Enantioselective total synthesis of borrelidin

Article abstract of DOI:10.1021/ja028941u

The first total synthesis of the natural product borrelidin is described. The propionate fragment of the molecule was concisely synthesized through catalytic enantioselective reductive aldol reactions, a catalytic Negishi coupling, and a catalytic directed hydrogenation. The propionate segment was then fused to the vinyl iodide fragment through a catalytic Sonogashira coupling. Subsequent catalytic hydrostannylation and catalytic cyanation allowed access to the target structure. Copyright

Full text of DOI:10.1021/ja028941u

Published on Web 01/16/2003
Enantioselective Total Synthesis of Borrelidin
Matthew O. Duffey, Arnaud LeTiran, and James P. Morken*
Department of Chemistry, Venable and Kenan Laboratories, The UniVersity of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
Received October 14, 2002 ; E-mail: morken@unc.edu
Scheme 1
Borrelidin (1) is a structurally unique macrolide first isolated
from Streptomyces rochei in 1949 by Berger and co-workers.1 The
originally investigated antibiotic activity of borrelidin was ultimately
found to arise from inhibition of threonyl-tRNA synthetase;2
however, further development of the compound was abandoned
when it was found to be a potent sensitizer.3 In addition to its
recently described CDK inhibitory activity,4 borrelidin has re-
Scheme 2 a
emerged as a potent angiogenesis inhibitor with an IC50 of 0.8 nM,
which is lower than its IC50 for tRNA synthetase inhibition.5 This
result implies an alternate biological target for borrelidin, which
may have implications for anticancer therapy. The gross structure
of borrelidin was first described in 1967,6 and the absolute
configuration was determined by Anderson et al. through crystal
structure analysis of a chiral solvate.7 The structure of borrelidin
is characterized by an 18-membered macrolactone carrying a
cyclopentane carboxylic acid and a unique conjugated cyanodiene
(Figure 1). The structural novelty and relevant biological activity
a TBSOTf, 2,6-lutidine (90%); (b) DIBAL (79%); (c) Dess-Martin
periodinane (92%); (d) CBr4, PPh3 (94%); (e) BuLi, MeI (97%); (f) (i)
Cp2ZrHCl, (ii) I2 (89%).
Scheme 3 a
of borrelidin present an exciting challenge for chemical synthesis
and are the focus of this report.8
a (a) TBSOTf, 2,6-lutidine (99%); (b) DIBAL (94%); (c) PPh3, I2 (96%);
(d) pseudoephedrine propionamide, LDA (93%); (e) LAB (93%); (f) PPh3,
I2 (95%).
Figure 1. Structure of borrelidin and retrosynthetic disconnections.
Our strategy for the synthesis of 1 focused on the use of an
iridium-indanepybox (2)-catalyzed enantioselective reductive aldol
reaction to establish the stereogenic centers at C3, C4, C10, and
C11.9 This represents the first example of the use of this
transformation in the context of complex natural product synthesis.
From a retrosynthetic perspective, disconnections of borrelidin at
the C1 macrolactone and C13-C14 linkage led to two fragments,
alkyne 3 and vinyl iodide 4, respectively (Figure 1).
For the construction of the cyanodiene functionality, we sought
to develop a method for the regio- and stereoselective introduction
of the nitrile group at C12. While hydrostannylation of alkynes is
frequently used for the synthesis of vinylstannanes,10 which may
be precursors to vinyl nitriles,11 this method suffers from the lack
of regiocontrol in the addition of tin hydride to internal unsym-
metrical alkynes. Recent studies have established that branching R
to the hydroxyl position of enynols promotes the formation of the
distal vinylstannane.12,13 To address the regiochemistry of the
requisite hydrostannylation, we examined the reaction of model
enyne 5 (Scheme 1). Varying the catalyst as well as reaction
conditions had little effect on the regioisomer ratio of the reaction
with the unprotected substrate (data not shown), and the undesired
isomer 6b was the major product. We then examined the impact
of hydroxyl protecting groups because we suspected that electronic
polarization of the alkyne by the C-O dipole might cause the
hydride to preferentially add to the more electron-deficient end of
the alkyne. This study revealed that by increasing the electron-
withdrawing ability of the hydroxyl protecting group, the desired
isomer 6a could be obtained albeit only by a small margin.14,15
With a method for stereoselective introduction of the cyanodiene
delineated, the synthesis of borrelidin commenced with reductive
aldol coupling of methyl acrylate and p-methoxybenzyloxyacetal-
dehyde to provide aldol adduct 7 with excellent enantio- and
diastereocontrol (Scheme 2). After protection of 7, the methyl ester
was converted to an aldehyde by a reduction/oxidation sequence,
and the aldehyde was then converted to a terminal alkyne by a
Corey-Fuchs reaction. Hydro-zirconation/iodination of the alkyne
gave vinyl iodide 8.
