Total synthesis of (-)-tirandamycin C

Article abstract of DOI:10.1021/ol203161u

Tirandamycin C is a newly isolated member of the tetramic acid family natural products. We described herein the first enantioselective synthesis of natural (-)-tirandamycin C, the postulated biosynthetic precursor of other members of this family. The high

Full text of DOI:10.1021/ol203161u

ORGANIC
LETTERS
2012
Vol. 14, No. 1
426–428
Total Synthesis of (À)-Tirandamycin C
Ming Chen and William R. Roush*
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458, United States
roush@scripps.edu
Received November 25, 2011
ABSTRACT
Tirandamycin C is a newly isolated member of the tetramic acid family natural products. We described herein the first enantioselective synthesis
of natural (À)-tirandamycin C, the postulated biosynthetic precursor of other members of this family. The highly stereoselective (>15:1)
mismatched double asymmetric γ-stannylcrotylboration reaction of aldehyde 8 with crotylborane reagent (R)-E-9 was utilized to access the key
anti,anti-stereotriad 18.
The naturally occurring tetramic acids are a structurally
diverse class of compounds that display a variety of bio-
logical activities, including anti-HIV-1, antimycotic, anti-
biotic, and antimicrobial activities.1 Tirandamycins A (3)
and B (4), two of the more well-known members of this
family, were isolated from Streptomyces species in the
1970s (Figure 1).2 Recently, two new tirandamycins, spe-
cifically tirandamycins C (1) and D (2), were isolated from
the marine Streptomyces sp. 307À9 (Figure 1).3 It was
postulated that tirandamycin C is the biosynthetic precur-
sor of other members of the family, which differ in the
oxidation state of the bicyclic ketal moiety.3 Recent studies
identified the biosynthetic gene cluster for this family of
natural products, including genes that encode candidate
tailoring enzymes for elaboration of the bicyclic ketal
system.4 Because the dienoyl tetramic acid side chains of
tirandamycins AÀD are identical, the structural variations
in the bicyclic unit are responsible for differences in their
biological activities and especially for the activity of these
compounds against vancomycin-resistant Enterococcus
faecalis.4,5
(1) Royles, B. J. L. Chem. Rev. 1995, 95, 1981.
(2) (a) Meyer, C. F. J. Antibiot. 1971, 24, 558. (b) Crum, G. F.;
Devries, W. H.; Eble, T. E. Arch. Microbiol. 1976, 109, 65.
(3) Carlson, J. C.; Li, S.; Burr, D. A.; Sherman, D. H. J. Nat. Prod.
2009, 72, 2076.
(4) (a) Carlson, J. C.; Fortman, J. L.; Anzai, Y.; Li, S.; Burr, D. A.;
Sherman, D. H. ChemBioChem 2010, 11, 564. (b) Carlson, J. C.; Li, S.;
Gunatilleke, S. S.; Anzai, Y.; Burr, D. A.; Podust, L. M.; Sherman, D. H.
Nat. Chem. 2011, 3, 628.
(5) (a) Temiakov, D.; Zenkin, N.; Vassylyeva, M. N.; Perederina, A.;
Tahirov, T. H.; Kashkina, E.; Savkina, M.; Zorov, S.; Nikiforov, V.;
Igarashi, N.; Matsugaki, N.; Wakatsuki, S.; Severinov, K.; Vassylyev,
D. G. Mol. Cell 2005, 19, 655. (b) Tuske, S.; Sarafianos, S. G.; Wang, X.;
Hudson, B.; Sineva, E.; Mukhopadhyay, J.; Birktoft, J. J.; Leroy, O.;
Ismail, S.; Clark, A. D.; Dharia, C.; Napoli, A.; Laptenko, O.; Lee, J.;
Borukhov, S.; Ebright, R. H.; Arnold, E. Cell 2005, 122, 541. (c) Vassylyev,
D. G.; Vassylyeva, M. N.; Zhang, J.; Palangat, M.; Artsimovitch, I.;
Landick, R. Nature 2007, 448, 163. (d) Miropolskaya, N.; Artsimovitch, I.;
Klimasauskas, S.; Nikiforov, V.; Kulbachinskiy, A. Proc. Natl. Acad. Sci.
U.S.A. 2009, 106, 18942. (e) Yu, Z; Vodanovic-Jankovic, S.; Ledeboer, N.;
Huang, S-X; Rajski, S. R.; Kron, M.; Shen, B. Org. Lett. 2011, 13, 2034. (f)
Mo, J.; Huang, H.; Ma, J.; Wang, Z.; Wang, B.; Zhang, S.; Zhang, C.; Ju, J.
Org. Lett. 2011, 13, 2212.
Figure 1. Tetramic acid containing natural products, tiranda-
mycins AÀD.
One synthetically challenging structural feature of the
tirandamycins is the anti,anti-dipropionate stereotriad unit
(6) (a) Hoffman, R. W. Angew. Chem., Int. Ed. Engl. 1987, 26, 489. (b)
Hoffmann, R. W.; Dahmann, G.; Andersen, M. W. Synthesis 1994, 629.
r
10.1021/ol203161u
Published on Web 12/07/2011
2011 American Chemical Society

