Enantioselective Deprotonation of meso-Cycloheptanone Derivative: Application to the Synthesis of a Potential Intermediate for Pseudomonic Acid B

Article abstract of DOI:10.1021/ol027192i

(Matrix Presented) A novel synthetic path to a potential intermediate for the synthesis of pseudomonic acid B was established by employing enantioselective deprotonation of a meso-cycloheptanone derivative bearing hydroxy groups at the 3,4,5,6-positions w

Full text of DOI:10.1021/ol027192i

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4567-4570
Enantioselective Deprotonation of
meso-Cycloheptanone Derivative:
Application to the Synthesis of a
Potential Intermediate for Pseudomonic
Acid B
Toshio Honda* and Nobuaki Kimura
Faculty of Pharmaceutical Sciences, Hoshi UniVersity, Ebara 2-4-41,
Shinagawa-ku, Tokyo 142-8501, Japan
honda@hoshi.ac.jp
Received October 28, 2002
ABSTRACT
A novel synthetic path to a potential intermediate for the synthesis of pseudomonic acid B was established by employing enantioselective
deprotonation of a meso-cycloheptanone derivative bearing hydroxy groups at the 3,4,5,6-positions with lithium (S,S′)-r,r′-dimethyldibenzylamide
as a key step.
The enantioselective deprotonation strategy has been recog-
nized as a powerful synthetic tool for introducing a chiral
center to meso or prochiral compounds.1 This methodology
has often been applied to five- or six-membered cycloal-
kanones generating the desired chirality with high enantio-
meric excess, aimed at the synthesis of biologically active
compounds, including natural products. However, little
attention has been paid to the introduction of chirality into
simple seven-membered cycloalkanones by application of
this strategy, probably due to their conformational flexibility.
Therefore, it is very interesting to investigate a further
applicability of the enantioselective deprotonation strategy
to cycloheptanone derivatives to develop its usefulness.2
Recently, we have been involved in the synthesis of
biologically active compounds using an enantioselective
deprotonation strategy.3 In connection with our continuous
interest in developing synthetic methods through the use of
enantioselective deprotonation reaction, we are interested in
a chiral synthesis of a potential intermediate for pseudomonic
acid B starting from a meso-cycloheptanone derivative, where
(2) To the best of our knowledge, no report for an enantioselective
deprotonation of simple cycloheptanone derivatives has been published. For
cyclooctanone derivatives; see: (a) Berkowitz, W. F.; Wu, Y. J. Org. Chem.
1997, 62, 1536. (b) Aggarwal, V. K.; Humphries, P. S.; Fenwick, A. Angew.
Chem., Int. Ed. 1999, 38, 1985. (c) Gambacorta, A.; Tofani, D.; Lupattelli,
P.; Tafi, A. Tetrahedron Lett. 2002, 43, 2195. For bicyclo[3.2.1]octanone
system; see: (d) Cox, P. J.; Simpkins, N. S. Synlett 1991, 321. (e) Majewski,
M.; Zheng, G.-Z. Synlett 1991, 173. (f) Bunn, B. J.; Simpkins, N. S.;
Spavold, Z.; Crimmin, M. J. J. Chem. Soc., Perkin Trans. 1 1993, 3113.
(g) Bunn, B. J.; Simpkins, N. S. J. Org. Chem. 1993, 58, 533. (h) Bunn, B.
J.; Cox, P. J.; Simpkins, N. S. Tetrahedron 1993, 49, 207. (i) Majewski,
M.; Lazny, R. Tetrahedron Lett. 1994, 35, 3653. (j) Majewski, M.; Lazny,
R. J. Org. Chem. 1995, 60, 5825. (k) Coggins, P.; Gaur, S.; Simpkins, N.
S. Tetrahedron Lett. 1995, 36, 1545. (l) MaGee, D. I.; Setiadji, S.; Martin,
R. A. Tetrahedron: Asymmetry 1995, 6, 639. (m) Newcombe, N. J.;
Simpkins, N. S. J. Chem. Soc., Chem. Commun. 1995, 831. (n) Majewski,
M.; Lazny, R. Synlett 1996, 785. (o) Gethin, D. M.; Simpkins, N. S.
Tetrahedron 1997, 53, 14417. (p) Simoni, D.; Roberti, M.; Rondanin, R.;
Kozikowski, A. P. Tetrahedron Lett. 1999, 40, 4425. (q) Majewski, M.;
DeCaire, M.; Nowak, P.; Wang, F. Synlett 2000, 1321. (r) Abe, H.; Tsujino,
T.: Tsuchida, D.; Kashino, S.; Takeuchi, Y.; Harayama, T. Heterocycles
2002, 56, 503.
(1) (a) Koga, K. J. Synth. Org. Chem., Jpn. 1990, 48, 463. (b) Koga, K.
Pure Appl. Chem. 1994, 66, 1487. (c) Koga, K.; Shindo, M. J. Synth. Org.
Chem., Jpn. 1995, 53, 1021. (d) Simpkins, N. S. Chem. Soc. ReV. 1990,
19, 335. (e) Cox, P. J.; Simpkins, N. S. Tetrahedron: Asymmetry 1991, 2,
1. (f) Simpkins, N. S. Pure Appl. Chem. 1996, 68, 691. (g) Hodgson, D.
M.; Gibbs, A. R.; Lee, G. P. Tetrahedron 1996, 52, 14361. (h) O’Brien, P.
J. Chem. Soc., Perkin Trans. 1 1998, 1439. (i) O’Brien, P. J. Chem. Soc.,
Perkin Trans. 1 2001, 95.
10.1021/ol027192i CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/15/2002

