Synthesis of l - Epi -capreomycidine derivatives via C-H amination

Article abstract of DOI:10.1021/ol201527k

The l-epi-capreomycidine (Cpm) derivatives were efficiently and stereoselectively synthesized via nitrene C-H insertion starting from a readily available d-Tyr. Design of a substrate that takes into account hydrogen bonding is a critical feature in order

Full text of DOI:10.1021/ol201527k

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4028–4031
Synthesis of L-epi-Capreomycidine
Derivatives via CꢀH Amination
Tetsuya Tanino, Satoshi Ichikawa,* and Akira Matsuda
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku,
Sapporo 060-0812, Japan
ichikawa@pharm.hokudai.ac.jp
Received June 9, 2011
ABSTRACT
The L-epi-capreomycidine (Cpm) derivatives were efficiently and stereoselectively synthesized via nitrene CꢀH insertion starting from a readily
available D-Tyr. Design of a substrate that takes into account hydrogen bonding is a critical feature in order to achieve high selectivity. Our
synthetic strategy could be a new access to epi-Cpm and its derivatives, which are found in several biologically active natural products.
The muraymycins (MRYs) (Figure 1), isolated from a
culture broth of Streptomyces sp.,1 are members of a class of
naturally occurring 60-N-alkyl-50-β-O-aminoribosyl-C-gly-
cyluridine antibiotics.2 The MRYs having a lipophilic side
chain have been shown to exhibit excellent antimicrobial
activity against Gram-positive bacteria. In particular, the
efficacy of the MRYs in S. aureus infected mice repre-
sents a promising lead for the development of new anti-
bacterial agents. The MRYs involve a cyclic guanidine amino
acid, L-epi-capreomycidine (Cpm). Most of the previous
syntheses of the Cpm class of amino acids were racemic.3
Although an elegant asymmetric synthesis of L-Cpm has
been reported by the Williams group,4 only a few asymmetric
Figure 1. Structures of muraymycin D2.
and stereoselectivesynthesesof itsepimer, L-epi-Cpm, have
been reported.5 Recently, we accomplished the first total
synthesis of MRY D2 (1) and its epimer.6 The L-epi-Cpm
moiety was synthesized via the nitrene CꢀH insertion7 of
(1) (a) McDonald, L. A.; Barbieri, L. R.; Carter, G. T.; Lenoy, E.;
Lotvin, J.; Petersen, P. J.; Siegel, M. M.; Singh, G.; Williamson, R. T.
J. Am. Chem. Soc. 2002, 124, 10260–10261. (b) Carter, G. T.; Lotvin,
J. A.; McDonald, L. A. WO 2002085310 A2.
(2) (a) Ochi, K.; Ezaki, M.; Iwani, M.; Komori, T.; Kohsaka, M. EP-
333177, 1989. (b) Yoshida, Y.; Yamanaka, H.; Sakane, K. JP H05ꢀ78385, 1993.
(3) (a) Bycroft, B. W.; Cameron, D.; Johson, A. W. J. Chem. Soc.
1971, 3041–3049. (b) Bycroft, B. W.; Cameron, D.; Croft, L. R.; Johson,
A. W. Chem. Commun. 1968, 1301–1302. (c) Yamashita, A.; Norton,
E. B.; Mansour, T. S. Synth. Commun. 2004, 34, 795–803.
(4) (a) DeMong, D. E.; Williams, R. M. Tetrahedron Lett. 2001, 42,
3529–3532. (b) DeMong, D. E.; Williams, R. M. J. Am. Chem. Soc. 2003,
125, 8561–8565.
(5) Teshima, T.; Konishi, K.; Shiba, T. Bull. Chem. Soc. Jpn. 1980,
53, 508–511.
(6) Tanino, T.; Ichikawa, S.; Shiro, M.; Matsuda, A. J. Org. Chem.
2010, 75, 1366–1377.
(7) For recent reviews, see: (a) Davies, H. M. L.; Beckwith, R. E. J.
Chem. Rev. 2003, 103, 2861–2903. (b) Davies, H. M. L.; Antoulinakis.,
E. G. J. Organomet. Chem. 2001, 617ꢀ618, 47–55.
r
10.1021/ol201527k
Published on Web 07/07/2011
2011 American Chemical Society