(highlighted in yellow in 1). The highly stereoselective
synthesis of this structural motif remains a significant
challenge.6 Many methods involving asymmetric aldol or
crotylboration reactions of highly enantioenriched alde-
hyde substrates fail to provide synthetically useful selectiv-
ities for the desired anti,anti-stereotriads. Consequently,
multistep, indirect methods have been employed to access
this stereotriad unit.7,8
We recently disclosed the synthesis of the chiral crotyl-
borylating reagent (R)-E-9 via the enantioconvergent
enantioselective hydroboration of racemic 1-tributylstan-
nyl-1,2-butadiene (()-17.9 To demonstrate the potential of
this reagent in the synthesis of stereochemically complex
natural products and, equally, to gain further insight into
the structureÀactivity relationships of the tirandamycins,
we report herein the enantioselective synthesis of natural
(À)-tirandamycin C (1) by a route featuring the highly
stereoselective synthesis of the requisite anti,anti-stereotriad
7 via the mismatched double asymmetric γ-stannylcrotyl-
boration of aldehyde 8 and reagent (R)-E-9 (Scheme 1).10
gave ester 13 in 86% yield. Ring closing metathesis of ester
13 using Grubbs’ second generation catalyst 14 (10%
catalyst loading) at 60 °C in the presence of 10% tetra-
fluoro-1,4-benzoquinone (TFBQ)12 provided lactone 15 in
76% yield.13 It is worth noting that without the addition of
tetrafluoro-1,4-benzoquinone, significant amounts of a five-
membered ring lactone product were obtained. Deprotec-
tionof theprimary TBDPS etheroflactone 15using TBAF
(buffered with HOAc) gave alcohol 16 in near-quantitative
yield. Subsequent oxidation of alcohol 16 with DessÀ
Martin periodinane14 provided aldehyde 8 in 95% yield.
The mismatched double asymmetric crotylboration of
aldehyde 8 was initiated by the synthesis of crotylborane
(R)-E-9 via the enantioconvergent hydroboration of race-
micallenylstannane(()-17withdiisopinocampheylborane
[(lIpc)2BH] in diethyl ether, as previously described.9 An
Et2O solution of aldehyde 8 was added to reagent (R)-E-9
at À78 °C, and the solution was allowed to warm to
ambient temperature and was stirred for 24 h. Gratify-
ingly, the desired anti,anti-stereotriad18was obtainedwith
excellent stereoselectivity (>15:1). This is a highly signifi-
cant result, since the intrinsic diastereofacial selectivity
of 8, as determined by reactions with the achiral pinacol
(E)-crotylboronate, favors production of the 3,4-anti-4,
5-syn homoallylic alcohol by an 89:11 ratio (with the anti,
anti stereoisomer 7 as the minor reaction product; see Sup-
porting Information). In general, it is exceedingly difficult
to overcome this level of intrinsic aldehyde face selectivity
by using a chiral reagent.6 Subsequent protodestannylation
of vinylstannane 18 under acidic conditions (TsOH•H2O)15
gavelactone7in 72% yield (over two steps from aldehyde 8).
The stereochemistry of 7 was assigned as detailed in the
Supporting Information.
Scheme 1. Tirandamycin C, Retrosynthetic Analysis
Treatment of lactone 7 with MeLi (2 equiv)16 at À78 °C
provided the lactol intermediate 19, which was used
directly in the subsequent ketalization without purifica-
tion. Exposure of lactol 19to a catalytic amount of pPTS in
(8) For studies on the synthesis of the tirandamycin, illustrating
strategies for synthesis of the anti,anti-stereotriad: (a) Ireland, R. E.;
Wutz, P. G. M.; Ernst, B. J. Am. Chem. Soc. 1981, 103, 3205. (b) Ireland,
R. E.; Smith, M. G. J. Am. Chem. Soc. 1988, 110, 854. (c) Iwata, Y.;
Maekawara, N.; Tanino, K.; Miyashita, M. Angew. Chem., Int. Ed.
2005, 44, 1532. (d) Pronin, S. V.; Kozmin, S. A. J. Am. Chem. Soc. 2010,
132, 14395. (e) Pronin, S. V.; Martinez, A.; Kuznedelov, K.; Severinov,
K.; Shuman, H. A.; Kozmin, S. A. J. Am. Chem. Soc. 2011, 133, 12172.
(9) Chen., M.; Roush, W. R. J. Am. Chem. Soc. 2011, 133, 5744.
(10) For synthetic applications of reagent (R)-E-9, see: (a) Sun, H.;
Abbott, J. R.; Roush, W. R. Org. Lett. 2011, 13, 2734. (b) Yin, M.;
Roush, W. R. Tetrahedron 2011, 67, 10274.
(11) (a) Johns, B. A.; Grant, C. M.; Marshall, J. A. Org. Synth. 2002,
79, 59. (b) Sun, H.; Roush, W. R. Org. Synth. 2011, 88, 87.
(12) (a) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 17160. (b) Winbush, S. M.; Roush, W. R. Org.
Lett. 2010, 12, 4344.
We envisioned that tirandamycin C (1) could be as-
sembled from the bicyclic aldehyde 5 and the phosphonate
reagent 67c via HornerÀWadsworthÀEmmons olefination
(Scheme 1). Aldehyde 5 would be accessed by elaboration
of lactone 7, which in turn would be obtained from the
mismatched double asymmetric stannyl-crotylboration of
aldehyde 8 with reagent (R)-E-9.9
Homoallylic alcohol 11 was synthesized in three steps
according to known procedures, starting from the com-
mercially available ester 10 (Scheme 2).11 Acylation of
homoallylic alcohol 11 with methacryloyl chloride (12)
(13) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953. (b) Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010,
110, 1746.
(14) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(15) He, W.; Huang, J.; Sun, X.; Frontier, A. J. J. Am. Chem. Soc.
2008, 130, 300.
(16) Collum, D. B.; McDonald, J. H.; Still, W. C., III. J. Am. Chem.
Soc. 1980, 102, 2120.
(17) Stewart, I. C.; Douglas, C. J.; Grubbs, R. H. Org. Lett. 2008, 10,
441.
(7) For total syntheses of tirandamycins A and B: (a) Schlessinger,
R. H.; Bebernitz, G. R.; Lin, P.; Poss, A. J. J. Am. Chem. Soc. 1985, 107,
1777. (b) DeShong, P.; Ramesh, S.; Elango, V.; Perez, J. J. Am. Chem.
Soc. 1985, 107, 5219. (c) Boeckman, R. K.; Starrett, J. E.; Nickell,
D. G.; Sum, P. E. J. Am. Chem. Soc. 1986, 108, 5549. (d) Neukom, C.;
Richardson, D. P.; Myerson, J. H.; Bartlett, P. A. J. Am. Chem. Soc.
1986, 108, 5559. (e) Shimshock, S. J.; Waltermire, R. E.; DeShong, P.
J. Am. Chem. Soc. 1991, 113, 8791. (f) Shiratani, T.; Kimura, K.; Yoshihara,
K.; Hatakeyama, S.; Irie, H.; Miyashita, M. Chem. Commun. 1996, 21.
Org. Lett., Vol. 14, No. 1, 2012
427

