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2-(Trimethylsilyl)thiazole

A Versatile Formyl Carbanion Equivalent for Organic Synthesis

2,2-Dimethyl-1, 3-dioxan-5-one

A Dihydroxyacetone Equivalent for Asymmetric Synthesis

Camphor Derivatives Oxazoline-N-oxides

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April 1998

New Chiral Auxiliaries for Asymmetric [2+3] Cycloadditions

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No 25: N,N-Diisopropyl-1-fluoro-2-methylpropenylamine, a powerful reagent for fluorination of alcohols under neutral conditions. 1,3,4-Triphenyl-4,5-dihydro-1H-1,2,4-triazol-5ylidene and 5-methoxy-1,3,4-triphenyl-4,5dihydro-1H-1,2,4-triazolin. The first commercially available stable carbene and a versatile precursor for its preparation and in situ formation. R,R- and S,S-bis(2,2-phenylthiomethyl)dihydropyrans. One pair in the series of Ley reagents. Efficient protecting and resolving agents for 1,2- diols. Asymmetric Catalysis with chiral dirhodium(II) carboxamidates. 2,2-Dimethyl-1,3-dioxan-5-one, a dihydroxyacetone equivalent for asymmetric synthesis. (R)-(-)-2-(2-Isoindolinyl)butan-1-ol, a novel chiral -aminoalcohol for asymmetric reduction of prochiral ketones. Camphor derivatives oxazoline-N-oxides, new chiral auxiliaries for asymmetric [2+3] cycloadditions. Bis-(2,4,6-trimethylpyridine)iodine(I)hexafluorophosphate, a powerful iodinating agent. Ethenyl-, ethynyl-, propadienyl- and 1-propynyltributylstannanes, useful unsaturated stannanes in organic synthesis. 2-(Trimethylsilyl)thiazole. 1,5-Diazabicyclo[4,3,0]non-5-ene (DBN). 2,2-Dimethyl-1,3-dioxan-5-one, a dihydroxyacetone equivalent for asymmetric synthesis. (S,E)-(-)-Methyl-4-(phenylmethoxy)-2-pentenoate, a synthetically useful enantiopure building block. To be continued

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Dipartimento di Chimica, Laboratorio di Chimica Organica, Universit, Via L. Borsari 46, 44100 Ferrara, Italy

Alessandro Dondoni

2-(Trimethylsilyl)thiazole

A Versatile Formyl Carbanion Equivalent for Organic Synthesis

The synthetic equivalence of 2-(trimethylsilyl)thiazole (2-TST) 2 to the formyl carbanion stems from the sequential addition to the aldehyde carbonyl and the cleavage of the thiazole ring of the resulting hydroxyalkylthiazole. This formulation has been previously exploited for higher and rare sugar synthesis and more recently for a-amino aldehyde homologation.
Scheme 1
N S 1 Br 1. BuLi 2. Me 3SiCl N S 2-TST, 2 SiMe 3

expeditious and operatively simple one-pot protocol involving a sequence of three high yield reactions, all occurring under almost neutral conditions, i. e. N-methylation, reduction, and hydrolysis (5). Since these operations are tolerated by a variety of substituents and protective groups and do not affect the stereocentres of the substrate, the scope of this thiazole-based synthesis of aldehydes (ThiazoleAldehyde Synthesis) has been proved to be quite large (6). The homologation of various chiral alkoxyaldehydes and dialdoses (7,8) by the iterative addition-deblocking sequence, demonstrates the remarkable implementation of this aldehyde synthesis in carbohydrate chemistry. Earlier (9) and recent observations (10) have shown that the sense of the diastereoselectivity of the addition of 2-TST 2 to chiral N-protected -amino aldehydes can be reversed to give either syn or anti amino alcohols by the use of singly or doubly protected derivatives respectively (Scheme 4 and Table 1). Based on this tunable stereoselectivity, efficient syntheses of chiral building blocks of important molecules, such as the potent anticancer agent Taxol (11) and the selective HIV protease inhibitor Ro-31-8959 (12) (Scheme 5), have been recently reported.

85%

Owing to a facile halogen-metal exchange and subsequent transmetalation, 2-(trimethylsilyl)thiazole (2-TST) 2 can be effectively prepared in multigram quantities (20-30 g) from 2-bromothiazole 1 by a welldetailed and independently checked high yield procedure (85%) (1) (Scheme 1). 2-TST 2 is a stable, moisture- and air-insensitive compound reacting with various C-electrophiles under very mild condiFor the synthesis of N-benzoyl-3-phenylisoserine 6, the Taxol sidetions (from room temperature to -20 C) and in the absence of a catachain, the installation of the hydroxyl group with the correct R-conlyst to give the corresponding 2-substituted thiazoles in very good figuration was effectively achieved by syn stereoselective addition (ds yields (2) (Scheme 2). A mechanistic rationale has been provided (3) to account for the unprecedented carbodesilylation reactions of the heteroaryl silane 2 withScheme 2 out the agency of any added catalyst. On the N N other hand desilylation of 2 does not occur R R CF3 R under mild basic conditions. This stability has S S O been conveniently exploited for the preparaR-CHO F 3C OSiMe 3 OSiMe 3 tion of 4- and 5-substituted thiazoles via selective functionalization of the thiazole ring at CN 4 and C-5 followed by desilylation (4).
N R 2C=C=O S 2 S R R + N N S CO 2 Et CO2 Et N S O N -(CH2)n -CO 2 R RCO2-(CH 2)n -COCl O SiMe 3 R-COCl

The model reaction of 2 with the chiral alkoxy aldehyde 3 (D-glyceraldehyde) to give the -hydroxyalkylthiazole 4 in high yield and diastereoselectivity followed by the liberation of the homologue aldehyde 5 (Derythrose) by cleavage of the thiazole ring, demonstrate the actual synthetic equivalence of 2-TST 2 to the formyl carbanion synthon (1) (Scheme 3). The cleavage of the thiazole ring into the formyl group is carried out by an

