Total synthesis of (-)-okilactomycin

Article abstract of DOI:10.1021/ja077569l

A highly convergent synthesis of (-)-okilactomycin is described. Key reactions of this synthesis include a strategy-level diastereoselective oxy-Cope rearrangement/oxidation sequence, a Petasis-Ferrier union/rearrangement tactic, and an efficient RCM reac

Full text of DOI:10.1021/ja077569l

Published on Web 11/13/2007
Total Synthesis of (-)-Okilactomycin
Amos B. Smith, III,* Kallol Basu, and Todd Bosanac
Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
Received October 1, 2007; E-mail: smithab@sas.upenn.edu
In 1987, Imai and co-workers reported the isolation and structure
of (+)-okilactomycin (1, Scheme 1), a novel polyketide antitumor
antibiotic isolated from a bioactive filtrate of Streptomyces griseofla-
Vus. The structure, comprising a highly functionalized cyclohexene
ring complete with a spirocenter and a 2,6-cis-tetrahydropyranone
moiety, appended in a 13-membered ring,1 was initially elucidated
via a combination of NMR experiments. The connectivity and
relative stereochemistry were subsequently confirmed by X-ray
analysis; however, the absolute stereochemistry remained undefined.
Importantly, (+)-okilactomycin exhibits significant in vitro cyto-
toxicity against the human cell lines P388 and lymphoid leukemia
L1210 (IC50 ) 0.09 and 0.037 µg/mL respectively). While this
antitumor antibiotic has attracted some interest in the synthetic
community,2 a total synthesis has not, as yet, been achieved. Herein,
we disclose the first total synthesis of (-)-1, the antipode of the
natural product.
the structure and relative stereochemistry of (+)-5 were verified
by X-ray analysis.
Scheme 2
Scheme 1
Construction of acetal 6 (Scheme 3) began with a diastereose-
lective Rawal Diels-Alder reaction9 between diene (+)-13 and
methyl crotonate, followed by reduction to provide carbinol (+)-
14. Protection of the primary alcohol as the benzyl ether and, in
turn, hydrolytic removal of the auxiliary mediated by HF furnished
enone (+)-15, which upon 1,4-reduction and capture of the resulting
enolate with PhNTf2 yielded (-)-16.10 A Pd-catalyzed carbonyla-
tion,11 followed by diastereoselective allylation,12 next led to
secondary alcohol (+)-17 as the major diastereomer (dr 15:1),
thereby setting the stage for a pivotal anion accelerated oxy-Cope
rearrangement13 to introduce the requisite R-allyl substituent at C(1).
Gratifyingly, this reaction proceeded with excellent stereocontrol,
presumably via a chair-like transition state to furnish an enolate
which was methylated (Me2SO4) to provide enol ether 18 as a
mixture of E/Z isomers (2:1). Upon exposure to m-CPBA in
methanol, a Rubottom-like oxidation14 led to R-hydroxylation from
the more accessible axial face followed by generation of the
corresponding hydroxy dimethyl acetal, which was subsequently
converted to 2-napthylmethyl ether15 (+)-6a, a single acetal with
complete orthogonal protection (vide infra).
Turning to the Petasis-Ferrier union/rearrangement tactic to
construct the tetrahydropyranone, we quickly discovered, initially
with 6b,16 that the terminal olefin preferentially undergoes an
intramolecular Prins cyclization17 (cf. 19 and 20) with the acetal
during attempted TMSOTf-promoted condensation with the bis-
silylated derivative of hydroxyl acid (+)-5, the first or union step
of the Petasis-Ferrier sequence (Scheme 3). To combat the Prins
process, we masked the olefin as the bromo derivative, (+)-21,
prepared by addition of the Schwartz reagent to (+)-6a followed
by NBS.18 Pleasingly, the Petasis-Ferrier tactic proceeded to furnish
From the retrosynthetic perspective, we envisioned 1 to be
constructed via oxidative elimination of a bis-selenide derived from
2 (Scheme 1), which in turn would arise from 3, exploiting ring
closing metathesis (RCM),3 followed by oxidation state adjustment.
Lactone 3 would in turn be generated from an orthogonally
protected tetrahydropyranone 4, the latter constructed from â-hy-
droxy acid 5 and dimethyl acetal 6, exploiting the powerful Petasis-
Ferrier union/rearrangement4 tactic recently developed in our
laboratory (vide infra).5
Synthesis of 5 (Scheme 2) began via diastereoselective alkylation
of the Myers pseudoephedrine-derived auxiliary 76 with known
iodide (+)-87 to yield amide (-)-9 as a single diastereomer.
