- Email: [email protected]
N-Boc-3-trichloromethyloxaziridine: a new, powerful reagent for electrophilic amination
Tetrahedron Letters 39 (1998) 8845-8848
Pergamon
TETRAHEDRON LETTERS
N-Boc-3-trichloromethyloxaziridine: a new, powerful reagent for electrophilic amination Jo~lle Vidal*, Jean-Christophe Hannachi, Gwdna~lle Hourdin, Jean-Christophe Mulatier, Andr6 Collet* F.cole normale supdrieure deLyon, Stgr$ochimie et Interactions moldculaires (UMR CNRS 117), 46, all~e d'ltalie, 69364 Lyon Cedex 07, France:
Received 22 August 1998; accepted 17 September 1998
Abstract: The aza-Wittig reaction of Ph3P=N-Boc with chloral, followed by the oxone oxidation of the resulting imine, afforded N-Boc-3-trichloromethyloxaziridine in excellent yield. This new oxaziridine proved to be a powerful electrophilic amination reagent. © 1998 Elsevier Science Ltd. All rights reserved. Kevwords: Amination Hydrazines Oxaziridines.
Electrophilic amination is an important synthetic reaction in which an electron-poor nitrogen carried by the reagent is transferred to a nucleophilic centre of the substrate to form a Nu-N bond in tile product [1,2,3,4]. Inspired by earlier work by Schmitz and co-workers [5], we have recently shown that this process can be achieved by means of N-alkoxycarbonyl-3aryloxaziridines, such as la-d [6]. These reagents deliver their N-CO~R fragment to nitrogen, carbon, sulphur or phosphorus nucleophiles to give, under mild conditions, their respective amination products in N-protected form (e. g., N-Boc from la). The synthetic value of this methodology has been illustrated by several applications [7,8,9,10,11]. Oxaziridine l a is commercially available [12]. X. ~ (~)--
/O\ C H--N--
PG
CI3C~C H " / ? ~1~1-- Boc
,a:
lb: le: ld:
PG=Boc;X=4-CN PG = Moc (*) ; X= H PG=Z ;X=H PG = Fmoc ; X = 2,4-diCl
2
(*) Moc = Methoxycarbonyl
The nitrogen transfer being faster when the C(3) substituent of the oxaziridine ring is electron-withdrawing in character [6], we set out to explore alternative structures of the same family that would fulfil this condition. This Letter describes the efficient synthesis of 2, a t Fax: +33(0)472728483 ; Email: [email protected] or [email protected]
0040-4039/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved. PH: S0040-4039(98)01983-2
8846
congener of l a - d in which the 3-aryl group is replaced by a 3-trichloromethyl group. This new oxaziridine actually proved to deliver its N-Boc fragment to nucleophiles at a much faster rate than its 3-aryl substituted analogues. The synthesis of 2 was achieved by oxone oxidation of imine 3, which could itself be prepared in two different ways. The reaction of tert-butylcarbamate with chloral gave the stable intermediate 4 (mp 154 °C) [13]; on reaction with SOC12 (1 eq.) and pyridine (1.05 eq.) ~in CH2C12 (1.5 h, reflux), 4 was cohverted to 5 (mp 87 °C); the latter was immediately treated with Et3N (1 eq., CH2C12, rt, 1 h) to give 3 in 54% yield from 4. Alternatively, the aza-Wittig reaction of the N-Boc iminophosphorane 6 [6] with chloral (toluene, reflux, 1 h) gave the same imine 3 in 90% yield. 2 This reaction thus works much faster with chloral than with aromatic aldehydes. For comparison, the reaction of 4-cyanobenzaldehyde with 6 gives 75% of the corresponding imine (precursor of la) only after 17 h in refluxing toluene [14]. The oxone oxidation of 3 to give 2 was carried out on the crude material resulting from the aza-Wittig reaction, in an overall yield of 84% from 6 (experimental details below). The similar synthesis of oxaziridine l a is much less efficient (41% from 6) [6]. This is mostly due to the formation of ca. 25% of the isomeric N-Boc-4-cyanobenzamide during the oxone oxidation of N-Boc-4-cyanobenzaldimine leading to la. In contrast, the conversion of 3 to 2 was clean and the isomeric amide (7) was not formed. Oxaziridine 2 was isolated by flash chromatography (75 g scale) as a colourless, smelling liquid. Variable temperature ~H-NMR spectra (-80 °C to +25 °C in CD2C12) showed the existence of a single stereoisomer3 in which the C13C and Boc substituents are presumably trans. This oxaziridine proved to be reasonably stable below 100 °C and decomposed to unidentified products on heating above 125 °C (by DSC). Boc-NH2