OSiMe 3 S

N R

Acros Organics Acta 4 - 1998

2-(Trimethylsilyl)thiazole - A Versatile Formyl Carbanion Equivalent for Organic Synthesis

Alessandro Dondoni Dipartimento di Chimica, Laboratorio di Chimica Organica, Universit, Via L. Borsari 46, 44100 Ferrara, Italy

Scheme 3
N S 2-TST, CHO 3 96% OH 4 (ds 95%) SiMe 3 2 O N O S 1. NaH / BnBr 2. CF3S O3Me 3. NaBH 4 4. HgCl 2-H 2O 62% O

the side-chain of Taxotere (15), a semisynthetic and more potent analogue of Taxol. Given the anti relationship between the amino and hydroxyl group in the N-Boc-O CHO amino--hydroxy-4-phenylbutanal 7, key intermediate for the preparation of the OBn hydroxyethylamine isosteric dipeptide 8 (16) 5 precursor of Ro 31-8959 (see Scheme 5), the addition of 2-TST 2 was carried out to the doubly N-protected L-phenylalaninal 13 (10) (Scheme 7). In addition to the tert-butoxycarbonyl (Boc) that was required in the target aldehyde 7, the second amino protective group was the p-methoxybenzyl (PMB) since this was expected to be easily and selectiveBoc N N ly removed. The anti selective addition of 2 to 13 (ds 75%) followed by simple elaborations S of the resulting main product 14 (removal of OH PMB under oxidative conditions, protection anti of the hydroxyl group, unmasking of the formyl group) afforded the aldehyde 15, a silyl derivative of 7, in 25% yield from Lphenylalanine, the chiral starting material of this synthesis. In conclusion, the fortunate occurrence of a set of positive features is bringing 2-(trimethylsilyl)thiazole 2 to increasing attention (17) as a valuable reagent in heterocyclic chemistry and an efficient formyl anion equivalent (18) for organic synthesis.

O O

CHO

Scheme 4
N R' N R CHO no catalyst Boc S 2-TST, SiMe 3 2 R OH syn S R' N Boc N R'

Table 1: addition of 2-(Trimethylsilyl)thiazole 2 to N-Boc a-Amino Aldehydesa (see Scheme 4)

Entry 1 2 3 4 5 6 7 8 9 10 11 12

R OCH2 PhCH2OCH2 (R) OCHMe (R) TBDPSOCHMe Ph Ph PhCH2 PhCH2 i-C4H9 i-C4H9 c-C10H11CH2 c-C10H11CH2

R CMe2 H CMe2 H PhCH2 H PhCH2 H PMB H PhCH2 H

Yieldb % 85 60 68 60 67 70 70 74 81 75 71 79

syn : anti 8 : 92 80 : 20 15 : 85 78 : 22 40 : 60 88 : 12 22 : 78 80 : 20 25 : 75 77 : 23 17 : 83 83 : 17

References
(1) Dondoni, A.; Merino, P. Org. Synth. 1993, 72, 21. (2) Dondoni, A. Pure & Appl. Chem. 1990, 62, 643; Dondoni, A.; Boscarato, A.; Formaglio, P.; Bgu, J.-P.; Benayoud, F. Synthesis, 1995, 654. (3) Dondoni, A.; Douglas, A. W.; Shinkai, I. J. Org. Chem. 1993, 58, 3196. (4) 4a) Dondoni, A.; Mastellari, A. R.; Medici, A.; Negrini, E.; Pedrini, P. Synthesis, 1986, 757. 4b) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P. Synthesis, 1987, 998. It is worth pointing out that the 1H NMR spectra for 4- and 5-trimethylstannylthiazole reported in ref. 4a were inadvertantly interchanged. Thanks are due to Professor T. R. Kelly (Boston College, Chestnut Hill, USA) for bringing this mistake to our attention. See: Kelly, T. R.; Lang, F. Tetrahedron Lett. 1995, 36, 9293. (5) Dondoni, A.; Marra, A. ; Perrone, D. J. Org. Chem. 1993, 58, 275. (6) For the illustration of a wider scope of the Thiazole-Aldehyde Synthesis by the use of thiazole based intermediates bearing various structural arrays at C-2, see: 6a) Dondoni, A. in New Aspects of Organic Chemistry II, Yoshida, Z.; Ohshiro, Y. Eds., Kodansha, Tokyo, and VCH, Weinheim, 1992, p. 105. 6b) Dondoni, A. in Modern Synthetic Methods, Scheffold, R., Ed., Verlag Helvetica Chimica Acta, Basel, 1992, p. 377. (7) 7a) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A. Angew. Chem. Int. Ed. Engl. 1986, 25, 835.

a Boc = tert-butoxycarbonyl; TBDPS = tert-butyldiphenylsilyl; PMB = pmethoxybenzyl. All reactions were carried out in CH2Cl2 at -20 to -30 C; desilylative workup was carried out with Bu4NF in THF. b Isolated chemical yields of mixtures of syn and anti amino alcohols.

95%) of 2 to the singly N-protected N-benzoylphenylglycinal 9 (13) (Scheme 6). The rest of the synthesis was straightforward since it required the protection of the amino alcohol 10 by acetonization and the release of the aldehyde 11 by the usual thiazolyl-to-formyl deblocking protocol. The almost quantitative oxidation of 11 by KMnO4 in buffered tert-butanol gave the oxazolidine-type protected 3-phenylisoserine 12 in 47% overall yield from L-phenylglycine, the chiral starting material employed for this synthesis. The same route was followed for the synthesis of the N-Boc analogue of 12, which has already proved (14) to be a convenient substrate for the construction of
4
Acros Organics Acta 4 - 1998

2-(Trimethylsilyl)thiazole - A Versatile Formyl Carbanion Equivalent for Organic Synthesis

Alessandro Dondoni Dipartimento di Chimica, Laboratorio di Chimica Organica, Universit, Via L. Borsari 46, 44100 Ferrara, Italy

