Synthetic studies on borrelidin: enantioselective synthesis of the C1-C12 fragment.

Article abstract of DOI:10.1021/ol034243i

[structure: see text] An efficient, enantioselective synthesis of the C1-C12 fragment 2 of borrelidin is presented. Construction of the "skipped" polymethylene chain of 2 was accomplished by iteration of Myers' alkylation, while formation of the C3 stereocenter was achieved by Roush's asymmetric allylboration methodology.

Full text of DOI:10.1021/ol034243i

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1617-1620
Synthetic Studies on Borrelidin:
Enantioselective Synthesis of the
C1−C12 Fragment
Binh G. Vong, Sunny Abraham, Alan X. Xiang, and Emmanuel A. Theodorakis*
Department of Chemistry and Biochemistry, UniVersity of California, San Diego,
9500 Gilman DriVe, La Jolla, California 92093-0358
etheodor@chem.ucsd.edu
Received February 11, 2003
ABSTRACT
An efficient, enantioselective synthesis of the C1−C12 fragment 2 of borrelidin is presented. Construction of the “skipped” polymethylene
chain of 2 was accomplished by iteration of Myers’ alkylation, while formation of the C3 stereocenter was achieved by Roush’s asymmetric
allylboration methodology.
First isolated from Streptomyces rochei in 1949,1 borrelidin
(1, Figure 1) is a macrolide antibiotic with a unique chemical
structure and exciting medicinal attributes.2 Initial studies
indicated that 1 exhibits a broad antiviral and antibacterial
profile3 that may arise by inhibiting the enzymatic activity
of threonyl-tRNA synthetase.4 In fact, borrelidin was so
named because of its specific cytotoxicity against Borrelia,1
the spirochete of relapsing fever.5 Recently, 1 was also found
to display antiangiogenic6 and antimitotic properties.7 The
latter may be due to inhibition of cyclin-dependent kinase
(CDK), a mode of action not previously manifested by any
other macrolide antibiotics.8
From a chemical point of view, borrelidin is an atypical
18-membered macrolide distinguished by a 1,3,5,7-“skipped”
methylene chain (C4-C10), a cyclopentane carboxylic acid
fragment, and a conjugated cyanodiene unit.9,10 The latter
motif is unprecedented in natural products structures and may
play an important role in the biological mode of action of
(1) Berger, J.; Jampolsky, L. M.; Goldberg, M. W. Arch. Biochem. 1949,
22, 476-478. For subsequent isolations of 1 from related Streptomyces
strains, see: Singh, S. K.; Gurusiddaiah, S.; Whalen, J. W. Antimicrob.
Agents Chemother. 1985, 27, 239-245. Maher, H.; Evans, R. H. J. Antibiot.
1987, 40, 1455-1456.
(2) Buck, M.; Farr, A. C.; Schnitzer, R. J. Trans. N. Y. Acad. Sci., Ser.
2 1949, 11, 207-209. Grunberg, E.; Eldrige, D.; Soo-hoo, G.; Kelly, D. R.
Trans. N. Y. Acad. Sci., Ser. 2 1949, 11, 210-212.
(3) Lumb, M.; Macey, P. E.; Spyvee J.; Whitmarsh, J. M.; Wright, R.
D. Nature 1965, 206, 263-265. Dickinson, L.; Griffiths, A. J.; Mason, C.
G.; Mills, R. F. N. Nature 1965, 206, 265-268. Schu¨z, T. C.; Za¨hner, H.
Microbiol. Lett. 1993, 114, 41-46.
(4) Cantt, J. S.; Bennett, C. A.; Arfin, S. M. Proc. Natl. Acad. Sci. U.S.A.
1981, 78, 5367-5370. Hirakawa, T.; Morinaga, H.; Watanabe, K. Agr. Biol.
Chem. 1974, 38, 85-89. Paetz, W.; Nass, G. Eur. J. Biochem. 1973, 35,
331-337. Nass, G.; Poralla, K.; Za¨hner, H. Naturwissensh. 1971, 58, 603-
610. Poralla, K.; Za¨hner, H. Arch. Microbiol. 1968, 61, 143-153. For a
review on threonyl-tRNA synthetase, see: Friest, W.; Gauss, D. H. Biol.