sulfamate 2 with the Rh2(esp)2 catalyst8 to form 3, con-
struction of the cyclic guanidine skeleton 5, desulfonyla-
tion upon acetolysis of the oxathiazinane ring, and
hydrolysis of the acetate group providing 6 (Scheme 1).
The key nitrene CꢀH insertion was largely dependent on
the nature of the protecting group at both amino groups.
Furthermore, the regio- and diastereoselectivity and the
yield of the desired cyclic sulfamate 3 were very poor and
needed to be improved. In particular, an unexpected
reversal of diastereoselectivity was observed, and the un-
desired cyclic sulfamate 4 was obtained predominantly
with the Cbz group as a protecting group for the amine
at the 2-position. Thus, it was considered necessary to
improve the synthetic route to the L-epi-Cpm for investi-
gating further structureꢀactivity relationships of MRYs.
Here, we describe the improvement of the synthesis of
suitably protected L-epi-Cpm derivatives 9.
Scheme 2. Improved Synthetic Route
nitrene was changed to a benzylic position such as 7, which
is generally known to be suitable for CꢀH insertion. By
doing so, the carboxylic acid could be masked as the stable
phenyl ring during the synthesis. In the CꢀH insertion of 7
without the free hydrogen atom on the amino group, the
TS4 with all the substituents oriented in equatorial posi-
tions would be more stable vs the TS3 that would provide
the undesired diastereomer. The stereochemical course of
this was suggested by Du Bois et al.9 The synthesis of
suitably protected L-epi-Cpm derivative 9 was initiated
from readily available D-Tyr (Scheme 3).
Scheme 1. Previous Synthetic Route
Scheme 3. CꢀH Insertion Sulfamate Protected with Phthaloyl
Group
We hypothesized that the reverse stereoselectivity ob-
servedinthe nitreneCꢀH insertion of 2could be attributed
to the existence of a free hydrogen atom attached to the
nitrogen atom at the 2-position. Namely, the unwanted
TS2 would be expected to be more stable than the desired
TS1 due to formation of an intramolecular hydrogen bond
with the oxygen atom attached to the sulfamate group,
affording the undesired diastereomer. This being the case,
uponremoval of theintramolecularhydrogen bonding, the
reaction would proceed via TS2. With this in mind, we
designed an improved synthetic strategy that uses a nitrene
CꢀH insertion as shown in Scheme 2. In order to control
the regioselectivity of the nitrene insertion as well as its
diastereoselectivity, the CꢀH moiety to be inserted by the
Sequential protection with the Boc and methyl groups
followed by reduction with LiBH4 gave 10 in 64% over
three steps. After the Boc group was changed to the
phthaloyl (Pht) group, the sulfamoyl group was installed
to give the sulfamate 11, the precursor for the nitrene CꢀH
insertion, in 65% yield over three steps. The precursor 11
was treated with 10 mol % of Rh2(esp)2 in the presence of
PhI(OAc)2 and MgO in CH2Cl2 at reflux for 40 min, and
the desireddioxo-oxathiazinane derivative12was obtained
(8) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem.
Soc. 2004, 126, 15378–15379.
(9) When, P. M.; Lee, J.; Du Bois, J. D. Org. Lett. 2003, 5, 4823–4826.
Org. Lett., Vol. 13, No. 15, 2011
4029

high selectivity in this particular case of nitrene CꢀH
insertion.
Scheme 4. CꢀH Insertion of Sulfamate with Donor Hydrogen
The nitrogen atom of the dioxo-oxathiazinane ring of 12
was protected with the Boc group to give 19 (Boc2O, NaH,
THF, 85%), which was homologated by Bu4NCN in
MeCN, upon ring-opening of the dioxo-oxathiazinane
and desufonylation; it gave 20 in 96% yield (Scheme 5).
After protecting group manipulation in 20 (hydrazine,
EtOHꢀMeCN, then (CF3CO)2O, DMAP, CH2Cl2, 94%
over two steps), the cyano group of 21 was reduced to the
primary amine, and this was converted to the S-methyli-
sothiourea 22, which was protected with the N-2,2,2-
trichloroethoxysulfonyl (Tces)10 group in 74% yield over
two steps. Treatment of 22 with HgBr2 in the presence of i-
Pr2NEt afforded the cyclic guanidine 23, and the trifluor-
oacetyl group was also removed in the same step. Finally,
in an excellent yield of 92% as the sole product. Neither the
diastereomer of 12nor the 1,5- or 1,8-insertion product was
detected. The structure of 12 was confirmed by several
NMR measurements, including COSY and NOE. As
expected, complete regio- and diastereoselectivity was
achieved. To address the issue of intramolecular hydrogen
bonding on the diastereoselectivity, the insertion reaction
of the sulfamates protected with the Boc group 13 and the
trifluoroacetyl group 16, which possess a free hydrogen
atom, wasalso investigated (Scheme4). TheCꢀH insertion
of 13 resulted in a significant decrease in diastereo-
selectivity (14:15 = 67:33). Furthermore, complete loss
of selectivity was observed in the reaction of 16 with the
more acidic hydrogen atom on the amino group (17:18 =
51:49). These results clearly indicate that intramolecular
hydrogen bonding in the transition state affects the diaster-
eoselectivity, as suggested by our previous study. There-
fore, the design of a substrate that takes into account
hydrogen bonding is a critical feature in order to achieve
Scheme 6. Synthesis of Truncated Muraymycin Analogues
Scheme 5. Synthesis of Protected L-epi-Capreomycidines
4030
Org. Lett., Vol. 13, No. 15, 2011