CI3CCHO 88%
-
X .~N.BO c CI3C H 4:X=OH -",- 1 5:X=CI
SOCI2 / pyr
7
Et3N (54% from 4) 1 (Ph3)P----N- Boc 6
CI3CCHO 90%
CI3C- C H- N- Boc 3
Oxone, K2CO3 H20 / CHCI3 (84% from 6)
-
O CI3C.,~N/Boo 2
The reaction of 2 with various amine nucleophiles was investigated. The amination of morpholine 8 proceeded rapidly in diethylether (-78 °C to 0 °C) to give the Boc-protected hydrazine 9 (mp. 128 °C) in 92% isolated yield. When 8 (0.015 mmol) was allowed to react This stoichiometry is critical. 2 Although this synthesis of 3 is shorter and more efficient than that using the reaction of tert-butylcarbamate with chloral, we wish to stress that 6 must itself be prepared from Boc-N3 which is considered to be a dangerous material (explosive). See: Smith PAS Derivatives of hydrazine and other hydronitrogens having N-N bonds. London: Benjamin Cummings, 1983:264. 3 In solution, the 3-aryl-N-alkoxycarbonyloxaziridines exist as slowly equilibrating mixtures of trans and cis stereoisomers in a ca. 9:1 ratio.
8847
with a 1:1 mixture of 2 and l b (0.05 mmol each, chloroform, 20 °C), only 9 and chloral were formed while neither 10 nor benzaldehyde were detected by 'H NMR or TLC. This experiment shows that 2 transferred its N-Boc fragment to morpholine at least 100-fold faster than l b did transfer its N-Moc group 4. O
(
/--'-N
~ ~ / Boc
.<] CI3C" ~N
O~__/N- NHBoc CDCI3, 20 °C
9
+
CI3C- C H O
(quantitative)
'--kN H + IC
8
Moc
6H5
Ok__..jN-NHMoc
lb
10
+ C6Hs-CHO
(not detected)
Although the amination properties of 2 were essentially the same as those of l a [6] (ignoring the kinetic difference), in most cases the yields were slightly better with 2. In general, this improvement was due to a simpler workup (chloral, which is volatile and water soluble, is easier to separate from the product than the 4-cyanobenzaldehyde released from la). In some cases however the faster rate of the N-Boc transfer might also be an advantage, in limiting the formation of certain side products. A typical example is ValOMe 11, which reacts slowly with l a (24 h, rt) to give the Np-Boc-hydrazino ester 12 in 44% yield [6], the main side product being 13, the imine of 11 and 4-cyanobenzaldehyde. The reaction of 1 1 with 2 was much easier (< 3 h, 0 °C), giving 12 in 56% yield; here the amination of 11 is clearly faster than its reaction with the released chloral. NH2 "'~CO2M '
H_N,NHB°c e
11
BZI~N H .~ MeO2C~CO2-;Me4 14
la : 44% 2 : 56% 2 ; -78 °C N+ CH2CI2
cN
/[,h..,
"'~CO2Me '
MeO2C
12
BzI"N'NHB°c = MeO2C~CO2-;DCH 15 (71%)
H
CO2H +
N~.~..~ 16
13 CO2H HN../' 17
The utilisation of oxaziridine 2 allowed an easy preparation of the multi-protected S-hydrazinoglutamic acid derivative 15 from 14 (71%, experimental details below). This transformation did not work satisfactorily with la. To our knowledge, hydrazinoglutamic acid had never been described before; its derivative 15 has an important synthetic potential. In our hands, it could be converted in four simple steps to S-dehydropiperazic and piperazic acids 16 and 17, respectively. This short synthesis of these interesting compounds [15,16,17], a s well as other applications of 2 will be reported separately. 4 For la-d, the relative amination rates of morpholine are 1.2, I, 0.8 and 5.5 respectively; see [6]. This acceleration is probably in line with the large pK, difference between CC13CO2H (0.63) and benzoic acids (= 4).