Scheme 5

AcO

OH

NHBz Ph OH CO2 H Ph

NHBz

O O O HO OBz OAc

OH

(8)
Taxol

(9)
Ph NHBoc Ph OH CHO H

R
BocHN OH O N

(10)
Ro 31-8959

(11)
NHBu-t

(12) (13) (14)

Scheme 6
S H Ph O 9

N SiMe3 Ph OH 10 (ds 95%) NHBz S two steps N

NHBz

(15)
74%

2-TST, 2

75%

(16)

BzN Ph O CHO KMnO 4 Ph 95%

BzN CO 2 H O

(17)

11

12

Scheme 7
N PMB N Ph CHO Boc S 2-TST, 2 SiMe 3 Ph N OH 14 (ds 75%) PMB N Boc S three steps Ph NHBoc CHO OSiMe 2Bu-t 15

(18)

87%
13

63%

7b) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.Tetrahedron 1987, 43, 3533. 7c) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P. J. Org. Chem. 1989, 54, 693. 7d) Dondoni, A.; Orduna, J.; Merino, P. Synthesis 1992, 201. The multigram synthesis of rare sugars such as D-talose and L-gulose will be reported in a forthcoming publication. Dondoni, A.; Marra, A. unpublished results. Dondoni, A.; Fantin, G.; Fogagnolo, M.; Pedrini, P. J. Org. Chem. 1990, 55, 1439. Dondoni, A.; Perrone, D.; Merino, P. J. Org. Chem. 1995, 60, 8074. Nicolaou, K. C.; Dai, W.-M; Guy, R. K. Angew. Chem. Int. Ed. Engl. 1994, 33, 15. Drugs Future 1995, 20, 321. Dondoni, A.; Perrone, D.; Semola, T. Synthesis 1995, 181. Bourzat, J. D.; Commeron, A. Tetrahedron Lett. 1993, 34, 6049. Gunard, D.; Guritte-Voegelein, F.; Potier, P. Acc. Chem. Res. 1993, 26, 160. Parkes, K. E. B.; Bushnell, D. J.; Crackett, P. H.; Dunsdon, S. J.; Freeman, A. C.; Gunn, M. P.; Hopkins, R. A.; Lambert, R. W.; Martin, J. A.; Merrett, J. H.; Redshaw, S.; Spurden, W. C.; Thomas, G. J. J. Org. Chem. 1994, 59, 3656. 17a) Hassner, A.; Stumer, C. Organic Syntheses Based on Name Reactions and Unnamed Reactions, Elsevier, Oxford, 1994, p. 100. 17b) Fieser, M. Reagents for Organic Synthesis, Wiley, New York, 1992, Vol. 16, p. 362. 17c) Maillard, Ph.; Huel, C.; Momenteau, M. Tetrahedron Lett. 1992, 33, 8081. 17d) Wagner, A.; Mollath, M. Tetrahedron Lett. 1993, 34, 619. 17e) Khare, N. K.; Sood, R. K.; Aspinall, G. O. Can. J. Chem. 1994, 72, 237. Dondoni, A.; Colombo, L. Advances in the Use of Synthons in Organic Chemistry, Dondoni, A., Ed., JAI Press, London, 1993.

Products available at ACROS ORGANICS

2-(Trimethylsilyl)thiazole, 96%................................................................................. [79265-30-8] 29229-0010 ........................................................................................................................................................... 29229-0050 2-Bromothiazole, 98+% (GC) .................................................................................................... [3034-53-5] 17091-0050 ....................................................................................................................................................................... 17091-0250 Methyl trifluoromethanesulfonate............................................................................................... [333-27-7] 41501-0250 1 ml 5 ml 5 ml 25 ml 25 g

Acros Organics Acta 4 - 1998

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Institut fr Organische Chemie, Rheinisch-Westflische Technische Hochschule, Professor Pirlet-Strae 1, 52074 Aachen, Germany

D. Enders*, B. Bockstiegel, W. Gatzweiler, U. Jegelka, B. Dcker

2,2-Dimethyl-1,3-dioxan-5-one

A Dihydroxyacetone Equivalent for Asymmetric Synthesis

For the SAMP/RAMP-hydrazone method, the title compound 2,2-dimethyl-1,3-dioxan-5-one (Figure 1) proved to be a versatile C3-building block and dihydroxyacetone equivalent in asymmetric synthesis. Dihydroxyacetone phosphate (DHAP) is used in nature as a C3-methylene compoO nent in enzyme-catalyzed aldol reactions to form 2-ketoses. Until very recently, chemical synthetic DHAP equivalents allowing O O the transfer of this simple C3 building block to electrophilic substrates by asymmetric H 3C CH 3 synthesis have not been available (1). The title dioxanone 1 (Figure 1) (2) in combination with the SAMP/RAMP-hydrazone method (3) has turned out to be broadly applicable in this respect and can be used to carry out highly diastereo- and enantioselective C-C bond formations.
Figure 1

manner, occurring regioselectively at the -position and without epimerization of the -stereogenic center. In this way, C2-symmetric ketones 4 are available in good overall yields and with virtually complete asymmetric induction (de, ee 98%) (Scheme 1) (4). The remarkable synthetic flexibility of this procedure is demonstrated by the use of two different electrophiles (boxed, Scheme 2), which give rise to ,-bisalkylated ketones 5 of very high diastereo- and enantiomeric purity. For instance, after removal of the protecting groups, the de novo synthesis of C5- to C9-deoxy sugars is possible (e.g. 6, de, ee 95%). In addition, after reduction of the keto group with lithium tri-sec-butylborohydride to 7, the corresponding polyols are also available (e.g. 8, de, ee 95%) (Scheme 2) (5). As is depicted in Scheme 3, the protocol can be further extended by the introduction of a nitrogen functionality, leading finally to hydroxylated piperidines (azasugars), potential glycosidase inhibitors. For instance, the bromide azide substitution variant via 9 leads to the piperidine 10 after intramolecular reductive amination and acetonide cleavage. Alternatively, the oxirane azide ring opening variant via 11 gives rise to the polyhydroxylated piperidine 12 (6). It should also be mentioned that 1,3-diols and polyols can be synthesized by reductive removal of the keto group in compounds of type 5 (7). ,-Bisbenzylation of 1, using the SAMP-hydrazone method, leads to the C2-symmetric ketone 13 in 70% overall yield with practically complete asymmetric induction. This opens an efficient entry via the bistriflate 14 and bisazide 15 to the diaminoalcohol 16, which is an important precursor of several HIV-1 protease inhibitors, e.g. A74704 of Abbott (Scheme 4) (8). Finally, the synthetic utility of the title dioxanone 1, is demonstrated in two efficient asymmetric syntheses of natural products, namely the 18-membered lichen macrolide (+)-aspicilin via 17 (Scheme 5) (9) and Lthreo-sphingosine, a subunit of many glycosphingolipids that
Acros Organics Acta 4 - 1998

