Total synthesis of (-)-virginiamycin M2

Article abstract of DOI:10.1002/anie.201002220

Has a nice ring to it: A concise and modular total synthesis of the naturally occurring antibiotic virginiamycin M2 is described. A Barbier-type cyclization was used to close the 23-membered macrocycle and deliver virginiamycin M2 in 19 steps from a chiral organosilane.

Full text of DOI:10.1002/anie.201002220

Angewandte
Chemie
DOI: 10.1002/anie.201002220
Natural Product Synthesis
Total Synthesis of (À)-Virginiamycin M2**
Jie Wu and James S. Panek*
The virginiamycins are naturally occurring antibiotics pro-
duced by Streptomyces, comprised of two principle groups of
compounds (types A and B; Figure 1). The realization that
iamycin group A compounds originally isolated by Todd and
co-workers.[5]
Our strategy for the synthesis of virginiamycin M2 is
illustrated in Scheme 1, where we envisioned formation of the
23-membered macrocycle through a SmI2-mediated intra-
molecular Barbier/Reformatsky-type cyclization[6] from the
acyclic framework 2. This material could be accessed by
means of esterification of the homoallylic alcohol 3 and the
proline intermediate 4. The (E,E)-diene subunit 3 could be
obtained through an efficient pathway; by using a titanium-
mediated reductive alkyne–alkyne cross-coupling between
the propargylic alcohol 5 and terminal alkyne 6a,[7] which
could be conveniently introduced through crotylation utiliz-
ing the organosilane (S)-7. This silane reagent has unique
À
features as it establishes the C1 C2 syn stereochemistry while
Figure 1. Synercid (dalfopristin + quinupristin).
natural and synthetic derivatives of virginiamycins have
displayed potent antibiotic activity against methicillin-, eryth-
romycin-, and vancomycin-resistant S.aureus,[1] by inhibiting
protein synthesis through synergistic binding of weak ribsome
binders, has resulted in an active research area in both
academia and industry.[2,3] These efforts resulted in the
development of Synercid (Figure 1), a mixture of dalfopristin
(type A) and quinupristin (type B), which was approved in
the United States for the treatment of severe Gram-positive
bacterial infections a little over a decade ago.[4] However,
production of dalfopristin-like compounds by semisynthesis
has been hampered by their sensitive functionalities and pH
instability.[2] Herein, we report a concise and modular total
synthesis of virginiamycin M2, a typical member of virgin-
Scheme 1. Retrosynthetic analysis of virginiamycin M2. TBDPS=tert-
butyldiphenylsilyl, TMS=trimethylsilyl.
[*] J. Wu, Prof. Dr. J. S. Panek
Department of Chemistry and Center for Chemical Methodology
and Library Development
Metcalf Center for Science and Engineering, Boston University
590 Commonwealth Avenue, Boston, MA 02215 (USA)
Fax: (+1)617-358-2847
À
simultaneously creating the C3 C5 (E)-unsaturated ester
subunit, thereby functioning as a vinylogous aldol reagent.[8]
Construction of the terminal alkyne 6a began with an
asymmetric crotylation between (S)-7 and isobutyraldehyde
to directly obtain the vinylogous-aldol product 8 as a single
diastereomer with 95% ee (Scheme 2A).[9] The organosilane
(S)-7 was obtained through an enantioselective carbene
insertion catalyzed by RhII with the ee value reaching
95%.[10] The ester 8 was subjected to Weinrebꢀs amidation
with propargylamine in the presence of AlMe3 to afford the
amide 6a. To achieve the C9–C13 fragment, the propargylic
alcohol 5 was prepared from known aldehyde 10 (two steps
from commercial 1,3-propandiol 9)[11] using the Carreira
E-mail: panek@bu.edu
Homepage: http://people.bu.edu/panek/
[**] Financial support was obtained from NIH CA 53604. The authors
are grateful to Dr. Baptiste Ronan at Sanofi-Aventis for 1H NMR
spectrum comparison of compound 22, Dr. Yun Zhang at Novartis
Institute (Cambridge, MA), Dr. Jason T. Lowe at the Broad Institute
(Cambridge, MA) for helpful discussions, Dr. Paul Ralifo and Dr.
Norman Lee at Boston University for assistance with NMR and
HRMS measurements.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002220.