all the carbon units of cycloheptanone should be incorporated
into the target compound.
Scheme 1a
Pseudomonic acids 1a-d, produced by a strain of
Pseudomonas flourescens as a member of a class of
C-glycosides,4 are known as competitive inhibitors of iso-
leucyl-tRNA synthetase, and pseudomonic acid A is used
clinically for the treatment of bacterial skin infections.5
Interestingly, these natural products not only possess anti-
bacterial activity against Gram positive bacteria but also
display exceptional potency toward multiresistant Staphy-
lococcus aureus (MRSA) strains.5 In view of their attractive
biological activities and also the challenging structural
features embodying a tetrasubstituted pyran nucleus, a
number of chiral syntheses and synthetic approaches to
pseudomonic acids have been developed to date,6 where
carbohydrates have mainly been employed as the starting
materials, after the first total synthesis of racemic pseudo-
minic acid C by Kozikowski et al.7 Our own interest in the
synthesis of the target compounds grew out of a desire to
find a new route for the synthesis of 2,3,4-trisubstituted
pyran-5-one, a potential intermediate for the synthesis of
pseudominic acid B.
a Reagents and conditions: (i) BnBr, NaH, TBAI, THF, reflux
(94%); (ii) OsO4, NMO, THF-H2O, rt (68%); (iii) 2,2-dimethoxy-
propane, p-TsOH, rt (92%); (iv) TBAF, THF, reflux (99%); (v)
PCC, NaOAc, 4 Å MS, CH2Cl2, rt (94%).
Although various conformations were considered for the
cycloheptanone derivative,9 we used lithium (S,S′)-R,R′-
dimethyldibenzylamide1d-f as the chiral base for the enan-
tioselective deprotonation of 7 in order to investigate the
mode of enantioselectivity.
Thus, we applied an enantioselective deprotonation strat-
egy to a meso-cycloheptanone derivative having four oxygen
functions at the 3,4,5,6-positions that was prepared as
depicted in Scheme 1.
Treatment of 7 with lithium (S,S′)-R,R′-dimethyldibenzy-
lamide in the presence of trimethylsilyl chloride in THF at
-78 °C afforded the corresponding silyl enol ether 8. Since
the enantiomeric excess of 8 could not be determined at this
stage, 8 was further subjected to oxidative bond cleavage
reaction. Ozonolysis of 8, followed by reductive workup with
triphenylphosphine, gave aldehyde 9, which without purifica-
tion was further reduced with sodium borohydride to yield
alcohol 10 in 92% yield from 7.
Benzylation of diol 2,8 readily accessible from tropone,
gave dibenzyl ether 3, which upon dihydroxylation with
osmium tetroxide furnished pentaoxygenated compound 4.
After protection of the newly introduced diol system as
acetonide 5, the silyl group was removed by treatment with
TBAF to give alcohol 6. Finally, oxidation of 6 with PCC
in the presence of sodium acetate gave the desired meso-
cycloheptanone 7.
Esterification of acid 10 with iodomethane in DMF in the
presence of potassium carbonate furnished ester 11, whose
ee was determined to be 96% by HPLC analysis with the
chiral column CHIRALPAK AD.
(3) (a) Honda, T.; Kimura, N. J. Chem. Soc., Chem. Commun. 1994, 77.
(b) Honda, T.; Ishikawa, F.; Kanai, K.; Sato, S.; Kato, D.; Tominaga, H.
Heterocycles 1996, 42, 109. (c) Honda, T.; Ono, S.; Mizutani, H.; Hallinan,
K. O. Tetrahedron: Asymmetry 1997, 8, 181. (d) Honda, T.; Endo, K.;
Ono, S. Chem. Pharm. Bull. 2000, 48, 1545. (e) Honda, T.; Endo, K. J.
Chem. Soc., Perkin Trans. 1 2001, 2915 and references therein.
(4) (a) Chain, E. B.; Mellows, G. J. Chem. Soc., Perkin Trans. 1 1977,
294. (b) Alexander, R. G.; Clayton, J. P.; Luk, K.; Rogers, N. H.; King, T.
J. J. Chem. Soc., Perkin Trans. 1 1978, 561. (c) Clayton, J. P.; O’Hanlon,
P. J.; Rogers, N. H.; King, T. J. J. Chem. Soc., Perkin Trans. 1 1982, 2827
(d) O’Hanlon, P. J.; Rogers, N. H.; Tyler, J. W. J. Chem. Soc., Perkin Trans.
1 1983, 2655.
(5) (a) Fuller, A. T.; Mellows, G.; Woolford, M.; Banks, G. T.; Barrow,
K. D.; Chain, E. B. Nature 1971, 234, 416. (b) Basker, M. J.; Comber, K.
R.; Clayton, J. P.; Hannan, P. C.; Mizen, L. W.; Rogers, N. H.; Slocombe,
B.; Sutherland, R. Curr. Chemother. Infect. Dis., Proc. Int. Congr.
Chemother. 1979, 1, 471. (c) Hughes, J.; Mellows, G. Biochem. J. 1978,
176, 305. (d) Hughes, J.; Mellows, G.; Southton, S. FEBS Lett. 1980, 122,
322. (e) Hughes, J.; Mellows, G. Biochem. J. 1980, 191, 209.
(6) For a review, see: Class, Y. J.; DeShong, P. Chem. ReV. 1995, 95,
1843 and references therein. For recent syntheses and synthetic approaches,
see: (a) Balog, A.; Yu, M. S.; Curran, D. P. Synth. Comm. 1996, 26, 935.
(b) Khan, N.; Xiao, H.; Zhang, B.; Cheng, X.; Mootoo, D. R. Tetrahedron
1999, 55, 8303. (c) Marko´, I. E.; Plancher, J.-M. Tetrahedron Lett. 1999,
40, 5259. (d) Mckay, C.; Simpson, T. J.; Willis, C. L.; Forrest, A. K.;
O’Hanlon, P. J. Chem. Commun. 2000, 1109. (e) Sugawara, K.; Imanishi,
Y.; Hashiyama, T. Tetrahedron: Asymmetry 2000, 11, 4529.
Although the absolute configuration was still obscure, this
result obviously revealed that enantioselective deprotonation
is an effective method for introducing a chiral center into
even a relatively simple cycloheptanone derivative.
To construct a 2,3,4,5-tetrasubstituted pyran ring system,
alcohol 11 was treated with 3 equiv of sodium hexameth-
yldisilazide at -78 °C in THF, affording two cyclization
products 12 and 13 as a mixture of diastereoisomers at the
2-position, where â-elimination of the benzyloxy group,
followed by Michael addition of the primary alcohol to the
resulting R,â-unsaturated ester, took place simultaneously.10
To determine the stereochemistry of the products, includ-
ing their absolute configurations, deacetalization of 12 and
13 by acid treatment was carried out to afford diol 14 and
lactone 15 in 67 and 24% yields, respectively. Thus, the
(7) (a) Kozikowski, A. P.; Schmiesing, R. J.; Sorgi, K. L. J. Am. Chem.
Soc. 1980, 102, 6577. (b) Kozikowski, A. P.; Schmiesing, R. J.; Sorgi, K.
L. Tetrahedron Lett. 1981, 22, 2059.
(8) Johnson, C. R.; Golebiowski, A.; Steensma, D. H.; Scialdone, M. A.
J. Org. Chem. 1993, 58, 7185.
(9) Allinger, N. L.; Chen, K.; Rahman, M.; Pathiaseril, A. J. Am. Chem.
Soc. 1991, 113, 4505 and references therein.
(10) Similar Michael addition was reported in the enantioselective
synthesis of pseudomonic acids; see: Scho¨nenberger, B.; Summermatter,
W.; Ganter, C. HelV. Chim. Acta 1982, 65, 2333.
4568
Org. Lett., Vol. 4, No. 25, 2002

