Biomimetic synthesis of fused polypyrans: Oxacyclization stereo- and regioselectivity is a function of the nucleophile

Article abstract of DOI:10.1021/ol034539o

(Matrix presented) The stereoselectivity of Lewis acid-induced endo-regioselective oxacyclizations of 1,4-diepoxides is dependent upon the nature of the terminating nucleophile. For instance, the tert-butyl carbonate-substituted diepoxide of 3,6-dimethylhepta-2,5-dien-1-ol provides a cis-fused bicyclic product, whereas the N,N-dimethylcarbamate derivative affords the trans-fused diastereomer. Stereospecific and regioselective conversion of the tertiary carbamate-terminated 1,4,7-triepoxide (I) to tricyclic all-trans-fused polypyran (II) is also demonstrated.

Full text of DOI:10.1021/ol034539o

ORGANIC
LETTERS
2003
Vol. 5, No. 12
2123-2126
Biomimetic Synthesis of Fused
Polypyrans: Oxacyclization Stereo- and
Regioselectivity Is a Function of the
Nucleophile†
Fernando Bravo, Frank E. McDonald,* Wade A. Neiwert,‡ Bao Do,‡ and
Kenneth I. Hardcastle‡
Department of Chemistry, Emory UniVersity, 1515 Pierce DriVe,
Atlanta, Georgia 30322
fmcdona@emory.edu
Received March 27, 2003
ABSTRACT
The stereoselectivity of Lewis acid-induced endo-regioselective oxacyclizations of 1,4-diepoxides is dependent upon the nature of the terminating
nucleophile. For instance, the tert-butyl carbonate-substituted diepoxide of 3,6-dimethylhepta-2,5-dien-1-ol provides a cis-fused bicyclic product,
whereas the N,N-dimethylcarbamate derivative affords the trans-fused diastereomer. Stereospecific and regioselective conversion of the tertiary
carbamate-terminated 1,4,7-triepoxide (I) to tricyclic all-trans-fused polypyran (II) is also demonstrated.
The red tide phenomenon has been intensively studied by
the scientific community due to its economic, environmental,
and health impacts. Red tide contamination occurs in warm
waters of the Atlantic Ocean and is associated with the
production of a family of fused polycyclic ether natural
products from the reddish blooms of marine dinoflagellates.1
A similar phenomenon, ciguatera, is observed in waters of
the Pacific Ocean. Representative fused polycyclic ether
toxins include the brevetoxins, ciguatoxin, gambierol,
yessotoxin, and maitotoxin.
of each oxacyclic ring,2-6 whereas the biosynthesis may
involve stereoselective polyepoxidation of an acyclic polyene
with formation of the fused polycyclic ether skeleton in a
single step via a cascade of endo-regioselective oxacycliza-
tions (Figure 1).7 We previously reported the stereoselective
(2) Total syntheses of hemibrevetoxin B: (a) Nicolaou, K. C.; Raja
Reddy, K.; Skokotas, G.; Sato, F.; Xiao, X.-Y.; Hwang, C.-K. J. Am. Chem.
Soc. 1993, 115, 3558. (b) Kadota, I.; Jung-Youl, P.; Koumura, N.; Pollaud,
G.; Matsukawa, Y.; Yamamoto, Y. Tetrahedron Lett. 1995, 36, 5777. (c)
Morimoto, M.; Matsukura, H.; Nakata, T. Tetrahedron Lett. 1996, 37, 6365.
(d) Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc. 1997, 119,
4557. (e) Kadota, I.; Yamamoto, Y. J. Org. Chem. 1998, 63, 6597. (f)
Rainier, J. D.; Allwein, S. P.; Cox, J. M. J. Org. Chem. 2001, 66, 1380.
(3) Total synthesis of brevetoxin B: (a) Nicolaou, K. C.; Theodorakis,
E. A.; Rutjes, F. P. J. T.; Tiebes, J.; Sato, M.; Untersteller, E.; Xiao,X.-Y.
J. Am. Chem. Soc. 1995, 117, 1171. (b) Nicolaou, K. C.; Rutjes, F. P. J. T.;
Theodorakis, E. A.; Tiebes, J.; Sato, M.; Untersteller, E. J. Am. Chem. Soc.
1995, 117, 1173. (c) Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E.; Nugiel,
D. A.; Abe, Y.; Reddy, K. B.; DeFrees, S. A.; Reddy, D. R.; Awartani, R.
A.; Conley, S. R.; Rutjes, F. P. J. T.; Theodorakis, E. A. J. Am. Chem. Soc.