8848
t-Butyl 2,2,2-trichloroethylidenecarbamate 3: A mixture of anhydrous chloral (38 mL, 390 mmol) and 6 (128.2 g, 340 mmol) in dry toluene (240 mL) was refluxed for 1 h under Ar. After evaporation of toluene in vacuo, Ph3PO (88.4 g, 94%) was precipitated by addition of dry hexane (250 mL) and filtered off. Evaporation of the filtrate gave crude 3 (97 g). An analytical sample of 3 (yield 90 %, 1.12 g fi'om 1.90 g of 6) was obtained as a white solid by vacuum distillation in a Kugelrohr apparatus. Bp 90 °C / 0.2 mbar; mp 58 °C; ~H NMR (200 MHz, CDC13): 5 8.04 (1H, s), 1.54 (9H, s); ~3C NMR (50 MHz, CDC13): 8 27.8, 84.6, 92.8, 159.0, 161.1; calcd for CTH~0C13NO2: C 34.11, H 4.09, N 5.68; found: C 34.10, H 4.05, N 5.66. t - B u t y l 3.trichloromethyl-2-oxaziridinecarboxylate 2: A solution of oxone (200 g) in chilled water (2 L) was added at 0 °C to a vigorously stirred mixture of the above crude 3 in CHC13 (1 L), I~CO 3 (160 g) and water (1.2 L). After 1-h stirring, the aqueous phase was discarded and replaced by fresh solutions of K2CO 3 and oxone. A total of 6 such cycles was effected. The organic phase was (3 x) washed with water, dried on MgSO 4 and concentrated in vacuo (bath temp. < 30 °C). Flash chromatography (520 g SiO 2, CH2C12) gave 74.7 g (84% from 6) of 2 as a stench and colourless oil; ~H NMR (200 MHz, CDCI3): 8 4.91 (1H, s), 1.54 (9H, s); ~3C NMR (50 MHz, CDC13): ~ 27.6 (s), 81.1(d, 2J(CH) = 197 Hz), 86.9 (s), 93.6 (d, 2J(CH) = 15 Hz), 157.9 (s); calcd for C7HIoC13NO3: C 32.03, H 3.84, N 5.34; found: C 31.95, H 3.78, N 5.33.
Dicyclohexylammonium
N-benzyI-N-t-butoxycarbonylamino-5-methyl
(L)-glutamate
15:
A suspension of N-benzyl-5-methyl glutamate (0.503 g, 2 mmol) in CHIC12 (10 mL) was treated at 0 °C by a 2.2 M solution of Me4NOH in MeOH (0.91 mL, 2 mmol), to give 14. After stirring for 5 min the solution was concentrated in vacuo. To the residue dissolved in CH2C12 (10 mL) was added dropwise at -78 °C a solution of 2 (0.551 g, 2.1 mrnol) in CH2C12 (10 mL). The cooling bath was allowed to warm slowly and the mixture was stirred overnight. The aqueous phase (200 mL) obtained after extraction of the reaction mixture was washed by CH2C12 (5 mL), acidified with KHSO 4 (0.272 g) and then extracted with CH~_CI2 (3 x 55 mL). The CH2CL- phase was dried over Na2SO 4 and concentrated in vacuo. ~H NMR (200 MHz, CDCI3) (65 / 35 mixture of two conformers): 87.45 and 6.41 (1H, two broad s), 7.24-7.39 (5 H, m), 4.10 (2H, m), 3.62 (3H, s) 3.47-3.51 (1H, m), 2.4-2.7 (2H, m), 1.80-2.20 (2H, m), 1.34 (9H, s). Addition of dicyclohexylamine (0.40 mL, 2 mmol) to the residue dissolved in iPr_~O (15 mL) afforded 0.773 g (71%) of 15 as a white solid. Mp 126 °C; [a]~~ = +34.3 (c 1, MeOH); calcd for C30H49N306: C 65.79, H 9.02, N 7.67; found: C 66.03, H 9.15, N 7.66.
