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`A Publication
`of Reliable Methods
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`2011;
`the
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`can
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`at
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`
`Lupin Ex. 1087 (Page 1 of 11)
`
`

`

`DOI:10.15227/orgsyn.063.0109
`
`Organic Syntheses, Coll. Vol. 7, p.153 (1990); Vol. 63, p.109 (1985).
`DIASTEREOSELECTIVE Į-ALKYLATION OF ȕ-
`HYDROXYCARBOXYLIC ESTERS THROUGH ALKOXIDE
`ENOLATES: DIETHYL (2S, 3R)-(+)-3-ALLYL-2-
`HYDROXYSUCCINATE FROM DIETHYL (S)-( í )-MALATE
`[Butanedioic acid, 2-hydroxy-3-(2-propenyl)-, diethyl ester, [S-(R,S)]]
`
`Submitted by Dieter Seebach, Johannes Aebi, and Daniel Wasmuth1.
`Checked by Brian Maxwell and Clayton H. Heathcock.
`
`1. Procedure
`
`
`
`
`
`A 500-mL, three-necked flask containing a magnetic stirring bar is equipped with a 100-mL
`pressure-equalizing and serum-capped dropping funnel, a three-way stopcock, and a low-temperature
`thermometer (Note 1). The dry apparatus is filled with argon and kept under an inert gas pressure of ca.
`100 mm against the atmosphere until the aqueous workup (Note 2); see Figure 1.
`Figure 1
`
`Lupin Ex. 1087 (Page 2 of 11)
`
`

`

`
`
`The flask is charged through serum cap B with 17 mL (120 mmol) of diisopropylamine (Note 3)
`and 200 mL of tetrahydrofuran (THF) (Note 4), using syringe techniques. It is cooled to í75°C in a dry
`ice bath. With stirring, exactly 100 mmol of butyllithium (hexane solution) (Note 5) is introduced from
`the dropping funnel (Note 6) within 10 min, followed after 0.5 hr, by a mixture of 9.51 g (50 mmol) of
`( í )-diethyl (S)-malate (Note 7) and 5 mL of THF, which is added dropwise through cap B at such a
`rate that the temperature does not rise above í60°C. The addition takes approximately 10 min (Note 8).
`The dry ice cooling bath is replaced by an ice–salt bath (ca. í15°C) in which the contents of the flask
`warm to í20°C within 0.5 hr. The solution is stirred at í20°C ± 2°C for 0.5 hr and then is cooled to
`í75°C.
`
`To the solution of the alkoxide enolate thus prepared is added by syringe within 5 min 10.7 mL (124
`mmol) of neat 3-bromo-1-propene (Note 9) at such a rate that the temperature of the reaction mixture
`does not rise above í70°C. Stirring is continued, first for 2 hr at í75°C, and then overnight while the
`temperature rises to í5°C (Note 10).
`
`The reaction mixture is quenched by adding a solution of 12 g (200 mmol) of glacial acetic acid in
`20 mL of diethyl ether at í50°C and is then poured into a 1-L separatory funnel containing 500 mL of
`ether and 70 mL of water. The organic layer is washed successively with 40 mL each of saturated
`sodium bicarbonate and sodium chloride solution, and the aqueous phases are extracted with two 200-
`mL portions of ether. The combined ethereal solutions are dried by vigorous stirring with dry MgSO4
`for 15 min. Removal of the solvent first with a rotary evaporator at a bath temperature no higher than
`35°C and then at room temperature under oil pump vacuum (0.1 mm) furnishes 10.4 g of a yellow oil
`consisting, according to capillary gas chromatography (GC) (Note 11), of 81.3% of the desired allylated
`(2S,3R) product (73.5% yield), 8.5% of the (2S,3S) diastereoisomer (90.5% ds2), and 6.3% of the
`starting diethyl malate (Note 12).
`
`The product is purified by flash chromatography (Note 13),(Note 14),(Note 15). A flash column of
`7-cm diameter is charged with 450 g of silica gel (Kieselgel 60, Merck, Korngrösse 0.040–0.063 mm,
`
`Lupin Ex. 1087 (Page 3 of 11)
`
`