Reduction6 followed by oxidation provided an aldehyde, which upon
methylenation led to alkene (+)-10. Removal of the TBDPS group
and oxidation then furnished aldehyde (+)-11, which upon a
diastereoselective Evans aldol reaction8 with oxazolidinone 12,
followed by hydrolytic removal of the auxiliary, afforded â-hydroxy
acid (+)-5. The overall yield for the eight-step sequence was 63%;
9
14872
J. AM. CHEM. SOC. 2007, 129, 14872-14874
10.1021/ja077569l CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
(+)-23, albeit in modest yield (28-32%) over the three steps. Not
withstanding the modest yield, this sequence constitutes the first
example of a Petasis-Ferrier union involving an acetal, possessing
a sterically demanding R-quaternary center. The requisite terminal
olefin could then be regenerated via conversion to selenide (+)-
24, followed by oxidative elimination. Although the bromide proved
to be a viable Petasis-Ferrier partner, we subsequently discovered
that selenide (+)-22, prepared by displacement of bromide (+)-
21,19 was the preferred Petasis-Ferrier substrate, given that the
bromide undergoes competitive elimination during the Petasis
olefination, resulting in the accumulation of several byproducts.
derived cis-alkene (J ) 10 Hz) produced macrocycle (-)-29 in
80-85% yield for the two steps. To achieve optimal yields,
destruction of the RCM catalyst by exposure of the reaction mixture
to “air” prior to concentration proved critical to avoid competitive
polymerization. Oxidation (TEMPO) to the corresponding acid,
followed by esterification, then furnished (-)-2, the requisite
precursor for bis-selenation and oxidative elimination26 to complete
construction of okilactomycin (1).
Scheme 4
Scheme 3
Unexpectedly, however, all attempts to produce the bis-selenide
led only to monoselenide (-)-30 (Scheme 5). Resubjection of the
monoselenide to a wide variety of selenation conditions resulted
only in the recovery of starting material and/or complete decom-
position. Surprisingly, during these efforts, epimerization at C(16)
did not occur, suggesting our inability to access the enolate at C(16),
presumably due to steric hindrance arising from the macrocycle.
Oxidative elimination of (-)-30 did provide exclusively dihydrook-
ilactomycin methyl ester (-)-31 in 63% yield.
From the perspective of material advancement, the Petasis-
Ferrier tactic employing (+)-22 proved quite effective; union with
(+)-5 readily furnished the corresponding dioxanone (Scheme 3),
which upon Petasis-Tebbe methylenation20 and subsequent rear-
rangement of the somewhat unstable enol-acetal furnished (+)-24
as a single diastereomer in 42-46% for the three steps.
Scheme 5
Continuing with the synthesis, oxidative elimination21 of the
selenide (Scheme 4), followed by removal of the orthogonal
2-napthylmethyl group employing DDQ,22 led to carbinol (+)-25,
the requisite intermediate envisioned for construction of lactone 3.
To this end, biscarbonate (-)-26 was subjected to chemoselective
methanolysis to form an intermediate sodium enolate, derived from
the enol carbonate, which in turn undergoes cyclization with the
tertiary carbonate to furnish lactone (-)-27 as a single diastere-
omer.23 The required RCM precursor (-)-3 was then generated by
installation of the C(11) methyl group (MeI/K2CO3).24
Undaunted, the decision was made to undertake an alternate
approach to install the C(16)-C(17) olefin. Toward this end, alcohol
(-)-29 was converted to the exocyclic alkene (-)-33 in three steps
(Scheme 6). X-ray analysis of iodide (-)-32 established the
structure, thereby confirming the connectivity and stereochemistry.
Pleasingly, the RCM reaction, employing the Hoveyda-Grubbs
second generation catalyst25 followed by hydrogenation of the
9
J. AM. CHEM. SOC. VOL. 129, NO. 48, 2007 14873

C O M M U N I C A T I O N S
new compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
We later established that (-)-29 could be converted directly to (-)-
33 in one step via the Grieco-Nishizawa protocol.27 Allylic
oxidation28 of (-)-33 next led to a mixture (2.5:1) of the desired
secondary allyl alcohol (62%, borsm), along with the regioisomeric
References
29
tertiary allylic alcohol. Rearrangement of the former with SOCl2
(1) (a) Imai, H.; Suzuki, K.; Morioka, M.; Numasaki, Y.; Kadota, S.; Nagai,
K.; Sato, T.; Iwanami, M.; Saito, T. J. Antibiot. 1987, 40, 1475. (b) Imai,
H.; Kaniwa, H.; Tokunaga, T.; Fujita, S.; Furuya, T.; Matsumoto, H.;
Shimizu, M. J. Antibiot. 1987, 40, 1483. (c) For a related structure,
chrolactomycin, see: Nakai, R.; Kakita, S.; Asai, A.; Chiba, S.; Akinaga,
S.; Mizukami, T.; Yamashita, Y. J. Antibiot. 2001, 54, 836.