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coupling strategy, which would lead directly to the
intermediate 14 without the requirement of generating
preactivated and stereodefined olefinic coupling part-
ners. In that regard, Micalizio and co-workers
employed a related approach in the synthesis of
callystatin A by using a homopropargylic ether.[7b]
However, in the present case, the coupling of the
propargylic ether 11 with a terminal alkyne did not
afford the desired diene 14 (Scheme 2C, entries 1 and
2); instead, only the regioisomer 12 and allene 13 were
isolated. We envisioned that the in situ generated
internal alkyne–titanium complex int-1[14] was allowed
to undergo carbometallation with the terminal alkyne
presumably through int-2 and int-3 to afford 12 and 13
respectively,[15] as functionalization of the terminal
alkyne substrate generally occurred at the terminal
carbon atom of the alkyne.[16] Notably, instead of
forming the trisubstituted diene after hydrolysis, the
corresponding allene compounds 13 were generated
presumably through b elimination of the OTBS group
in int-3 (Scheme 2).[17] To overcome the influence of
the propargylic ether, we planned to evaluate the
directing ability of the secondary hydroxy group in 5
since there was a possibility that the proximal heter-
oatom (hydroxy group) would coordinate with the
neighboring metal center.[18] The reactions were ini-
tiated by preforming the lithium oxide using nBuLi,[19]
which would undergo ligand exchange with titanium[20]
to produce lithium isopropoxide, and lead to the
presumed metallacyclopropene intermediate int-4.[21]
If the structure of tethered alkoxide int-4 was retained
À
during the C C bond formation, it would preferentially
afford the metallacyclopentadiene intermediate int-6,
since int-5 would encounter significant strain when
forming the bridgehead alkene.[21] Although the coor-
dination of alkoxide with titanium was expected to
exhibit considerable ring strain in the bicyclic metal-
lacyclopropene int-4,[21a] diene 14c was obtained with
excellent regioselectivity and good yield (entry 3), and
without detection of by-products 12c or 13c. The
terminal alkyne 6 also reacted in a regioselective
manner to give the desired diol product 14d (entry 4),
which was accompanied by a small amount of allene
by-product 13d.[22]
The synthesis of the C14–C19 subunit (Scheme 3A)
commenced with hydrolysis of the oxazole ester 18,[23]
and subsequent coupling with d-proline benzyl ester
hydrochloride. A subsequent Lewis acid promoted
cleavage of the benzyl ester provided amide subunit 4
as a 3:1 mixture of rotamers.
Scheme 2. A) Synthesis of C1–C8 fragment: a) Isobutyraldehyde, TiCl4, CH2Cl2,
À208C, 63%, d.r. >20:1, 95% ee; b) AlMe3, propargylamine, 87%. B) Synthesis
of C9–C13 fragment: c) Zn(OTf)2, (À)-N-methylephedrine, propyne, Et3N,
80%, 95% ee; d) TBSOTf, 2,6-lutidine, 96%. C) Alkyne–alkyne reductive cou-
pling: e) Ti(OiPr)3Cl, cyclopentyl magnesium chloride, toluene, À788C to
À308C; f) nBuLi, Ti(OiPr)3Cl, cyclopentyl magnesium chloride, Et2O, À788C to
À308C. The reported yields are those for the product isolated after column
chromtography. The yields reported for entry 4 are based on recovered starting
material. OTf=trifluoromethanesulfonate, TBS=tert-butyldimethylsilyl.
protocol[12] and subsequent silylation with TBSOTf to afford
the propargylic ether 11 (Scheme 2B). Asymmetric addition
In making use of the difference in the steric environment
using Carreiraꢀs protocol proceeded efficiently with propyne,
and without evidence of self-aldol condensation of the
starting aldehyde.