1995, 117, 10227. (d) Nicolaou, K. C.; Theodorakis, E. A.; Rutjes, F. P. J.
T.; Sato, M.; Tiebes, J.; Xiao, X.-Y.; Hwang, C.-K.; Duggan, M. E.; Yang,
Z.; Couladouros, E. A.; Sato, F.; Shin, J.; He, H.-M.; Bleckman, T. J. Am.
Chem. Soc. 1995, 117, 10239. (e) Nicolaou, K. C.; Rutjes, F. P. J. T.;
Theodorakis, E. A.; Tiebes, J.; Sato, M.; Untersteller, E. J. Am. Chem. Soc.
1995, 117, 10252.
The challenges presented by the molecular complexity of
these fused polycyclic ether natural products have encouraged
numerous groups to explore their chemical synthesis. These
syntheses have generally been based on sequential formation
† Dedicated to Prof. Fredric M. Menger on the occasion of his 65th
birthday.
‡ Emory University X-ray Crystallography Laboratory.
(1) (a) Shimizu, Y. In Marine Natural Products; Scheuer; P. J., Ed.;
Academic Press: New York, 1978; Vol. 1, Chapter 1. (b) Tayler, D. L.;
Seliger; H. H. In Toxic Dinoflagellate Blooms; Elsevier/North-Holland, New
York, 1979. (c) Baden, D. G.; Bikkazi, G.; Decker, S. J.; Foldes, F. F.;
Leung, I. Toxicon 1984, 22, 75. (d) Scheuer, P. J. Tetrahedron 1994, 50, 3.
(e) Lewis, R. J. Toxicon 2001, 39, 97.
10.1021/ol034539o CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/21/2003

Scheme 1. Stereoselective Synthesis of Diepoxide- tert-Butyl
Carbonate (4)a
Figure 1. Biosynthesis hypothesis for fused polycyclic ether natural
products.
construction of trans-fused seven-membered cyclic ethers
(polyoxepanes) by Lewis acid activation of 1,5,...-poly-
epoxides derived from the acyclic isoprenoid polyenes
geraniol, farnesol, and geranylgeraniol.8 In the course of
extending this strategy to the synthesis of six-membered
cyclic ethers (polypyrans) from the corresponding 1,4- and
1,4,7-polyepoxides,9 we have uncovered novel aspects of the
mechanism of polyepoxide oxacyclizations with critical
implications for the stereo- and regioselectivity of the
oxacyclization process.
a Key: (a) D-(-)-DIPT, Ti(O-i-Pr)4, t-BuOOH, CH2Cl2, -18 °C
(100%); (b) 5, Oxone, dimethoxymethane/CH3CN/H2O, pH ) 11.4,
0 °C (70%; dr 85:15); (c) (Boc)2O, N3-Me-imidazole, toluene, 0
°C to rt (91%).
sequentially epoxidized, first with hydroxyl-directed Sharp-
less asymmetric epoxidation to 2,12,13 followed by the
asymmetric epoxidation method developed by Shi for isolated
alkenes.14 As we had earlier observed that a carbonyl group
was required as a terminating nucleophile in tandem endo-
selective oxacyclizations,8 the primary alcohol of the resulting
1,4-diepoxide 3 was derivatized as the tert-butyl carbonate15
to provide the substrate 4 in 64% overall yield (three steps).
Our studies began with synthesis of the 1,4-diepoxide
precursor from the known dienyl alcohol 1 (Scheme 1),
obtained from isoprene in three steps.10,11 The alkenes were
(4) Total synthesis of brevetoxin A: (a) Nicolaou, K. C.; Bunnage, M.
E.; McGarry, D. G.; Shi, S.; Somers, P. K.; Wallace, P. A.; Chu, X.-J.;
Agrios, K. A.; Gunzner, J. L.; Yang, Z. Chem. Eur. J. 1999, 5, 599. (b)
Nicolaou, K. C.; Wallace, P. A.; Shi, S.; Ouellette, M. A.; Bunnage, M. E.;
Gunzner, J. L.; Agrios, K. A.; Shi, G.-Q.; Gartner, P.; Yang, Z. Chem.
Eur. J. 1999, 5, 618. (c) Nicolaou, K. C.; Shi, G.-Q.; Gunzner, J. L.; Gartner,
P.; Wallace, P. A.; Ouellette, M. A.; Shi, S.; Bunnage, M. E.; Agrios, K.