Alkyl iodide 12 was prepared by a second reductive aldol
coupling between methyl acrylate and benzyloxyacetaldehyde to
afford propionate 9 (Scheme 3). Compound 9 was converted to
iodide 10, which was then utilized in a Myers’ asymmetric
alkylation to properly set the C8 methyl stereocenter in 11.16 The
auxiliary was reductively removed to give the primary alcohol,
which was subsequently converted to alkyl iodide 12.
9
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10.1021/ja028941u CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4 a
cocatalyst22 followed by MOM protection of the secondary alcohols,
removal23 of the TIPS ether, and saponification of the methyl esters
provided a single stereoisomer of vinyl nitrile 20. Selective
macrolactonization of diacid 20 was subsequently performed by
carboxyl activation with trichlorobenzoyl chloride.24 Final depro-
tection of the MOM ethers produced synthetic borrelidin, whose
spectral data (1H, 13C, and HRMS) are in agreement with the
reported values for 1.
In conclusion, we have reported the first total synthesis of
borrelidin, which relied on our ability to execute large-scale
asymmetric reductive aldol reactions and also required introduction
of methods for reversing the usual regioselection in hydrostannyl-
ation of propargyl alcohols. Our synthesis sequence allows for late
stage derivatization of the cyanodiene core, which may allow for
discovery of nontoxic analogues of the natural product. These efforts
are currently underway.
a (a) (i) t-BuLi, ZnCl2, (ii) Pd(PPh3)4, 8 (58%); (b) TBAF (87%); (c) H2
(600 psi), 30 mol % Rh[(nbd)dppb]BF4 (86%); (d,e) see the Supporting
Information for these details.
Scheme 5 a
Acknowledgment. The authors thank Prof. David Ball of CSU
Chico for a generous donation of natural borrelidin. This work was
supported by the NIGMS (GM64451-01). J.P.M. thanks Astra-
Zeneca, Bristol-Myers Squibb, Dow, DuPont, GlaxoSmithKline,
and the Packard Foundation for support. M.O.D. is the recipient of
a Wellcome Trust Fellowship.
a (a) KOH, H2O2, MeOH (73%); (b) (COCl)2; (c) H2 (60 psi), 10% Pd/
C, 2,6-lutidine (74%, two steps); (d) (+)-Ipc2B(allyl) (82%); (e) 1 N NaOH,
MeOH (99%); (f) MeI, NaHCO3 (92%); (g) TIPSOTf, 2,6-lutidine (96%);
(h) OsO4, NMO, then NaIO4 (93%); (i) CrCl2, CHI3 (83%).
Scheme 6 a
Supporting Information Available: Characterization data and
experimental procedures (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(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) Lumb, M.; Macey, P. E.; Spyvee, J.; Whitmarsh, J. M.; Wright, R. D.
Nature 1965, 206, 263.
(4) Tsuchiya, E.; Yukawa, M.; Miyakawa, T.; Kimura, K.; Takahashi, H. J.
Antibiot. 2001, 54, 84.
(5) Wakabayashi, T.; Kageyama, R.; Naruse, N.; Tsukahara, N.; Funahashi,
Y.; Kitoh, K.; Watanabe, Y. J. Antibiot. 1997, 50, 671.
(6) Keller-Schierlein. HelV. Chim. Acta 1967, 54, 44.
(7) (a) Anderson, B. F.; Herlt, A. J.; Rickards, R. W.; Robertson, G. B. Aust.
J. Chem. 1989, 42, 717. See also: (b) Kuo, M.-S.; Yurek, D. A.;
Kloosterman, D. A. J. Antibiot. 1989, 42, 1006.
(8) For partial syntheses, see: (a) Haddad, N.; Brik, A.; Grishko, M.
Tetrahedron Lett. 1997, 38, 6079. (b) Xiang, A. X. Dissertation Thesis,
University of California at San Diego, 2000.
(9) (a) Zhou, C.-X.; Duffey, M. O.; Taylor, S. J.; Morken, J. P. Org. Lett.
2001, 3, 1829. (b) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am.
