Total synthesis of (-)-virginiamycin M2 using second-generation vinylogous urethane chemistry

Article abstract of DOI:10.1021/ja954311z

Antibiotics known as the virginiamycins consist of two groups-polyunsaturated macrolactones (type A) and peptidic macrolactones (type B). Mixtures of type A and type B virginiamycins exhibit very high potency against a variety of bacteria. Total syntheses

Full text of DOI:10.1021/ja954311z

J. Am. Chem. Soc. 1996, 118, 3301-3302
3301
Scheme 1
Total Synthesis of (-)-Virginiamycin M2 Using
Second-Generation Vinylogous Urethane Chemistry
R. H. Schlessinger* and Yu-Jang Li
Department of Chemistry, UniVersity of Rochester
Rochester, New York 14627
ReceiVed December 28, 1995
The ever-expanding crisis in antibiotic resistance of bacterial
pathogenssthe result of either chromosomal changes or the
exchange of genetic material Via plasmids and transposonssis
of increasing concern to the medical community.1 This has
prompted increased efforts to find and study new and effective
antibiotic species.2 Total synthesis can play an important role
in defining the chemistry of an antibiotic, often leading to its
improved efficacy.
Antibiotics known as the virginiamycins consist of two
groupsspolyunsaturated macrolactones (type A) and peptidic
macrolactones (type B).3 Mixtures of type A and B virginia-
mycins exhibit very high potency against a variety of bacteria.4
Total syntheses of the peptidic virginiamycins (type B) have
been reported.5 However, the synthesis of type A virginiamy-
cins has not been achieved6sperhaps due in part to their extreme
pH sensitivity.7 We describe the total synthesis of virginiamycin
M2 (1), a type A structure of this antibiotic family.8
Scheme 2a
Antibiotic 1 is a 23-membered ring macrolide which possesses
one ester and two amide linkages. The compound also contains
four stereogenic centers, two of which are proximal to each
other. The other two stereogenic centers consist of the amino
acid D-proline and an allylic â-ketoalcohol. Also contained
within the 23-membered ring is a 2,4-disubstituted oxazole
moiety. Our strategy for the construction of 1 starts with
cleavage of the amide and ester linkages of it, which reveals
fragments 2 and 3 (Scheme 1). These fragments were further
cleaved, as indicated, to afford subunits 4, 5, 6, and 7. Critical
to the assemblage of 1 from these subunits was the nature of
the protecting groups carried on them and the timing of their
conjoining.
a Reagents and conditions: (a) LDA, THF, isobutyraldehyde, -78-0
°C, 87%. (b) Li, NH3, t-BuOH, THF, 92%. (c) m-CPBA, THF, -78
°C, pyridine, 0 °C, 82%. (d) N-((2,2,2-trichloroethoxy)carbonyl)-D-
proline, DCC, DMAP, CH2Cl2, 92%. (e) NH2SO3H, NaClO2, THF, H2O,
0 °C, 88%.
We commenced this synthesis with the construction of an
analogue of 2 using a new stereoselective aldol lactonization
reaction.9 The lithium enolate of vinylogous urethane 8, a
species which does not contain a C2 symmetric chiral auxiliary,
reacts with isobutyraldehyde to afford the vinylogous urethane
lactone 9 (87% yield, 96% de)10 (Scheme 2). Compound 9 was
re-formed into the unsaturated aldehyde homoallylic alcohol 10
in two steps by dissolving metal reduction of the former to the
amino lactol 11 (92%) followed by oxidative elimination of the
amine (82%). The aldehyde alcohol 10 proved only moderately
stable and, therefore, was immediately esterified with N-((2,2,2-
trichloroethoxy)carbonyl)-D-proline (92%). Oxidation of the
resulting aldehyde ester 12 under Lindgren’s conditions smoothly
formed the corresponding acid ester 13 (88%).11
Next, we turned our attention to the amine 6, beginning this