Chem., Hoppe-Seyler 1995, 376, 213-224.
Figure 1. Chemical structure of borrelidin.
10.1021/ol034243i CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/10/2003

Scheme 1. Synthesis of Fragment 3 via Myers’ Iterative
Alkylation Processa
Figure 2. Retrosynthetic analysis of borrelidin.
this natural product. The combination of unusual chemical
architecture and diverse biological profile has prompted the
development of synthetic routes toward borrelidin11 that have
recently culminated to the first total synthesis of 1 by Morken
and collaborators.12 In continuation of our synthetic effort,13
we present herein an enantioselective synthesis of the C1-
C12 fragment (2) of borrelidin.
A plausible scenario for the synthesis of 1 could rely upon
the union of two fragments across the macrolactone func-
tionality and the C12-C13 double bond. On the basis of
this approach, ketonitrile 2, carrying six of the nine total
stereocenters of borrelidin, was selected as a key synthetic
intermediate (Figure 2). Further disconnection across the
C11-C12 bond and C2-C3 bond of 2 results in fragment
3, which is highlighted by the presence of the skipped
methylene motif.14 Among the different strategies for con-
struction of this type of scaffold,15 the most applicable to
a Reagents and conditions: (a) 1.1 equiv of TiCl4, 1.1 equiv of
iPr2EtN, 2.0 equiv of BnOCH2Cl (6), CH2Cl2, 0 °C, 6 h, 85%; (b)
2.2 equiv of LiBH4, 2.2 equiv of H2O, THF, 0 °C, 1 h, 80%; (c)
1.2 equiv of PPh3, 1.35 equiv of I2, 1.5 equiv of imid, 2 h, 0 °C,
96% for 7, 95% for 11, 97% for 13; (d) 2.1 equiv of (+) 8, 4.0
equiv of LDA, 12 equiv of LiCl, THF, 0 °C, 18 h, 97%; (e) 4.0
equiv of LiH2N‚BH3, -78 to 0 °C, 3 h, 90% for 10, 95% for 12;
(f) 2.1 equiv of (-) 8, 4.0 equiv of LDA, 12.2 equiv of LiCl, THF,
0 °C, 18 h, 89%; (g) 5.0 equiv of nBu4NOH, tBuOH/H2O 3/1,
reflux, 24 h, 84%.
our case appeared to be Myers’ alkylation.16,17 This iterative
approach could ensure the construction of the chiral centers
with a high degree of enantio- and diastereoselectivity.18 On
the basis of these considerations, compound 4 was projected
to be the starting material for our synthetic effort (Figure
2).
Our synthesis of the C1-C12 fragment of borrelidin is
delineated in Schemes 1 and 3 and departs from readily
available oxazolidinone 5.19 Stereoselective alkylation of 5
(5) Montgomery, R. R.; Palmarozza, R. E.; Beck, D. S.; Ngo, E.; Joiner,
K. A.; Malawista, S. E. Inflammation 2000, 24, 277-288. Montgomery,
R. R.; Nathanson, M. H.; Malawista, S. E. J. Immunol. 1993, 150, 909-
915.
(6) Wakabayashi, T.; Kageyama, R.; Naruse, N.; Tsukahara, N.; Funahashi,
Y.; Kitoh K.; Watanabe Y. J. Antibiot. 1997, 50, 671-676.
(7) Tsunchiya, E.; Yukawa, M.; Miyakawa, T.; Kimura, K.; Takahashi,
H. J. Antibiot. 2001, 54, 1, 84-90. Poralla, K. In Mechanism of Action of
Antimicrobial and Antitumor Agents; Corcoran, J. W., Hahn, F. E., Eds.;
Springer: Berlin, 1975; pp 365-388.
