Asymmetric total synthesis of (+)-K01-0509 B: Determination of absolute configuration

Article abstract of DOI:10.1021/ol062282z

K01-0509 B is a novel natural product which contains a carbamoylated cyclic guanidine. Our asymmetric total synthesis features a Sharpless asymmetric epoxidation and a stereocontrolled construction of the cyclic guanidine via an asymmetric nitroaldol reac

Full text of DOI:10.1021/ol062282z

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5577-5580
Asymmetric Total Synthesis of
)-K01-0509 B: Determination of
Absolute Configuration
(+
Satoshi Tsuchiya,† Toshiaki Sunazuka,†,‡,§ Tomoyasu Hirose,§ Ryuma Mori,†
Toshiaki Tanaka,† Masato Iwatsuki,§ and Satoshi Omura*,†,‡,§
h
Kitasato Institute for Life Sciences, Graduate School of Infection Control Sciences, and
The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
omura-s@kitasato.or.jp
Received September 16, 2006
ABSTRACT
K01-0509 B is a novel natural product which contains a carbamoylated cyclic guanidine. Our asymmetric total synthesis features a Sharpless
asymmetric epoxidation and a stereocontrolled construction of the cyclic guanidine via an asymmetric nitroaldol reaction, followed by
intramolecular SN2 cyclization. These reactions allowed the cyclic guanidine and the adjacent hydroxy group to be assembled, facilitating the
asymmetric total synthesis and determination of the absolute stereochemistry of K01-0509 B.
K01-0509 B (1), a novel natural compound comprised of a
carbamoylated cyclic guanidine, an adjacent hydroxy group,
and a carboxylic acid, was isolated from the culture broth
of Streptomyces sp. K01-0509 during a search for selective
inhibitors of type III secretion system.1 The type III secretion
system is used by many Gram-negative pathogens, including
enteropathogenic Escherichia coli (EPEC), enterohemoragic
E. coli (EHEC), Pseudomonas aeruginosa, Salmonella spp.,
and Shigella spp.2 to deliver their effector proteins into the
host cell during the infection process.3
inhibitors as typified by guadinomines A (2), B (3), and C
(4) (Figure 1), which are also novel cyclic guanidine natural
products, all derived from the same culture broth.4,5 The
planar structures of 1 and guadinomines were elucidated by
detailed analysis of their 1-D and 2-D NMR spectra, but the
relative and absolute configuration remained undefined due
to insufficient quantities of the natural products. Moreover,
the evidence for the connected positions of these carbamoyl
groups were inconclusive because of the weak signals in the
C-H long-range coupled NMR spectrum (HMBC) between
Consequently, a potent, selective inhibitor of type III
secretion systems could prove to be a novel anti-infective
drug. During recent screening of microbial resources for
candidate compounds, we discovered three potent, selective
(2) Cornelis, G. R.; Gijsegem, F. V. Annu. ReV. Microbiol. 2000, 54,
735-774.
(3) (a) Hueck, C. J. Microbiol. Mol. Biol. ReV. 1998, 62, 379-433. (b)
Cheng, L. W.; Schneewind, O. Trends Microbiol. 2000, 8, 214-220. (c)
Abe, A.; Heczko, U.; Hegele, R. G.; Finlay, B. B. J. Exp. Med. 1998, 188,
1907-1916. (d) DeVinney, R.; Gauthier, A.; Abe, A.; Finlay, B. B.
Cell Mol. Life Sci. 1999, 55, 961-976.
(4) Ohmura, S.; Tomoda, H.; Abe, A.; Iwatsuki, M.; Takahashi, Y. PCT
WO 2006/304843 A1, March 7, 2006.
(5) Ohmura, S.; Tomoda, H.; Abe, A.; Iwatsuki, M.; Takahashi, Y. PCT
WO 2005/090384 A1, September 29, 2005.
† Graduate School of Infection Control Sciences, Kitasato University.
‡ Kitasato Institute for Life Sciences, Kitasato University.
§ The Kitasato Institute.
(1) Iwatsuki, M.; Tomoda, H.; Uchida, R.; Yoshijima, H.; Kim, Y.-P.;
Ui, H.; Matsumoto, A.; Takahashi, Y.; Abe, A.; Ohmura, S. J. Antibiot. 2006,
submitted.
10.1021/ol062282z CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/27/2006

