Total synthesis of glycocinnasperimicin D

Article abstract of DOI:10.1002/anie.200500892

(Chemical Equation Presented) A three-fragment coupling strategy afforded the antibiotic glycocinnasperimicin D (1). The convergent total synthesis features a Heck reaction to form the cinnamoyl glycoside, the [3,3] sigmatropic rearrangement of an allyl c

Full text of DOI:10.1002/anie.200500892

Communications
co-workers.[1] This molecule belongs to a family of glycocin-
namoylspermidine antibiotics which also includes LL-
BM123b (2), LL-BM123g1 (3), and LL-BM123g2 (4); these
members contain three different types of unusual amino
sugars.[2,3] Glycocinnasperimicin D contains the two highly
functionalized amino sugars: 2-ureidopentose (left) and 2-
guanidino-4-ureido-6-deoxy-a-d-glucopyranose (right) with
the p-cinnamoylspermidine aglycone. Moreover, these two
unusual amino sugars are joined through a unique glycosyl
urea linkage.
The amino sugar antibiotic 1 is of special interest because
of its broad-spectrum activity against Gram-negative organ-
isms; however, the natural product was no longer available as
a result of mutation of the Nocardia strain.[4] Its intriguing
structural features, coupled with its unique biological activity
and the lack of availability from natural sources, encouraged
us to explore the synthesis of this molecule. We report herein
the first total synthesis of glycocinnasperimicin D (1).
It is evident that the construction of the urea glycoside in
the presence of a variety of nitrogen-containing functional
groups constitutes the major challenge in the total synthesis of
1. Recently, we developed a new approach to the synthesis of
urea glycosides which involves the reaction of a highly
reactive glycosyl isocyanate with amines.[5] It was envisaged
that our protocol could be applied to the synthesis of 1 as
represented in the retrosynthetic analysis shown in Scheme 1.
Oxidation of the glycosyl isonitrile 7 could generate the
glycosyl isocyanate 5, which would react with the amino sugar
6 at the position indicated. The amino sugar 6 could be
obtained by the Heck reaction of the iodophenyl glycoside 8
with the acrylamide 9, which contains the spermidine moiety.
We anticipated that this convergent tactic for the synthesis of
the cinnamoyl glycoside would avoid the problems associated
with the glycosidation of a poorly nucleophilic phenol bearing
an electron-withdrawing substituent.[6]
Amino Sugar Synthesis
Total Synthesis of Glycocinnasperimicin D**
Taihei Nishiyama, Minoru Isobe, and
Yoshiyasu Ichikawa*
Glycocinnasperimicin D (1) was isolated from the fermenta-
tion broth of the producing strain (Nocardia), and its structure
was elucidated by spectroscopic studies by Umezawa and his
[*] Prof. Dr. Y. Ichikawa
Faculty of Science
Kochi University
Akebono-cho, Kochi 780-8520 (Japan)
Fax: (+81)88-844-8359
E-mail: ichikawa@cc.kochi-u.ac.jp
T. Nishiyama, Prof. Dr. M. Isobe
Laboratory of Organic Chemistry
School of Bioagricultural Sciences, Nagoya University
Chikusa, Nagoya 464-8601 (Japan)
[**] We thank Dr. Yoshikazu Takahashi (Microbial Chemistry Research
Center) for cellulose TLC analysis, antimicrobial assays, and
valuable discussions about glycocinnasperimicin D. The authors
are grateful for Grants-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports, and Culture of Japan for
financial support.
The synthesis of the left-hand amino sugar in the form of 7
began with the stereoselective synthesis of an allyl amine on
the basis of a protocol developed recently by our research
group[7] (Scheme 2). Thus, the enantioselective addition of
diethylzinc to the a,b-unsaturated aldehyde 10 in the presence
of the Soai catalyst 11[8] proceeded smoothly to afford the
allylic alcohol 12 in 79% yield and with high diastereoselec-
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
4372
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200500892
Angew. Chem. Int. Ed. 2005, 44, 4372 –4375

