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Comments on anAttempted Synthesis of 1-Aminocyclopropane-1,2-Dicarboxylic AcidEdward C. Taylor a & Baihua Hu aa Department of Chemistry , Princeton UniversityPrinceton , New Jersey, 08544Published online: 21 Aug 2006.

To cite this article: Edward C. Taylor & Baihua Hu (1996) Comments on anAttempted Synthesis of 1-Aminocyclopropane-1,2-Dicarboxylic Acid, SyntheticCommunications: An International Journal for Rapid Communication of SyntheticOrganic Chemistry, 26:5, 1041-1049, DOI: 10.1080/00397919608003709

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SYNTHETIC COMMUNICATIONS, 26(5), 1041-1049 (1996)

COMMENTS ON AN ATTEMPTED SYNTHESIS OF

1-AMINOCY CLOPROPANE-1,2-DICARBOXYLIC ACID

Edward C. Taylor* and Baihua Hu

Department of Chemistry, Princeton University Princeton, New Jersey 08544

Abstract: Arninolysis of dirnethyl I-brornocyclopropane- 1,2-dicarboxylate in the presence of KHMDS was reinvestigated. Dirnethyl I-rnethoxycyclopropane- 1,2-dicarboxylate instead of the putative dirnethyl I-aminocyclopropane- 1,2-dicarboxylate was isolated from the reaction.

A wide variety of cyclopropyl amino acids have been synthesized as

mechanistic probes and as enzyme inhibitors. Cis/trans 1-

aminocyclopropane- 1,2-dicarboxylic acids ( 1 and 2 ) are particularly

intriguing, since they represent cyclic single-conformation analogues of

glutamic acid.2 To our knowledge, three previous attempted preparations of

these compounds have been reported. lb, Id, 3 Cyclopropanation of the

HOOC "ANH2 COOH HOOC HNooH NH2 2 1

*To whom correspondence should be addressed.

1041

Copyright 0 1996 by Marcel Dekker, Inc.

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1042 TAYLOR AND HU

dehydroalanine 3 followed by amine deprotection was attempted by

Stammer,ld but no cyclopropane product could be isolated (eq. 1). An

attempted synthesis by Burgess, through oxidation of the 2,3-

methanohomoserine derivative 6 to give 7 followed by amine deprotection,

also resulted in decomposition of the presumed cyclopropane diacids 1 and 2

(eq. 2).

NHC0,R N2CHC02R' P < C 0 2 R +l and 2 (eq.1) 4 - R " 0 & NHCO2R co 2 R

* 5 3

A C 0 2 t - B u -1 and 2 (eq.2) -

HOH2C H02 C NH-BOC 6 7

However, a successful synthesis of d t r a n s 1-aminocyclopropane- 1,2 -

dicarboxylic acid was reported by Kraus in 1990.3 Aminolysis of dimethyl 1-

bromocyclopropane- 1,2-dicarboxylate (9) with liquid ammonia and potassium

hexamethyldisilazane (KHMDS) followed by basic hydrolysis was reported to

give the final diacids 1 and 2. All intermediates and final products were

characterized by IR spectra, as well as by IH and 13C NMR spectra. Some

were further characterized by mass spectral or elemental analysis. We

followed the reported aminolysis procedure exactly. The requisite starting

material 9 was prepared in our hands from dimethyl a,a'-dibromoglutarate (8)

and sodium hydride in DMF by the procedure of McDonald and re it^.^

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1 -AMINOCYCLOPROPANE-1 ,2-DICARBOXYLIC ACID 1043

However, the aminolysis reaction produced as the only isolated product a

small amount of dimethyl 1 -methoxpcyclopropane- 1,2-dicarboxylate (10 )