Chem. Soc. 2000, 122, 4528.
a (a) Pd(PPh3)4, CuI, TEA (94%); (b) Ac2O, DMAP (94%); (c)
PdCl2(PPh3)2, Bu3SnH; (d) I2 (97%, two steps, 1:1 regioisomer mixture);
(e) K2CO3, MeOH, -25 °C (66%); (f) Bu3SnCN, CuI, Pd(PPh3)4 (97%);
(g) (MeO)2CH2, P2O5 (85%); (h) TASF (77%); (i) 3 M NaOH, THF (84%);
(j) 2,4,6-trichlorobenzoyl chloride, TEA, DMAP; (k) Me2BBr, -78 °C
(36%, two steps).
(10) Nicolau, K. C.; Webber, S. E. J. Am. Chem. Soc. 1984, 106, 5734.
(11) (a) Sakakibara, Y.; Enami, H.; Ogawa, H.; Fujimoto, S.; Kato, H.;
Kunitake, K.; Sasaki, K.; Sakai, M. Bull. Chem. Soc. Jpn. 1995, 68, 3137.
(b) Hinojosa, S.; Delgado, A.; Llebaria, A. Tetrahedron Lett. 1999, 40, 1057.
(12) (a) Alami, M.; Ferri, F. Synlett 1996, 755. For a review on metal-catalyzed
hydrostannation of alkynes, see: (b) Smith, N. D.; Mancuso, J.; Lautens,
M. Chem. ReV. 2000, 100, 3257.
Coupling of 8 and 12 ultimately allowed for synthesis of 3
(Scheme 4). In this approach, alkyl iodide 12 was converted to the
mixed dialkyl zinc and used in a modified Negishi coupling with
vinyl iodide 8 to give 13.17 After deprotection of the silyl ethers,
the C6 stereocenter was established through a directed hydrogena-
tion to give 14.18 Our attention then turned to the conversion of
compound 14 to fragment 3. This was accomplished in an expedient
manner in a 35% overall yield through the intermediacy of 15.19
Vinyl iodide 4, which is required for coupling to alkyne 3, was
prepared from the known chiral bis-menthyl ester 16, which was
readily accessed via efficient carbocyclization of (+)-dimenthyl-
succinate as described by Yamamoto (Scheme 5).20 Monosaponi-
fication followed by Rosenmund reduction and Brown allylboration
furnished the enantiopure alcohol 17, which was converted to 4 in
32% overall yield from 16.
The critical cross coupling of the subtargets 3 and 4 was best
achieved by a Sonogashira reaction to give, after treatment with
acetic anhydride, enyne 18 (Scheme 6).21 Hydrostannylation of
enyne 18, followed by iodination and deacetylation of the resulting
vinyl stannane, afforded vinyl iodide 19 along with its regioisomer,
which was removed via silica gel chromatography (1:1 ratio,
Scheme 6). Palladium-catalyzed cyanation of 19 using CuI as a
(13) For the Pd(0)-catalyzed hydrostannation of terminal alkynol derivatives,
see: Rice, M. B.; Whitehead, S. L.; Horvath, C. M.; Muchnij, J. A.;
Maleczka, R. E., Jr. Synthesis 2001, 1495.
(14) 1H NMR analysis showed that all reactions proceeded to completion.
(15) It is also tenable that a directing effect accounts for the turnover in
regioselectivity (see ref 13). However, these reactions provide similar levels
of selectivity in both CH2Cl2 and THF solvents.
(16) Myers, A. G.; Yang, B. H.; Chen, H.; Mckinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(17) Smith, A. B.; Beauchamp, Y. J.; LaMarche, M. J.; Kaufman, M. D.; Qiu, Y.;
Arimoto,H.;Jones,D.R.;Kobayashi,K.J.Am.Chem.Soc.2000,122,8654.
(18) Brown, J. M. Angew. Chem., Int. Ed. Engl. 1987, 26, 190.
(19) See the Supporting Information for synthetic schemes and procedures.
(20) Misumi, A.; Iwanaga, K.; Furuta, K.; Yamamoto, H. J. Am. Chem. Soc.
1985, 107, 3343.
(21) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16,
4467. (b) Chang, J.; Paquette, L. A. Org. Lett. 2002, 4, 253.
(22) For rate enhancements with the use of CuI in Stille coupling reactions,
see: Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S.
J. Org. Chem. 1994, 59, 5905.
(23) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey, D. S.;
Roush, W. R. J. Org. Chem. 1998, 63, 6436.
(24) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989.
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