the methoxyphenyl group of 23 was oxidized to give the
carboxylic acid 9a in 48% yield (RuCl3, NaIO4,
MeCNꢀCCl4ꢀH2O). The Cbz-protected derivative 3e
was also prepared from 9b.
in 60% yield, respectively. The analogues 29a and 29b
showed potent antibacterial activity against drug-resistant
bacteriaS. aureusSR3637 (MRSA) and E. faecalisSR7914
(VRE) with the MICs ranging 4ꢀ8 μg/mL.
Finally, truncated MRY analogues lacking the L-Val
residue were synthesized by an Ugi four component as-
semblage (Scheme 6). Thus, 9a, hexadecanal 24, 2,4-
dimethoxybenzylamine 25, and the isonitrile of aminor-
ibosyluridine derivative 266,11 were reacted in EtOH, and
fullly protected analogues 27 were obtained as a 1:1
mixture of diastereomers. Treatment of 27 with Zn fol-
lowed by aq TFA gave 28a and 28b in 8% yield over three
steps from 9a, respectively, after HPLC separation. Final
deprotection of the 2,4-dimethoxybenzyl (DMB) group
was achieved by TFA in the presence of thioanisole to
afford the truncated analogue 29a and its diastereomer 29b
In conclusion, the L-epi-Cpm derivatives were efficiently
and stereoselectively synthesized via the nitrene CꢀH inser-
tion starting from readily available D-Tyr. Our synthetic
strategy could be a new access to epi-Cpm and its deriva-
tives, which are found in several biologically active natural
products.12ꢀ14 Synthesis of MRY derivatives and their
biological evaluation are currently underway and will be
described.
Acknowledgment. This work was supported by grants-
in-aid for scientific research from the Ministry of Educa-
tion, Science, Sports, and Culture (Grant-in-Aid for En-
couragement of Young Scientists A) and the Japan Society
for Promotion of Sciences (T.T.). We thank Ms. S. Oka
and Ms. A. Tokumitsu (Center for Instrumental Analysis,
Hokkaido University) for measurement of the mass
spectra.
(10) Kim, M.; Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Org. Lett.
2006, 8, 1073–1076.
(11) Tanino, T.; Ichikawa, S.; Al-Dabbagh, B.; Bouhss, A.; Matsuda,
A. ACS Med. Chem. Lett. 2010, 1, 258–262.
(12) (a) Bycroft, B. W.; Cameron, D.; Johson, A. W. J. Chem. Soc.
1971, 3041–3049. (b) Bycroft, B. W.; Cameron, D.; Croft, L. R.; Johson,
A. W. Chem. Commun. 1968, 1301–1302. (c) Yamashita, A.; Norton,
E. B.; Mansour, T. S. Synth. Commun. 2004, 34, 795–803.
(13) (a) DeMong, D. E.; Williams, R. M. Tetrahedron Lett. 2001, 42,
3529–3532. (b) DeMong, D. E.; Williams, R. M. J. Am. Chem. Soc. 2003,
125, 8561–8565.
Supporting Information Available. Experimental pro-
cedures and NMR spectra for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Teshima, T.; Konishi, K.; Shiba, T. Bull. Chem. Soc. Jpn. 1980,
53, 508–511.
Org. Lett., Vol. 13, No. 15, 2011
4031