instead of dimethyl 1 -aminocyclopropane- 1,2-dicarboxylate (12). The

identity of our material was established by analytical data and by 'H NMR

spectral data in carbon tetrachloride,Sa which were in agreement with data

previously reported for Interestingly, the *H NMR spectrum of cis-10 in

deuteriochloroform matched almost precisely the reported I H NMR spectrum

for cis-12,Sb except that the integration of protons at 3.4 ppm was 3 rather

Scheme 1

L 12

than 2. Significantly, the molecular ion reported for the purported cis-12

actually more closely matches the calculated molecular ion for cis-10 less a

methyl group.6 We suggest that the action of liquid ammonia and potassium

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1044 TAYLOR AND HU

hexamethyldisilazane upon 9 effects initial dehydrobromination to give the

cyclopropene 11, and that the small amount of methanol produced by

inevitable aminolysis of one or both of the two ester functionalities of 9 then

adds Michael-fashion to 11 to give the observed methoxy derivative 10. The

mechanism of formation of 10 is thus analogous to that proposed by

McDonald and Reitz.4 A similar Michael addition of ammonia to the double

bond of the cyclopropene 11 would give 12; however, extensive subsequent

decomposition of 12 (Scheme 1) presumably takes place through amine-

assisted cyclopropane ring cleavage due to the fragile nature of the push-pull

cyclopropane 12. This hypothesis is supported by the previously reported

failures to prepare 1 and 2 (eq. 1 and 2); the decompositions following amino

group deprotection were also ascribed to facile amine-assisted ring

cleavage. 1b,d

The suggestion that dimethyl 1 -aminocyclopropane- 1,2-dicarboxylate

is inherently unstable is strongly supported by the results of an alternative

synthetic pathway which we have also explored (Scheme 2). Thus,

cyclopropanation of ethyl a-azidoacrylate ( 13)’ with ethyl diazoacetate led to

a mixture of cis- and trans-diethyl l-azidocyclopropane-1,2-dicarboxylates

(14). An attempt to apply the well-known Staudinger methodology to 14 by

addition of triphenylphosphine in ethanol at room temperature led to the ring-

opened phosphinimine 15. This result, together with other previous attempted

syntheses, appear to confirm the instability of I-aminocyclopropane- 1,2-

dicarboxylic acid and its esters, and suggests that the recent report3 of the

preparation of 12 is in error.

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I-AMINOCYCLOPROPANE- 1 ,ZDICARBOXYLIC ACID

Scheme 2

13

1045

Experimental

General. 1H NMR and 13C NMR data were obtained at 300 and 75 MHz,

respectively, on a General Electric QE-300 MHz instrument. IR spectra were

determined using a Nicolet FT-IR instrument. High resolution mass spectral

data were determined by Dr. Dorothy Little on AEI MS-902 and Kratos

MSSOTC spectrometers. Elemental analyses were preformed by Eli Lilly and

Co., Indianapolis, Indiana.

Dimethyl 1-Methoxycyclopropane-(cis/trans)-l,2-dicarboxylate (10):

The literature procedure reported by Kraus3 was followed exactly. To a

stirred solution of dimethyl a,a'-dibromogl~tarate~ (180 mg, 0.75 mmol) in

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1046 TAYLOR AND HU

liquid ammonia ( 5 mL) and THF ( 5 mL) at -78 "C was rapidly added

potassium hexamethyldisilazane (0.5 M in toluene, 1.5 mL, 0.75 mmol). The

resulting light red solution was stirred at -78 "C for 1 h, warmed to room

temperature, and then quenched with water (100 mL), extracted with CH2C12

(200 mL), dried (Na2S04), and concentrated. The crude mixture was purified

by chromatography using ethyl acetate-hexanes (1:3) as the eluent to afford

-10 mg (7%) of a mixture of cis/trans isomers of 10 as a colorless oil. Cis

isomer: IR (neat) 1731 cm-1; see refs. 5 and 6 for comparisons of 1H NMR

and HRMS data with data reported for cis-12. Anal. Calcd for CsH1205: C,

5 1.06; H, 6.43. Found: C, 5 1.34; H, 6.15. Trans isomer (mixed with the cis

isomer): 'H NMR (CDCl3) 6 3.71 (s, 3 H), 3.64 (s, 3 H), 3.37 (s, 3 H), 2.44

(dd, J=9.1,7.3 Hz, 1 H), 1.87 (dd, J=7 .3 , 5.5 Hz, 1 H), 1.58 (dd,J =9.1, 5.5

Hz, 1 H). Anal. Found: C, 5 1.25; H, 6.39.

