A stereodivergent synthesis of virantmycin by an enzyme-mediated diester desymmetrization and a highly hindered aryl amination

Article abstract of DOI:10.1002/anie.200461327

(Chemical equation presented). Both enantiomers of the antiviral agent virantmycin were synthesized in a sequence of reactions in which the key steps were a highly stereoselective porcine liver esterase(PLE) mediated desymmetrization of a prochiral dieste

Full text of DOI:10.1002/anie.200461327

Angewandte
Chemie
Stereoselective Synthesis
A Stereodivergent Synthesis of Virantmycin by an
Enzyme-Mediated Diester Desymmetrization and
a Highly Hindered Aryl Amination**
Thomas G. Back* and Jeremy E. Wulff
(ꢀ)-Virantmycin (1) is an unusual chlorinated tetrahydroqui-
noline that was isolated from a strain of Streptomyces
nitrosporeus in 1980.[1] It was found to possess both strong
inhibitory activity against RNA and DNA viruses, and
antifungal activity.[2] The initial structure elucidation of
virantmycin was reported in the 1980s,[2,3] but not until 1990
was the correct stereochemistry established by NMR meth-
ods,[4] and later confirmed by synthesis.[5] To date, racemic
syntheses of 1 have been completed by Hill and Raphael,[6]
Morimoto, Shirahama et al.,[5,7] and by Steinhagen and
Corey.[8] The preparation of the (+)-antipode of the naturally
occurring antibiotic has also been reported.[9] Very recently,
Kogen et al. achieved the first enantioselective synthesis of
(ꢀ)-1 from (S)-indoline-2-carboxylic acid.[10] The latter report
prompted us to disclose our own efforts in this area, which
have resulted in a stereodivergent route to both (+)-1 and
(ꢀ)-1.
The principal challenge in the synthesis of virantmycin
involves the stereoselective construction of the two contig-
uous stereocenters, which include the quaternary carbon atom
at C2. Our plan was to construct the latter center by the
desymmetrization of a key intermediate diester 2 b y an
enzyme-mediated partial hydrolysis. After appending the aryl
moiety by a Claisen-like condensation, we envisaged the
stereoselective introduction of the amino group to the highly
hindered stereocenter by a Curtius rearrangement and ring-
closure to complete the tetrahydroquinoline skeleton by an
intramolecular aryl amination reaction (Scheme 1).
Diester 2 was readily obtained by sequential alkylation of
the enolate derived from dimethyl malonate by using NaH
with 5-iodo-2,3-dimethyl-2-pentene[11] and methoxymethyl
chloride. Scheme 2 illustrates the desymmetrization of 2,
which was achieved by partial hydrolysis with porcine liver
esterase (PLE)[12] to afford the half-ester 3 in 89% yield and
95% ee, as determined by integration of the NMR spectrum
of the salt formed from 3 and (S)-(ꢀ)-a-methylbenzylamine.
[*] Prof. Dr. T. G. Back, J. E. Wulff
Department of Chemistry
University of Calgary
Calgary, AB, T2N 1N4 (Canada)
Fax: (+1)403-289-9488
E-mail: tgback@ucalgary.ca
[**] We thank the Natural Sciences and Engineering Research Council of
Canada (NSERC) for financial support. J.E.W. thanks, the NSERC,
the Alberta Heritage Foundation for Medical Research, and the
Izaak Walton Killam Foundation for Postgraduate Scholarships. We
thank Dr. B. A. Keay for helpful discussions and a generous gift of
BINAPFu.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 6493 –6496
DOI: 10.1002/anie.200461327
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6493