With the two alkyne reaction partners now available, our
next objective was to assemble the conjugated diene fragment
14. Although there were several options available for the
construction of branched conjugated dienes,[13] we were
interested in the use of a titanium-mediated reductive cross-
of the two secondary hydroxy groups in 14d, the C11 hydroxy
group was selectively silylated as a TBDPS ether 3. Subse-
quent fragment coupling with 4 proceeded efficiently under
the Yamaguchi condition[24] to yield 19 as a mixture of 1:1
rotamers (Scheme 3B). The final stages of the synthesis began
with the selective removal of the primary silyl group of 19, and
oxidation of the derived primary alcohol using IBX afforded
the advanced aldehyde 2.[3b] Treatment of the chloroaldehyde
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silane (S)-7 in a 6.0% overall yield. Notable features of
our approach include the application of chiral silane (S)-
7 for the asymmetric synthesis of the syn vinylogous
aldol product, use of an alkoxide-directed reductive
coupling to construct the (E,E)-diene, and a SmI2-
promoted Barbier-type cyclization, which afforded the
largest macrocycle (23-membered) among SmI2 medi-
ated macrocyclizations to date.[6]
Received: April 14, 2010
Revised: May 18, 2010
Published online: July 19, 2010
Keywords: antibiotics · macrocycles · natural products ·
.
silanes · total synthesis
[1] a) K. E. Brighty, P. R. McGuirk, Annu. Rep. Med. Chem.
1991, 26, 123; b) T. A. Mukhtar, G. D. Wright, Chem. Rev.
2005, 105, 529 – 542.
Scheme 3. A) Synthesis of the C14—C19 subunit: a) LiOH, THF/H2O (4:1),
95%; b) EDCI·HCl, (R)-NH(HCl)-Pro-OBn, Et3N, 80%; c) BCl3, À208C to
08C, 70%. B) Completion of the synthesis: d) TBDPSCl, imidazole, 08C,
92%; e) 4, 2,4,6-trichlorobenzoyl chloride, benzene, DIPEA, DMAP, 86%;
f) CSA, CH2Cl2, MeOH, 08C, 62% (85% brsm); g) IBX, DMSO, 92%; h) NaI,
acetone, 95%; i) SmI2, benzene, 2, 40%; j) SmI2, benzene, 20, 42%; k) TFAA,
DMSO, CH2Cl2, À788C to À458C, acetylacetone, Et3N, À608C to À358C,
84%; l) HF·2pyridine, CH2Cl2, 70%. THF=tetrahydrofuran, EDCI=N-(3-
dimethylaminopropyl)-N’-ethylcarbodiimide, DIPEA=N,N-diisopropylethyl-
amine, DMAP=4-dimethylaminopyridine, CSA=(Æ)-camphorsulfonic acid,
IBX=ortho-iodoxybenzoic acid, DMSO=dimethyl sulfoxide, TFAA=trifuoro-
acetic acid.
[2] a) B. Ronan, E. Bacquꢁ, J. Barriꢂre, S. Sablꢁ, Tetrahedron
2003, 59, 2929 – 2937; b) B. Ronan, E. Bacquꢁ, J. Barriꢂre,
Tetrahedron 2004, 60, 3819 – 3824; c) E. Bacquꢁ, Chimia
2004, 58, 128 – 132; d) K. Nott, M. Paquot, S. Dufour, M.
Eeman, M. Deleu, Colloids Surf. B 2009, 69, 268 – 275.
[3] For total synthesis of virginiamycin M2, see a) R. H.
Schlessinger, Y.-J. Li, J. Am. Chem. Soc. 1996, 118, 3301 –
3302; b) P. Breuilles, D. Uguen, Tetrahedron Lett. 1998, 39,
3149 – 3152. Formal synthesis of virginiamycin M2, see
c) M. S. Mortensen, J. S. Osbourn, G. A. OꢀDoherty, Org.
Lett. 2007, 9, 3105 – 3108. For total synthesis of related
type A virginiamycin natural products, see d) F. Tavares,
J. P. Lawson, A. I. Meyers, J. Am. Chem. Soc. 1996, 118,
3303 – 3304; e) A. K. Ghosh, W. Liu, J. Org. Chem. 1997, 62,
7908 – 7909; f) D. A. Entwistle, S. I. Jordan, J. Montgomery, G.
Pattenden, Synthesis 1998, 603 – 612; g) C. A. Dvorak, W. D.
Schmitz, D. J. Poon, D. C. Pryde, J. P. Lawson, R. A. Amos, A. I.
Meyers, Angew. Chem. 2000, 112, 1730 – 1732; Angew. Chem. Int.
Ed. 2000, 39, 1664 – 1666.