Angewandte
Chemie
tivity (15:1, checked by 1H NMR spectroscopic analysis of the
corresponding acetates). The allylic alcohol 12 was then
transformed into the allyl carbamate 13 by treatment with
trichloroacetyl isocyanate followed by hydrolysis with potas-
sium carbonate in aqueous methanol. Upon dehydration of
the carbamate 13 with triphenylphosphane, carbon tetrabro-
mide, and triethylamine at ꢀ408C, the resulting allyl cyanate
14 underwent a spontaneous [3,3] sigmatropic rearrangement
to afford the allyl isocyanate 15 with a high degree of 1,3-
chirality.[9] Subsequent trapping of 15 with 2,2,2-trichloro-
ethanol gave the Troc carbamate 16 in 82% yield from 13.[10]
Hydrolysis of the isopropylidene ketal in 16 was more
problematic than we had initially anticipated; the acetonide
16 was subjected to a number of deprotection protocols
without success, possibly as a result of silyl-group migration to
the adjacent hydroxy groups. Fortunately, Lewis acid cata-
lyzed deprotection with ferric chloride hexahydrate
(FeCl3·6H2O) was found to be successful.[11] After treatment
of 16 with FeCl3·6H2O in chloroform followed by workup, the
resulting mixture was treated immediately with acetic anhy-
dride and pyridine to prevent silyl-group migration. The
required acetate 17 was obtained in acceptable yield (80%
based on the consumed starting material) along with recov-
ered 16 (23%). Careful cleavage of the tert-butyldiphenylsilyl
ether 17 (HF·pyridine, THF)[12] followed by oxidative cleav-
age of the alkene (O3, CH2Cl2, ꢀ788C) gave the correspond-
ing lactol, which was subsequently treated with acetic
anhydride and pyridine to furnish predominantly the a-O-
acetyl glycoside 18 in 71% yield over three steps. Treatment
of 18 with trimethysilyl azide in the presence of tin(vi)
chloride furnished the b-glycosyl azide 19 exclusively
(86%).[13] The isonitrile group at the anomeric position was
constructed in a three-step sequence by 1) Staudinger reac-
tion of the glycosyl azide 19, 2) formylation of the resulting
iminophosphorane with acetic formic anhydride (72% yield
over two steps), and 3) dehydration of the formamide 20 by
the modified Appel procedure[14] to afford the isonitrile
glycoside 7 (85% yield).
Scheme 1. Retrosynthetic analysis of glycocinnasperimicin D.
The synthesis of the right-hand amino sugar in the form of
6 commenced with the a-phenyl 2-azido-d-galactoside 21,[15]
which was prepared from d-galactal in a four-step sequence
(Scheme 3). Tosylation of the primary alcohol in 21 followed
by displacement with iodide anion gave the iodide 22 in 73%
yield over two steps. After selective protection of the
equatorial hydroxy group at C3 in 22 as a benzoate group
(93% yield), reductive hydrogenolysis of the iodide 23 was
carried out with concomitant reduction of the azide group.
Subsequent protection of the resulting amine as its Troc
carbamate gave the 6-deoxypyranose 24 in 81% yield.[16]
The cinnamic spermidine amide attached to the amino
sugar was constructed from the phenyl glycoside 24 by a two-
step protocol. Thus, treatment of 24 with ceric ammonium
nitrate (CAN) and an iodine salt (nBu4NI) in acetonitrile at
708C furnished the iodophenyl galactoside 8 in 86% yield.[17]
The Heck reaction of 8 with acrylamide 9 proceeded smoothly
to furnish the cinnamoyl galactoside 25 in 73% yield.
Cleavage of the Troc carbamate in 25 (Zn, AcOH, THF)
followed by treatment of the resulting amine with N,N-di-
(tert-butoxycarbonyl)-S-methylisothiourea and mercuric
Scheme 2. Synthesis of the left-hand amino sugar moiety: a) Et2Zn,
cyclohexane, 08C!RT (79%); b) CCl3CONCO, CH2Cl2; c) aqueous
K2CO3, MeOH (93% over two steps); d) PPh3, CBr4, Et3N, CH2Cl2,
ꢀ408C; e) CCl3CH2OH, room temperature, overnight (82% over two
steps); f) FeCl3·6H2O, CHCl3; g) Ac2O, pyridine (80%); h) HF·pyridine,
THF; i) O3, CH2Cl2, Me2S; j) Ac2O, DMAP, pyridine (71% over three
steps); k) TMSN3, SnCl4, CH2Cl2, (86%); l) PPh3, THF, H2O;
m) AcOCHO (72% over two steps); n) PPh3, CBr4, Et3N, CH2Cl2,
(85%). DMAP=4-dimethylaminopyridine, TMS=trimethylsilyl,
Troc=2,2,2-trichloroethoxycarbonyl.
Angew. Chem. Int. Ed. 2005, 44, 4372 –4375
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4373