Scheme 2a
Figure 1.
transition structures,9 including mainly the conformers TS-1
(twist-chair) and TS-2 (twist-boat), it would be assumed that
TS-2 seemed to be favorable relative to TS-1, where
unfavorable 1,3-diaxial interactions are observed as depicted
in Figure 2.12 This speculation regarding the conformational
a Reagents and conditions: (i) O3, MeOH-CH2Cl2, -78 °C, then
PPh3, from -78 to 0 °C; (ii) NaBH4, MeOH, rt (92%); (iii) Mel,
K2CO3, DMF, rt (92%).
major product 14 was confirmed to have the desired
stereochemistry. Lactone 15 was further converted into the
enantiomer of the known diol 16 by hydrogenolysis over
palladium hydroxide. The spectroscopic data of lactone 16
were identical with those reported.11 Moreover, the sign of
optical rotation of our synthetic compound 16 corresponds
to those of the antipode,11 [R]D +163.6 (c 0.1, H2O) (lit.11
[R]D -159.7 (c 1.3, H2O)); therefore, the absolute stereo-
chemistries of both pyrans 12 and 13 are now unambiguously
determined as depicted in Scheme 3.
Figure 2.
Scheme 3a
changes would be consistent with the observed enantiose-
lectivity for prochiral cycloalkanones on the basis of
consideration of the previous works.2,3
The major compound 14 was further transformed to the
known potential intermediate for the synthesis of pseudo-
monic acid B13 as shown in Scheme 4.
Treatment of 14 with cyclohexanone and p-toluenesulfonic
acid gave cyclohexylidene derivative 17. After hydrolysis
of ester 17 in the usual manner, the resulting carboxylic acid
18 was treated with methyllithium at 0 °C to give the desired
methyl ketone 19 together with its epimer at the 2-position,
probably arising via a retro-Michael reaction, in a ratio of
3:1. Ester 17 was therefore transformed to Weinreb amide
20 prior to introducing a methyl group. Again, treatment of
amide 20 with methylmagnesium bromide afforded the
a Reagents and conditions: (i) NaHMDS, THF, -78 °C (73%);
(ii) p-TsOH, MeOH, rt (67% for 14, 24% for 15); (iii) H2, Pd(OH)2,
EtOAc, rt (92%).
(12) We have examined the conformational stability of compound 7 and
its relatives without acetonide or benzyloxy groups by MM2 and MOPAC
AM1 methods; however, those calculations revealed that twist-chair
conformations are more stable than those of twist-boat forms, as already
reported by Allinger.9 Since those calculations are inconsistent with our
experimental results, we are currently investigating the relationships between
the conformational stability of cycloheptanone derivatives, including
substitution effect and the mode of enantioselectivity.
Although it was considered, on the basis of examination
of molecular models of a substrate having substituents with
a cis-relationship at the 4,5-positions of cycloheptanone, that
enantioselective deprotonation could proceed through various
(11) Ko¨ll, P.; Wernicke, A.; Kova´cs, J.; Luˆtzen, A. J. Carbohydr. Chem.
2000, 19, 1019.
(13) (a) Curran, D. P.; Suh, Y.-G. Tetrahedron Lett. 1984, 25, 4179. (b)
Curran, D. P.; Suh, Y.-G. Carbohydr. Res. 1987, 171, 161.
Org. Lett., Vol. 4, No. 25, 2002
4569