`

`230–400 mesh ASTM) and 10.4 g of the crude product. A 1 : 1 mixture of ether and pentane is used
`for elution, with a running rate of 5-cm column length per minute (pressure 1.25 atm). After a 200-mL
`forerun, 33-mL fractions are collected. No attempt is made to separate the two diastereoisomers;
`fractions 22–40 are combined to give 8.0 g (70%) of pure allylated product [ratio of diastereoisomers
`92 : 8 (Note 11)], after removal of the solvent; [Į]D + 11.2° (chloroform, c 2.23) (Note 16).
`20
`2. Notes
`
`1. A Pt-100 thermometer (Testoterm KG, Lenzkirch, Germany) was used by the submitters. This is
`preferred to a conventional thermometer because it is more accurate and more convenient to read.
`Careful temperature control is essential for the present procedure. Unless stated otherwise, all
`temperatures given are those of the reaction mixture. The checkers found that a +30 to í100°C alcohol
`thermometer is satisfactory.
`2. The glass components of the apparatus are dried overnight in a 170°C oven and allowed to cool in a
`desiccator over a drying agent before assembly. The apparatus is filled with argon by evacuating and
`pressurizing several times through the three-way stopcock, as described previously.3
`3. Diisopropylamine was freshly distilled from calcium hydride.
`4. Tetrahydrofuran (THF) was first distilled under an inert atmosphere from KOH and then from the
`blue solution obtained with potassium and benzophenone, as described previously.3 [However, see
`warning notice, Org. Synth., Coll. Vol. V 1973, 976–977.]
`5. Before use, the commercial 1.6 M solution of butyllithium in hexane was titrated acidimetrically
`using diphenylacetic acid as an indicator.4
`6. The dropping funnel was calibrated before use in this procedure. With standard graduated dropping
`funnels and syringes, the submitters noticed up to 10% deviation from true volumes! Syringe techniques
`were applied; the dropping funnel was rinsed with ca. 5 mL of dry THF.
`7. Commercial (S)-( í )-malic acid was esterified under standard conditions, following a procedure by
`20
`Fischer and Speier.5 The freshly distilled ester employed by the submitters had an [Į]D í10.5° (neat)
`(d20 = 1.128 g/cm3), which corresponds to an optical purity of 100%.6
`4
`8. The flask, in which the ester/THF mixture was prepared, and the syringe are rinsed with a total of ca.
`5 mL of dry THF.
`9. Commercial allyl bromide was distilled before use.
`10. The submitters used a 2-L Dewar cylinder holding, besides the flask, ca. 1 L of ethanol as a cooling
`liquid. If no excess dry ice was present at the beginning of the warm-up period, it took ca. 12 hr to reach
`í5°C.
`11. GLC-analysis were performed using the following column and conditions: 0.3-mm × 20-m glass
`capillary column Pluronic L 64, program 120°C, (3 min), 10°C/min up to 200°C, temperature of injector
`and detector 200°C, carrier gas: hydrogen (1.3 atm).
`12. A total of ca. 4% of four minor side products with longer retention times is also present.
`13. This is the fastest method, although it consumes large amounts of solvent and of silica gel. The
`procedure is that of Still et al.7 Conventional chromatography is also possible but is more time-
`consuming.
`14. Kugelrohr distillation does not separate the starting material, diethyl malate. Distillation through a
`30-cm Vigreux column (silvered vacuum jacket) leads to loss of material (only 40% yield,
`diastereoisomer ratio 90 : 10, free of starting material).
`the crude product yields, after recrystallization, pure (2S,3R)-3-allyl-2-
`15. Hydrolysis of
`hydroxysuccinic acid, mp 96.0–97.5°C, [Į]D +14.7° (acetone, c 1.69).
`25
`16. The boiling point is 77–78°C (0.07 mm). Previously, a specific rotation of [Į]D + 11.9°
`(chloroform, c 1.77) was reported.8 The 13C NMR spectrum (CDCl3) of the (2S, 3R) isomer shows the
`following signals į (off-resonance multiplicity, assignment): 14.12 (q, CO2CH2CH3), 32.21 (t, C(3)
`CH2), 48.25 [d, C(3)], 60.86 and 61.81 (2 t, CO2CH2CH3), 70.36 [d, C(2)], 117.78 [t, C(3)CH2CH=CH2],
`134.94 [d, C(3)CH2CH=CH2], 171.92 and 173.48 (2 s, CO2CH2CH3).
`3. Discussion
`
`20
`
`The compound described here had not been known prior to our first synthesis of it.8 9 10 Generally,
`aldol derivatives of this configuration are prepared by the addition of E enolates of esters to
`aldehydes,11,12 1
` 2 in Scheme 1.
`
`Lupin Ex. 1087 (Page 4 of 11)
`
`