Scheme 1. Retrosynthetic Analysis of K01-0509 Ba
Figure 1. Structure of K01-0509 B and guadinomines.
carbamoyl carbon and H-5′ in 1 as well as guadinomines A
(2), B (3), and C (4).
Although there are three natural products (enduracidin,6
minosaminomycin,7 and an amino acid derivative from the
marine ascidian8) which contain a 5-membered cyclic guani-
dine (2-iminoimidazolidine), the structure is quite rare in
natural products. Moreover, although the antimicrobacterial
activity of such compounds is known, no other biological
activity has been reported. Consequently, we undertook the
total synthesis of guadinomines.
Although K01-0509 B (1) itself has no bioactivity against
the type III secretion system, we regarded the compound as
a key starting point. We expected that K01-0509 B (1) was
a biosynthetic intermediate en route to guadinomines. Thus,
the relative and absolute configuration of K01-0509 B (1)
became of some importance for determining relative and
absolute configurations and for refining the possible stereo-
isomers for a total synthesis of the guadinomines.
a PMB ) p-methoxybenzyl.
of carbamoyl group, followed by full deprotection. The
stereocontrolled construction of the cyclic guanidine, which
is the key procedure of this total synthesis, uses intra-
molecular SN2 cyclization of guanidine 7 and anti-selective
asymmetric nitroaldol reaction of chiral aldehyde 9. The syn-
selective asymmetric nitroaldol reaction of 9 allowed us to
synthesize the syn-nitroaldol 11 for the precursor of another
diastereomer, (5R,4′S)-10.
An enantioselective synthesis of aldehyde (-)-9 is outlined
in Scheme 2. Sharpless asymmetric epoxidation of allyl
For determination of the relative and absolute stereochem-
istry of 1, our approach was to devise an efficient synthesis
that relied on readily available chiral material derived from
a highly reliable asymmetric synthesis. Our strategy was
designed to provide rapid access to all possible diastereomers
to allow comparison of spectral data between synthetic and
natural compounds.
Scheme 2. Synthesis of Aldehyde (-)-9a
Our synthetic strategy is shown in Scheme 1. We set up
the absolute configuration of the hydroxy group at the C-5
position (R) and planned a divergent synthetic route to the
two diastereomers (5R,4′R) and (5R,4′S). The regioselective
introduction of the carbamoyl group into the 1′-nitrogen of
(5R,4′R)-5 was configured in the final phase. Thus, the
synthesis of (5R,4′R)-5 was planned from 1′-nitrogen un-
protected cyclic guanidine 6 by oxidation and introduction
a (-)-DET ) (-)-diethyl D-tartrate, DIPEA ) N,N-diisopropyl-
ethylamine.
(6) (a) Horii, S.; Kameda, Y. J. Antibiot. 1968, 21, 665-667. (b)
Higashide, E.; Hatano, K.; Shibata, M.; Nakazawa, K. J. Antibiot. 1968,
21, 126-137. (c) Higashide, E.; Hatano, K.; Shibata, M.; Nakazawa, K. J.
Antibiot. 1968, 21, 138-146.
(7) (a) Hamada, M.; Kondo, J.; Yokoyama, T.; Miura, K.; Iinuma, K.;
Yamamoto, H.; Maeda, K.; Takeuchi, T.; Umezawa, H. J. Antibiot. 1974,
27, 81-83. (b) Iinuma, K.; Kondo, S.; Maeda, K.; Umezawa, H. J. Antibiot.
1975, 28, 613-615.
(8) Garcia, A.; Va´zquez, M. J.; Quin˜oa´, E.; Riguera, R.; Debitus, C. J.
Nat. Prod. 1996, 59, 782-785.
alcohol 129 provided the epoxy alcohol (+)-13 in 93% yield
and 97% ee.10 Reductive opening of the epoxide with Red
(9) Nacro, K.; Baltas, M.: Gorrichon, L. Tetrahedron 1999, 55, 14013-
14030.
5578
Org. Lett., Vol. 8, No. 24, 2006