Communications
Scheme 1. Retrosynthesis of (ꢀ)-virantmycin (1).
Scheme 2. Desymmetrization of diester 2 to generate chiral intermedi-
ates 4 and 5: a) porcine liver esterase (PLE), DMSO-pH 8.0 phosphate
buffer (1:4), 7 days, RT, 89%, 95% ee; b) cyanuric fluoride, pyridine,
dichloromethane, 1 h, 08C, 71% for 4 and 75% for 5; c) 2-(trimethyl-
silyl)ethanol, 1,3-dicyclohexylcarbodiimide (DCC), N,N-dimethylamino-
pyridine (DMAP), dichloromethane, 3 days, RT, 77%; d) 10% aqueous
KOH, methanol, 15 h, 458C, 88% (based on 20% of recovered 3.
Scheme 3. Coupling of diester 6 with chiral intermediate 5: a) lithium
hexamethyldisilazide (LiHMDS), Et2O, 08C, 10 min; then 5, Et2O, 1 h
at 08C!20 h at RT, 63%; b) 10% aqueous NaCl, DMSO, 20 h, 1258C,
78%; c) NaBH4, methanol, 2.5 h, 08C, 83%; d) pyridinium chlorochro-
mate (PCC), dichloromethane, 3 days, RT, 77%.
mediated by diphenylphosphoryl azide (DPPA),[16] followed
by workup with sodium borohydride, to afford formamide 11
(Scheme 4). The crucial intramolecular Buchwald–Hartwig
aryl amination[17] step was then attempted under a variety of
conditions, with generally unsatisfactory results. However, we
were pleased to discover that the treatment of formamide 11
with [Pd2(dba)3] in the presence of the Keay ligand BINAPFu
(12)[18] under the conditions shown in Scheme 4 resulted in
quantitative cyclization to 13.
The selection of BINAPFu as the Pd ligand of choice was
based on model studies of the aryl aminations of other a-
quaternary amines (1-adamantylamine and methyl a,a-dime-
thylglycinate) with methyl 4-bromo-3-methylbenzoate. Other
ligands, such as BINAP,[19a] DPPF,[19b] PCy3,[19c] o-biphenyl-
PCy2,[19d] o-biphenylPtBu2,[19d] DPEphos,[19e] MAP,[19f] and
IMES hydrochloride[19g] failed to effect coupling or produced
very low yields of the corresponding aryl amines under a wide
variety of conditions. The successful intramolecular aryl
amination of formamide 11 using the BINAPFu ligand is
particularly noteworthy because very few examples of aryl
aminations of aliphatic amines containing a-quaternary
centers are known.[20] BINAPFu is a less strongly donating
ligand than other commonly employed bidentate phosphines
such as BINAP.[18] Moreover, the reductive elimination steps
The absolute configuration of 3 was assumed to be (S) on the
basis of earlier studies[12b,c] of PLE-mediated hydrolyses of
other b-diesters, and this assignment was confirmed unequiv-
ocally by the ultimate conversion of 3 to essentially pure
enantiomers of the final products. Thus, half-ester 3 was
converted separately into each of the pseudo-enantiomeric
acyl fluorides 4 and 5 (Scheme 2),[13] which in turn served as
respective precursors of (+)-1 and (ꢀ)-1. Acylation of the
enolate of diester 6[14] with 5 afforded triester 7 (Scheme 3),
which was subjected to selective Krapcho decarboxylation[15]
of the less hindered b-keto ester moiety to furnish 8. The
reduction of the ketone group of 8, which was required to
introduce a hydroxy group to serve as the chlorination site for
the final product, resulted in poor stereoselectivity under a
variety of conditions. However, the undesired epimer 10 was
easily separated from 9 and recycled back to ketone 8 with
PCC. The configurations of epimers 9 and 10 were assigned on
the basis of NOE experiments conducted on the correspond-
ing b-lactones (Scheme 3).
Alcohol 9 was acetylated and the trimethylsilylethyl ester
was selectively removed with fluoride ion. The resulting
carboxylic acid was subjected to a Curtius rearrangement
6494
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 6493 –6496