Transformation of 1 into the corresponding SAMP-hydrazone, together with -alkylation affords the hydrazones 2, which are oxidatively cleaved to the -alkylated ketones 3 in good overall yields and with excellent enantiomeric excesses (2a,b,4). Furthermore, a second alkylation of the monoalkylated hydrazones 2 is possible in the same
Scheme 1

N O 1. SAMP, toluene 2. t BuLi 3. RX O CH 3 1 1. t BuLi 2. RX 3. O 3, CH 2Cl 2 O R O H 3C 4 O CH 3 R de,ee 98 % cy = 30 - 65 % O H 3C 2 N R O CH 3 OCH 3 O3, CH 2Cl 2 O H 3C 3 ee = 88 - 98 % cy = 32 - 71 % O R O CH 3

O H 3C

2,2-Dimethyl-1,3-dioxan-5-one - A Dihydroxyacetone Equivalent for Asymmetric Synthesis

D. Enders*, B. Bockstiegel, W. Gatzweiler, U. Jegelka, B. Dcker Institut fr Organische Chemie, Rheinisch-Westflische Technische Hochschule, Professor Pirlet-Strae 1, 52074 Aachen, Germany

Scheme 2
O R 1X R 2X O R2 O H 3C 5 O CH 3 R1 1. Pd-C, H2 2. 3 N HCl, MeOH >95 % O H 3C HO OH OH

O H 3C

O CH 3

SAMP-hydrazone method cy = 30 - 62 %

6 de,ee 95 %

mediate cell recognition events. One of the key steps in the sphingosine synthesis is the aldol reaction of 1 with racemic -phenylselenylpentadecanal to introduce the unsaturated side chain via 18 (Scheme 6) (10). In conclusion, from the few examples presented here, it is evident that 2,2-dimethyl-1,3-dioxan-5one constitutes a synthetically very useful C3-building block and dihydroxyacetone equivalent in asymmetric synthesis.

LiB[CH(CH3)C 2H 5]3H, toluene

68 %

[ R1 = CH 2OBn, R 2 = Me ]

R 1 = H, Me, O

O H 3C

OH OBn O H 3C 7 O CH 3 1. 3 N HCl, MeOH 2. Pd-C, H 2 >95 % H 3C HO

OH OH OH

R =

O
, CH 2OBn,

8 de,ee 95 %

References
(1) Enders, D. Enzymemimetic C-C and C-N Bond Formations in Stereoselective Synthesis, Ottow, E.; Schllkopf, K.; Schulz, B.-G. (Eds.), Springer Verlag, Berlin, 1993, p. 63-90. (2) a) Enders, D.; Bockstiegel, B. Synthesis 1989, 493-496. b) Bockstiegel, B. dissertation, Technical University of Aachen, 1989. c) Araki, Y.; Nagasawa, J.; Ishido, Y. J. Chem. Soc. Perkin Trans. I 1981, 12-23. (3) a) Enders, D. in Asymmetric Synthesis, Morrison, J. D. (Ed.), Academic Press, Orlando, 1984, vol. 3, p. 275-339. b) Enders, D.; Fey, P.; Kipphardt, H. Org. Synth. 1987, 65, 173-182, 183-202. c) Enders, D.; Klatt, M. in Encyclopedia of Reagents for Organic Synthesis, Paquette, L. A. (Ed.), Wiley, New York, 1995, in press.

Scheme 3

O N3 O 4 steps O CH 3 9 1. Pd-C, H 2 2. HCl, MeOH 50 % N OH OH

H 3C

64 %

H 10 de = 98 %, ee = 85 %

O H 3C

O CH 3

5 steps 45 % H 3C O H 3C O CH 3 11 HO O N3 HO 1. Pd-C, H 2 2. HCl, MeOH 93 % N H OH OH

*
CH 3

12 de = 24 %, ee 95 %

Scheme 4
O SAMP-hydrazone method O H 3C O CH 3 70 % Ph O H 3C O CH 3 14 de,ee 95 % O Ph 4 steps 83 % Ph TfO OTf OBn Ph

13 de,ee 98 %

tetramethylguanidiniumazide

85 %

OH Ph Ph Ph H 2N

OH Ph NH 2

Pd-C, H2, MeOH 73 %

OBn Ph N3 15 N3 Ph

CbzValNH H NValCbz (R ,R) -A-74704 (Abbott)

16 de,ee 98 %

HIV-1 protease inhibitors

Acros Organics Acta 4 - 1998

2,2-Dimethyl-1,3-dioxan-5-one - A Dihydroxyacetone Equivalent for Asymmetric Synthesis

D. Enders*, B. Bockstiegel, W. Gatzweiler, U. Jegelka, B. Dcker Institut fr Organische Chemie, Rheinisch-Westflische Technische Hochschule, Professor Pirlet-Strae 1, 52074 Aachen, Germany

Scheme 5

O RAMP-hydrazone method O H 3C O CH 3 4 steps (52 %) BnO O H 3C

CH 3
9

OTBS

O CH 3 17

OH OH 26 % 9 steps

(+)-aspicilin
OH de 91 %, ee 96 % H 3C
Scheme 6

O O

(4) Enders, D.; Gatzweiler, W.; Jegelka, U. Synthesis 1991, 1137-1141. (5) Enders, D.; Jegelka, U. Tetrahedron Lett. 1993, 34, 2453-2456. (6) Enders, D.; Jegelka, U. Synlett 1992, 999-1001. (7) Enders, D.; Scharfbillig, I.; Lampe, C.; Jegelka, U. unpublished results. (8) Enders, D.; Jegelka, U.; Dcker, B. Angew. Chem. 1993, 105, 423-425; Angew. Chem. Int. Ed. Engl. 1993, 32, 423-425. (9) Enders, D.; Prokopenko, O. F. Liebigs Ann. 1995, 1185-1191. (10) Enders, D.; Whitehouse, D.; Runsink, J. Chem. Eur. J. 1995, 1, 382-388.