(8) Tsuchiya, E.; Yukawa, M.; Miyakawa, T.; Kimura, K.; Takahashi,
H. J. Antibiot. 2001, 54, 84-90.
(9) Anderton, K.; Rickards, R. W. Nature 1965, 498, 269. Kuo, M. S.;
Yurek, D. A.; Kloosterman, D. A. J. Antibiot. 1989, 42, 1006-1007. Keller-
Schierlein, W. Experientia 1966, 22, 355-359. Keller-Schierlein, W. HelV.
Chim. Acta 1967, 50, 731-753.
(10) The structure and absolute stereochemistry of 1 have been deter-
mined from a single-crystal X-ray analysis. See: Anderson, B. F.; Herlt,
A. J.; Rickards, R. W.; Robertson, G. B. Aust. J. Chem. 1989, 42, 717-
730.
(11) Haddad, N.; Grishko, M.; Brik, A. Tetrahedron Lett. 1997, 38,
6075-6078. Haddad, N.; Brik., A.; Grishko, M. Tetrahedron Lett. 1997,
38, 6079-6082. Zhao, C.-X.; Duffey, M. O.; Taylor, S. J.; Morken, J. P.
Org. Lett. 2001, 3, 1829-1831.
(12) Duffey, M. O.; LeTiran, A.; Morken, J. P. J. Am. Chem. Soc. 2003,
125, 1458-1459.
(13) Xiang, A. X. Dissertation Thesis, University of California, San
Diego, 2000.
(15) For selected examples of related syntheses, see: Evans, D. A.; Ennis,
M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737-1742. Evans, D.
A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J. Am. Chem. Soc.
1990, 112, 5290-5312. Calter, M. A.; Liao, W.; Struss, J. A. J. Org. Chem.
2001, 66, 7500-7504. Abiko, A.; Masamune, S. Tetrahedron Lett. 1996,
37, 1081-1084. Birkbeck, A. A.; Enders, D. Tetrahedron Lett. 1998, 39,
7823-7826. Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989,
30, 5603-5606. Masamune, S.; Abiko, A.; Moriya, O.; Filla, S. A., Angew.
Chem., Int. Ed. Engl. 1995, 34, 793-795. Hanessian, S.; Murray, P. J. Can.
J. Chem. 1986, 64, 2231-2234.
(16) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem.
Soc. 1994, 116, 9361-9362. Myers, A. G.; Yang, B. H.; Chen, H.;
McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997,
119, 6496-6511.
(14) The skipped methylene motif constitutes a common structural
element in many natural products of polyketide origins including ionomycin,
rapamycin, and related macrolides. For a recent monograph on macrolides,
see: Macrolide Antibiotics Chemistry, Biology, and Practice, 2nd ed.;
Omura, S., Ed.; Academic Press: London, 2002; pp 1-637.
(17) Use of other chiral auxiliaries in conjunction with â-branched iodides
are low yielding due to the reduced reactivity of the electrophile. This,
however, is not an issue for the pseudoephedrine-based alkylation reported
by Myers and collaborators (ref 16). See also: Myers, A. G.; Yang, B. H.;
Chen, H.; Kopecky, D. J. Synlett 1997, 457-459.
1618
Org. Lett., Vol. 5, No. 10, 2003

Scheme 2. Confirmation of Stereochemistry of Alkylation via
Scheme 3. Synthesis of the Fragment 2 of Borrelidina
Symmetry Elementsa
a Reagents and conditions: (a) 1.4 equiv of NaH, 1.3 equiv of
BnBr, 0.1 equiv of TBAI, THF, 0 °C, 3 h, 92% for 14, 95% for
15, 96% for 16; (b) 5.0 equiv of LAH, Et2O, 10 h, 84%.
with benzyl chloromethyl ether (6) followed by reductive
cleavage of the chiral auxiliary with LiBH4 afforded alcohol
4, containing the C4 methyl group, in 68% yield (Scheme
1). Treatment of 4 with triphenylphosphine, iodine, and
imidazole produced iodide 7 (96% yield)20 and set the stage
for the installation of the second methyl group (C6 center).