A.; Veale, C. A.; Hwang, C.-K.; Hutchinson, J.; Prasad, C. V. C.; Ogilvie,
W. W.; Yang, Z. Chem. Eur. J. 1999, 5, 628. (d) Nicolaou, K. C.; Gunzner,
J. L.; Shi, G.-Q.; Agrios, K. A.; Gartner, P.; Yang, Z. Chem. Eur. J. 1999,
5, 646.
(5) Total synthesis of ciguatoxin CTX 3C: Hirama, M.; Oishi, T.; Uehara,
H.; Inoue, M.; Maruyama, M.; Oguri, H.; Satake, M. Science 2001, 294,
1904.
(6) Total synthesis of gambierol: (a) Fuwa, H.; Sasaki, M.; Satake, M.;
Tachibana, K. Org. Lett. 2002, 4, 2981. (b) Fuwa, H.; Kainuma, N.;
Tachibana, K.; Sasaki, M. J. Am. Chem. Soc. 2002, 124, 14983. (c) Kadota,
I.; Takamura, H.; Sato, K.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am.
Chem. Soc. 2003, 125, 46.
(7) (a) Nakanishi, K. Toxicon 1985, 23, 473. (b) Chou, H.-N.; Shimizu,
Y. J. Am. Chem. Soc. 1987, 109, 2184. (c) Lee, M. S.; Qin, G.-W.;
Nakanishi, K.; Zagorski, M. G. J. Am. Chem. Soc. 1989, 111, 2184.
(8) (a) McDonald, F. E.; Wang, X.; Do, B.; Hardcastle, K. I. Org. Lett.
2000, 2, 2917. (b) McDonald, F. E.; Bravo, F.; Wang, X.; Wei, X.; Toganoh,
M.; Rodr´ıguez, J. R.; Do, B.; Neiwert, W. A.; Hardcastle, K. I. J. Org.
Chem. 2002, 67, 2515.
(9) Shortly before our first work in this area was submitted for publication
(ref 8a), Tokiwano et al. reported the La(OTf)3-promoted endo-selective
oxacyclization to trans-syn-trans-fused bis- and tristetrahydropyrans. How-
ever, regioselective oxacyclization requires the presence of chelating
alkoxymethyl substituents at each epoxide, which adds an undesirable degree
of complexity to substrate synthesis as well as product structures, which
are also produced in yields lower than those generally reported by our
strategy. See: Tokiwano, T.; Fujiwara, K.; Murai, A. Synlett 2000, 335.
(10) (a) Preparation of 4-chloro-3-methyl-(E)-propen-1-ol in three
steps: Lambertin, F.; Wende, M.; Quirin, M. J.; Taran, M.; Delmond, B.
Eur. J. Org. Chem. 1999, 1489, 9. (b) Preparation of (3E)-3,6-dimethyl-
2,5-heptadien-1-ol (1): Mori, K.; Okada, K. Tetrahedron 1985, 41, 557.
(11) A minor modification was introduced from the procedure described
in ref 10a: the reaction of isoprene with tert-butyl hypochlorite in acetic
acid at -10 °C gave directly the 1,4 addition of chlorine and acetate in
99:1 E/Z ratio (GC/MS).
Reaction of the diepoxide tert-butyl carbonate 4 with 1
equiv of BF3‚OEt2 at -40 °C gave only a trace amount of
the desired trans-fused product 10, with the cis-fused
diastereomer 11 as the major product, along with the tert-
butyl ether (12, also cis-fused) as a minor product (Table 1,
entry 1). The production of tert-butyl ether byproduct 12
was diminished by conducting the reaction in refluxing
CH2Cl2 at relatively dilute concentration (0.05 M, entry 2).
Crystallographic analysis of 1116 revealed cis-ring fusion of
the cyclic carbonate-pyran products, resulting from apparent
retention of configuration at the carbon undergoing nucleo-
philic addition of the carbonyl oxygen, rather than the
expected trans-fused product 10 from inversion of config-
uration.17
(12) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(13) The enantioselectivity was determined to be 95:5 er for the benzoate
derivative of 2 by HPLC analysis. See the Supporting Information for
details.
(14) (a) Wang, Z.; Tu, Y.; Frohn, M.; Zhang, J.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224. (b) Cao, G.-A.; Wang, Z.-X.; Tu, Y.; Shi, Y.
Tetrahedron Lett. 1998, 39, 4425. (c) Zhu, Y.; Tu, Y.; Tu, H.; Shi, Y.
Tetrahedron Lett. 1998, 39, 7819. (d) Shi, Y.; Wang, Z.-X. J. Org. Chem.
1998, 63, 3099.
(15) Basel, Y.;Hassner, A. J. Org. Chem. 2000, 65, 6368.