References [1] Mulzer J, Altenbach H-J, Braun M, Krohn K, Reissig H-U Organic Synthesis Highlights. Weinheim: VCH, 199l:45-53. [2] Erdik E, Ay M Chem. Rev. 1989;89:1947-1980. [3] Greck C, Gen~t J-P Synlett 1997:741-748and refs therein. [4] Alberti A, Can~ F, Dembech P, Lazzari D, Ricci A, Seconi G J. Org. Chem. 1996;61:1677-1681. [5] Andreae S. Schmitz E Synthesis 1991:327-341 and refs therein. [6] Vidal J, Damestoy S, Guy L, Hannachi J-C, Aubry A, Collet A Chem. Eur. J. 1997;3:1691-1709. [7l Aubry A, Mangeot J-P, Vidal J, Collet A, Zerkout S, Marraud M Int. J. Pept. Protein Res. 1994;43:305-311. [8] Niederer DA, Kapron JT, Vederas JC TetrahedronLett. 1993;34:6859--6862. [9] Klinguer C, Melnyk O, Loing E, Gras-Masse H, Tetrahedron Lett. 1996;40:7259-7262. [10] Charnas R, Gubernator K, Heinze I, Hubschwerlen C (Hoffmann-La Roche), Eur. Patent 1992:508234. Chem. Abstr. 1993;119:117025. [11] Collet A, Vidal J, Hannachi J-C, Guy L (CNRS) Brevet Fran~ais 1995:10685. PCT 1997 WO 09303. Chem. Abstr. 1997; 126:264365. [12] Vidal J, Guy L, Sterin S, Collet A Acros Organics Acta 1995;1: 58. Acros reference 29709. [13] This is a peculiarity of chloral chemistry. See Ulrich H, Tucker B, Sayigh AAR J. Org. Chem. 1968;33:2887-2889. [14] Vidal J, Guy L, St6rin S, Collet A J. Org. Chem. 1993;58:4791-4793. [15] Hale KJ, Cai J, Williams G Synlett 1998:149-152 and refs therein. [16] Ciufolini MA, Xi N J. Org. Chem. 1997;62:2320-2321 and refs therein. [17] Schmidt U, Braun C, Sutoris H Synthesis 1996:223-229and refs therein.
Pergamon
TETRAHEDRON LETTERS
N-Boc-3-trichloromethyloxaziridine: a new, powerful reagent for electrophilic amination Jo~lle Vidal*, Jean-Christophe Hannachi, Gwdna~lle Hourdin, Jean-Christophe Mulatier, Andr6 Collet* F.cole normale supdrieure deLyon, Stgr$ochimie et Interactions moldculaires (UMR CNRS 117), 46, all~e d'ltalie, 69364 Lyon Cedex 07, France:
Received 22 August 1998; accepted 17 September 1998
Abstract: The aza-Wittig reaction of Ph3P=N-Boc with chloral, followed by the oxone oxidation of the resulting imine, afforded N-Boc-3-trichloromethyloxaziridine in excellent yield. This new oxaziridine proved to be a powerful electrophilic amination reagent. © 1998 Elsevier Science Ltd. All rights reserved. Kevwords: Amination Hydrazines Oxaziridines.