2 with NaI in acetone provided iodide 20 in 95% yield. At this
stage we were faced with the challenge of closing the 23-
membered macrocycle and our initial experiments were
unsuccessful. For instance, exposure of the advanced inter-
mediate 20 to a THF solution of freshly prepared SmI2[6c] led
to a disappointing yield (approximately 10%) of the desired
macrocyclic lactone 21, with the majority identified as the
reduced aldehyde and deiodinated material. The lower yield
(< 5%) obtained from highly dilute THF solution (0.002m)
indicated that the initially formed benzylic-like radical
abstracted a hydrogen atom from THF, thus preventing the
generation of the desired organosamarium intermediate.[25]
The desired product was isolated in moderate yield (42%) as
a 1:1 diastereomeric mixture when benzene was used as the
reaction solvent. The less reactive chloromethyloxazole 2
underwent cyclization with similar yield. To the best of our
knowledge, this is the first example of a SmI2-mediated
macrocyclization that uses benzene to suppress the compet-
itive dehalogenation pathway. Subsequent oxidation of the
resulting secondary alcohol using a modified TFAA/DMSO
Swern procedure yielded the corresponding ketone in good
yield. The addition of acetylacetone was used to help prevent
further enolization of the ketone product.[26] Final removal of
the C11 TBDPS ether using pyridine buffered HF gave
virginiamycin M2 in 70% yield. The spectral data and
analytical data (1H and 13C NMR, IR, HRMS, optical
rotation) were identical with the published data.[3a]
[4] a) J. C. Barriꢂre, J. M. Paris, Drugs Future 1993, 18, 833; b) J. C.
Barriꢂre, D. Bouanchaud, J. F. Desnoottes, J. M. Paris, Expert
Opin. Invest. Drugs 1994, 3, 115 – 131.
[5] G. R. Delpierre, F. W. Eastwood, G. E. Gream, D. G. I. King-
ston, A. R. Lord Todd, D. H. Williams, J. Chem. Soc. C 1966,
1653.
[6] a) D. J. Edmonds, D. Johnston, D. J. Procter, Chem. Rev. 2004,
104, 3371 – 3404; b) K. C. Nicolaou, S. P. Ellery, J. S. Chen,
Angew. Chem. 2009, 121, 7276 – 7301; Angew. Chem. Int. Ed.
2009, 48, 7140 – 7165; c) J. T. Lowe, J. S. Panek; T. Hu, J. Org.
Chem. 1997, 62, 4912 – 4913, Org. Lett. 2008, 10, 3813 – 3816.
[7] For selective recent examples of titanium mediated alkyne-
alkyne reductive coupling, see a) H. L. Shimp, G. C. Micalizio,
Org. Lett. 2005, 7, 5111 – 5114; b) H. A. Reichard, J. C. Rieger,
G. C. Micalizio, Angew. Chem. 2008, 120, 7955 – 7958; Angew.
Chem. Int. Ed. 2008, 47, 7837 – 7840.
[8] For reviews and recent examples of vinylogous aldol reaction,
see a) G. Rassu, F. Zanardi, L. Battistini, G. Casiraghi, Chem.
Soc. Rev. 2000, 29, 109 – 118; b) G. Casiraghi, F. Zanardi, G.
Appendino, G. Rassu, Chem. Rev. 2000, 100, 1929 – 1972; c) S. E.
Denmark, J. R. Heemstra, Jr., G. L. Beutner, Angew. Chem.
2005, 117, 4760 – 4777; Angew. Chem. Int. Ed. 2005, 44, 4682 –
4698; d) J. Hassfeld, M. Christmann, M. Kalesse, Org. Lett. 2001,
3, 3561 – 3564; e) M. Kalesse, S. Simsek, Tetrahedron Lett. 2009,
50, 3485 – 3488; f) S. E. Denmark, G. L. Beutner, J. Am. Chem.
Soc. 2003, 125, 7800 – 7801; g) S.-U. Hormuth, H. Reissig, D.
In summary, virginiamycin M2 (1) has been synthesized in
19 steps with the longest linear sequence of 10 steps from
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Dorsch, Angew. Chem. 1993, 105, 1513 – 1514; Angew. Chem. Int.
Ed. Engl. 1993, 32, 1449 – 1450.
[17] Allene product generation was also observed in the titanium-
mediated reductive coupling of propargylic ethers and carbonyl
compounds; see a) K. Yamashita, F. Sato, Tetrahedron Lett. 1996,
37, 7275 – 7278; b) T. Nakagawa, A. Kasatkin, F. Sato, Tetrahe-
dron Lett. 1995, 36, 3207 – 3210.
