Asymmetric Synthesis of the Roche Ester and its Derivatives
FULL PAPERS
be hydrogenated in high selectivity. The trisubstituted Preparative Scale Asymmetric Hydrogenation of
substrate with an additional phenyl group at the 3-po- Methyl 2-Hydroxymethylacrylate (2a)
sition, is less reactive and forms the product as a race-
mate. Hydrogenation of the structurally related a-
methylcinnamic acid 5 results in moderate activity
INDOLPHOS ligand 4b (309 mg, 0.55 mmol) and [Rh-
(nbd)2]BF4 (187 mg, 0.50 mmol) were dissolved in dryDCM
(50 mL). Methyl 2-hydroxymethylacrylate 2a (5.8 g,
50 mmol) was added and the mixture was transferred to a
150-mL stainless steel autoclave equipped with a glass insert
and a mechanical stirrer. The autoclave was cooled to
À408C and subsequentlypurged three times with 15 bar of
dihydrogen and pressurized at 20 bar H2. The reaction mix-
ture was stirred for 15 h at À408C after which it was allowed
to warm to room temperature. The pressure was reduced to
1.0 bar and the solvent was removed under reduced pres-
sure. Et2O (50 mL) was added to the residue and the result-
ing yellow suspension was filtered through a plug of SiO2
which was rinsed twice with Et2O (250 mL). Removal of
the solvent under reduced pressure gave a colourless oil;
yield: 5.16 g (87%); 98% ee (chiral GC); [a]2D0: +15.4 (c 3.1,
CHCl3); 1H NMR (CDCl3, 500 MHz, 298 K): d=3.72 (m,
5H), 2.68 (m, 1H), 2.10 (br s, 1H), 1.18 (d, J=7.5 Hz, 3H);
13C NMR (CDCl3, 125.5 MHz, 298 K): d=176.14 (Cq), 64.57
(CH2), 51.83 (CH3), 41.62 (CH), 13.40 (CH3).
and high enantioselectivityup to 78% ee.
Experimental Section
General Procedure for the Synthesis of
Indolylphosphines 3a–d
To a solution of 3-methylindole (1.78 g, 13.6 mmol) in THF
(40 mL) was added dropwise 5.7 mL of n-BuLi (2.5M in
hexanes) at À708C. The resulting suspension was stirred at
À708C for 20 min. Carbon dioxide was bubbled through the
suspension for 10 min to give a clear pale yellow solution
which was allowed to warm to room temperature after
which the solvent was removed under vacuum. The resulting
white residue was dissolved in THF (40 mL) to give a clear
pale yellow solution which was cooled to À708C. To this so-
lution, 8.4 mL of t-BuLi (1.7M in pentanes) was added and
the resulting orange solution was stirred at À708C for 1 h.
The appropriate chlorophosphine (13.6 mmol) was added
and the reaction mixture was stirred for 16 h while being al-
lowed to warm to room temperature. The resulting yellow
solution was washed with 40 mL degassed saturated aqueous
NH4Cl. The organic layer was dried over MgSO4, filtered
and the solvent was removed under vacuum. The crude,
pale yellow solid was recrystallized from hot MeOH to yield
the product as colourless crystals.
Supporting Information
Spectroscopic and analytical data of ligands, additional ex-
perimental details for the AMTEC SPR16, catalytic results,
and gas-uptake profiles are available in the Supporting In-
formation.
Acknowledgements
Dicyclohexyl(3-methyl-2-indolyl)phosphine (3c): Yield:
2.84 g (64%).
Di-(o-Tolyl)-(3-methyl-2-indolyl)phosphine (3d): Yield:
3.88 g (83%).
We gratefully acknowledge NRSC-C and the European
Union (RTN Revcat MRTN-CT-2006–035866) for financial
support.
References
General Procedure for the Synthesis of
INDOLPHOS Ligands 4a–f
[1] a) J. G. de Vries, C. J. Elsevier, The Handbook of Ho-
mogeneous Hydrogenation, Wiley-VCH, Weinheim,
2007; b) N. B. Johnson, I. C. Lennon, P. H. Moran, J. A.
Ramsden, Acc. Chem. Res. 2007, 40, 1291–1299.
[2] W. J. Tang, X. M. Zhang, Chem. Rev. 2003, 103, 3029–
3069.
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[5] a) V. F. Slagt, P. W. N. M. van Leeuwen, J. N. H. Reek,
Chem. Commun. 2003, 2474–2475; b) V. F. Slagt, M.
Rçder, P. C. J. Kamer, P. W. N. M. van Leeuwen,
J. N. H. Reek, J. Am. Chem. Soc. 2004, 126, 4056–4057;
c) M. Kuil, P. E. Goudriaan, P. W. N. M. van Leeuwen,
J. N. H. Reek, Chem. Commun. 2006, 4679–4681;
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Chem. Commun. 2007, 2287–2289; e) M. Kuil, P. E.
Goudriaan, A. W. Kleij, D. M. Tooke, A. L. Spek,
P. W. N. M. van Leeuwen, J. N. H. Reek, Dalton Trans.
To a solution of the corresponding indolylphosphine 3
(1.46 mmol) in THF (5 mL) was added dropwise 0.58 mL of
n-BuLi (2.5M in hexanes) at À708C. The resulting pale
yellow solution was stirred for 0.5 h at À708C. To this solu-
tion, a solution of (S)-(À)-2,2’-bisnaphthol phosphorochlori-
dite (0.51 g, 1.46 mmol) in THF (4 mL) was added at
À708C. The reaction mixture was stirred for 1 h at À708C
and then allowed to warm to room temperature. The result-
ing pale yellow solution was concentrated under vacuum.
Toluene (5 mL) was added and the suspension was filtered
over Celite after which the solvent was removed under
vacuum to obtain a white powder. In selected cases the
crude product was further purified bySiO chromatography.
2
Dicyclohexyl{1-[(S)-3,5-dioxa-4-phosphacyclohepta[2,1-
a;3,4-a’]dinaphthalen-4-yl]-3-methyl-2-indolyl}phosphine
(4c): Yield: 553 mg (59%).
Di-(o-Tolyl)-{1-[(S)-3,5-dioxa-4-phosphacyclohepta[2,1-
a;3,4-a’]dinaphthalen-4-yl]-3-methyl-2-indolyl}phosphine
(4d): Yield: 749 mg (78%).
Adv. Synth. Catal. 2008, 350, 1610 – 1614
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1613