(16) See the Supporting Information for essential data and thermal
ellipsoid diagrams for compounds 10-12 and 18. The detailed crystal-
lographic data can be obtained from the Cambridge Crystallographic Data
Center (CCDC) free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html.
Compound 10: CCDC 202087. Compound 11: CCDC 202085. Compound
12: CCDC 202086. Compound 18: CCDC 202088.
2124
Org. Lett., Vol. 5, No. 12, 2003

Table 1. Oxacyclizations of 1,4-Diepoxide Substrates
T
time
entry substratea (°C) (min)
products (isolated yield)
1
2
3
4
5
6
7
8
4
4
-40
+40
10
2
10
10b
10b
2b
10b
10b
10 (<4%), 11 (56%), 12 (12%)
11 (65%), 12 (4%)
11 (42%), 12 (10%)
11 (70%)
10 (35%), 11 (10%)
10 (55%), 11 (21%)
10 (32%), 11 (8.5%)
10 (34%), 11 (13%)
4 (0.5 M) -40
Figure 2. Possible mechanism for oxacyclization process.
6
7
7
8
9
-40
-40
+20
-40
-40
The dependence of ring fusion stereochemistry on the
nature of the nucleophile (tert-butyl carbonate gives cis-
fusion, N,N-dimethyl carbamate gives trans-fusion) may be
explained by the mechanism of Figure 2, in which the
nucleophile intercepts at different points in the continuum
between epoxonium ion at one extreme and tertiary carbo-
cation at the other. We propose that cis-fused products arise
from nucleophilic addition in the continuum closer to the
tertiary carbocation, whereas the trans-fused products are
favored with a better nucleophile, i.e., the tertiary carbamate,
which intercepts a tight ion-pair intermediate20 nearer in
structure to the epoxonium ion.
With these results in hand, we explored the formation of
the fused tricyclic product from the corresponding 1,4,7-
triepoxide. The synthesis of the triepoxide precursors was
initiated from epoxide 2 (see Scheme 1), which after
protection of the alcohol was subjected to regioselective
allylic oxidation to provide 13 (Scheme 2).21 Sharpless
asymmetric epoxidation and conversion of the hydroxyl to
the bromide 14 was followed by substitution with 1-lithio-
2-methyl-1-propene22 and desilylation to afford diepoxy
alcohol 15 in good yield. This compound was converted into
the triepoxide substrates 16 and 17 by a sequence involving
protection of the hydroxyl group and Shi epoxidation of the
remaining alkene.
a Concentration was 0.05 M of substrate in CH2Cl2, unless otherwise
stated. b The reaction mixture was subsequently stirred with aq NaHCO3
for 2 h to hydrolyze iminium ions.
Under the assumption that the cis-fused product 11 was
formed via the intermediacy of a carbocation intermediate
(resulting in retention of configuration at the site of carbonyl
oxygen addition), we considered that increasing the nucleo-
philicity of the terminating carbonyl might favor inversion
of stereoselectivity. With this aim, other derivatives were
tested, including carbamates 6 and 7.18 Although the N-
phenylcarbamate 6 also provided the cis-fused product 11
(Table 1, entry 4) after hydrolysis of the initial iminocar-
bonate, the N,N-dimethylcarbamate 7 afforded the trans-fused
bicyclic product 10 as the major product (entry 5). X-ray
crystallography analysis of 1016 confirmed the structural and
stereochemical assignment, consistent with stereochemistry
inversion occurring at the site of carbonyl oxygen addition.
The reaction was optimized to furnish a 55% yield of 10
when conducted at room temperature19 (entry 6), with an
additional 21% yield of the cis-fused byproduct 11. Similar
results were obtained with the N-pyrrolidinocarbamate 8 and
N-morpholinocarbamate derivatives 9 (entries 7 and 8).
As expected from the earlier results with diepoxide
cyclizations, the BF3‚OEt2-promoted oxacyclization of the
(17) Minor byproducts obtained from cyclization of 4 included a
regioisomeric five-membered cyclic carbonate i attached to a tetrahydro-
furanol ring (4% isolated yield for Table 1, entry 1). At higher concentration
(Table 1, entry 3), byproduct i was isolated in 6% yield along with the
corresponding tert-butyl ether ii (7% yield). Minor traces (<5%) of
(19) Temperatures for the cyclizations of 4 and 7 were optimized by
exploring a range from -95 to +40 °C, with only the best results shown
in the tables. Although formation of the tert-butyl ether byproduct 12 relative
to alcohol 11 is diminished at higher temperatures, the stereo- and
regioselectivity for fused bicyclic products 11 and 12 vs byproducts i and
ii remains constant. For cyclizations of 7, optimized results are obtained
with a short reaction time (Table 1, entry 6), as more side products are
formed with the longer reaction times required for lower temperature
experiments.