O O C 13H 27 SePh O H 3C O CH 3 SAMP-hydrazone method 52 % O H 3C

OH

* *
O CH 3 18

C 13H 27

SePh

74 %

5 steps

L- threo sphingosine
de,ee 98 %

NH 2 HO OH C 13H 27

Products available at ACROS ORGANICS

2,2-Dimethyl-1,3-dioxan-5-one.....................................................................................[74181-34-3] 30078-0010 (S)-(-)-1-Amino-2-(methoxymethyl)pyrrolidine, 98% ............................................................ [59983-39-0] 25437-0010
Synonym: SAMP

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(R)-(+)-1-Amino-2-(methoxymethyl)pyrrolidine, 98% (GC) .................................................. [72748-99-3]

Synonym: RAMP

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tert.-Butyllithium, 1.5 M solution in pentane.............................................................................. [594-19-4] ....................................................................................................................................................................... Lithium tri-sec-butylborohydride, 1M solution in THF .......................................................... [38721-52-7] .......................................................................................................................................................................

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the Dihydroxyacetone equivalent: Dihydroxyacetone Phosphate is used in nature as a C3methylene component in enzyme catalyzed aldol reactions to form 2-ketoses. Until very recently, chemical synthetic DHAP equivalents allowing the transfer of this simple C3 building block to electrophylic substrates by asymetmetric synthesis have not been available. 2,2-Dimethyl-1,3-dioxan-5-one, now available from Acros Organics, in combination with the SAMP/RAMP hydrazone method has turned out to be broadly applicable in this respect, and can be used to carry out highly diastereo- and enantioselective C-C bond formations.

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O R

O N O N OCH 3 H 3C

O CH 3

1. SAMP, toluene 2. tBuLi 3. RX

O CH 3 O CH 3 O H 3C O CH 3

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O R R

1. tBuLi 2. RX 3. O3, CH2 CL2

O H 3C

O CH 3

dd,ee > 98 %

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O CH 3 O O CH3 CH 3 O OH CH 3

cat. OS O 4

OH

arabi no (2,3-syn-3,4-anti)
+ xy lo,ribo and xy lo forms as minor diastomers

the Formyl Carbanion equivalent: (S,E)-(-)-Methyl-4-(phenylmethoxy)-2-pentenoate is another enantiopure starting material for organic synthesis, with many useful applications such as the asymmetric synthesis of polyhydroxylated compounds and branched chain sugars with high chemical yields.

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the stable Carbene equivalent: 1,3,4-Triphenyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidine is a stable, crystalline solid, provided that exposure to oxygen and moisture is avoided. The reagent shows the characteristic behavior of a nucleophilic carbene. It inserts into the O-H and N-H bonds of alcohols and amines, respectively yielding the corresponding alkoxytriazolines or alkylaminotriazolines. Published reactions include reactions with chalcogens, heterocumulenes, double activated bonds and formation of organometallic complexes.

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Laboratoire de Synthse des Substances Naturelles, associ au CNRS, ICMO, Universit de Paris-sud, 91405 Orsay, France

Y. Langlois

Camphor Derivatives Oxazoline-N-oxides

New Chiral Auxiliaries for Asymmetric [2+3] Cycloadditions

The camphor derivatives oxazoline-N-oxides have proved to be versatile dipoles for asymmetric cycloaddition with electron-poor dipolarophiles and cyclopentadiene. The resulting cycloadducts have been subsequently transformed into anti -hydroxyketone, -lactone and carbonucleosides such as Carbovir and -hydroxy--aminoacids. equivalents of nitrile oxides. The development of an asymmetric version of this reaction, and further transformation of cycloadducts constitutes a new versatile method providing access to a large variety of chiral compounds.

(+)-3-Hydroxylamino isoborneol 4a (2) was prepared in three steps from camphoroquinone 1 (overall yield 70%) (Scheme 1). Condensation of the corresponding hydrochloride 4b with various orthoesters gave rise to oxazoline-N-oxides 6a-6d (3, 4). Both rate and yield of these reactions were increased by the use of trimethoxy Condensation of -hydroxylamino alcohols with orthoesters gives orthoesters in the presence of 4 molecular sieves as methanol scavrise to oxazoline-N-oxides (1), which can be considered as chiral enger. The fast hydrolysis of oxazoScheme 1 line-N-oxides precluded their isolation and therefore these dipoles were directly submitted to cycloadNHOH a b c, d dition reactions with various elecO NOH NOH OH OH tron-poor dipolarophiles (Scheme O O 4a 2 3 1 2, table). 4b : 4a, HCl
a: NH2OH HCl, AcOK, EtOH, H 2O. b: NaBH 4, EtOH. c: NaBH3CN, AcOH, THF. d: HCl, Et 2O.