[18] For recent reviews of alkoxide-directed reductive coupling, see
H. A. Reichard, M. McLaughlin, M. Z. Chen, G. C. Micalizio,
Eur. J. Org. Chem. 2010, 391 – 409.
[9] For ee analysis, see the Supporting Information.
[10] a) H. M. Davies, T. Hansen, J. Rutberg, P. R. Bruzinski, Tetrahe-
dron Lett. 1997, 38, 1741 – 1744; b) J. Wu, Y. Chen, J. S. Panek,
Org. Lett. 2010, 12, 2112 – 2115.
[11] A. Fꢃrstner, M. D. B. Fenster, B. Fasching, C. Godbout, K.
Radkowski, Angew. Chem. 2006, 118, 5632 – 5636; Angew.
Chem. Int. Ed. 2006, 45, 5506 – 5510.
[19] Control experiments were carried out to test the effect of nBuLi;
see the Supporting Information.
[12] D. E. Frantz, R. Fassler, E. M. Carreira, J. Am. Chem. Soc. 2000,
122, 1806 – 1807.
[20] Titanium alkoxide undergoes rapid and reversible ligand
exchange; see a) K. B. Sharpless, S. S. Woodard, M. G. Finn,
Pure Appl. Chem. 1983, 55, 1823 – 1836; b) S. S. Woodard, M. G.
Finn, K. B. Sharpless, J. Am. Chem. Soc. 1991, 113, 106 – 113.
[21] For the possibility of generating metallacyclopropene intermedi-
ate, see a) L. J. Perez, H. L. Shimp, G. C. Micalizio, J. Org. Chem.
2009, 74, 7211 – 7219. The possibility to generate other metalla-
cycles should not be excluded; see b) A. B. Bahadoor, G. C.
Micalizio, Org. Lett. 2006, 8, 1181 – 1184.
[22] To clarify the role of functional groups and illustrate the
generality of alkyne–alkyne reductive coupling using propagylic
alcohol, more substrates were tested; see the Supporting
Information.
[13] For selected examples, see: a) J. S. Panek; T. Hu, J. Org. Chem.
1997, 62, 4912 – 4913; b) E.-I. Negishi, Z. Huang, G. Wang, S.
Mohan, C. Wang, H. Hattori, Acc. Chem. Res. 2008, 41, 1474 –
1485; c) G. D. Allred, L. S. Liebeskind, J. Am. Chem. Soc. 1996,
118, 2748 – 2749.
[14] Generation of the internal metallacyclopropene int-1 is crucial
À
for titanium alkoxide mediated C C bond formation; see
a) O. G. Kulinkovich, A. DeMeijere, Chem. Rev. 2000, 100,
2789 – 2834; b) F. Sato, H. Urabe, S. Okamoto, Chem. Rev. 2000,
100, 2835 – 2886. Attempted generation of metallacyclopropene
of terminal alkyne has been reported to be unsuccessful: c) K.
Harada, H. Urabe, F. Sato, Tetrahedron Lett. 1995, 36, 3203 –
3206. Our control experiment attempting generation of tita-
nium–acetylene complex on 6c was not successful; see the
Supporting Information.
[23] S. A. Hermitage, K. S. Cardwell, T. Chapman, J. W. B. Cooke, R.
Newton, Org. Process Res. Dev. 2001, 5, 37 – 44.
[24] a) J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi,
Bull. Chem. Soc. Jpn, 1979, 52, 1989 – 1993; b) D. Ma, B. Zou, G.
Cai, X. Hu, J. O. Liu, Chem. Eur. J. 2006, 12, 7615 – 7626.
[25] M. Kunishima, S. Tanaka, K. Kono, K. Hioki, S. Tani, Tetrahe-
dron Lett. 1995, 36, 3707.
[26] D. R. Williams, A. A. Kiryanov, U. Emde, M. P. Clark, M. A.
Berliner, J. T. Reeves, Proc. Natl. Acad. Sci. USA 2004, 101,
12058 – 12063.
[15] The regioselectivity observed was influenced significantly by the
structure of the terminal alkyne. For additional control experi-
ments, see the Supporting Information.
[16] T. Hamada, D. Suzuki, H. Urabe, F. Sato, J. Am. Chem. Soc.
À
1999, 121, 7342 – 7344. C C formation at C2 of the terminal
alkyne would affored more strained transition intermediate.
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