A β-lactone-based strategy applied to the total synthesis of (8S,21S,22S,23R)- and (8R,21S,22S,23R)-okinonellin B

Full text of DOI:10.1021/jo9722360

2058
J . Org. Chem. 1998, 63, 2058-2059
A â-La cton e-Ba sed Str a tegy Ap p lied to th e
Tota l Syn th esis of (8S,21S,22S,23R)- a n d
(8R,21S,22S,23R)-Ok in on ellin B
William D. Schmitz, N. Brian Messerschmidt, and
Daniel Romo*
Department of Chemistry, Texas A&M University,
P.O. Box 300012, College Station, Texas 77843-3012
Received December 11, 1997
Although â-lactones undergo a number of unique and
stereospecific reactions,1 they have had limited use as
intermediates in the context of natural product total syn-
thesis.2 This may in part be due to the lack of direct and
general methods for their synthesis in optically pure form.3
As part of a program aimed at the utilization of â-lactones
as intermediates in natural product synthesis, we now report
the application of a â-lactone-based strategy to the first total
F igu r e 1. Retrosynthesis of okinonellin B showing the two-step
â-lactone-based strategy for the synthesis of butyrolactone 4 from
aldehyde 6.
readily available iodides (S)- and (R)-89 and 3-(bromometh-
yl)furan (10)10 to give the dialkylated dithianes 11 (Scheme
1). A two-stage reduction involving Raney nickel and
dissolving metal reduction with calcium cleaved the dithiane
and benzyl ether and provided the alcohols 12. Swern
oxidation11 followed by Takai reaction12 provided the re-
quired vinyl iodides 3 for Negishi coupling to the butyro-
lactone 4.
syntheses of (8S,21S,22S,23R)-okinonellin
B (1) and
(8R,21S,22S,23R)-okinonellin B (2). Isolated by Fusetani
and co-workers,4 the cytotoxin okinonellin B is a member of
a family of marine furanosesterterpenes that display a
variety of biological activities, including antibacterial, cy-
totoxic, and antispasmodic activity.5 The reduced butenolide
of okinonellin B makes it unique from other sesterterpenoids
in this class of marine natural products. Fusetani described
the relative stereochemistry of the butyrolactone, but the
relative stereochemistry between the butyrolactone and the
C8 stereocenter in addition to the absolute stereochemistry
were not determined. The present synthesis demonstrates
the utility of â-lactones as intermediates in the synthesis of
natural products and, specifically, in the concise synthesis
of all-syn-trisubstituted butyrolactones.
It was envisioned that a tandem Mukaiyama aldol-
lactonization (TMAL) reaction (6 f 5)6 and a tandem
transacylation-debenzylation of a benzyloxy-substituted
â-lactone (5 f 4)7 would deliver the butyrolactone 4 in a
highly stereocontrolled manner (Figure 1). A Negishi cou-
pling of the (R)- and (S)-vinyl iodide 3 and the butyrolactone
fragment 4 would then complete the synthesis in a concise
fashion.8 Both enantiomers of vinyl iodide 3 would be
synthesized and coupled in order to assign the relative
configuration at C8 as well as the absolute configuration of
the natural product.
The synthesis of the butyrolactone 4 began by conversion
of the known lactone 1313 to the Weinreb amide followed by
silylation to give amide 14 (Scheme 2). A carefully controlled
addition14 of the Grignard reagent derived from bromide 1515
to amide 14 gave the desired ketone 16 in 87% yield. Tebbe
methylenation,16 simultaneous desilylation of the silyl ether
and silylacetylene, and Swern oxidation delivered the alde-
hyde 6 required for the TMAL reaction. In the event,
treatment of aldehyde 6 with ZnCl2 and the ketene acetal
19 at ambient temperature for 14 h gave the â-lactone 5 as
a single diastereomer17 in 73% yield18 and with <4%
(9) The enantiomeric iodides 8 are available in three steps from (S)- and
(R)-methyl 3-hydroxy-2-methylpropanoate, see: White, J . D.; Kawasaki, M.
J . Org. Chem. 1992, 57, 5292-5300.
(10) The unstable furanyl bromide 10 was prepared immediately prior
to use from 3-furanmethanol using PPh3/Br2: Bernasconi, S.; Colombo, M.;
J ommi, G.; Sisti, M. Gass. Chem. Ital. 1986, 116, 69-71.
(11) Mancuso, A. J .; Swern, D. Tetrahedron Lett. 1981, 35, 2473-2476.
(12) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986, 108, 7408-
7410.
The synthesis of the enantiomeric vinyl iodides 3 began
with two sequential alkylations of 1,3-dithiane using the
(13) Lactone 13 is available in four steps from (-)-malic acid; see:
Bernardi, A.; Cardani, S.; Scolastico, C.; Villa, R. Tetrahedron 1990, 46,
1987-1998.
