB-MS m/z: 1246 (Mꢄ), 986,
417. HR-FAB-MS m/z: 1246.1804 (Calcd for C56H56N4O16Rh2: 1246.1801).
Anal. Calcd for C56H56N4O16Rh2·2EtOAc: C, 54.02; H, 5.10; N, 3.94.
Found: C, 53.80; H, 5.03; N, 4.26. The enantiopurity of the methyl ester of 2
recovered from aqueous NaHCO3 layers was determined to be ꢀ99% ee by
HPLC, indicating that no racemization occurred during the ligand exchange
reaction.
Experimental
Melting points were determined on a Büchi 535 digital melting point ap-
paratus and are uncorrected. NMR spectra were obtained with a JEOL JNM-
AL400 spectrometer (13C at 100 MHz), with tetramethylsilane (d 0.0, 1H) or
chloroform-d1 (d 77.0, 13C) as an internal standard. Infrared spectra were
recorded on a JASCO FT/IR-5300 spectrometer. Optical rotations were mea-
sured on a Jasco DIP-370 digital polarimeter. Electron impact (EI) mass
spectra were obtained on a JEOL DX-303 spectrometer, operating with an
ionization energy of 70 eV. FAB-MS were obtained on a JEOL JMS-HX110
spectrometer. Column chromatography was performed on Merck silica gel
60 (70—230 mesh). Analytical HPLC was performed on a JASCO PU-1580
intelligent HPLC pump with a JASCO UV-1575 intelligent UV/VIS detec-
tor. Detection was at 254 nm. A Chiralcel OJ column (0.46 cmꢃ25 cm) from
Daicel was used. Retention times (tR) and peak ratios were determined with
Shimadzu C-R6A chromatopac integrator. Reactions were carried out in
flame-dried glassware under argon atmosphere. (S)-tert-Leucine was pur-
chased from Daiichi Pure Chemicals Co., Ltd. Rh2(OAc)4·2MeOH was pur-
chased from Furuya Metal Co., Ltd. Reagents and solvents were purified by
standard means.
N-Phthaloyl-(S)-tert-leucine (2) A 100-ml round-bottom flask was
equipped with a stirring bar and charged with (S)-tert-leucine (3, 2.50 g,
19.1 mmol), phthalic anhydride (2.82 g, 19.1 mmol) and toluene (60 ml). Tri-
ethylamine (741 mg, 1.9 mmol) was added and the mixture was heated to re-
flux, while the solvent was distilled off at a rate such that ca. 7 ml of the sol-
vent was removed per 10 min. After heating the mixture for 0.5 h, 5% hy-
drochloric acid (15 ml) was added and resulting solution was extracted with
EtOAc (2ꢃ30 ml). The combined organic layers were washed with brine
(20 ml) and dried over anhydrous Na2SO4. Filtration and concentration
in vacuo provided a white solid (4.73 g). Recrystallization was perform-
ed by dissolving the solid in 8 ml of hot ethyl acetate and then adding
24 ml of hexane. Colorless plates formed at room temperature after
standing overnight, and were collected by suction, washed with 3 ml of
Acknowledgements This research was partially supported by a Grant-
in-Aid for Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. We thank Ms. H. Matsumoto, A.
Maeda, S. Oka, and M. Kiuchi of the Center for Instrumental Analysis,
Hokkaido University, for technical assistance in the MS and elemental
analysis.
References and Notes
1) Doyle M. P., McKervey M. A., Ye T., “Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds,” Wiley-Interscience, New
York, 1996.
2) Lydon K. M., McKervey M. A., “Comprehensive Asymmetric Cataly-
sis,” Vol. 2, Chap. 16.2, ed. by Jacobsen E. N., Pfaltz A., Yamamoto
H., Springer, Berlin, 1999, pp. 539—603.
3) Doyle M. P., “Catalytic Asymmetric Synthesis,” 2nd ed., Chap. 5, ed.
by Ojima I., Wiley-VCH, New York, 2000, pp. 191—228.
4) Davies H. M. L., Beckwith R. E. J., Chem. Rev., 103, 2861—2903
(2003).
5) Hashimoto S., Watanabe N., Anada M., Ikegami S., J. Synth. Org.
Chem., Jpn., 54, 988—999 (1996).
6) Saito H., Oishi H., Kitagaki S., Nakamura S., Anada M., Hashimoto
S., Org. Lett., 4, 3887—3890 (2002).
7) Takahashi T., Tsutsui H., Tamura M., Kitagaki S., Nakajima M.,
Hashimoto S., Chem. Commun., 2001, 1604—1605 (2001).
8) Watanabe N., Ogawa T., Ohtake Y., Ikegami S., Hashimoto S., Synlett,
1996, 85—86 (1996).
9) Kitagaki S., Yasugahira M., Anada M., Nakajima M., Hashimoto S.,
Tetrahedron Lett., 41, 5931—5935 (2000).