Electrophilic amination is an important synthetic reaction in which an electron-poor nitrogen carried by the reagent is transferred to a nucleophilic centre of the substrate to form a Nu-N bond in tile product [1,2,3,4]. Inspired by earlier work by Schmitz and co-workers [5], we have recently shown that this process can be achieved by means of N-alkoxycarbonyl-3aryloxaziridines, such as la-d [6]. These reagents deliver their N-CO~R fragment to nitrogen, carbon, sulphur or phosphorus nucleophiles to give, under mild conditions, their respective amination products in N-protected form (e. g., N-Boc from la). The synthetic value of this methodology has been illustrated by several applications [7,8,9,10,11]. Oxaziridine l a is commercially available [12]. X. ~ (~)--
/O\ C H--N--
PG
CI3C~C H " / ? ~1~1-- Boc
,a:
lb: le: ld:
PG=Boc;X=4-CN PG = Moc (*) ; X= H PG=Z ;X=H PG = Fmoc ; X = 2,4-diCl
2
(*) Moc = Methoxycarbonyl
The nitrogen transfer being faster when the C(3) substituent of the oxaziridine ring is electron-withdrawing in character [6], we set out to explore alternative structures of the same family that would fulfil this condition. This Letter describes the efficient synthesis of 2, a t Fax: +33(0)472728483 ; Email: [email protected] or [email protected]
0040-4039/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved. PH: S0040-4039(98)01983-2
8846
congener of l a - d in which the 3-aryl group is replaced by a 3-trichloromethyl group. This new oxaziridine actually proved to deliver its N-Boc fragment to nucleophiles at a much faster rate than its 3-aryl substituted analogues. The synthesis of 2 was achieved by oxone oxidation of imine 3, which could itself be prepared in two different ways. The reaction of tert-butylcarbamate with chloral gave the stable intermediate 4 (mp 154 °C) [13]; on reaction with SOC12 (1 eq.) and pyridine (1.05 eq.) ~in CH2C12 (1.5 h, reflux), 4 was cohverted to 5 (mp 87 °C); the latter was immediately treated with Et3N (1 eq., CH2C12, rt, 1 h) to give 3 in 54% yield from 4. Alternatively, the aza-Wittig reaction of the N-Boc iminophosphorane 6 [6] with chloral (toluene, reflux, 1 h) gave the same imine 3 in 90% yield. 2 This reaction thus works much faster with chloral than with aromatic aldehydes. For comparison, the reaction of 4-cyanobenzaldehyde with 6 gives 75% of the corresponding imine (precursor of la) only after 17 h in refluxing toluene [14]. The oxone oxidation of 3 to give 2 was carried out on the crude material resulting from the aza-Wittig reaction, in an overall yield of 84% from 6 (experimental details below). The similar synthesis of oxaziridine l a is much less efficient (41% from 6) [6]. This is mostly due to the formation of ca. 25% of the isomeric N-Boc-4-cyanobenzamide during the oxone oxidation of N-Boc-4-cyanobenzaldimine leading to la. In contrast, the conversion of 3 to 2 was clean and the isomeric amide (7) was not formed. Oxaziridine 2 was isolated by flash chromatography (75 g scale) as a colourless, smelling liquid. Variable temperature ~H-NMR spectra (-80 °C to +25 °C in CD2C12) showed the existence of a single stereoisomer3 in which the C13C and Boc substituents are presumably trans. This oxaziridine proved to be reasonably stable below 100 °C and decomposed to unidentified products on heating above 125 °C (by DSC). Boc-NH2
CI3CCHO 88%
-
X .~N.BO c CI3C H 4:X=OH -",- 1 5:X=CI
SOCI2 / pyr
7
Et3N (54% from 4) 1 (Ph3)P----N- Boc 6
CI3CCHO 90%
CI3C- C H- N- Boc 3
Oxone, K2CO3 H20 / CHCI3 (84% from 6)
-
O CI3C.,~N/Boo 2
The reaction of 2 with various amine nucleophiles was investigated. The amination of morpholine 8 proceeded rapidly in diethylether (-78 °C to 0 °C) to give the Boc-protected hydrazine 9 (mp. 128 °C) in 92% isolated yield. When 8 (0.015 mmol) was allowed to react This stoichiometry is critical. 2 Although this synthesis of 3 is shorter and more efficient than that using the reaction of tert-butylcarbamate with chloral, we wish to stress that 6 must itself be prepared from Boc-N3 which is considered to be a dangerous material (explosive). See: Smith PAS Derivatives of hydrazine and other hydronitrogens having N-N bonds. London: Benjamin Cummings, 1983:264. 3 In solution, the 3-aryl-N-alkoxycarbonyloxaziridines exist as slowly equilibrating mixtures of trans and cis stereoisomers in a ca. 9:1 ratio.
