Total synthesis of (-)-borrelidin

Article abstract of DOI:10.1021/ol049356w

Matrix presented. The total synthesis of borrelidin has been achieved. The best feature of our synthetic route is Sml₂-mediated intramolecular Reformatsky-type reaction for macrocyclization after esterification between two segments. The two key segments were synthesized through chelation-controlled carbotitanation, chelation-controlled hydrogenation, stereoselective Reformatsky reaction, and MgBr₂·Et₂O-mediated chelation-controlled allylation.

Full text of DOI:10.1021/ol049356w

ORGANIC
LETTERS
2004
Vol. 6, No. 11
1865-1867
Total Synthesis of (−)-Borrelidin
Tohru Nagamitsu,† Daisuke Takano,† Takeo Fukuda,† Kazuhiko Otoguro,‡
,‡,§
Isao Kuwajima,§ Yoshihiro Harigaya,† and Satoshi Ohmura*
School of Pharmaceutical Science, Kitasato UniVersity, Kitasato Institute for Life
Sciences, Kitasato UniVersity, and The Kitasato Institute, 5-9-1 Shirokane, Minato-ku,
Tokyo 108-8641, Japan
omura-s@kitasato.or.jp
Received April 8, 2004
ABSTRACT
The total synthesis of borrelidin has been achieved. The best feature of our synthetic route is SmI2-mediated intramolecular Reformatsky-type
reaction for macrocyclization after esterification between two segments. The two key segments were synthesized through chelation-controlled
carbotitanation, chelation-controlled hydrogenation, stereoselective Reformatsky reaction, and MgBr2‚Et2O-mediated chelation-controlled allylation.
Borrelidin (1), a structurally unique 18-membered macrolide,
was first isolated from Streptomyces rochei in 1949 by Berger
et al. as an antibiotic possessing anti-Borrelia activity.1 Other
useful biological activities of borrelidin such as its inhibitory
activities against threonyl-tRNA synthetase2 and cyclin-
dependent kinase3 and its potent antiangiogenesis activity4
were reported later. The planar structure of borrelidin was
elucidated by Keller-Schierlein in 1967,5 and the absolute
configuration was determined by Anderson et al. through
X-ray crystallography of a chiral solvate.6 Recently, we found
that borrelidin also shows potent antimalarial activity against
chloroquine-resistant strains, both in vitro and in vivo.7 This
biological profile, as well as its structural complexity,
prompted substantial synthetic effort toward the total syn-
thesis of (-)-borrelidin. To date, two elegant total syntheses
of borrelidin have been reported, by Morken et al.8 and
Hanessian et al.,9 respectively, and two synthetic studies
toward total synthesis have also been described.10 We report
herein the stereocontrolled total synthesis of (-)-borrelidin
(1), by a convergent strategy that features SmI2-mediated
intramolecular Reformatsky-type reaction of R-bromo-
R,â:γ,δ-unsaturated nitrile 2 for macrocyclization at C11-
12 after esterification between acid 10 and alcohol 15, as
shown in Figure 1.
We started from a known chiral alcohol 3 (97% ee), which
was readily obtained from the meso-diol by enzymatic
desymmetrization,11 to lead to the C1-C11 segment 10
(Scheme 1). The conversion of 3 to aldehyde 412 was
efficiently accomplished by a series of protections and
deprotections followed by TPAP oxidation. 1,2-Addition of
† School of Pharmaceutical Science, Kitasato University.
‡ The Kitasato Institute.
§ Kitasato Institute for Life Sciences, Kitasato University.
(1) Berger, J.; Jampolsky, L. M.; Goldberg, M. W. Arch. Biochem. 1949,
22, 476.
(2) Paetz, W.; Nass, G. Eur. J. Biochem. 1973, 35, 331.
(3) Tsuchiya, E.; Yukawa, M.; Miyakawa, T.; Kimura, K.; Takahashi,
H. J. Antibiot. 2001, 54, 84.
(4) Wakabayashi, T.; Kageyama, R.; Naruse, N.; Tsukahara, N.; Funahashi,
Y.; Kitoh, K.; Watanabe, Y. J. Antibiot. 1997, 50, 671.
(5) Keller-Schierlein, W. HelV. Chim. Acta 1967, 50, 75.
(6) Anderson, B. F.; Herlt, A. J.; Rickards, R. W.; Robertson, G. B. Aust.
J. Chem. 1989, 42, 717.
(7) Otoguro, K.; Ui, H.; Ishiyama, A.; Kobayashi, M.; Togashi, H.;
Takahashi, Y.; Masuma, R.; Tanaka, H.; Tomoda, H.; Yamada, H.; Ohmura,
S. J. Antibiot. 2003, 56, 727.
(8) Duffey, M. O.; LeTiran, A.; Morken, J. P. J. Am. Chem. Soc. 2003,
125, 1458.
(9) Hanessian, S.; Yang, Y.; Giroux, S.; Mascitti, V.; Ma, J.; Raeppel,
F. J. Am. Chem. Soc. 2003, 125, 13784.
(10) (a) Haddad, N.; Grishko, M.; Brik, A. Tetrahedron Lett. 1997, 38,
6075. (b) Vong, B. G.; Abraham, S.; Xiang, A. X.; Theodorakis, E. A.
Org. Lett. 2003, 4, 1617.
(11) Fujita, K.; Mori, K. Eur. J. Org. Chem. 2001, 66, 493.
10.1021/ol049356w CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/08/2004