10) Kitagaki S., Yanamoto Y., Tsutsui H., Anada M., Nakajima M.,
Hashimoto S., Tetrahedron Lett., 42, 6361—6364 (2001).
hexane–EtOAc (3 : 1) and dried in vacuo to give 2 (4.30 g, 86%). TLC Rf 11) Tsutsui H., Matsuura M., Makino K., Nakamura S., Nakajima M.,
0.36 (10 : 1 CHCl3/MeOH). mp 153.5—154.0 °C. [a]D24 ꢁ60.6° (cꢂ1.60,
Kitagaki S., Hashimoto S., Isr. J. Chem., 41, 283—295 (2001).
12) Callot H. J., Metz F., Tetrahedron, 41, 4495—4501 (1985).
EtOH). IR (KBr) cmꢁ1: 3241, 2965, 1759, 1713, 1391. 1H-NMR (400 MHz,
CDCl3) d: 1.19 (9H, s, t-Bu), 4.74 (1H, s, CH), 7.73—7.78 (2H, m, ArH), 13) Sheehan J. C., Chapman D. W., Roth R. W., J. Am. Chem. Soc., 74,
7.85—7.90 (2H, m, ArH). 13C-NMR (100 MHz, CDCl3) d: 28.0 (CH3), 35.7
3822—3825 (1952).
(C), 59.8 (CH), 123.5 (CH), 131.5 (C), 134.1 (CH), 167.8 (CꢂO), 173.6 14) Nefkens G. H. L., Tesser G. I., Nivard J. F., Recl. Trav. Chim. Pays-
(CꢂO). FAB-MS m/z: 262 (MꢄꢄH), 216. HR-FAB-MS m/z: 262.1101
Bas, 79, 688—698 (1960).
(Calcd for C14H16NO4: 262.1079). Anal. Calcd for C14H15NO4: C, 64.36; H, 15) Casimir J. R., Guichard G., Briand J.-P., J. Org. Chem., 67, 3764—
5.79; N, 5.36. Found: C, 64.18; H, 5.91; N, 5.27. The enantiopurity of 2 was
determined to be ꢀ99% ee by comparison of HPLC retention time with the
racemic sample after conversion to the corresponding methyl ester obtained
by the treatment of 2 with diazomethane in ether [Daicel Chiralcel OJ; elu-
ent: 9 : 1 hexane/2-propanol; flow rate: 1.0 ml/min; retention time: tR 8.1 min
3768 (2002).
16) N-[2-(Ethoxycarbonyl)aminocarbonyl]benzoyl-(S)-tert-leucine was also
obtained as a major product in 64% yield. Colorless viscous oil. TLC
Rf 0.33 (4 : 1 CHCl3/MeOH). [a]D24 ꢁ4.4° (cꢂ0.92, EtOH). IR
(CHCl3) cmꢁ1: 3400, 1773, 1715. H-NMR (400 MHz, CDCl3, 50 °C)
1

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Vol. 53, No. 10
d: 1.03 (9H, s, t-Bu), 1.21 (3H, m, CH2CH3), 4.13 (2H, m, CH2CH3),
4.57 (1H, d, Jꢂ8.9 Hz, CH), 6.91 (1H, d, Jꢂ8.9 Hz, NH), 7.40—7.47
(4H, m, ArH), 9.2 (1H, s, NH). 13C-NMR (100 MHz, CDCl3, 50 °C) d:
14.0 (CH3), 26.6 (CH3), 34.6 (C), 61.1 (CH), 62.3 (CH2), 127.3 (CH),
127.7 (CH), 130.4 (CH), 130.5 (CH), 133.7 (C), 134.6 (C), 151.6
(CꢂO), 168.3 (CꢂO), 169.0 (CꢂO). FAB-MS m/z: 351 (MꢄꢄH),
262. HR-FAB-MS m/z: 351.1553 (Calcd for C17H23N2O6: 351.1556).
t-Bu), 3.86 (3H, s, OCH3), 4.69 (1H, d, Jꢂ9.0 Hz, CH), 6.40 (1H, d,
Jꢂ9.0 Hz, NH), 7.49—7.55 (3H, m, ArH), 7.88 (1H, d, Jꢂ7.2 Hz,
ArH). 13C-NMR (100 MHz, CDCl3, 50 °C) d: 26.6 (CH3), 34.7 (C),
60.6 (CH), 127.5 (CH), 129.1 (C), 129.8 (CH), 130.0 (CH), 131.8
(CH), 137.2 (C), 166.9 (CꢂO), 169.4 (CꢂO), 174.3 (CꢂO). EI-MS
m/z: 294 (Mꢄ), 262, 248, 163. HR-EI-MS m/z: 294.1342 (Calcd for
C15H20NO5: 294.1341).
17) N-(2-Methoxycarbonyl)benzoyl-(S)-tert-leucine was obtained as
a
18) Bose A. K., Greer F., Price C. C., J. Org. Chem., 23, 1335—1338
major product in 83% yield. Colorless viscous oil. TLC Rf 0.57 (4 : 1
(1958).
CHCl3/MeOH). [a]D24 ꢁ23.8° (cꢂ1.38, CHCl3). IR (CHCl3) cmꢁ1
:
19) Bose A. K., “Organic Synthesis,” Collect. Vol. V, Wiley, New York,
1973, pp. 973—975.
1
3426, 1725, 1671. H-NMR (400 MHz, CDCl3, 50 °C) d: 1.11 (9H, s,