Diethyl l-Azido-cyclopropane-(cis/trans)-1,2-dicarboxylate (14):

A solution of ethyl a-azidoacrylate7 (13) ( 1 1.4 g, 78 mmol) and ethyl

diazoacetate (1 1.4 g, 100 mmol) in 250 mL of CH2C12 was heated under

reflux for a week. The solvent was removed under reduced pressure and the

residue was purified by column chromatography on silica gel using ether-

hexanes (0: 100 to 1 :9) as the eluent to give a partially separable mixture of cis

and trans isomers of 14 (10.4 g, 58%) as a colorless oil. NMR analysis

indicated that the ratio of cis to trans was 1 to 2. The stereochemistry was

assigned by comparison of NMR spectra with the spectrum of dimethyl I-t-

butoxy-(cis/trans)-cyclopropane- 1,2-di~arboxylate.~ Trans isomer: H NMR

(CDCl3) 6 4.25 (4, J = 7.0 Hz, 2 H), 4.20 (q, J = 7.0 Hz, 2 H), 2.54 (dd, J =

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1 -AMINOCYCLOPROPANE-I .ZDICARBOXYLIC ACID 1047

9.1, 7.5 Hz, 1 H), 1.79 (dd, J = 7.5, 5.7 Hz, 1 H), 1.73 (dd, J = 9.1, 5.7 Hz, 1

H), 1.31 (t, J = 7.0 Hz, 3 H), 1.28 (t, J = 7.0 Hz, 3 H); 13C NMR (CDC13) 6

168.9, 167.3, 62.5, 61.4, 47.2, 29.7, 19.4, 14.0, 13.9; MS m/z (re1 intensity)

277 (M+, 0.4), 226 (2), 200 (3), 182 (4), 170 (23), 154 (38), 153 (57), 150

(30), 142 (13); HRMS calcd for CsH13N04 (Mf - N2) : 199.0844. Found

199.0848. Anal. Calcd for CgHyjN304: C, 47.57; H, 5.77; N, 18.49. Found:

C, 47.53; H, 5.48; N, 18.70. Cis isomer (mixed with the trans isomer): IH

N M R ( C D C ~ ~ ) ~ ~ . ~ ~ ( ~ , J = ~ . O H Z , ~ H ) , ~ . ~ O ( ~ , J = ~ . O H Z , ~ H ) , ~ . ~ ~ ( ~ ~ ,

J = 9.9,8.1 Hz, 1 H), 1.95 (dd, J = 8.1, 5.8 Hz, 1 H), 1.44 (dd, J = 9.9,5.8 Hz,

1 H), 1.28 (t, J = 7.0 Hz, 3 H), 1.24 (t, J = 7.0 Hz, 3 H); IR (cidtrans mixture)

2120, 1730 cm-l. Anal. Found: C, 47.74; H, 5.80; N, 18.64.

Diethyl 2-Triphenylphosphiniminopent-2-ene-l,5-dicarboxylate (15):

Triphenylphosphine (0.26 g, 1 mmol) was added to a stirred solution of

diethyl 1-azidocyclopropane-(cis/trans)- 1,2-dicarboxylate (1 4) (0.23 g, 1

mmol) in 30 mL of ethanol at room temperature. After overnight stirring, the

solvent was removed and the residue was purified by column chromatography

on neutral aluminum oxide using ethyl acetate-hexanes (1:9) as the eluent to

give 15 (0.38 g, 83%) as a colorless oil which crystallized upon trituration

with hexanes; mp 79 "C. IR (neat) 1728, 1704 cm-1; 'H NMR (CDC13) 6

7.80-7.60 (m, 6 H), 7.50-7.30 (m, 9 H), 6.03 (td, J = 7.0,4.6 Hz, 1 H), 4.06 (q,

J = 7.0 Hz, 2 H), 3.83 (q, J = 7.0 Hz, 2 H), 3.50 (dd, J = 7.0, 1.7 Hz, 2 H),

1.20 (t, J = 7.0 Hz, 3 H), 0.97 (t, J = 7.0 Hz, 3 H); 13C NMR (CDC13) 6

172.5, 166.8, 138.5, 133.6, 132.3, 132.1, 130.8, 128.0, 127.8, 60.2, 60.1, 33.5,

14.1, 13.8; MS m/z (re1 intensity) 461 (M+, 27), 416 (13), 404 (36), 388 (93,

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1048 TAYLOR AND HU

277 (32), 263 (80), 262 (loo), 261 (43), 219 (26), 202 (21), 201 (93), 183

(97), 108 (58); HRMS calcd for C27H2gN04P (M+): 461.1756. Found:

461.1747. Anal. Calcd for C27H28N04P: C, 70.27; H, 6.12; N, 3.04. Found:

C, 70.26; H, 6.39; N, 3.01.