To this end, alkylation of the enolate of (+)-pseudoephedrine
propionamide 8 with â-branched iodide 7 afforded the 1,3-
syn-alkylated substrate 9. Reduction of amide 9 with lithium
amidotrihydroborate (LAB) gave rise to alcohol 10 in 90%
yield as a single diastereomer (>95% de), as evidenced by
1H and 13C NMR studies. Unequivocal proof for the
stereochemistry of 10 was obtained by alkylation of the
hydroxyl group with benzyl bromide (Scheme 2). Such a
maneuver produced benzyl ether 14 that was expected to be
a meso structure based on the anticipated alkylation outcome.
a Reagents and conditions: (a) 1.2 equiv of EtOH, 1.4 equiv of
DCC, 0.1 equiv of DMAP, CH2Cl2, 2 h, 25 °C, 95%; (b) 2.0 equiv
of CH3CN, 2.0 equiv of nBuLi, THF, -78 °C, 1 h, 90%; (c) 1.2
equiv of NaBH4, MeOH, 1 h, 96%; (d) 1.5 equiv of TIPSCl, 2.0
equiv of 2,6-lutidine, 0.1 equiv of DMAP, CH2Cl2, 6 h, 25 °C,
94%; (e) H2, 0.1 equiv of Pd/C (10%), 60 psi, 12 h, THF, 89%
(+5% SM recovered); (f) 1.5 equiv of Dess-Martin reagent, 2.0
equiv of pyridine, CH2Cl2, 1 h, 0 °C, 92%; (g) 1.4 equiv of 22,
toluene, 4 Å MS, -78 °C, 1 h, 87%; (h) 5.0 equiv of MEMCl, 8.0
equiv of iPrNEt2, 92%; (i) cat. OsO4, 2.0 equiv of NMO, tBuOH/
THF/H2O 10/3/1, 6 h; then 1.5 equiv of Pb(OAc)4, CH2Cl2, 0 °C
10 min, 74%; (j) 3.0 equiv of NaClO2, 3.0 equiv of NaH2PO4, 3.0
equiv of 2-methyl-2-butene, tBuOH/H2O 2/1, 0.5 h, 81%; (k) 1.6
equiv of TMSCH2N2, MeOH/CH3CN 1/1, 20 min, 91%; (l) 1.5
equiv of TBAF‚THF, THF, 2 h, 84%; (m) 3.0 equiv of PCC,
CH2Cl2, 12 h, 75%.
1
Indeed, both the symmetry displayed in H and 13C NMR
data and the absence of specific rotation for 14 demonstrated
unambiguously that the two methyl groups are syn to each
other.
Conversion of alcohol 10 to the corresponding iodide 11
provided the appropriate electrophile for a second round of
alkylation. Along this line, quenching of the lithium enolate
of (+)-8 with 11 produced, after reduction with LAB, the
homologated alcohol 12 (89% over two steps). The syn,-
syn-relationship of the C4, C6, and C8 methyl groups was
again examined following benzylation of alcohol 12 (Scheme
2). The newly produced benzyl ether 15 was proved to be a
meso structure on the basis of the absence of specific rotation.
Installation of the C10 methyl group with the desired
stereochemistry required use of the unnatural enantiomer of
pseudoephedrine derivative (-) 8 as the chiral auxiliary.
Iteration of the alkylation sequence was accomplished by
initially converting alcohol 12 to the corresponding iodide
13 (97%). Subsequent treatment of 13 with the lithium
enolate of (-) 8 followed by hydrolysis of resulting
homologated amide with excess tetra-n-butylammonium
hydroxide produced carboxylic acid 3 in 75% yield (over
two steps). As with the previous alkylations, compound 3
was reduced to the corresponding alcohol and transformed
(18) For selected applications of Myers’ alkylation in natural products
synthesis, see: Sudau, A.; Munch, W.; Bats, J. W.; Nubbemeyer, U. Eur.
J. Org. Chem. 2002, 19, 3315-3325. Myers, A. G.; Siu, M.; Ren, F. J.
Am. Chem. Soc. 2002, 124, 4230-4232. Bode, J. W.; Carreira, E. M. J.