Angewandte
Chemie
Scheme 5. Synthesis of (+)-virantmycin from acyl fluoride 4: a) 10%
aqueous KOH, methanol, 20 h, RT; b) NaH, nPrSH, HMPA, 4.75 h, RT;
c) SOCl2, methanol, 1 h at ꢀ108C!3 h at reflux, 46% overall yield for
steps a–c.
favourably with the literature value [a]2D4 = + 11.28 (c = 0.125,
chloroform).[9]
Scheme 4. Synthesis of (ꢀ)-virantmycin (1) from intermediate 9:
a) N,N-dimethylaminopyridine (DMAP), pyridine, acetic anhydride, 3
days, RT; b) 1.0m tetrabutylammonium fluoride in tetrahydrofuran,
1 h, RT; c) diphenylphosphoryl azide (DPPA), N,N-dimethylaminopyri-
dine (DMAP), triethylamine, toluene, 2.25 h, reflux; then NaBH4, tetra-
hydrofuran, 12.5 h, RT, 84% overall yield for steps a–c; d) [Pd2(dba)3],
12, Cs2CO3, toluene, 6.5 h, 908C, 100%; e) 0.13m NaOH in methanol,
24 h, RT, 84%.
In conclusion, the present method provides a new route to
both enantiomers of the antiviral agent virantmycin (1). It
employs as key steps a highly enantioselective enzyme-
mediated desymmetrization and a remarkably effective intra-
molecular aryl amination of a hindered a-quaternary ali-
phatic amine. The procedure is also potentially amenable to
the preparation of analogues for the purpose of structure–
activity studies.
of aryl aminations and related Pd-catalyzed coupling reac-
tions are enhanced by weakly coordinating phosphine
ligands.[21] It is therefore possible that reductive elimination
is the rate-determining step in the present case because of the
high degree of steric hindrance associated with coupling an
ortho-substituted aryl bromide with an a-quaternary amine
derivative. The particular efficacy of BINAPFu may be
attributed to its ability to facilitate this step.
Received: July 16, 2004
Keywords: aryl amination · enzyme catalysis · esterases ·
.
natural products · total synthesis
¯
[1] S. Omura, A. Nakagawa, H. Hashimoto, R. Oiwa, Y. Iwai, A.
Hirano, N. Shibukawa, Y. Kojima, J. Antibiot. 1980, 33, 1395.
[2] A. Nakagawa, Y. Iwai, H. Hashimoto, N. Miyazaki, R. Oiwa, Y.
Takahashi, A. Hirano, N. Shibukawa, Y. Kojima, S. Omura, J.
Antibiot. 1981, 34, 1408.
[3] Y. Morimoto, K. Oda, H. Shirahama, T. Matsumoto, S. Omura,
Chem. Lett. 1988, 909.
[4] C. M. Pearce, J. K. M. Sanders, J. Chem. Soc. Perkin Trans. 1
1990, 409.
[5] Y. Morimoto, F. Matsuda, H. Shirahama, Synlett 1991, 202.
[6] a) M. L. Hill, R. A. Raphael, Tetrahedron Lett. 1986, 27, 1293;
b) M. L. Hill, R. A. Raphael, Tetrahedron 1990, 46, 4587.
[7] Y. Morimoto, F. Matsuda, H. Shirahama, Tetrahedron 1996, 52,
10609.
[8] H. Steinhagen, E. J. Corey, Org. Lett. 1999, 1, 823.
[9] Y. Morimoto, H. Shirahama, Tetrahedron 1996, 52, 10631.
[10] M. Ori, N. Toda, K. Takami, K. Tago, H. Kogen, Angew. Chem.
2003, 115, 2644; Angew. Chem. Int. Ed. 2003, 42, 2540.
[11] a) T. G. Back, R. J. Bethell, M. Parvez, D. Wehrli, J. Org. Chem.
1998, 63, 7908; b) A. N. De Silva, C. L. Francis, A. D. Ward,
Aust. J. Chem. 1993, 46, 1657.
Deacetylation and concomitant deformylation of tetrahy-
droquinoline 13 provided the free alcohol 14, which was
converted into (ꢀ)-1 by the same method used previously by
Morimoto and Shirahama[9] in their synthesis of (+)-1
(Scheme 4). The product displayed NMR spectra consistent
¯
¯
with the literature[4,6,9] and gave a specific rotation [a]2D0
=
ꢀ118 (c = 0.13, chloroform) that compared favorably with
that reported for the natural product: [a]2D4 = ꢀ11.18 (c =
0.175, chloroform).[9]
Finally, acyl fluoride 4 was converted into the unnatural
antipode (+)-1 by a similar process (Scheme 5), except that
the aromatic and aliphatic ester moieties of 15 were converted
to the free carboxylic acids in 16 by saponification of the
former and dealkylation with sodium propanethiolate of the
latter, followed by selective reesterification of the aromatic
carboxylic acid and Curtius rearrangement of the remaining
aliphatic acid (Scheme 5). Completion of the synthesis was
achieved as in the case of (ꢀ)-1. The NMR spectra of the
product were identical to those of (ꢀ)-1 and the optical
rotation data [a]2D0 = + 138 (c = 0.14, chloroform), compared
[12] a) For a general review, see: H. G. Davies, R. H. Green, D. R.
Kelly, S. M. Roberts, Biotransformations in Preparative Organic
Chemistry, Academic Press, London, 1989, chap. 2; b) F. Björk-
Angew. Chem. Int. Ed. 2004, 43, 6493 –6496
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6495