construction with the alkylation of the lithium enolate of the
vinylogous urethane lactone 14 with isopropyl bromoacetate
(Scheme 3). The ester 15, obtained (93%) as a single stereo-
isomer from this reaction,12 was selectively reduced to the
corresponding primary alcohol (91%) and then silylated with
TBSCl (88%) to afford 16.
(1) Neu, H. C. Science 1992, 257, 1064-1073.
(2) Service, R. E. Science 1995, 270, 724-727.
(3) Virginiamycins are also known as streptogramins, pristinamycins,
or synergimycins. For leading reviews of virginiamycin chemistry, see: (a)
Di Giambattista, M.; Cocito, C. J. Antimicrob. Chemother. 1989, 24, 485.
(b) Paris, J. M.; Barriere, J. C.; Smith, C.; Bost, P. E. In Recent Progress
in the Chemical Synthesis of Antibiotics; Lukacs, G., Ohno, M., Eds.;
Springer-Verlag: Berlin, 1990; pp 183-248. For structure determination
of 1, see: Kingston, D. G. I.; Sarin, P. S.; Todd, L.; Williams, D. H. J.
Chem. Soc. C 1966, 1856.
(4) For biological properties of this class of antibiotics, see: (a) Sachiko,
G.; Miyazaki, S.; Kaneko, Y. J. Antimicrob. Chemother. 1992, 30 (Suppl.
A), 25. (b) Brumfitt, W.; Hamilton-Miller, J. M. T.; Shah, S. J. Antimicrob.
Chemother. 1992, 30 (Suppl. A), 29. (c) Corsi, M.; Dal Foeno, G.; Oliosi,
B.; Pietra, C.; Van Amsterdam, F. T.; Trist, D. G. Ann. N.Y. Acad. Sci.
1994, 713, 353. (d) Lam, Y. K. T.; Dai, P.; Zink, D. L.; Smith, A. J.; Lee,
N. W.; Freeman, S.; Salvatore, M. J. J. Antibiot. 1993, 46, 623.
(5) For the total synthesis of virginiamycin type B systems, see: (a)
Kessler, H.; Kuhn, M.; Loschner, T. Liebigs Ann. Chem. 1986, 1. (b)
Anteunis, M. J. O.; Van der, A. C.; Vanfleteren, L.; Borremans, F. Bull.
Soc. Chim. Belg. 1988, 97, 135.
With the single stereogenic center present in 6 established in
compound 16, we submitted the lactonic portion of the latter to
(6) Synthetic studies toward virginiamycin type A systems have been
described: (a) Meyers, A. I.; Lawson, J. P.; Amos, R. A.; Walker, D. G.;
Spohn, R. F. Pure Appl. Chem. 1982, 54, 2537. (b) Wood, R. D.; Ganem,
B. Tetrahedron Lett. 1983, 24, 4391. (c) Fujita, E. Heterocycles 1984, 21,
41. (d) Meyers, A. I.; Spohn, R. F.; Linderman, R. J. J. Org. Chem. 1985,
50, 3633. (e) Schlessinger, R. H.; Iwanowicz, E. J.; Springer, J. P. J. Org.
Chem. 1986, 51, 3070. (f) Liu, L.; Tanke, R. S.; Miller, M. J. J. Org. Chem.
1986, 51, 5332. (g) Adje, N.; Breulles, P.; Uguen, D. Tetrahedron Lett.
1992, 33, 2151. (h) Bergahl, M.; Hett, R.; Friebe, T. L.; Gangloff, A. R.;
Iqbal, J.; Wu, Y.; Helquist, P. Tetrahedron Lett. 1993, 34, 7371.
(7) (a) Rollmann, B.; Rondelet, J. J. Pharm. Belg. 1973, 28, 425. (b)
Rollmann, B.; Rondelet, J. Pharm. Acta. HelV. 1972, 47, 698.
(8) We warmly congratulate Professor A. I. Meyers and co-workers on
the synthesis of madumycin.
(9) A detailed description of this aldol lactonization reaction will be
published in the near future.
(10) The absolute stereochemistry of 9 was determined by single-crystal
X-ray analysis. For references on other vinylogous urethane enolates to
form vinylogous urethane lactones as well as on the chemistry of these
lactones, see: (a) Schlessinger, R. H.; Poss, M. A,; Richardson S. J. Am.
Chem. Soc. 1986, 108, 3112. (b) Schlessinger, R. H.; Mjalli, A. M. M.;
Adams, A. D.; Springer, J. P. and Hoogsteen, K. J. Org. Chem. 1992, 57,
2992 and references cited therein.
(11) Lindgren, B. O.; Nilsson, T. Acta. Chem. Scand. 1973, 27, 888.
(12) The stereoselectivity of this reaction was determined by HPLC
analysis. For other examples of reactions of this lactone enolate, see ref
10b.
0002-7863/96/1518-3301$12.00/0 © 1996 American Chemical Society