Communications
Scheme 4. Final coupling and completion of the synthesis of
glycocinnasperimicin D (1): a) pyridine N-oxide, I2 (cat.), 3-ꢀ molecular
sieves, CH3CN (85% for 28); b) Zn, AcOH, THF; c) CCl3CONCO,
CH2Cl2; d) Et3N, MeOH (77% over two steps); e) TFA, CH2Cl2; f) 28%
aqueous NH3, CH3OH; g) HPLC purification, lyophilization
(23%). TFA=trifluoroacetic acid.
sugar 6. Gratifyingly, this procedure gave the desired coupling
product 28 in good yield (85%). Removal of the Troc group in
28 and subsequent treatment of the resulting amine with
trichloroacetyl isocyanate, followed by methanolysis, gave the
fully protected glycocinnasperimicin D 29 in 77% yield.
Finally, removal of the Boc group in 29 with trifluoroacetic
acid and subsequent cleavage of the benzoyl and two acetyl
groups in a mixture of aqueous ammonia and methanol
yielded glycocinnasperimicin D (1). To our delight, careful
and laborious purification by HPLC provided pure synthetic
material 1 (23% yield, isolated as the hydrochloride), the
spectral data (1H NMR, 13C NMR, HRMS), TLC behavior,
and antimicrobial activity of which were in good agreement
with those of the natural glycocinnasperimicin D.
Scheme 3. Synthesis of the right-hand amino sugar unit: a) TsCl,
pyridine (81%); b) NaI, nBu4NI, DME (91%); c) BzCl, pyridine (93%);
d) H2, Pd-C (5%), Et3N, EtOH; e) TrocCl, pyridine (81% over two
steps); f) nBu4NI, CAN, CH3CN (86%); g) Pd(OAc)2, P(o-Tol)3, Et3N,
CH3CN, 708C (73%); h) Zn, AcOH, THF; i) HgCl2, Et3N, DMF (72%
over two steps); j) Tf2O, pyridine, CH2Cl2; k) NaN3, DMF (73% over
two steps); l) HS(CH2)3SH, Et3N, MeOH (73%). Boc=tert-butoxycar-
bonyl, Bz=benzoyl, DME=dimethoxyethane, DMF=N,N-dimethyl-
formamide, Tf=trifluoromethanesulfonyl, Tol=tolyl.
chloride in DMF afforded the bis(Boc)-protected guanidine
26 in 72% yield for the two steps.[18] The amino group at C4
was introduced by SN2 displacement of a triflate with azide
anion; thus the hydroxyl group in 26 was transformed into the
corresponding triflate, and the rather unstable product was
subjected immediately to treatment with sodium azide in
DMF to furnish 27 in 73% yield over two steps. Whereas
reduction of the azide group in 27 with PPh3, SnCl2,[19]
nBu3SnH,[20] or H2/Pd-C[21] was unsuccessful, careful treat-
ment with propanedithiol and triethylamine in MeOH[22]
furnished the amino sugar 6 in 73% yield to set the stage
for the coupling reaction.
With both key amino sugars 6 and 7 in hand, we next
investigated their coupling to construct the urea glycosyl
linkage (Scheme 4). In the event, oxidation of the isonitrile 7
with pyridine N-oxide in the presence of 3-Š molecular sieves
and a catalytic amount of iodine in acetonitrile generated the
isocyanate 5,[5] which was treated directly with the amino
In conclusion, the first total synthesis of glycocinnasper-
imicin D (1) has been carried out by a convergent route on the
basis of a three-fragment coupling strategy. Our synthesis
features a Heck reaction to form the cinnamoyl glycoside, the
stereoselective formation of an allyl amine by the [3,3]
sigmatropic rearrangement of an allyl cyanate, and the
construction of the urea glycoside by the coupling of a
glycosyl isocyanate with an amino sugar. In particular, the
oxidation of an isonitrile glycoside afforded a highly reactive
isocyanate glycoside, which was key to the crucial coupling
step.
Received: March 10, 2005
Published online: June 14, 2005
Keywords: amino sugars · antibiotics · natural products ·
.
sigmatropic rearrangement · total synthesis
4374
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org Angew. Chem. Int. Ed. 2005, 44, 4372 –4375