Communications
ling, J. Boutelje, S. Gatenbeck, K. Hult, T. Norin, P. Szmulik,
Tetrahedron 1985, 41, 1347; c) E. J. Toone, M. J. Werth, J. B.
Jones, J. Am. Chem. Soc. 1990, 112, 4946.
[13] The acyl fluorides were prepared by the general method of: S.
Grob, S. Laabs, A. Scherrmann, A. Sudau, N. Zhang, U.
Nubbemeyer, J. Prakt. Chem. 2000, 342, 711.
[14] Diester 6 was prepared by treatment of methyl 4-bromo-3-
bromomethylbenzoate with NaCN, followed by alkaline hydrol-
ysis of the corresponding benzyl nitrile and Fischer esterification
with methanol.
[15] A. P. Krapcho, A. J. Lovey, Tetrahedron Lett. 1973, 957.
[16] T. Shioiri, K. Ninomiya, S. Yamada, J. Am. Chem. Soc. 1972, 94,
6203.
[17] For selected reviews, see: a) J. P. Wolfe, S. Wagaw, J.-F. Marcoux,
S. L. Buchwald, Acc. Chem. Res. 1998, 31, 805; b) J. F. Hartwig,
Acc. Chem. Res. 1998, 31, 852; c) J. F. Hartwig in Handbook of
Organopalladium Chemistry for Organic Synthesis, Vol. 1 (Ed.:
E. Negishi), Wiley, Hoboken, NJ, 2002, pp. 1051 – 1096.
[18] a) N. G. Andersen, M. Parvez, R. McDonald, B. A. Keay, Can. J.
Chem. 2004, 82, 145; b) for a review of 2-furylphosphine ligands
in transition-metal-mediated reactions, see: N. G. Andersen,
B. A. Keay, Chem. Rev. 2001, 101, 997.
[19] a) BINAP = 2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl: J. P.
Wolfe, S. Wagaw, S. L. Buchwald, J. Am. Chem. Soc. 1996, 118,
7215; b) DPPF = 1,1’-bis(diphenylphosphanyl)ferrocene: M. S.
Driver, J. F. Hartwig, J. Am. Chem. Soc. 1996, 118, 7217; c) PCy3:
N. P. Reddy, M. Tanaka, Tetrahedron Lett. 1997, 38, 4807; d) o-
biphenylPCy2 and o-biphenylPtBu2: J. P. Wolfe, H. Tomori, J. P.
Sadighi, J. Yin, S. L. Buchwald, J. Org. Chem. 2000, 65, 1158;
e) DPEphos = 2,2’-bis(diphenylphosphanyl)-1,1’-diphenyl
ether: J. P. Sadighi, M. C. Harris, S. L. Buchwald, Tetrahedron
Lett. 1998, 39, 5327; f) MAP = 2’-dimethylamino-2-(diphenyl-
ˇ
ˇ
phosphanyl)-1,1’-binaphthalene: S. Vyskocil, M. Smrcina, P.
ˇ
´
Kocovsky, Tetrahedron Lett. 1998, 39, 9289; g) IMES hydrochlo-
ride = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene hydro-
chloride: G. A. Grasa, M. S. Viciu, J. Huang, S. P. Nolan, J.
Org. Chem. 2001, 66, 7729.
[20] For an aryl amination with tert-butylamine, see: a) H. Siebe-
neicher, I. Bytschkov, S. Doye, Angew. Chem. 2003, 115, 3151;
Angew. Chem. Int. Ed. 2003, 42, 3042; b) I. Bytschkov, H.
Siebeneicher, S. Doye, Eur. J. Org. Chem.
2003, 2888; for an aryl amination with N-tert-
butylaniline, see: c) M. Prashad, X. Y. Mak,
ˇ
Y. Liu, O. Repic, J. Org. Chem. 2003, 68,
1163.
[21] G. Mann, Q. Shelby, A. H. Roy, J. F. Hart-
wig, Organometallics 2003, 22, 2775.
6496 ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 6493 –6496