8847
with a 1:1 mixture of 2 and l b (0.05 mmol each, chloroform, 20 °C), only 9 and chloral were formed while neither 10 nor benzaldehyde were detected by 'H NMR or TLC. This experiment shows that 2 transferred its N-Boc fragment to morpholine at least 100-fold faster than l b did transfer its N-Moc group 4. O
(
/--'-N
~ ~ / Boc
.<] CI3C" ~N
O~__/N- NHBoc CDCI3, 20 °C
9
+
CI3C- C H O
(quantitative)
'--kN H + IC
8
Moc
6H5
Ok__..jN-NHMoc
lb
10
+ C6Hs-CHO
(not detected)
Although the amination properties of 2 were essentially the same as those of l a [6] (ignoring the kinetic difference), in most cases the yields were slightly better with 2. In general, this improvement was due to a simpler workup (chloral, which is volatile and water soluble, is easier to separate from the product than the 4-cyanobenzaldehyde released from la). In some cases however the faster rate of the N-Boc transfer might also be an advantage, in limiting the formation of certain side products. A typical example is ValOMe 11, which reacts slowly with l a (24 h, rt) to give the Np-Boc-hydrazino ester 12 in 44% yield [6], the main side product being 13, the imine of 11 and 4-cyanobenzaldehyde. The reaction of 1 1 with 2 was much easier (< 3 h, 0 °C), giving 12 in 56% yield; here the amination of 11 is clearly faster than its reaction with the released chloral. NH2 "'~CO2M '
H_N,NHB°c e
11
BZI~N H .~ MeO2C~CO2-;Me4 14
la : 44% 2 : 56% 2 ; -78 °C N+ CH2CI2
cN
/[,h..,
"'~CO2Me '
MeO2C
12
BzI"N'NHB°c = MeO2C~CO2-;DCH 15 (71%)
H
CO2H +
N~.~..~ 16
13 CO2H HN../' 17
The utilisation of oxaziridine 2 allowed an easy preparation of the multi-protected S-hydrazinoglutamic acid derivative 15 from 14 (71%, experimental details below). This transformation did not work satisfactorily with la. To our knowledge, hydrazinoglutamic acid had never been described before; its derivative 15 has an important synthetic potential. In our hands, it could be converted in four simple steps to S-dehydropiperazic and piperazic acids 16 and 17, respectively. This short synthesis of these interesting compounds [15,16,17], a s well as other applications of 2 will be reported separately. 4 For la-d, the relative amination rates of morpholine are 1.2, I, 0.8 and 5.5 respectively; see [6]. This acceleration is probably in line with the large pK, difference between CC13CO2H (0.63) and benzoic acids (= 4).
8848
t-Butyl 2,2,2-trichloroethylidenecarbamate 3: A mixture of anhydrous chloral (38 mL, 390 mmol) and 6 (128.2 g, 340 mmol) in dry toluene (240 mL) was refluxed for 1 h under Ar. After evaporation of toluene in vacuo, Ph3PO (88.4 g, 94%) was precipitated by addition of dry hexane (250 mL) and filtered off. Evaporation of the filtrate gave crude 3 (97 g). An analytical sample of 3 (yield 90 %, 1.12 g fi'om 1.90 g of 6) was obtained as a white solid by vacuum distillation in a Kugelrohr apparatus. Bp 90 °C / 0.2 mbar; mp 58 °C; ~H NMR (200 MHz, CDC13): 5 8.04 (1H, s), 1.54 (9H, s); ~3C NMR (50 MHz, CDC13): 8 27.8, 84.6, 92.8, 159.0, 161.1; calcd for CTH~0C13NO2: C 34.11, H 4.09, N 5.68; found: C 34.10, H 4.05, N 5.66. t - B u t y l 3.trichloromethyl-2-oxaziridinecarboxylate 2: A solution of oxone (200 g) in chilled water (2 L) was added at 0 °C to a vigorously stirred mixture of the above crude 3 in CHC13 (1 L), I~CO 3 (160 g) and water (1.2 L). After 1-h stirring, the aqueous phase was discarded and replaced by fresh solutions of K2CO 3 and oxone. A total of 6 such cycles was effected. The organic phase was (3 x) washed with water, dried on MgSO 4 and concentrated in vacuo (bath temp. < 30 °C). Flash chromatography (520 g SiO 2, CH2C12) gave 74.7 g (84% from 6) of 2 as a stench and colourless oil; ~H NMR (200 MHz, CDCI3): 8 4.91 (1H, s), 1.54 (9H, s); ~3C NMR (50 MHz, CDC13): ~ 27.6 (s), 81.1(d, 2J(CH) = 197 Hz), 86.9 (s), 93.6 (d, 2J(CH) = 15 Hz), 157.9 (s); calcd for C7HIoC13NO3: C 32.03, H 3.84, N 5.34; found: C 31.95, H 3.78, N 5.33.