Angewandte
Chemie
[20] H. H. Wasserman, K. R. Brunner, J. D. Buynak, C. G. Carter, T.
[1] K. Dobashi, K. Nagaoka, Y. Watanabe, M. Nishida, M. Hamada,
H. Naganawa, T. Takita, T. Takeuchi, H. Umezawa, J. Antibiot.
1985, 1166.
Oku, R. P. Robinson, J. Am. Chem. Soc. 1985, 107, 519.
[21] E. J. Corey, K. C. Nicolaou, R. D. Balanson, Y. Machida, Syn-
thesis 1975, 590.
[2] a) G. A. Ellestad, D. B. Cosulich, R. W. Broschard, J. H. Martin,
M. P. Kunstmann, G. O. Morton, J. E. Lancaster, W. Fulmor,
F. M. Lovell, J. Am. Chem. Soc. 1978, 100, 2515; b) S. H. L. Chiu,
R. Fiala, R. Kennett, L. Wozniak, M. W. Bullock, J. Antibiot.
1984, 1000; c) H.-R. Tsou, R. R. Fiala, P. C. Mowery, M. W.
Bullock, J. Antibiot. 1984, 1382.
[22] H. Bayley, D. N. Stadring, J. R. Knowles, Tetrahedron Lett. 1978,
19, 3633.
[3] For synthetic studies of glycocinnamoylspermidine antibiotics,
see: a) K. Araki, K. Miyazawa, H. Hashimoto, J. Yoshimura,
Tetrahedron Lett. 1982, 23, 1705; b) K. Araki, H. Hashimoto, J.
Yoshimura, Carbohydr. Res. 1982, 109, 143; c) K. Araki, M.
Kawa, K. Miyazawa, H. Hashimoto, J. Yoshimura, Bull. Chem.
Soc. Jpn. 1986, 59, 3137.
[4] Personal communication from Dr. H. Naganawa and Dr. Y.
Takahashi.
[5] a) Y. Ichikawa, T. Nishiyama, M. Isobe, Synlett 2000, 1 253; b) Y.
Ichikawa, T. Nishiyama, M. Isobe, J. Org. Chem. 2001, 66, 4200.
[6] T. Nishiyama, Y. Ichikawa, M. Isobe, Synlett 2004, 89.
[7] a) Y. Ichikawa, T. Ito, T. Nishiyama, M. Isobe, Synlett 2003, 1034;
b) Y. Ichikawa, T. Ito, M. Isobe, Eur. J. Org. Chem. 2005, 1949.
[8] K. Soai, A. Ookawa, T. Kaba, K. Ogawa, J. Am. Chem. Soc. 1987,
109, 7111.
[9] For representative examples of the allylic cyanate-to-isocyanate
rearrangement, see: a) C. Christophersen, A. Holm, Acta Chem.
Scand. 1970, 24, 1512; b) L. E. Overman, M. Kakimoto, J. Org.
Chem. 1978, 43, 4564; c) Y. Ichikawa, Synlett 1991, 238; d) K.
Banert, S. Groth, Angew. Chem. 1992, 104, 865; Angew. Chem.
Int. Ed. Engl. 1992, 31, 866.
[10] a) Y. Ichikawa, K. Tsuboi, M. Isobe, J. Chem. Soc. Perkin Trans.
1 1994, 2791; b) Y. Ichikawa, M. Osada, I. Ohtani, M. Isobe, J.
Chem. Soc. Perkin Trans. 1 1997, 1449.
[11] K. S. Kim, Y. H. Song, B. H. Lee, C. S. Hahn, J. Org. Chem. 1986,
51, 404.
[12] D. A. Evans, S. W. Kaldor, T. K. Jones, J. Clardy, T. J. Stout, J.
Am. Chem. Soc. 1990, 112, 7001.
[13] H. Paulson, Z. Gyorgydeak, M. Friedman, Chem. Ber. 1974, 107,
1568.
[14] a) Y. Ichikawa, J. Chem. Soc. Perkin Trans. 1 1992, 2135; b) I. A.
OꢀNeil in Comprehensive Organic Functional Group Trans-
formations, Vol. 3 (Eds.: A. Katritzky, O. Meth-Cohn, C. W.
Ress), Pergamon, Oxford, 1995, pp. 696.
[15] Multigram quantities of the phenyl glycoside 21 were readily
obtained in 51% yield from d-galactal by the following three-
step synthesis: 1) azidonitration of the d-galactal I followed by
acetolysis to give II (see: R. U. Lemieux, R. M. Ratcliffe, Can. J.
Chem. 1979, 57, 1244), 2) Lewis acid catalyzed glycosylation of II
with phenol (86%, a/b 4:1), and 3) deprotection of the acetyl
groups and purification of the resulting triol by recrystallization.
[16] For recent examples of C6 deoxygenation, see: A. Medgyes, E.
Farkas, A. Liptak, V. Pozsgay, Tetrahedron 1997, 53, 4159.
[17] T. Sugiyama, Bull. Chem. Soc. Jpn. 1981, 54, 2847.
[18] Z. X. Guo, A. N. Cammidge, D. Horwell, Synth. Commun. 2000,
30, 2933.
[19] S. N. Maiti, J. Beres, M. P. Singh, R. G. Micetich, Tetrahedron
Lett. 1986, 27, 1423.
Angew. Chem. Int. Ed. 2005, 44, 4372 –4375
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4375