A novel β-D-glycosyl carbamate forming reaction

Article abstract of DOI:10.1016/S0040-4039(00)01642-7

The synthesis and use of a novel and versatile 1-β-O-D-glycosyl active carbamate is described. This active carbamate is prepared from an in situ generated isocyanate and is used to prepare 1-β-O-D-glycosyl carbamates of multi-functionalized primary or secondary amines in high yield and with 100% β-diastereoselectivity. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01642-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9173–9175
A novel b- -glycosyl carbamate forming reaction
D
Ruben G. G. Leenders† and Hans W. Scheeren*
Department of Organic Chemistry, NSR-Center for Molecular Structure, Design and Synthesis,
University of Nijmegen, Toernooiveld, 6525 ED Nijmegen, The Netherlands
Received 13 September 2000; accepted 20 September 2000
Abstract
The synthesis and use of a novel and versatile 1-b-O-
D
-glycosyl active carbamate is described. This
-glycosyl
active carbamate is prepared from an in situ generated isocyanate and is used to prepare 1-b-O-
D
carbamates of multi-functionalized primary or secondary amines in high yield and with 100%
b-diastereoselectivity. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
In an attempt to couple the carboxylic acid group of 1a to the amino group of daunorubicin
2 using the BOP coupling reagent, instead of the expected amide product, carbamate 3a was
obtained in 89% yield together with 6(5H)-phenanthridinone (4) (Scheme 1). Variation of the
peptide coupling reagent, solvent and base did not lead to the desired product; in all cases
b-
lowed for the galactosyl analogue leading to daunorubicin-b-
-glycosyl carbonyl-transfer reaction with
D
-glucuronyl carbamate 3a was isolated.1 This unexpected reaction sequence was also fol-
D
-galactosyl carbamate 3b. In the
literature, comparable examples of the present 1-b-O-
D
phenanthridinone 4 acting as a leaving group have not been reported.
As reported earlier by us, glycosyl carbamates can be prepared by the addition reaction of an
anomeric hydroxyl group of a glycosyl donor to an isocyanate.2 This was found to proceed with
high b-diastereoselectivity and was used in our work on anthracycline prodrugs.3 In the specific
case of daunorubicin 2 however, the 3%-amino group could not be converted to an isocyanate
group in order to react with glycosyl donor 9 (Scheme 3) and yield 3, because the 4%-hydroxy
reacted with the 3%-isocyanate group to form cyclic carbamate 5 (Scheme 1).
The unexpected sequence depicted in Scheme 1 can be rationalized as follows (see Scheme 2).
The coupling reagent (i.e. BOP) activates the carboxylic acid 1 in the normal manner. Then an
* Corresponding author. Tel: +31(0)243652331; fax: +31(0)243652929; e-mail: leenders@mercachem.com;
jsch@sci.kun.nl
†
Present address: MercaChem BV, PO Box 31070; 6503 CB Nijmegen, The Netherlands.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01642-7

9174
intramolecular reaction with the carbamate nitrogen takes place to give the N-phenanthridinone
O-b- -glucuronyl carbamate 6. The phenanthridinone moiety serves as a leaving group in the
D
subsequent reaction of 6 with daunorubicin 2 to give compound 3 and phenanthridinone 4.
Scheme 1.
Unequivocal evidence for this mechanism was obtained by a reaction of 1a with coupling
reagent BOP in the absence of a nucleophilic amine. This reaction led to the high yield
formation of compound 6 (90%). An independent reaction of active carbamate 6 with daunoru-
bicin 2 led to carbamate 3a and phenanthridinone 4.
2. Application of the novel transfer reaction
Application of the reaction to the synthesis of b-
D
-glucuronyl carbamates of primary or
secondary amines is of interest because these b-
D
-glucuronyl carbamates are well known
metabolites4 of drugs containing a primary5 or a secondary6 amino group respectively. Synthesis
of these metabolites, however, is not always straightforward: (a) Other nucleophilic groups in
the substrate molecule (e.g. ꢀOH, ꢀNHR, ꢀCO2H) can impede isocyanate formation by reaction
with it (see e.g. by-product 5). (b) An isocyanate group cannot be formed from a secondary
amine. (c) When glycosyl donor 9 is reacted with a chloroformamide prepared from a secondary
amine, principally a- and not b-
D
-glucuronyl carbamates are formed. Our new synthetic route
to b- -glucuronyl carbamates avoids these problems.
D
Scheme 2.

9175
The novel b-
D
-glycosyl carbamate forming reaction was first tested in a model system (Scheme
3). When 1,2,3,4-tetrahydroisoquinoline 11 was reacted with N-2-biphenyl-2%-carboxylic acid
O-(methyl 2,3,4-tri-O-acetyl b- -glucuronyl) carbamate (6, Scheme 2), the b- -glucuronyl
carbamate 12 was obtained in 70% yield.
D
D
Scheme 3.
Furthermore, using our new method, synthesis of the protected precursor 14a of the metabolite
14c of the anti-hypertensive drug carvedilol 137 was successfully achieved in 92% yield from
( )-carvedilol (Scheme 3). Metabolite 14c had previously been prepared in vitro using dog and
rat liver microsomes8 for use as a reference compound.
Glucuronyl carrier 1 was prepared from 10 (previously prepared by us2 from 7 and 9) in 93%
by a palladium(0) mediated allylester demasking reaction (Scheme 3).
In conclusion, the preparation of N-daunorubicinyl- and N-carvediloyl O-b-
D
-glucuronyl
carbamates 3a and 14a, respectively, exemplifies the value of the present novel reaction in the
preparation b- -glucuronyl carbamates of relatively complicated primary and secondary amines.
D
References
1. This compound was previously prepared by us in a more complicated fashion during the synthesis of a daunorubicin
prodrug. See: Leenders, R. G. G.; Scheeren, H. W.; Houba, P. H. J.; Boven, E.; Haisma, H. J. Bioorg. Med. Chem.
Lett. 1995, 5, 2975.
2. Leenders, R. G. G.; Ruytenbeek, R.; Damen, E. W. P.; Scheeren, H. W. Synthesis 1996, 1309.
3. Leenders, R. G. G.;Damen, E. W. P.;Bijsterveld, E. J. A.;Scheeren, H. W.;Houba, P. H. J.;vanderMeulen-Muileman,
I. H.; Boven, E.; Haisma, H. J. Bioorg. Med. Chem. 1999, 7, 1597.
4. (a) Kaspersen, F. M.; van Boeckel, C. A. A. Xenobiotica 1987, 17, 1451; (b) Stachalski, A. V.; Jenkins, G. N. Nat.
Prod. Prep. 1998, 15, 173.
5. See for example: (a) Dow, J.; Piriou, F.; Wolf, E.; Dulery, B. D.; Haegele, K. D. Drug Metabol. Disp. 1994, 22,
738; (b) Brown, S. Y.; Garland, W. A.; Fukada, E. K. Drug Metabol. Disp. 1990, 18, 546.
6. See for example: (a) Tremaine, L. M.; Stroh, J. G.; Ronfeld, R. A. Drug Metabol. Disp. 1989, 17, 58; (b) Straub,
K.; Davis, M.; Hwang, B. Drug Metabol. Disp. 1988. 16, 359.
7. Fujimaki, M.; Hakusui, H. Xenobiotica 1990, 20, 1025.
8. Schaefer, W. H. Drug Metabol. Disp. 1992, 20, 130.