* To whom correspondence should be addressed: Tel: 409-845-9571;
Fax: 409-862-7963; E-mail: romo@chemvx.tamu.edu.
(1) For a recent review, see: Pommier, A.; Pons, J .-M. Synthesis 1993,
441-449.
(2) We are aware of only a few examples of the use of â-lactones as
intermediates in asymmetric, natural product total synthesis: (a) Bourgean-
ic Acid: White, J . D.; J ohnson, A. T. J . Org. Chem. 1994, 59, 3347-3358.
(b) Lactacystin: Corey, E. J .; Reichard, G. A.; Kania, R. Tetrahedron Lett.
1993, 34, 6977-6980.
(3) For some recent asymmetric methods for â-lactone synthesis, see:
Yang, H. W.; Romo, D. J . Org. Chem. 1998, 63, 1344-1347 and references
therein.
(4) Kato, Y.; Fusetani, N.; Matsugaga, S.; Hashimoto, K. Experientia
1986, 42, 1299.
(5) (a) Crews, P.; Naylor, S. Fortschr. Chem. Org. Naturst. 1985, 48, 203-
268. (b) Rochfort, S. J .; Atkin, D.; Hobbs, L.; Capon, R. J . J . Nat. Prod.
1996, 59, 1024-1028.
(6) (a) Hirai, K.; Homma, H.; Mikoshiba, I. Heterocycles 1994, 38, 281-
282. (b) Yang, H. W.; Romo, D. J . Org. Chem. 1997, 38, 4-5. (c) Yang, H.
W.; Zhao, C.; Romo, D. Tetrahedron 1997, 53, 16471-16488. (d) Reference
3.
(14) Best results were obtained after titration of the generated Grignard
reagent; see: Bergbreiter, D. E.; Pendergrass, E. J . Org. Chem. 1981, 46,
219-220.
(15) Bromide 15 was obtained by a four-step sequence from commercially
available 4-pentyn-1-ol: (a) DHP, TsOH; (b) n-BuMgBr, thexyldimethylsilyl
chloride; (c) BF3‚OEt2, EtSH; (d) PPh3, Br2.
(16) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J . Am. Chem. Soc. 1978,
100, 3611-3613.
(17) No minor diastereomers could be detected in either CDCl3 or C6D6
(300 MHz 1H NMR).
(18) An interesting byproduct i was obtained (5-10%) in the TMAL
reaction. We are currently studying this presumed Zn(II) (or trace metal)-
mediated reaction. For possible related palladium- and ruthenium-mediated
processes, see: Trost, B. M., Tanoury, G. J . J . Am. Chem. Soc. 1988, 110,
1636-1638. Chatani, N.; Morimoto, T.; Muto, T.; Murai, S. J . Am. Chem.
Soc. 1994, 116, 6049-6050.
(7) (a) Zemribo, R.; Champ, M. S.; Romo, D. Synlett 1996, 278-280. (b)
Arrastia, I.; Lecea, B.; Cossio, F. P. Tetrahedron Lett. 1996, 37, 245-248.
(8) Negishi, E.; Okukado, N.; King, A. O.; Van Horn, D. E.; Speigel, B. I.
J . Am. Chem. Soc. 1978, 100, 2254-2256.
S0022-3263(97)02236-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/12/1998

Communications
J . Org. Chem., Vol. 63, No. 7, 1998 2059
Sch em e 1a
conditions developed by Wipf21 followed by addition of ZnCl2,
the Pd(0)/Ph3As catalyst system reported by Farina,22 and
vinyl iodides (S)-3 or (R)-3 gave (8S)-okinonellin B (1) and
(8R)-okinonellin B (2), respectively (Scheme 2). Significant
amounts (∼40%) of quenched vinylmetallic species derived
from 4 and methylated products derived from vinyl iodides
3 account in part for the low yields obtained in this
carboalumination/coupling sequence.23
Not unexpectedly, the diastereomers of okinonellin B (1
and 2) did not exhibit any differences by either 1H or 13C
NMR. A significant difference in the CD spectrum of the
two diastereomers was observed. However, neither a CD
spectrum of the natural product nor the natural product
itself was available for comparison.24 At this time, we can
only speculate based on the optical rotation data25 that
natural okinonellin B possesses the 8R,21R,22R,23S stere-
ochemistry that is enantiomeric to our synthetic
(8S,21S,22S,23R)-okinonellin B (1).
a
Key: (a) -45 f -20 °C, 57 h; (b) THF, -78 f -45 °C, 10 h, then
10, THF, 15 h; (c) EtOH, 40 °C, 3 h; (d) -33 °C, 1.5 h; (e) DMSO,
(COCl)2, CH2Cl2, -78 °C, Et3N, -78 f 0 °C, 25 min; (f) THF, 0 °C, 4
h.