`

`
`
`The method of preparing Į-branched ȕ-hydroxy esters by alkylation of dianion derivatives of the
`parent compounds was first discovered by Herrmann and Schlessinger.13 It is highly diastereoselective14
`and applicable without racemization to optically active derivatives, as first demonstrated independently
`by Fráter with ȕ-hydroxybutanoate15 and by us with malate8 9 10,16 17 18 (see 3
` 2 and 3
` 5 in Scheme
`1). In the meantime, many applications have been published.19 20,21 A related method of preparing
`derivatives belonging to the same diastereoisomeric series is the alkylation of ȕ-lactone enolates.22
`
`Examples of alkylation of malic esters are listed in Table I, together with those of double alkylation,
` 4 in Scheme 1. Since the (S) and the (R) forms of malic acid are
`which can also be achieved, see 2
`both readily available,23 the enantiomers of all structures shown in Table I can be prepared as well. The
`method is also applicable to ȕ-hydroxy Ȗ-lactones of type 6, the alkylations of which lead24 25 26 to
`derivatives of opposite configuration 8, see 6
` 7 in Scheme 2. Finally, the dilithio derivative 9 of di-
`tert-butyl N-formylaspartate is alkylated (
` 10; see Scheme 2)27 with the same relative topicity,28 ul, as
`the malate dianion derivative (Table I).
`
`TABLE I
`PRODUCTS OF MONO- AND DIALKYLATION WITH RELATIVE TOPICITY ula OF (S)-MALIC ESTE
`RATIOS OF DIASTEREOISOMERS (SEE % ds) WAS DETERMINED BY 1H or 13C NMR SPE
`
`
`
`Lupin Ex. 1087 (Page 5 of 11)
`
`

`

`Product R1
`
`R2
`
`R3
`
`a CH3
`
`CH3
`
`—
`
`Yield (%)
`
`(Malate
`65
`
`a)
`
`CH3
`
`C(OH)(CH3)
`2
`
`—
`
`C2H5
`
`CH3
`
`—
`
`C2H5 CH2C6H5
`
`—
`
`C2H5
`
`I
`
`—
`
`CH3 CH2CH2NO2
`
`—
`
`CH3
`
`C2H5
`
`—
`
`CH3 CH2CH=CH2
`
`—
`
`55
`
`88
`
`48
`
`80
`
`31
`
`64
`
`63
`
`Lupin Ex. 1087 (Page 6 of 11)
`
`

`

`b CH3
`
`CH3
`
`CH3
`
`CH3
`
`CH3
`
`C2H5
`
`CH3
`
`C2H5
`
`CH3
`
`CH3
`
`CH3
`
`CD3
`
`CH3
`
`CH3
`
`13CH3
`
`CH3
`
`CH3
`
`CH2CH=CH2
`
`CH3
`
`CH3
`
`H
`
`b)
`
`(a
`94
`
`36
`
`92
`
`81
`
`74
`
`>98
`
`Lupin Ex. 1087 (Page 7 of 11)
`
`

`

`aSee 28.
`bSee 2.
`
`In Table II, a series of useful chiral building blocks is shown, which are accessible through
`alkylations of malic acid derivatives; the table also contains some natural products that were synthesized
`from such building blocks.
`
`The alkylation of doubly deprotonated ȕ-hydroxy esters, an example of which is described in the
`procedure above, is not just a useful alternative to the diastereoselective aldol-type addition, but can
`supply enantiomerically pure products from appropriate precursors, and it can be used for the
`preparation of Į,Į-disubstituted derivatives (see 4 in Scheme 1). These were hitherto not available
`stereoselectively from enolates of Į-branched esters and aldehydes. 29,30
`
`This preparation is referenced from:
`
`z Org. Syn. Coll. Vol. 8, 420
`
`TABLE II
`CHIRAL, NONRACEMIC BUILDING BLOCKS AND NATURAL PRODUCTS SYNTHESIZED
`THROUGH ALKYLATION OF MALIC ACID DERIVATIVESa
`
`Products and Intermediates from (S)-Malic Acid
`
`
`
`
`
`
`
`
`
`
`
`
`
`Lupin Ex. 1087 (Page 8 of 11)
`
`