Scheme 2
RC(OMe) 3 5

_ +
N O R R1 a R2 7 N O R1 O 6a: R=H 6b : R=Me 6c : R=Pr 6d : R=(CH 2)4OBn

NHOH,HCl OH 4b

O R

R2

a: see table

Scheme 3
O Pr _ O Pr a b, c 8 O N + O 10 Me _ Pr HO Pr 2 e: HCl, MeOH e N OH OH + Pr 11 O OH Pr N O Me O Pr Pr d N + O Me O Pr Pr

With 1,2-substituted electron-poor dipolarophiles, the reaction is highly regio- and stereoselective, endo adducts 7 being the only products isolated. Better yields were obtained with unsubstituted oxazoline-N-oxide 6a (entries 1-4). This dipole can be considered as a chiral equivalent of fulminic acid. , Unsaturated esters, sulfones, nitriles and nitro compounds are the dipolarophiles of choice. Alkyl monosubstituted alkenes can also be used (5). Exo adducts 7j and 7n were isolated albeit in low yield in the latter case (entries 10 and 14). Further transformations of the adducts illustrated the usefulness of these cycloadditions. The ester group in adduct 7m has been converted to a methyl group by a sequence of classical reactions. The resulting compound 8 has in turn been submitted to a two step oxidative cleavage affording anti Acros Organics Acta 4 - 1998

N O t-BuO 2C 7m

a: LiAlH 4, Et 2O. b: TsCl, C 5H 5 N. c: LiAlH 4 , Et 2O. d: mCPBA, CH 2Cl 2.

11

Camphor Derivatives Oxazoline-N-oxides - New Chiral Auxiliaries for Asymmetric [2+3] Cycloadditions
Y. Langlois Laboratoire de Synthse des Substances Naturelles, associ au CNRS, ICMO, Universit de Paris-sud, 91405 Orsay, France

hydroxyketone 11 in good overall yield (64% from adduct 7m) (Scheme 3). Conversely by the same hydrolytic process, adduct 7n afforded hydroxyketone 12. This compound, after deprotection, led to 13, a spiroketalic pheromone of Dacus oleae (3) (overall yield from 7n: 78%) (Scheme 4). Cyclopentadiene is also an efficient dipolarophile in such cycloadditions. Exo adduct 14 is the only product isolated in that case (75%). Subsequent oxidative methanolysis led to ketal derivative 16. Stereoselective reduction followed by an acylation with methylchloroformate afforded dicarbonate 17 which, by a known procedure, led to the antiviral carbonucleoside Carbovir 19 (6) (Scheme 5). Adduct 7b, after reduction and protection of the primary alcohol, produced 21. Via oxidative hydrolysis this compound led to aldehyde 22, which was oxidized without isolation into carboxylic acid 23. Classical lactonisation and deprotection gave rise to -lactone 24 as a model of a family of bioactive natural products (overall yield from adduct 7b: 62%) (Scheme 6) (7). Finaly, nitro adducts such as 7d were easily reduced to the corresponding amino derivatives. These compounds are potential precusors of -hydroxy-aminoacids and -hydroxy-aminoalcohols (8). In conclusion, the camphor derivatives oxazoline-N-oxides 6 are powerful dipoles for producing adducts 7 with high regio- and stereoselectivities. Adducts 7 bearing masked alcohol and keto groups have been transformed in high overall yield into a large variety of chiral compounds useful for further syntheses.

Table 1

Entry

Dipole

Dipolarophile R1 R2 Me Pr Pr Bu Me Me Pr Me (CH2)2OBn (CH2)2OBn Me Pr Pr (CH2)2OBn

Temp. c (Time h)

Solvent

Yield%

Adduct

1 2 3 4 5 6 7 8 9 10 11 12 13 14

6a 6a 6a 6a 6b 6b 6b 6b 6d 6b 6c 6c 6c 6d

CO 2Bn CO 2Bn CO 2tBu NO 2 CO 2Me CO 2Bn CO 2Bn SO 2Ph SO 2Ph H CO 2Bn CO 2Me CO 2tBu H

40 (8) 80 (18) 80 (18) 40 (2) 80 (5) 80 (2) 40 (24) 40 (30) 40 (60) 100 (4) 40 (24) 40 (48) 80 (18) 80 (18)

CH 2Cl2 PhMe PhMe CH 2Cl2 PhMe PhMe CH 2Cl2 CH 2Cl2 CH 2Cl2 PhMe CH 2Cl2 CH 2Cl2 PhMe PhMe

62 90 80 70 58 52 52 42 25 50 52 53 63 23

7a 7b 7c 7d 7e 7f 7g 7h 7i 7j 7k 7l 7m 7n

Scheme 4
OBn N O 7n b O OBn a BnO 3 12 O OH OBn + 2

O O HO 13

a: mCPBA, MeOH, HCl. b: H 2, Pd-C, MeOH

12

Acros Organics Acta 4 - 1998

Camphor Derivatives Oxazoline-N-oxides - New Chiral Auxiliaries for Asymmetric [2+3] Cycloadditions
Y. Langlois Laboratoire de Synthse des Substances Naturelles, associ au CNRS, ICMO, Universit de Paris-sud, 91405 Orsay, France

Scheme 5

References:
_ +
N O H a + OMe OH d, e OH N HO NH 2 N 19 f, g N NH 2 (+)-Carbovir N N O 14 OCO 2 Me O OH 15 N N H N Cl N 18 MeO + 16 17 OCO 2 Me O H O

6a b, c

a: 40 C, 24h, CH 2Cl 2. b: mCPBA, CH 2Cl 2. c: CSA, MeOH. d: CSA, MeCN, H 2O, NaBH4. e: ClCO 2 Me, C 5H 5N. f: Pd(PPh 3)4, 18, THF, DMSO. g: NaOH(1M).

Scheme 6

N 7b e O BnO 2C

O H

Pr

a, b

N 20: R=H 21: R=Bn f, g O ROCH 2

O H

Pr c, d H

OH Pr OBn + 15

O OH

(1) Ashburn, S. P.; Coates, R. M. J. Org. Chem. 1984, 49, 3127. (2) Baldwin, S. W.; McFayden, R.B.; Aub, J.; Wilson, J. D. Tetrahedron Lett. 1991, 32, 4431. (3) Berranger, T.; Langlois, Y. J. Org. Chem. 1995, 60, 1720. (4) For an alternative preparation of oxazoline-N-oxides from chiral -aminoalcohols, see: Berranger, T.; Andr-Barrs, A.; Kobayakawa, M.; Langlois, Y. Tetrahedron Lett. 1993, 34, 5079. (5) For an intramolecular version of this reaction, see: Kobayakawa, M.; Langlois, Y. Tetrahedron Lett. 1992, 33, 2353. (6) Berranger, T.; Langlois, Y. Tetrahedron Lett. 1995, 31, 5523. (7) Dirat, O.; Berranger, T.; Langlois, Y. Synlett, 1995, 935 (8) Berranger, T.; Kouklovsky, C.; Mauduit, M.; Langlois, Y. unpublished results.