Scheme 4a
Scheme 5a
a Reagents and conditions: (i) cyclohexanone, CuSO4, p-TsOH,
benzene, rt (97%); (ii) 2 N KOH, MeOH, rt (93%); (iii) MeLi,
Et2O, 0 °C (42%).
a Reagents and conditions: (i) Me(OMe)NH2Cl, n-BuLi, THF,
-78 °C (91%); (ii) MeMgBr, THF, 0 °C (92%); (iii) H2, Pd/C,
MeOH, rt (59%); (iv) Ac2O, Et3N, DMAP, CH2Cl2, rt (95%).
desired methyl ketone 19 as the sole product in 92% yield.
Finally, debenzylation of 19 under catalytic hydrogenation
conditions, followed by acetylation of the resulting alcohol
21 with acetic anhydride, furnished the known acetate 22,
whose spectroscopic data, including the specific optical
rotation [R]D +1.3 (c 0.2, CHCl3) (lit.13b [R]D +1.3 (c 1.15,
CHCl3)), were identical to those reported.13b Since this acetate
was assumed to be a potential intermediate for pseudomonic
acid B,11 this synthesis provided an alternative approach to
this type of biologically important natural product.
cycloheptanone derivative. Further utilization of this proce-
dure in the synthesis of other biologically active compounds,
including natural products such as shikimic acid and cyclitols,
is in progress in our laboratory.
Acknowledgment. This work was supported by the
Ministry of Education, Culture, Sports, Science and Technol-
ogy of Japan.
In summary, we were able to prove that enantioselective
deprotonation was an effective method for introducing
chirality into even a relatively simple seven-membered
cycloalkanone; we also established a novel synthetic proce-
dure for a potential intermediate in the synthesis of
pseudomonic acid B by application of this strategy to a meso-
Supporting Information Available: Experimental details
and compound characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL027192I
4570
Org. Lett., Vol. 4, No. 25, 2002