In conclusion, the described total syntheses of
(8S,21S,22S,23R)- and (8R,21S,22S,23R)-okinonellin B dem-
onstrate the utility of â-lactones in natural product synthesis
and specifically their use for the synthesis of highly substi-
tuted and functionalized butyrolactones. A two-step proce-
dure efficiently and stereoselectively converted the chiral
aldehyde 6 to the all-syn-butyrolactone 4. The sequence
employed a tandem Mukaiyama aldol-lactonization and a
tandem debenzylation-transacylation reaction as key steps.
We are currently exploring further novel transformations
of â-lactones and their application to natural product
synthesis.
Sch em e 2a
Ack n ow led gm en t. Support of this work by the NSF
in the form of a CAREER award (CHE 9624532) and the
NIH (GM 52964-01) is gratefully acknowledged. We thank
Prof. Nubihiro Fusetani (University of Tokyo) for providing
spectral data of natural okinonellin B and Prof. Phil Crews
(UC Santa Cruz) for helpful discussions. We also thank Dr.
Lloyd Sumner and Dr. Barbara Wolf of the Texas A&M
Center for Characterization for mass spectral analyses
obtained on instruments acquired by generous funding
from the NSF (CHE-8705697) and the TAMU Board of
Regents Research Program.
a
Key: (a) C6H6, 0 °C, 1.5 h; (b) DMF, 24 °C, 2.5 h; (c) reflux then
Su p p or tin g In for m a tion Ava ila ble: Physical and spectral
listings, procedures, and 1H and 13C NMR spectra of selected
intermediates; chiral HPLC traces of â-lactone 5; CD spectra of 1
and 2 (29 pages).
added to 14, Et2O, -78 f 0 °C, 39 h; (d) -40 °C, 3 h; (e) THF, 0 f 24
°C, 3 h; (f) DMSO, (COCl)2, CH2Cl2, -78 °C, Et3N, -78 °C, 1 h; (g)
CH2Cl2, 25 °C, 14 h; (h) CH2Cl2, -78 °C, 15 min; (i) CH2Cl2, -23 °C,
2 h; (j) (1:4, Pd (8 mol %):ligand), NMP, 25 °C, 7.5 h.
J O9722360
epimerization.19 The stereochemical outcome is consistent
with a chelation-controlled initial aldol reaction as deter-
mined by conversion to the all-syn-butyrolactone 4.20 The
tandem transacylation-debenzylation of â-lactone 5 to the
all-syn-butyrolactone was effected using BCl3, which gave
improved results over the originally reported FeCl3 (29%).7a
Thus, in two steps aldehyde 6 is transformed into the highly
functionalized, all-syn-butyrolactone 4 in a highly stereo-
controlled fashion.
For the fragment coupling to provide okinonellin B, we
relied on the single-pot procedure of Negishi involving alkyne
carboalumination followed by transmetalation to Zn(II) and
a Pd(0)-mediated coupling to a vinyl halide.8 In the event,
carboalumination of alkyne 4 using the water-accelerated
(21) Wipf, P.; Lim, S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1068-1071.
(22) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585-9595.
(23) It was noted that complete consumption of the vinyl iodide 3 occurred
rapidly during the reaction, and a byproduct derived from this material
was the methylated olefin ii. As a result, substantial amounts of the olefin
iii were obtained on quenching the reaction. In a separate experiment,
the vinyl iodide iv could be obtained in 57% yield by iodinolysis. For a
lead reference to related reactions of vinyl triflates, see: Saulnier, M.;
Kadow, J .; Tun, M. M.; Langley, D.; Vyas, D. J . Am. Chem. Soc. 1989, 111,
8320-8321.
(24) An authentic sample of okinonellin B was no longer available as it
had degraded. In addition, recent re-extraction of the sponge did not afford
any detectable okinonellin B (private communication from N. Fusetani and
S. Matsunaga, University of Tokyo). We have also noted the instability of
okinonellin B even when frozen in benzene.
(19) The enantiomeric purity was determined by chiral HPLC (Chiralcel
OD) on comparison to the racemic â-lactone. See the Supporting Informa-
tion for details.
(20) Our current mechanistic understanding of the Zn(II)-mediated
TMAL reaction will be described in a separate report: Zhao, C.; Yang, H.
W.; Romo, D. Manuscript in preparation.
(25) Natural okinonellin B: [R]20D ) 17.9 (c 0.15, EtOH). (8S,21S,22S,23R)-
Okinonellin
B
(1): [R]24
) -7.6 (c 0.19, EtOH). (8R,21S,22S,23R)-
D
Okinonellin B (2): [R]24 ) -98.0 (c 0.15, EtOH).
D