22 Pr O

O HO 23

OH Pr OBn

HO 24 O

a: LiAlH 4, Et 2O. b: NaH, BnBr, Bu 4NI, THF, DMF. c: mCPBA, CH 2Cl 2. d: HCl(2M), THF. e: NaClO 2, H2O2, MeCN, H 2O. f: PhSO 2Cl, C 5 H 5N. g: H 2, Pd-C, AcOEt.

Products available at ACROS ORGANICS

(+)-3-Hydroxylamino isoborneol hydrochloride ......................................................................... 30138-2500 d-Camphoroquinone.....................................................................................................[2767-84-2] 40275-0250 Trimethyl orthoformate, 99% .......................................................................................................[149-73-5] 14866-1000 ....................................................................................................................................................................... 14866-5000 ....................................................................................................................................................................... 14866-0010 Trimethyl orthoacetate, 98%.......................................................................................................[1445-45-0] 21818-1000 ....................................................................................................................................................................... 21818-5000 Sodium cyanoborohydride, 95+%............................................................................................[25895-60-7] 16855-0100 ....................................................................................................................................................................... 16855-0500 Sodium borohydride, 99+%......................................................................................................[16940-66-2] 20005-1000 Dicyclopentadiene, 95%, stabilized with 150-200 ppm p-tert.-butylcatechol..............................[77-73-6] 15076-0050 ....................................................................................................................................................................... 15076-1000 ....................................................................................................................................................................... 15076-0010 ....................................................................................................................................................................... 15076-0025 3-Chloroperoxybenzoic acid, 70-75% ..........................................................................................[937-14-4] 25579-1000 (balance 3-chlorobenzoic acid and water) .................................................................................................. 25579-0010 250 mg 25 g 100 g 500 g 1 kg 100 ml 500 ml 10 g 50 g 100 g 5 ml 100 ml 1l 2.5 l 100 g 1 kg
13

Acros Organics Acta 4 - 1998

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Reconnaissance et Organisation Molculaire et Biomolculaire UPRES A du CNRS. Laboratoire de Chimie Industrielle, Universit LYON I, 43 boulevard du 11 Novembre 1918, 69622 Villeurbanne Cdex, France

F. Vocanson and R. Lamartine

The Chemistry of the p-Isopropylcalixarenes

In supramolecular chemistry, calixarenes have been the object of numerous developments over the last few years (1,2). These molecules can be used as a molecular platform after functionalization (3). The pisopropylcalixarene series has been studied to a considerably less extent than the p-tert-butylcalixarene series (4,5,6). However, these macrocycles (Fig. 1) present interesting properties of complexation because of the p-isopropyl group (7). energy of activation for inversion between pleated loop conformers is 15 kcal / mol. In pyridine, at low and at high temperature, only one singlet is observed for the methylene protons. The interconversion of calix[8]arene cannot be blocked out at low temperature. For the p-isopropylcalix[6]arene, conformational studies (4) have shown that the calix[6]arene can exist in eight different conformations (1). The calix[6]arene is more flexible than either the calix[4]arene or calix[8]arene. For the p-isopropyldihomooxacalix[4]arene, because of the presence of one dimethyleneoxa bridge (Fig. 1), the size of the cavity is almost the same as that of the calix[5]arene, but the flexibility is greater (1,4,12). The dihomooxacalix[4]arene adopts a cone conformation at low temperature : 1H NMR spectrum in CDCl3 contains two sets of pairs of doublets. The conformational flexibility increases with the temperature. On the other hand, the flexing of the dimethyleneoxa bridge produces conformers in which the oxygen is either inside or outside the cavity. The asymmetric calix[4]arene presents the same conformation in solution as the p-isopropylcalix[4]arene (9). In summary, the different p-isopropylcalixarenes adopt the same conformations in solution as their homologs in the p-tert-butylcalixarene series do.

1. Preparation
Some one step syntheses have been described in the literature. The pisopropylcalixarenes are formed by the condensation of formaldehyde and p-isopropylphenol in the presence of KOH (Table I), in tetralin as solvent. Vicens et al. (9,10) synthesized an asymmetric p-isopropylcalix[4]arene by cyclo-condensation (Fig. 2) of the trinuclear oligomer with 2,6-bisbromomethyl-4-isopropyl-3-methylphenol.

2. Chemical modifications
A few modifications of p-isopropylcalixarenes have been described in the literature. Bourakhouadar (4) has prepared the acetates (Fig. 3). The chlorination by gas of p-isopropylcalix[4,6,8]arene has been studied in the solid state in mild conditions (11). Analyses have shown that all the calixarenes react, the number of chlorine atoms introduced per phenolic moiety usually varying between 2 and 3.