(2) (a) Takeda, K.; Shimotani, A.; Yoshii, E. Heterocycles 1992, 34, 2259.
(b) Paquette, L. A.; Boulet, S. L. Synthesis 2002, 888. (c) Paquette, L.
A.; Boulet, S. L. Synthesis 2002, 895.
(3) For recent reviews on the utility of the RCM for macrocycle construction,
see: (a) Gradillas, A.; Pe´rez-Castells, J. Angew. Chem., Int. Ed. 2006,
45, 6086. (b) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199.
(4) (a) Petasis, N. A.; Lu, S. P. Tetrahedron Lett. 1996, 37, 141. (b) Ferrier,
R. J.; Middleton, S. Chem. ReV. 1993, 93, 2779. (c) For an extension of
this methodology to the conversion of cyclopropyl diols to oxepanes,
see: O’Neil, K. E.; Kingree, S. V.; Minbiole, K. P. C. Org. Lett. 2005, 7,
515.
furnished allylic chloride (-)-34, securing the requisite trisubstituted
C(16)-C(17) olefin required for okilactomycin (1). Installation of
a phenyl selenide at C(9), followed by Ganem oxidation,30 provided
aldehyde (-)-35, which upon selenoxide elimination and Pinnick
oxidation31 completed construction of (-)-okilactomycin (1),1
spectroscopically identical in all respects (1H, 13C, HRMS) to an
authentic sample obtained from the natural source,1a with exception
of the chiroptic properties {[R]20D ) -37 (c ) 0.03, MeOH); lit.1a
[R]20 ) +34 (c ) 1, MeOH)}.
D
Scheme 6
(5) (a) Smith, A. B., III; Verhoest, P. R.; Minibiole, K. P.; Lim, J. J. Org.
Lett. 1999, 1, 909. (b) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.;
Beauchamp, T. J. Org. Lett. 1999, 1, 913. (c) Smith, A. B., III; Minbiole,
K. P.; Verhoest, P. R.; Schelhass, M. J. Am. Chem. Soc. 2001, 123, 10942.
(d) Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc.
2002, 124, 11102. (e) Smith, A. B., III; Sfouggatakis, C.; Gotchev, D.
B.; Shirakami, S.; Bauer, D.; Zhu, W.; Doughty, V. A. Org. Lett. 2004,
6, 3637. (f) Smith, A. B., III; Mesaros, E. F.; Meyer, E. A. J. Am. Chem.
Soc. 2005, 127, 6948. (g) Smith, A. B., III; Simov, V. Org. Lett. 2006, 8,
3315.
(6) Myers, A. G.; Yang, B. H.; Chen, H.; Mckinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(7) Yao, G.; Steliou, K. Org. Lett. 2002, 4, 485.
(8) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.
(9) (a) Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1997, 119, 7165. (b)
Kozmin, S. A.; Rawal, V. H. J. Org. Chem. 1997, 62, 5252. (c) Kozmin,
S. A.; Rawal, V. H. J. Am. Chem. Soc. 1999, 121, 9562. (d) For an early
racemic version of this Diels-Alder tactic, see: Smith, A. B., III; Wexler,
B. A.; Tu, C.-Y.; Konopelski, J. P. J. Am. Chem. Soc. 1985, 107, 1308.
(10) Crisp, G. T.; Scott, W. J. Synthesis 1985, 335.
(11) (a) Baillargeon, V. P.; Stille, J. K. J. Am. Chem. Soc. 1983, 105, 7175.
(b) Baillargeon, V. P.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 452.
(12) Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am. Chem. Soc.
1989, 111, 5493.
(13) (a) Evans, D. A.; Golob, A. M. J. Am. Chem. Soc. 1975, 97, 4765. For a
review on anionic oxy-Cope, see: Paquette, L. A. Tetrahedron 1997, 53,
13971.
(14) (a) Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron Lett.
1974, 15, 4319. (b) Hassner, A.; Reuss, R. H.; Pinnick, H. W. J. Org.
Chem. 1975, 40, 3427.