1
byproduct i were observed by H NMR from cyclization of 7.
(20) (a) Sneen, R. A. Acc. Chem. Res. 1973, 6, 46. (b) Jencks, W. P.
Acc. Chem. Res. 1980, 13, 161. We thank Prof. Peter Beak for suggesting
ion-pair phenomena as a mechanistic explanation for these results.
(21) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526.
(22) Corey, E. J.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 1229.
(18) Compound 6 was prepared by reaction of diepoxyalcohol 3 with
phenyl isocyanate and Et3N in CH2Cl2. Compounds 7-9 were prepared by
reacting a THF solution of 3 with either n-BuLi (for 7) or NaH (for 8 and
9) and the corresponding carbamoyl chloride.
Org. Lett., Vol. 5, No. 12, 2003
2125

Scheme 2. Stereoselective Syntheses of Triepoxidesa
Table 2. Oxacyclizations of 1,4,7-Triepoxide Substrates
a Key: (a) TBDPSCl, imidazole, CH2Cl2 (100%); (b) SeO2 (10
mol %), t-BuOOH/H2O, CH2Cl2; then NaBH4, MeOH, 0 °C (75%);
(c) D-(-)-DIPT, Ti(O-i-Pr)4, t-BuOOH, CH2Cl2, -18 °C (100%);
(d) CBr4, PPh3, CH2Cl2, 0 °C (98%); (e) Me2CdCHLi, THF/
HMPA, -94 °C (85%); (f) Bu4NF, THF, 0 °C (100%); (g) n-BuLi,
THF, then ClC(O)NMe2 (90%); (h) 0.3 equiv of 5, Oxone,
dimethoxymethane/CH3CN/H2O, pH ) 11.4, 0 °C (90%); (i) 0.3
equiv of 5, Oxone, dimethoxymethane/CH3CN/H2O, pH ) 11.4, 0
°C; (j) (Boc)2O, N3-Me-imidazole, toluene, 0 °C to rt (70%, two
steps).
dimethylcarbamate triepoxide 16 gave the desired all-fused
trans,trans tricyclic product 18 as the major characterizable
product in 31% isolated yield (Table 2, entry 1). This product
results from inversion of configuration in each ring-forming
event, and the structural assignment was secured by X-ray
crystallography.16 The corresponding reaction of the tert-
butyl carbonate triepoxide 17 was also explored under a
variety of reaction conditions. In this case, the major tricyclic
product was determined to be structure 19 (Table 2, entry
2), resulting from a combination of exocyclization and
endocyclization processes. Although crystalline samples of
this product could not be obtained for X-ray diffraction
analysis, NOESY NMR spectroscopy is consistent with the
structure depicted for 19, which has a cis-ring fusion between
the five- and six-membered cyclic ethers.23 When the
cyclization reaction was conducted at higher temperature
(Table 2, entry 3), a small amount of the all-fused trans,trans
tricyclic product 18 was found along with 19 as the major
tricyclic product and the elimination product 20 as a principal
byproduct (stereochemistry not determined for 20).
cyclization of the epoxide proximal to the carbonyl nucleo-
phile. Current research is directed toward the application of
this biomimetic synthesis strategy to the efficient construction
of polypyran and structurally related polycyclic ether natural
products.
Acknowledgment. This research was supported by the
National Science Foundation (Grant No. CHE-9982400). We
also acknowledge the use of shared instrumentation (NMR
spectroscopy, X-ray diffractometry) provided by grants from
the National Institutes of Health, the National Science
Foundation, and the Georgia Research Alliance.
In summary, we have demonstrated that the choice of the
terminal nucleophile can drive the cascade endo-oxacycliza-
tion of 1,4-diepoxides to proceed with retention or inversion
of configuration at the ring fusion. For 1,4,7-diepoxides, this
dependence of stereoselectivity on the nature of the nucleo-
phile is also accompanied by different regioselectivity in the
Supporting Information Available: Experimental pro-
cedures; characterization data; thermal ellipsoid figures and
essential data for compounds 10-12 and 18. This material
is available free of charge via the Internet at http://pubs.acs.org.
(23) See the Supporting Information for details on chemical degradation
and NOESY experiments resulting in the structural assignment for
compound 19.
OL034539O
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Org. Lett., Vol. 5, No. 12, 2003