`

`
`
`
`
`
`
`aThe four-carbon unit of the structure derived from malic acid is indicated by heavy
`lines.
`
`References and Notes
`
`1. Laboratorium für Organische Chemie, ETH-Zentrum, Universitätstrasse 16, CH-8092 Zürich,
`Switzerland.
`2. Seebach, D.; Naef, R. Helv. Chim. Acta 1981, 64, 2704.
`3. Seebach, D.; Beck, A. K. Org. Synth., Coll., Vol. VI 1988, 316, 869; Seebach, D.; Hidber, A.
`Org. Synth., Coll. Vol. VII 1990, 447.
`4. Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41, 1879.
`5. Fischer, E.; Speier, A. Chem. Ber. 1895, 28, 3252.
`6. Kuhn, R.; Wagner-Jauregg, T. Chem. Ber. 1928, 61, 504.
`7. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
`8. Seebach, D.; Wasmuth, D. Helv. Chim. Acta 1980, 63, 197;
`9. Aebi, J. D. Master's Thesis, ETH Zürich, 1981;
`10. Aebi, J. D.; Sutter, M. A.; Wasmuth, D.; Seebach, D. Liebigs Ann. Chem. 1983, 2114; Aebi, J.
`D.; Sutter, M. A.; Wasmuth, D.; Seebach, D. Liebigs Ann. Chem. 1984, 407.
`11. Heathcock, C. H. Science 1981, 214, 395; Heathcock, C. H. "Asymmetric Synthesis," Morrison,
`J. D., Ed.; Academic Press: New York, 1983, Vol. 3.
`12. Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1.
`13. Herrmann, J. L.; Schlessinger, R. H. Tetrahedron Lett. 1973, 2429.
`14. Kraus, G. A.; Taschner, M. J. Tetrahedron Lett. 1977, 4575.
`15. Fráter, G. Helv. Chim. Acta 1979, 62, 2825, 2829; Fráter, G. Helv. Chim. Acta 1980, 63, 1383;
`Fráter, G. Tetrahedron Lett. 1981, 22, 425.
`16. Züger, M.; Weller, Th.; Seebach, D. Helv. Chim. Acta 1980, 63, 2005;
`17. Wasmuth, D.; Arigoni, D.; Seebach, D. Helv. Chim. Acta 1982, 65, 344, 620;
`18. Wasmuth, D. Ph. D. Thesis No. 7033, ETH Zürich, 1982.
`19. Hoffmann, R. W.; Ladner, W.; Steinbach, K.; Massa, W.; Schmidt, R.; Snatzke, G. Chem. Ber.
`1981, 114, 2786;
`20. Hoffmann, R. W.; Helbig, W. Chem. Ber. 1981, 114, 2802.
`21. Kramer, A.; Pfander, H. Helv. Chim. Acta 1982, 65, 293.
`22. Mulzer, J.; Kerkmann, T. Angew. Chem. 1980, 92, 470; Mulzer, J.; Kerkmann, T. Angew. Chem.
`Int. Ed. Engl. 1980, 19, 466.
`23. Hungerbühler, E.; Seebach, D.; Wasmuth, D. Helv. Chim. Acta 1981, 64, 1467.
`24. Shieh, H.-M.; Prestwich, G. D. J. Org. Chem. 1981, 46, 4319;
`25. Chamberlin, A. R.; Dezube, M. Tetrahedron Lett. 1982, 23, 3055;
`26. Shieh, H.-M.; Prestwich, G. D. Tetrahedron Lett. 1982, 23, 4643.
`27. Seebach, D.; Wasmuth, D. Angew. Chem. 1981, 93, 1007; Seebach, D.; Wasmuth, D. Angew.
`
`Lupin Ex. 1087 (Page 9 of 11)
`
`

`

`Chem., Int. Ed. Engl. 1981, 20, 971.
`28. Seebach, D.; Prelog, V. Angew. Chem. 1982, 94, 696; Seebach, D.; Prelog, V. Angew. Chem. Int.
`Ed. Engl. 1982, 21, 654.
`29. Mori, K.; Iwasawa, H. Tetrahedron, 1980, 36, 87.
`30. Lawson, K., unpublished results, ETH Zürich, 1982.
`
`Appendix
`Chemical Abstracts Nomenclature (Collective Index Number);
`(Registry Number)
`
`allylated product
`
`(S) and the (R) forms of malic acid
`
`ethanol (64-17-5)
`
`acetic acid (64-19-7)
`
`ether,
`diethyl ether (60-29-7)
`
`hydrogen (1333-74-0)
`
`chloroform (67-66-3)
`
`sodium bicarbonate (144-55-8)
`
`sodium chloride (7647-14-5)
`
`Allyl bromide,
`3-bromo-1-propene (106-95-6)
`
`acetone (67-64-1)
`
`Benzophenone (119-61-9)
`
`potassium (7440-09-7)
`
`Diphenylacetic acid (117-34-0)
`
`Pentane (109-66-0)
`
`
`MgSO4 (7487-88-9)
`
`malic acid,
`(617-48-1)
`
`malate
`
`Lupin Ex. 1087 (Page 10 of 11)
`
`

`

`butyllithium (109-72-8)
`
`Tetrahydrofuran,
`THF (109-99-9)
`
`hexane (110-54-3)
`
`argon (7440-37-1)
`
`calcium hydride (7789-78-8)
`
`diisopropylamine (108-18-9)
`
`diethyl malate,
`,
`(626-11-9)
`
`ȕ-hydroxybutanoate
`
`DIETHYL (2S, 3R)-(+)-3-ALLYL-2-HYDROXYSUCCINATE (73837-97-5)
`
`Butanedioic acid, 2-hydroxy-3-(2-propenyl)-, diethyl ester, [S-(R,S)]
`
`(2S,3R)-3-allyl-2-hydroxysuccinic acid
`
`(S)-Malic Acid (97-67-6)
`
`Copyright © 1921-2005, Organic Syntheses, Inc. All Rights Reserved
`
`Lupin Ex. 1087 (Page 11 of 11)
`
`