Al proceeded at the C-2 position with excellent regioselec-
tivity and furnished the 1,3-diol (+)-14; the primary alcohol
(-)-15 was then synthesized by chemoselective protection
of secondary alcohol through the acetalization and reductive
cleavage of the resulting acetal ring. Subsequent Swern
oxidation of (-)-15 afforded aldehyde (-)-9 in 97% yield.
After the precursor was obtained for the nitroaldol reaction,
we examined the asymmetric nitroaldol reaction of aldehyde
(-)-9. Initially, we used Trost’s asymmetric catalyst,12 which
involves a dinuclear zinc complex center with a chiral semi-
azacrown ligand for this asymmetric nitroaldol reaction.
Unfortunately, the attempts to use this catalyst were unsuc-
cessful. The stereoselectivity was very high (up to 92% de),
but the yield (55%) of desired product was unsatisfactory.
We subsequently applied Yamada’s conditions13 for this
step on account of its mildness and convenience. Further-
more, both enantiomers of the catalysts (16a, 16b) are
available commercially and more easily at hand. The results
of our asymmetric nitroaldol reaction toward the aldehyde
(-)-9 are shown in Table 1.
the yield was still low (entry 2). For improvement in yield,
we examined the type of base. By using DBU as a base, the
reaction afforded the product (-)-8 in 94% yield, with no
selectivity (entry 4). Varying the equivalents of catalyst and
DIPEA (entries 5-7), revealed that the best conditions were
as in entry 7, which requires 0.1 equiv of catalyst, 2.5 equiv
of DIPEA; this afforded a high yield (89%) of product with
excellent selectivity (97% de). However, in the case of
application of (S,S)-salen cobalt complex (16b), we obtained
the corresponding syn-diastereomer (-)-11 in high yield
(92%) with good selectivity (78% de) (entry 8).
The construction of the cyclic guanidine part is shown in
Scheme 3. Introduction of guanidyl group was achieved
Scheme 3. Synthesis of Cyclic Guanidine (-)-6a
Table 1. Investigation of Asymmetric Nitroaldol Reaction of
(-)-9 Using Salen Cobalt Complexes ((R,R) ) 16a, (S,S) )
16b)
a Ms2O ) methanesulfonic anhydride.
through reduction of the nitro group to the primary amine
with Pd and ammonium formate, followed by guanylation
with the reagent 17.15 After the preparation of guanidine
compound (-)-7, we chose to investigate the SN2 cyclization
procedure for construction of 5-membered cyclic guanidine.
Treatment of guanidine compound (-)-7 with Ms2O, pyri-
dine, and DMAP in CH2Cl2 provided the corresponding
mesylate. Then exposure of the mesylate to tertiary amine
and heat allowed us to obtain the desired cyclic guanidine
(-)-6 in 97% yield with inversion of the C-4′ stereocenter.
To deliver the (5R,4′R)-K01-0509 B (5) from (-)-6,
introduction of the carbamoyl function and oxidation to
carboxylic acid remained. Deprotection of the TBS group
with TBAF, followed by oxidation of the resulting primary
alcohol, furnished the aldehyde (-)-18 in excellent yield
(Scheme 4). With this aldehyde, we introduced the carbamoyl
function on the guanidyl nitrogen. Further oxidation by
treatment with NaClO2 under standard conditions (NaH2PO4,
2-methyl-2-butene) gave the carboxylic acid (-)-19. Re-
moval of the PMP group using CAN in a mixture (1:1) of
time
(h)
yielde selectivityk
entrya cat. (equiv) bases (equiv)
(%)
(% de)
1b
2
3c
4
16a (0.02) DIPEA (1.0)
16a (0.02) DIPEA (1.0)
63
62
8:f 22g
8: 31h
8: 71i
46
78
34
0
98
81
97
78
16a (0.02) DIPEA (1.0) 129
16a (0.02) DBU (1.0)
0.75 8: 94
5
16a (0.1)
DIPEA (1.0) 129
8: 29j
6
16a (0.02) DIPEA (3.0)
97
60
69
8: 73
8: 89
11: 92
7
8d
16a (0.1)
16b (0.1)
DIPEA (2.5)
DIPEA (2.5)
a Unless otherwise noted, all reactions were run at -40 °C. b Carried
out at -78 °C. c Carried out at -20 °C. d (S,S)-salen cobalt complex (16b)
was used. e Isolated yields. f The absolute stereochemistry was determined
by analysis of the Mosher’s ester of compound 7.14 g 65% of 9 was
recovered. h 39% of 9 was recovered. i 17% of 9 was recovered. j 15% of
9 was recovered. k Diastereomeric excesses were determined by HPLC using
Chiralcel OD and hexane/2-propanol (99/1) as eluent.
(11) Finan, J. M.; Kishi, Y. Tetrahedron Lett. 1982, 27, 2719-2722.
(12) (a) Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41,
861-863. (b) Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org. Lett.
2002, 4, 2621-2623.
(13) (a) Kogami, Y.; Nakajima, T.; Ashizawa, T.; Kezuka, S.; Ikeno,
T.; Yamada, T. Chem. Lett. 2004, 33, 614-615. (b) Kogami, Y.; Nakajima,
T.; Ikeno, T.; Yamada, T. Synthesis 2004, 12, 1947-1950.
(14) The synthesis of Mosher’s ester of 6 and the results of the analysis
are described in the Supporting Information.
We carried out the reaction at various temperatures under
the standard conditions12b reported by Yamada et al. At -78
and -20 °C, the selectivity was very low (entries 1 and 3).
When we effected the reaction at -40 °C, the diastereo-
selectivity of the anti-product (-)-8 was up to 78% de, but
(15) (a) Bernatowicz, M. B.; Wu, Y.; Matsueda, G. R. Tetrahedron Lett.
1993, 34, 3389-3392. (b) Drake, B.; Patek, M.; Lebl, M. Synthesis 1994,
2, 579-582.
(10) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K. J.
Am. Chem. Soc. 1989, 111, 5335-5340.
Org. Lett., Vol. 8, No. 24, 2006
5579