ether formation, deprotection of the TBDPS ether, and TPAP
oxidation efficiently produced aldehyde 9. Stereoselective
Reformatsky reaction of 9 with (R)-4-benzyl-3-bromoacetyl-
2-oxazolidinone using SmI2 under Fukuzawa’s conditions19
afforded the corresponding adduct with the desired C3
stereochemistry (15:1),20 which was subjected to TBS
protection followed by removal of the chiral auxiliary to give
carboxylic acid 10.
The C12-C23 segment 15 was prepared from the known
chiral diol 11, which was readily derived from succinic acid
by Yamamoto asymmetric carbocyclization21 (Scheme 2).
Scheme 2a
Figure 1. Structure and retrosynthesis of borrelidin (1).
lithium acetylide (which was easily prepared from 513) to 4
was quenched with MeO2CCl to furnish the corresponding
methyl carbonate, which was treated with Pd(acac)2/Bu3P/
14
HCO2NH4 to give 6 after PMB deprotection. Subsequent
a Conditions: (a) PMBCl, NaH; (b) Dess-Martin periodinane
(89%, two steps); (c) allyltrimethylsilane, MgBr2‚Et2O (95%, 20:
1); (d) TBSOTf, 2,6-lutidine (99%); (e) OsO4, NMO; (f) NaIO4
(100%, two steps); (g) Ph3PdCHCHO (73%); (h) (EtO)2P(O)CH-
(Br)CN, DBU, LiCl (96%); (i) HF‚pyridine (94%).
Scheme 1a
Monoselective PMB protection of diol 11 followed by Dess-
Martin oxidation gave aldehyde 12. Reaction with allylmag-
nesium bromide or Brown’s allylboration22 of 12 to produce
13 led to low stereoselectivity. Therefore, chelation-
controlled allylation of 12 with allyltrimethylsilane in the
presence of Lewis acids was investigated. It was found that
(12) For another synthetic route, see: (a) Smith, A. B., III; Condon, S.
M.; McCauley, J. A.; Leazer, J. L., Jr.; Leahy, J. W.; Maleczka, R. E., Jr.
J. Am. Chem. Soc. 1997, 119, 947. (b) Smith, A. B., III; Maleczka, R. E.,
Jr.; Leazer, J. L., Jr.; Leahy, J. W.; McCauley, J. A.; Condon, S. M.
Tetrahedron Lett. 1994, 35, 4911. Also see: Roush, W. R.; Hoong, L. K.;
Palmer, M. A. J.; Straub, J. A.; Palkowitz, A. D. J. Org. Chem. 1990, 55,
4117.
(13) Paquette, L. A.; Guevel, R.; Sakamoto, S.; Kim, I. H.; Crawford, J.
J. Org. Chem. 2003, 68, 6096.
(14) Randinov, R.; Hutchings, S. D. Tetrahedron Lett. 1999, 40, 8955.
(15) Schiavelli, M. D.; Plunkett, J. J.; Thompson, D. W. J. Org. Chem.
1981, 46, 807.
(16) Stereochemistry was confirmed by NOE. Also see Supporting
Information.
(17) Evans, D. A.; Morrissey, M. M.; Dow, R. L. Tetrahedron Lett. 1985,
26, 6005.
(18) Stereochemistries of C8 and C11 were confirmed by the achievement
of the total synthesis of borrelidin (1).
a Conditions: (a) TBSCl, imidazole (98%). (b) K2CO3, MeOH
(98%). (c) TBDPSCl, imidazole. (d) PPTS (97%, two steps). (e)
TPAP, NMO, 4 Å MS (88%). (f) (i) 5, n-BuLi; (ii) 4, then
MeO2CCl. (g) Pd(acac)2, Bu3P, HCO2NH4 (90%, two steps). (h)
DDQ (97%). (i) Me3Al, TiCl4 (80%). (j) H2 (1 MPa), Rh[(nbd)-
dppb]BF4 (91%). (k) Dihydropyrane, PPTS (100%). (l) TBAF
(96%). (m) TPAP, NMO, 4 Å MS (89%). (n) (R)-4-Benzyl-3-
bromoacetyl-2-oxazolidinone, SmI2 (98%, 15:1). (o) TBSOTf, 2,6-
lutidine. (p) LiOH, H2O2 (84%, two steps).
(19) Fukuzawa, S.; Matsuzawa, H.; Yoshimitsu, S. J. Org. Chem. 2000,
65, 1702.
chelation-controlled carbotitanation of the homoallylic al-
cohol 6 under slightly modified Thompson’s conditions15
produced the desired trisubstituted (Z)-olefin 7 as the sole
product.16 Chelation-controlled hydrogenation17 of 7 using
catalytic Rh[(nbd)dppb]BF4 under high pressure (1 MPa)
gave rise to 8 with the desired C8 methyl stereocenter.18 THP
(20) Stereochemistry was determined by the modified Mosher procedure;
see: Ohtani, I.; Kusumi, J.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092. Also see Supporting Information.
(21) (a) Misumi, A.; Iwanaga, K.; Furuta, K.; Yamamoto, H. J. Am.
Chem. Soc. 1985, 107, 3343. (b) Fujimura, O.; de la Mata, F. J.; Grubbs,
R. H. Organometallics 1996, 15, 1865.
(22) Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.; Racherla,
U. S. J. Am. Chem. Soc. 1990, 112, 2389.
1866
Org. Lett., Vol. 6, No. 11, 2004