Scheme 2. Total Synthesis of (À)-Tirandamycin C (1)
THF provided bicyclic ketal 20 in 75% yield from
alcohol 7. Cross metathesis of bicyclic ketal 20 with
methacrolein (21) using 10% GrubbsÀHoveyda cata-
lyst 2217 in refluxing CH2Cl2 gave aldehyde 5 with
excellent selectivity (>20:1). Although the conversion
of this cross metathesis reaction was moderate, recov-
ered spiroketal 20 can be recycled. In this way, alde-
hyde 5 was obtained in 61% yield over two reaction
cycles (93% based on recovered starting material).
Treatment of phosphonate 67c with KOt-Bu in THF
followed by addition of aldehyde 5 gave N-dimethox-
ybenzyl (DMB) protected tirandamycin C (23) in 74%
yield. Finally, deprotection of 23 by treatment with TFA7
provided synthetic (À)-tirandamycin C (1) in 31% yield
(64% based on recovered starting material). The spectro-
scopic data (1H NMR, 13C NMR, [R]D) of synthetic (À)-
tirandamycin C were in excellent agreement with the data
previously reported for the natural product.3
In summary, the enantioselective total synthesis of
natural (À)-tirandamycin C has been accomplished in 14
steps starting from ester 10. Most importantly, the mis-
matched double asymmetric γ-stannylcrotylboration of
aldehyde 8 with crotylborane reagent (R)-E-9 proceeded
with excellent selectivity (>15:1) to give the requisite anti,
anti-stereotriad 18. Application of this methodology to the
synthesis of other members of tirandamycin family will be
reported in due course.
Acknowledgment. Financial support provided by the
National Institutes of Health (GM038436) is gratefully
acknowledged.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org
428
Org. Lett., Vol. 14, No. 1, 2012