Org. Chem. 2001, 66, 6410-6424. Kopecky, D. J.; Rychnovsky, S. D. J.
Am. Chem. Soc. 2001, 123, 8420-8421. Keck, G. E.; Knutson, C. E.; Wiles,
S. A. Org. Lett. 2001, 3, 707-710. Snider, B. B.; Song, F. Org. Lett. 2001,
3, 1817-1820.
(19) Ireland, R. E.; Thaisrivongs, S.; Dussault, P. H. J. Am. Chem. Soc.
1988, 110, 5768-5779.
(20) Garegg, P. J.; Samuelson, B. J. Chem. Soc., Perkin Trans. 1 1980,
2866-2870. See also ref 17.
Org. Lett., Vol. 5, No. 10, 2003
1619

to the benzyl ether 16 (Scheme 2). As predicted, this
compound exhibited a specific rotation, indicating that it was
not a meso structure. This, in turn, confirmed the anti,syn,-
syn,syn orientation of the four methyl stereocenters.
one-pot dihydroxylation and oxidative cleavage of the
terminal alkene followed by (2) oxidation of the resulting
aldehyde to the carboxylic acid and (3) esterification with
TMS-diazomethane. This manipulation produced methyl
ester 24 in 63% yield. Exposure of 24 to TBAF as a fluoride
source and oxidization of the newly generated secondary
alcohol gave rise to â-ketonitrile 2 representing the fully
functionalized C1-C12 fragment of borrelidin.
In conclusion, we have presented herein an efficient and
enantioselective synthesis of the C1-C12 fragment of
borrelidin (1). Highlights of our strategy include the con-
struction of the skipped polymethylene segment of 1 by
iteration of Myers’ alkylation methodology and the formation
of the C3 stereocenter using Roush’s allylboration reaction.
Both methods proceeded in high yield with exceptional
stereocontrol. Extension of the above strategy to a total
synthesis of borrelidin and structural activity investigation
is currently underway in our laboratories.
Elaboration of carboxylic acid 3 to ketonitrile 2 is shown
in Scheme 3. Esterification of acid 3 with ethanol and DCC
afforded ethyl ester 17 that upon alkylation with the lithium
salt of acetonitrile produced â-ketonitrile 18 in 86% yield.
Since this functionality was found to be incompatible with
subsequent synthetic manipulations, it was reduced to the
corresponding secondary alcohol and subsequently protected
with TIPS chloride. This maneuver afforded silyl ether 20
in 90% yield as a 1.3:1 mixture of stereoisomers at the C11
center. This product was carried forth as a mixture since the
hydroxyl group was projected eventually to be reoxidized
to the desired ketone.
Exposure of benzyl ether 20 to hydrogenation produced
the corresponding alcohol, which after treatment with Dess-
Martin periodinane gave rise to aldehyde 21 (82% over two
steps). Concerned with potential epimerization of the C4
center, we treated aldehyde 21 immediately after extraction
with allyl boronate 22 using Roush’s asymmetric allylbo-
ration conditions.21 The resulting homoallylic alcohol was
then protected with MEMCl to afford ether 23 in 80% overall
yield as a single diastereomer at the C3 center.
Acknowledgment. Financial support from the NIH (CA
086079) is gratefully acknowledged. We also thank the
Department of Education for a GAANN Fellowship to
B.G.V. and Professor M. S. VanNieuwenhze (UCSD) for
helpful discussions.
Supporting Information Available: 1H and 13C NMR
spectra for compounds 2-4, 7, and 10-18 and selected
experimental procedures for compounds 7, 9, 10, 3, and 17.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Transformation of compound 23 to methyl ester 24 was
achieved by a sequence of three steps that included (1) a
(21) Hoong, L. K.; Palmer, M. A.; Park, J. C.; Roush, W. R. J. Org.
Chem. 1990, 55 4109-4117. Hoong, L. K.; Palmer, M. A.; Park, J. C.;
Palkowitz, A. D.; Roush, W. R. J. Org. Chem. 1990, 55, 4117-4126.
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