4. Solid state inclusion complexes and applications

The p-isopropylcalix[4]arene, which crystallizes in the cone conformation, forms complexes (2,13) with chloroform (1:1) and p-xylene (1:1). But with p-xylene, heating of the complex causes half of the guest molecules to be lost and a new complex (2:1) is produced.
Figure1: p-isopropylcalixarenes and p-isopropyldihomooxacalix[4]arene
CH 2-O OH CH 2 OH CH 2

3. Conformational properties
The conformational mobility of p-isopropylcalixarene (4) has been studied with temperature-dependent 1H NMR spectroscopy. For the p-isopropylcalix[4]arene, the Ar-CH2-Ar methylene protons, which are singlet at 60C, are transformed into a pair of doublets at 5C : there is an AB system. The calixarene exists in the cone conformation at low temperature, and is interconverted when the temperature increases (4). The free energy of activation for inversion is 14.8 kcal / mol (1). For the p-isopropylcalix[8]arene, a similarity (4) in the temperaturedependent 1H NMR spectra is observed with the cyclic tetramer in CDCl3 : one singlet for the Ar-CH2-Ar methylene protons at 60C and a pair of doublets at 5C. Similar to the p-tert-butylcalix[8]arene, the pisopropylcalix[8]arene presents a pleated loop conformation. The free

n n = 4,6,7,8

Acros Organics Acta 4 - 1998

15

The Chemistry of the p-Isopropylcalixarenes

F. Vocanson and R. Lamartine Reconnaissance et Organisation Molculaire et Biomolculaire UPRES A du CNRS. Laboratoire de Chimie Industrielle, Universit LYON I, 43 boulevard du 11 Novembre 1918, 69622 Villeurbanne Cdex, France

Table I : synthesis pathways for p-isopropyl-calixarenes

P-isopropylcalixarenes Calix[4]arene Bishomooxacalix[4]arene Calix[6]arene Calix[7]arene Calix[8]arene

Yield (%)

ratio phenol/ formaldehyde/KOH 10 /10 / 0.26 18.2 / 31.7 / 1.55 10 / 10 / 1.3 6.23 / 20 / 1.9 10 / 30 / 0.26

Reference

Figure 3 : p-isopropylcalixarene acetates

18 14 54 4 31.2

4 5 4 8 4

OCOCH 3 CH 2

n = 4,6,8

Figure 2 : synthesis of asymmetric calix[4]arene

OH OH OH OH

+ Br

Br

Single crystals of p-isopropylcalix[6]arene have been obtained by slow evaporation at room temperature of a solution of carbon disulfidebenzene. The calixarene adopts a cone conformation (7) and forms a (1:3) complex with benzene.

References
(1) Gutsche, C.D. in Calixarenes, The Royal Society of Chemistry, Cambridge, 1989. (2) Vicens, J.; Bhmer, V. in Calixarenes, a versatile class of macrocycle, Kluwer Academic Publishers, Dordrecht, 1991. (3) Bhmer, V. Angew. Chem. Int. Ed. Engl. 1995, 34, 713. (4) Bourakhouadar, M. Thesis, University Lyon - I 1989. (5) Perrin, R.; Bourakhouadar, M.; Duchamp, C. C.R. Acad.Sci.Paris 1990, 310 srie II, 1053. (6) Vicens, J.; Pilot, T.; Gamet, D.; Lamartine, R.; Perrin R. C.R. Acad.Sci.Paris 1986, 302 srie II, 15. (7) Halit, M.; Oehler, D.; Perrin, M.; Thozet, A.; Perrin, R.; Vicens, J.; Bourakhouadar, M. J. of Incl. Phenom. 1988, 6, 613. (8) Vocanson, F.; Lamartine , R. unpublished results. (9) Ueda, Y.; Fujiwara, T.; Tomita , K.I.; Asfari, Z.; Vicens, J. J. of Incl. Phenom. 1993, 15, 341. (10) Casabianca, H.; Royer, J.; Satrallah, A.; Taty-C., A.; Vicens, J. Tetrahedron Lett. 1987, 6595. (11) Lamartine, R.; Perrin, R.; Perrin, M.; Lecocq, S.; Duchamp, C. Mol. Cryst. Liq. Cryst. 1994, 248, 61. (12) Vocanson, F.; Lamartine, R. Acros Organics Acta 1996, 2, 1, 6. (13) Perrin, M.; Gharnati, F.; Oehler, D.; Perrin, R.; Lecocq, S. J. of Incl. Phenom. 1992, 14, 257. (14) Suzuki, K.; Armah, A.E.; Fuj, S.; Tomita, K.I.; Asfari, Z.; Vicens, J. Chem. Lett. 1991, 1699. (15) Vicens, J.; Armah, A.E.; Fuj, S.; Tomita, K.I.; Asfari, Z. J. of Incl. Phenom. 1991, 10,159.

OH OH HO OH

The p-isopropyldihomooxacalix[4]arene forms a complex (1:1) with oxylene and adopts a cone conformation (14). The properties of complexation of o-and p-xylene by the calix[4]arenes have been used for studying the separation of xylenes by extractive crystallisation with cyclic tetramers (4,15). The two previous calixarenes have been recrystallized from 1:1:1 mixtures of the three xylene isomers. The different analyses, by 1H NMR and Gas Chromatography, have shown that p-isopropylcalix[4]arene extracts pxylene with 86% selectivity and p-isopropyldihomooxacalix[4]arene extracts o-xylene with 84% selectivity. m-xylene is only extracted by p-isopropylcalix[4]arene with 14% selectivity. Consequently, molecular recognition is possible with these calixarenes. The asymmetric calix[4]arene forms a complex (1:1) with acetone and adopts a cone conformation (9).

Products available at ACROS ORGANICS

4-Isopropylcalix[4]arene ............................................................................................. 29931-2500 4-Isopropyldihomooxacalix[4]arene ......................................................................... 29935-1000 4-Isopropylcalix[6]arene ............................................................................................. 29932-2500 4-Isopropylcalix[8]arene ............................................................................................. 29933-2500
16
Acros Organics Acta 4 - 1998

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Available in Windows format !

For more information, please contact your local dealer

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Contains full sub-structure searching capability for the products in the Acros Organics catalogue.

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CambridgeSoft
Desktop Chemistry Software LeaderLeader Desktop Chemistry Software Der Fhrer in Chemie-Software Leader des logiciels de chimie

Drawing, Modeling and Information

Other CambridgeSoft products available at your Acros Organics dealer

CS Chem3D

CS ChemDraw

CS ChemInfo

TM

Molecular Modeling and Analysis

Chemical Structure Drawing Standard

Structures, Models and Information

Windows is a registered trademark of Microsoft Corporation

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