Acknowledgement: We are indebted to Eli Lilly & Company, Indianapolis,

Indiana, for support of this work.

References

1. For reviews on cyclopropyl amino acids see: (a) Salaun, J.; Baird, M.

S. Curr. Med. Chem. 1995, 2, 511; (b) Burgess, K.; Ho, K.-K.; Moye-

Sherman, D. Synlett. 1994, 575; (c) Alami, A.; Calmes, M; Daunis, J . and

Jacquier, R. Bull. Soc. Chim. Fr. 1993, 130, 5 ; (d) Stammer, C. H.

Tetrahedron 1990, 46 , 2231; (e) Vilsmaier, E. in "The Chemistry of the

Cycfopropyl Group"; Rappoport, Z. Ed.; John Wiley & Sons Ltd.; New York,

1987, 1341.

2. For recent discussions of the potential importance of such glutamic

acid mimics, see: (a) Knopfel, T.; Kuhn, R. and Allgeier, H. J. Med. Chem.

1995, 38, 1417; (b) Moody, C. M.; Young, D. W. Tetrahedron Lett. 1994,35,

7277.

3.

Taylor, J. E. Synth. Commun. 1990,20, 2667.

4.

5.

Kraus, G. A.; Kim, H.; Thomas, P. J.; Metzler, D. E.; Metzler, C. M.;

McDonald, R. N.; Reitz, R. R. J. Org. Cliem. 1972, 37, 2418.

(a) Reported IH NMR spectrum for ~ i s - 1 0 : ~ (cC14 with TMS (z 10) as

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1-AMINOCYCLOPROPANE- 1 ,ZDICARBOXYLIC ACID 1049

the internal standard) T 6.30 (s, 3 H), 6.33 (s, 3 H), 6.59 (s, 3 H), 7.89 (dd, 1

H), 8.23 (dd, 1 HI, 8.62 (dd, 1 H); Jtrans = 7.5 Hz, Jcis = 10.0 Hz, Jgem = 5.4

Hz. Found lH NMR spectrum for cis-10: (CCl4 plus 2 drops of DMSO-dtj

with TMS (z 10) as the internal standard) z 6.30 (s, 3 H), 6.37 (s, 3 H), 6.60 (s,

3 H), 7.88 (dd, 1 H), 8.24 (dd, 1 H), 8.59 (dd, 1 H); = 7.9 Hz, Jcis = 10.1

Hz, Jgem = 5.8 Hz. (b) Reported IH NMR spectrum for ~ i s - 1 2 : ~ (CDC13) 6

3.76 (s, 3 H), 3.69 (s, 3 H), 3.46 (s, 2 H), 2.28 (dd, J = 10.2, 8.1 Hz, 1 H), 1.88

(dd, J = 8.1, 5.7 Hz, 1 H), 1.53 (dd, J = 10.2, 5.7 Hz, 1 H). 1H NMR spectrum

found for cis-10: (CDC13) 6 3.73 (s, 3 H), 3.66 (s, 3 H), 3.43 (s, 3 H), 2.25 (dd,

J = 10.1, 8.1 Hz, 1 H), 1.85 (dd, J = 8.1, 5.9 Hz, 1 H), 1.49 (dd, J = 10.1, 5.9

Hz, 1 H).

6. Reported HRMS for C7H 11N04:3 calcd 173.0688; found 173.0452.

HRMS for 10 (CgH1205) less CH3: calcd 173.0450; found 173.0450. HRMS

for C8H12O5 (M+): calcd 188.0685; found 188.0697.

7. Kakimoto, M.; Kai, M.; Kondo, K. Chem. Lett. 1982,525.

(Received i n the USA 2 1 August 1 9 9 5 )

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