3302 J. Am. Chem. Soc., Vol. 118, No. 13, 1996
Communications to the Editor
Scheme 3a
Scheme 4a
a Reagents and conditions: (a) t-BuLi, THF, isobutyl bromoacetate,
-78-0 °C, 93%. (b) LiBH4, MeOH, THF, 0 °C, 91%. (c) TBSCl,
imidazole, CH2Cl2, 0 °C, 88%. (d) Li, NH3, t-BuOH, THF, 86%. (e)
m-CPBA, 0 °C, pyridine, 0 °C to rt, 75%. (f) TBDPSCl, imidazole,
CH2Cl2, 0 °C, 82%. (g) cyanomethyl diisopropylphosphonate, t-BuOK,
THF, -78 °C, 87%. (h) AlH3, THF, 0 °C, 78%.
Birch reduction which afforded (86%) the amino lactol 17.
Oxidative elimination of the amine residue from 17 gave (75%)
the R,â-unsaturated aldehyde allylic alcohol 18.
a Reagents and conditions: (a) 2-chloro-1-methylpyridinium iodide,
n-Bu3N, CH2Cl2, rt, 89%. (b) 70% HF, pyridine, THF, 0 °C, 82%. (c)
Dess-Martin periodinane, CH2Cl2, rt, 87%. (d) 2.2 equiv of methyl
2-bromomethyl-5-oxazolecarboxylate, 2.4 equiv of Zn dust, 1 equiv
of Et2AlCl, rt to 35 °C, 67%. (e) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C,
83%. (f) 40 equiv of Zn dust, aq NH4OAc, THF, 92%. (g) LiOH, THF/
H2O, 9/1, 2-chloro-1-methylpyridinium iodide, n-Bu3N, CH2Cl2, 0.001
N, rt two steps in 52%. (h) THF, AcOH, H2O, (10/4/1). Dess-Martin
periodinane, CH2Cl2, rt, two steps in 61%. (i) 10 equiv of HF‚pyridine
(1/2), CH2Cl2, rt, 78%.
The choice of protecting group for the secondary allylic
alcohol present in 18 was critical to this synthesis. It was our
plan to complete the synthesis of 1 by removal of this protecting
group. Thus, this group had to withstand the gauntlet of
reactions necessary to prepare the penultimate synthetic inter-
mediate and yet exhibit sufficient lability to allow its removal
under conditions compatible with the limited stability of the
natural product.
After tedious experimentation, we settled on the TBDPS
group and accordingly prepared (82%) compound 19 from
alcohol 18. Horner-Emmons vinylogation of 19 gave (87%)
the (E)-nitrile 20, which on reduction with AlH3 afforded (78%)
the allylic amine 21.13
Acid 13 and amine 21 were then combined using Mukaiyama
coupling conditions to afford (89%) the corresponding amide
2214 (Scheme 4). This amide was then converted (two steps)
into its corresponding aldehyde 23 by removal of the TBS
protecting group on the primary alcohol (70% HF‚pyridine,
82%) followed by oxidation with Dess-Martin periodinane
(87%).15 Compound 23 suffered (67%) Reformatsky addition
of 716 onto the aldehyde residue in the presence of Zn dust and
Et2AlCl to give a diastereomeric mixture of secondary alcohols
which were immediately silylated (83%) to afford 24.17
The stage was now set for establishing the 23-membered ring
of 1, utilizing the following sequence of reactions. Zinc-
mediated removal of the N-((2,2,2-trichloroethoxy)carbonyl)
group from the proline residue, selective hydrolysis with LiOH
of the methyl ester carried by the oxazole ring, and, finally,
Mukaiyama amide coupling gave (three steps, 48% overall yield)
the desired macrocyclic product 25.18
At this juncture there remained the problems of re-forming
the TES-protected secondary alcohol of 25 into its corresponding
ketone 26 and removal of the TBDPS protecting group from
this species to unmask the allylic â-hydroxyketone ensemble
required by the natural product. Treatment with acetic acid
smoothly removed the TES residue, and Dess-Martin perio-
dinane oxidation provided (61% yield over two steps) the
penultimate synthetic intermediate 26.19 Lastly, reaction of 26
with HF‚pyridine (1/2) smoothly desilylated (78%) 26 to give
synthetic virginiamycin M2 (1), which proved identical in all
respects to an authentic sample of the natural product.
Acknowledgment. This work is dedicated to Professor Marshall
D. Gates on the occasion of his 80th birthday. Financial support of
this work by Grant CA-28544 (NIH), by Sherman Clarke fellowship
(to Y.-J. L.), and by Merck Sharp and Dohme fellowship (to Y.-J. L.)
is gratefully acknowledged. We thank Professor D. G. I. Kingston for
providing an authentic virginiamycin M2 sample, and Dr. J. M. Paris
(Rhone-Poulenc Rorer, France) for providing 2H Virginiamycin M2
spectra. We thank Thomas R. R. Pettus for invaluable help in preparing
this manuscript. Early contributors to this problem include Dr. Vinod
Patel, Dr. Derek Von Langen, Dr. Edwin Iwanowicz, and Dr. Peter
Lin.
Supporting Information Available: Experimental procedures for
1, 9-13, and 15-26; 1H COSY spectra of natural and synthetic 1 (13
pages). This material is contained in many libraries on microfiche,
immediately follows this article in the microfilm version of the journal,
can be ordered from the ACS, and can be downloaded from the Internet;
see any current masthead page for ordering information and Internet
access instructions.
(13) Yoon, N. M.; Brown H. C. J. Am. Chem. Soc. 1968, 90, 2927.
(14) Mukaiyama, T.; Bald, E.; Saigo, K. Chem Lett. 1975, 1163.
(15) Martin, J. C.; Dess, D. B. J. Org. Chem. 1983, 48, 4156.
(16) Compound 7 was prepared starting with tert-butyl 2-bromometh-
yloxazole-4-carboxylate (see ref 6c), followed by TFA deprotection of the
ester and esterification with diazomethane.
(17) Tsuji, J.; Mandai, Tadakatsu. Tetrahedron Lett. 1978, 21, 1817.
(18) This macrocyclization sequence occurs with remarkable alacrity
because compound 13 has proven to be an excellent â-turn mimic.
JA954311Z
(19) Olah, G. A.; Welch, J. T.; Vanker, Y. D.; Nojima, M.; Kerekes, I.;
Olah, J. A. J. Org. Chem. 1979, 44, 3872.