ester, which was converted to the aldehyde, the key
intermediate for the intramolecular Reformatsky-type reac-
tion, by THP deprotection followed by TPAP oxidation.
Next, we explored the SmI2-mediated intramolecular Refor-
matsky-type reaction of 2. Treatment of 2 with SmI2 at -78
°C gave no reaction, and a rise in the reaction temperature
(to 0 °C) afforded a trace amount of cyclized compounds
accompanied by decomposition. We next examined the effect
of HMPA as an additive at -78 °C.28 Consequently,
treatment of 2 with a 3:2 ratio mixture of SmI2 and HMPA
at -78 °C gave the best result, to produce cyclized products
18 and 1916,18 with the desired Z stereochemistry at C12-
C13 in a 40% total yield, accompanied by the protonated
uncyclized compound 16 (13%) and the cyclized compound
17 with the undesired E stereochemistry16 at C12-C13
(22%). Inversion of the hydroxyl group at C11, namely,
conversion of epimer 18 into 19, by Dess-Martin oxidation
followed by Luche reduction proved to be quite effective
(12:1). TBS protection of 19, removal of the PMB ether,
and a tandem oxidation approach provided the corresponding
carboxylic acid, which was subjected to deprotection of the
TBS ether with HF‚pyridine, to give borrelidin (1). Synthetic
borrelidin (1) was identical to an authentic sample in all
Scheme 3a
1
respects ([R]D, mp, H and 13C NMR, IR, FAB-MS).
In summary, we have achieved the total synthesis of
borrelidin (1). The best feature of our synthetic route is SmI2-
mediated intramolecular Reformatsky-type reaction for mac-
rocyclization after esterification between two segments, and
this strategy differs significantly from those of the total
syntheses reported previously. The other noteworthy features
are as follows: chelation-controlled carbotitanation of a
homoallylic alcohol to construct the trisubstituted (Z)-olefin
7, MgBr2‚Et2O-mediated stereoselective allylation of 12, and
effective inversion of the hydroxyl group for the conversion
of 18 to 19. Improvement of the key intramolecular Refor-
matsky-type reaction and development of borrelidin ana-
logues as antimalarial agents are currently in progress in our
laboratory.
a Conditions: (a) 10, 2,4,6-trichlorobenzoyl chloride, Et3N then
15, DMAP (97%); (b) PPTS (93%); (c) TPAP, NMO, 4 Å MS
(79%); (d) SmI2, HMPA; (e) Dess-Martin periodinane; (f) NaBH4,
CeCl3‚7H2O; (71%, two steps, 12:1); (g) TBSOTf, 2,6-lutidine
(75%); (h) DDQ (90%); (i) Dess-Martin periodinane; (j) NaClO2,
NaH2PO4‚2H2O, 2-methyl-2-butene; (k) HF‚pyridine (85%, three
steps).
MgBr2‚Et2O gave the best result,23,24 affording 13 with high
yield and stereoselectivity (20:1).20 Dihydroxylation after
TBS protection of 13 followed by treatment with NaIO4
afforded the corresponding aldehyde, which was subjected
to a Wittig reaction with Ph3PdCHCHO to give (E)-
unsaturated aldehyde 14. Subsequent Horner-Emmons ole-
fination of 14 with (EtO)2P(O)CH(Br)CN25 using DBU and
LiCl26 furnished the corresponding (E)-vinyl bromide as a
single isomer, which was exposed to HF‚pyridine to form
alcohol 15.
Acknowledgment. This work was supported in part by
a Grant from the 21st Century COE Program, Ministry of
Education, Culture, Sports, Science and Technology, Japan.
T.N. acknowledges a Kitasato University research grant for
young researchers.
Esterification between 10 and 15 was performed under
Yamaguchi conditions27 to give rise to the corresponding
Supporting Information Available: Characterization
data and experimental procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
(23) Use of other Lewis acids led to low stereoselectivity.
(24) For the effectiveness of MgBr2‚Et2O in chelation-controlled
allylation, see: Williams, D. R.; Klingler, F. D. Tetrahedron Lett. 1987,
28, 869.
OL049356W
(25) Iorga, B.; Ricard, L.; Savignac, P. J. Chem. Soc., Perkin Trans. 1
2000, 3311.
(26) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(27) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamagauchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(28) Inanaga, J.; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987, 1485.
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