Dicyclohexylammonium
N-benzyI-N-t-butoxycarbonylamino-5-methyl
(L)-glutamate
15:
A suspension of N-benzyl-5-methyl glutamate (0.503 g, 2 mmol) in CHIC12 (10 mL) was treated at 0 °C by a 2.2 M solution of Me4NOH in MeOH (0.91 mL, 2 mmol), to give 14. After stirring for 5 min the solution was concentrated in vacuo. To the residue dissolved in CH2C12 (10 mL) was added dropwise at -78 °C a solution of 2 (0.551 g, 2.1 mrnol) in CH2C12 (10 mL). The cooling bath was allowed to warm slowly and the mixture was stirred overnight. The aqueous phase (200 mL) obtained after extraction of the reaction mixture was washed by CH2C12 (5 mL), acidified with KHSO 4 (0.272 g) and then extracted with CH~_CI2 (3 x 55 mL). The CH2CL- phase was dried over Na2SO 4 and concentrated in vacuo. ~H NMR (200 MHz, CDCI3) (65 / 35 mixture of two conformers): 87.45 and 6.41 (1H, two broad s), 7.24-7.39 (5 H, m), 4.10 (2H, m), 3.62 (3H, s) 3.47-3.51 (1H, m), 2.4-2.7 (2H, m), 1.80-2.20 (2H, m), 1.34 (9H, s). Addition of dicyclohexylamine (0.40 mL, 2 mmol) to the residue dissolved in iPr_~O (15 mL) afforded 0.773 g (71%) of 15 as a white solid. Mp 126 °C; [a]~~ = +34.3 (c 1, MeOH); calcd for C30H49N306: C 65.79, H 9.02, N 7.67; found: C 66.03, H 9.15, N 7.66.
References [1] Mulzer J, Altenbach H-J, Braun M, Krohn K, Reissig H-U Organic Synthesis Highlights. Weinheim: VCH, 199l:45-53. [2] Erdik E, Ay M Chem. Rev. 1989;89:1947-1980. [3] Greck C, Gen~t J-P Synlett 1997:741-748and refs therein. [4] Alberti A, Can~ F, Dembech P, Lazzari D, Ricci A, Seconi G J. Org. Chem. 1996;61:1677-1681. [5] Andreae S. Schmitz E Synthesis 1991:327-341 and refs therein. [6] Vidal J, Damestoy S, Guy L, Hannachi J-C, Aubry A, Collet A Chem. Eur. J. 1997;3:1691-1709. [7l Aubry A, Mangeot J-P, Vidal J, Collet A, Zerkout S, Marraud M Int. J. Pept. Protein Res. 1994;43:305-311. [8] Niederer DA, Kapron JT, Vederas JC TetrahedronLett. 1993;34:6859--6862. [9] Klinguer C, Melnyk O, Loing E, Gras-Masse H, Tetrahedron Lett. 1996;40:7259-7262. [10] Charnas R, Gubernator K, Heinze I, Hubschwerlen C (Hoffmann-La Roche), Eur. Patent 1992:508234. Chem. Abstr. 1993;119:117025. [11] Collet A, Vidal J, Hannachi J-C, Guy L (CNRS) Brevet Fran~ais 1995:10685. PCT 1997 WO 09303. Chem. Abstr. 1997; 126:264365. [12] Vidal J, Guy L, Sterin S, Collet A Acros Organics Acta 1995;1: 58. Acros reference 29709. [13] This is a peculiarity of chloral chemistry. See Ulrich H, Tucker B, Sayigh AAR J. Org. Chem. 1968;33:2887-2889. [14] Vidal J, Guy L, St6rin S, Collet A J. Org. Chem. 1993;58:4791-4793. [15] Hale KJ, Cai J, Williams G Synlett 1998:149-152 and refs therein. [16] Ciufolini MA, Xi N J. Org. Chem. 1997;62:2320-2321 and refs therein. [17] Schmidt U, Braun C, Sutoris H Synthesis 1996:223-229and refs therein.