Scheme 4. Synthesis of (+)-(5R,4′R)-K01-0509 B (5)a
Scheme 5. Synthesis of (-)-(5R,4′S)-K01-0509 B (10)
a PMP ) p-methoxyphenyl. DMP [O] ) Dess-Martin periodi-
nane.
CH3CN and H2O at 0 °C,16 followed by deprotection of three
protective groups in aqueous TFA, produced the desired
compound. After purification by HPLC, we obtained the final
compound (+)-(5R,4′R)-K01-0509 B (5).
To obtain the anti-diastereomer (5R,4′S)-K01-0509 B (10),
we started synthesis from the syn-nitroaldol product (-)-11
(Scheme 5). The guanylation process involved reduction and
nucleophilic addition to reagent 17, affording (-)-20 in 96%
yield. SN2 cyclization via the O-mesylate provided (5R,4′S)-
cyclic guanidine (+)-21. Introduction of the carbamoyl
function and formation of carboxylic acid was carried out
in the same way as for the synthesis of (5R,4′R)-isomer (-)-
19. Total deprotection of compound (+)-22 gave the anti-
diastereomer (-)-(5R,4′S)-K01-0509 B (10).
all respects and was more labile than the natural compound
(+)-1. Therefore, the synthetic compound 5 corresponds to
natural K01-0509 B.
In conclusion, we have achieved asymmetric total synthesis
of (+)-K01-0509 B and its diastereomer. As a result of these
syntheses, we have elucidated the relative and absolute
configuration of (+)-K01-0509 B and confirmed the con-
nected position of the carbamoyl group. We expect that the
stereochemistry of K01-0509 B will provide insights and
guidance for the future total synthesis and determination of
the absolute stereochemistry of the closely related guadi-
nomines.
Acknowledgment. This work was supported by the Grant
of the 21st Century COE Program, Ministry of Education,
Culture, Sports, Science and Technology (18790022). We
also thank Ms. A. Nakagawa, Ms. C. Sakabe, and Ms. N.
Sato (School of Pharmaceutical Sciences, Kitasato Univer-
sity) for various instrumental analyses.
We compared the spectral data of the two diastereomers
(+)-5 and (-)-10 with natural (+)-1. (+)-(5R,4′R)-K01-0509
B (5) was completely identical to the natural product in all
1
respects including the H NMR (300 MHz, in D2O), 13C
NMR (75 MHz, in D2O), HPLC,17 HRMS, IR, optical
rotation (synthetic: (+)-(5R,4′R)-K01-0509 B (5), [R]26
D
+32.4, c 0.16, MeOH; natural: K01-0509 B (+)-1, [R]25
D
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
+31.9, c 0.10, MeOH). On the other hand, (-)-(5R,4′S)-
K01-0509 B (10) was not identical to the natural material in
(16) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982,
47, 2765-2768.
(17) The 1H NMR spectra and HPLC charts of synthetic compounds
and natural K01-0509 B are given in the Supporting Information.
OL062282Z
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Org. Lett., Vol. 8, No. 24, 2006