(15) Gaunt, M. J.; Yu, J.; Spencer, J. B. J. Org. Chem. 1998, 63, 4172.
(16) Benzyl ether 6b was prepared by treatment of intermediate tertiary alcohol
with NaH and BnBr in 94% yield.
(17) Wo¨lfling, J.; Frank, EÄ .; Mernya´k, E.; Bunko´czi, G.; Seijo, J. A. C.;
Schneider, G. Tetrahedron 2002, 58, 6851.
(18) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115.
(19) Reich, H. J.; Clark, M. C.; Willis, W. W., Jr. J. Org. Chem. 1982, 47,
1618.
(20) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
(21) Davis, F. A.; Stringer, O. D.; Billmers, J. M. Tetrahedron Lett. 1983, 24,
1213. Other oxidants (e.g., H2O2, m-CPBA, NaIO4) gave poor yields.
(22) Xia, J.; Abbas, S. A.; Locke, R. D.; Piskorz, C. F.; Alderfer, J. L.; Matta,
K. L. Tetrahedron Lett. 2000, 41, 169.
(23) Cf. Goldsmith, D. J.; John, T. K.; Van Middlesworth, F. Synth. Commun.
1980, 10, 551.
(24) Barco, A.; Benetti, S.; Pollini, G. P. Synthesis 1973, 316.
(25) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 8168.
In summary, the first total synthesis of (-)-okilactomycin (1)
has been achieved. Key features of this synthetic venture include
a highly diastereoselective oxy-Cope rearrangement/oxidation
sequence to secure the C(1) and C(13) stereocenters, a Petasis-
Ferrier union/rearrangement to construct the highly congested 2,6-
cis-tetrahydropyranone ring, a novel tactic to elaborate the fused
bicyclic lactone, and an efficient RCM reaction to generate the 13-
membered macrocyclic ring. The longest linear sequence proceeded
in 29 steps. Importantly, this synthetic venture not only provides a
viable route to this interesting antitumor antibiotic, as well as to
potential analogues thereof, but also establishes the absolute
stereochemistry of natural (+)-okilactomycin (1).
(26) (a) Reich, H. J.; Wollowitz, S. In Organic Reactions; Paquette, L. A.,
Ed.; John Wiley & Sons: New York, 1993; p 1. (b) Clive, D. L. J.
Tetrahedron 1978, 34, 1049. (c) Curtis, N. R.; Holmes, A. B.; Looney,
M. G. Tetrahedron 1991, 47, 7171. (d) Hirsenkorn, R.; Schmidt, R. R.
Leibigs Ann. Chem. 1990, 883.
Acknowledgment. Support was provided by the National
Institutes of Health (National Cancer Institute) through Grant CA-
19033, and by a postdoctoral fellowship (CA-101532) to T.B. We
also thank Drs. G. Furst, R. K. Kohli, and P. Carroll for assistance
in obtaining NMR spectra, high-resolution mass spectra, and X-ray
crystallographic data, respectively. We also appreciate the assistance
of Dr. Jim Hall from AstraZeneca to obtain NMR spectra. Finally,
we thank the Yamanouchi Pharmaceutical Co., Ltd. (now Astellas
Pharmaceutical Co.) for an authentic sample of (+)-okilactomycin.
(27) Grieco, P. A.; Nishizawa, M. J. Org. Chem. 1977, 42, 1717.
(28) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526.
(29) For representative examples, see: (a) Young, W. G.; Caserio, F.; Brandon,
D. Science 1953, 117, 473. (b) Young, W. G.; Caserio, F.; Dennis, G. E.;
DeWolfe, R. H. J. Am. Chem. Soc. 1955, 77, 4182. (c) Ireland, R. E.;
Wrigley, T. I.; Young, W. G. J. Am. Chem. Soc. 1958, 80, 4604. (d)
Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe, A.
L.; Ueno, Y. J. Am. Chem. Soc. 1997, 119, 12976.
(30) (a) Godfrey, A. G.; Ganem, B. Tetrahedron Lett. 1990, 31, 4825. (b)
Griffith, W. P.; Jolliffe, J. M.; Ley, S. V.; Springhorn, K. F.; Tiffin, P. D.
Synth. Commun. 1992, 22, 1967. (b) Paquette, W. D.; Taylor, R. E. Org.
Lett. 2004, 6, 103.
(31) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37,
2091.
Supporting Information Available: Experimental procedures and
spectroscopic and analytical data for key transformations and related
JA077569L
9
14874 J. AM. CHEM. SOC. VOL. 129, NO. 48, 2007