Stereoselective Intramolecular Nicholas Reaction Using Epoxides as Nucleophiles

Article abstract of DOI:10.1021/ol0363570

(Matrix presented) The intramolecular nucleophilic attack of the epoxides on the exo-Co₂(CO)₆-propargylic cations provided cyclic ethers in good yields. The use of substrates with stereochemically defined oxiranes provided polysubsti

Full text of DOI:10.1021/ol0363570

ORGANIC
LETTERS
2004
Vol. 6, No. 4
565-568
Stereoselective Intramolecular Nicholas
Reaction Using Epoxides as
Nucleophiles
Fernando R. P. Criso´stomo, Toma´s Mart´ın, and V´ıctor S. Mart´ın*
Instituto UniVersitario de Bio-Orga´nica “Antonio Gonza´lez”, UniVersidad de La
Laguna,C/Astrof´ısico Francisco Sa´nchez, 2, 38206 La Laguna, Tenerife, Spain
Vmartin@ull.es
Received December 3, 2003
ABSTRACT
The intramolecular nucleophilic attack of the epoxides on the exo-Co2(CO)6-propargylic cations provided cyclic ethers in good yields. The use
of substrates with stereochemically defined oxiranes provided polysubstituted tetrahydropyrans and oxepanes with a high degree of stereocontrol.
The cyclization is sensitive to the nature of the protecting group used at the primary alcohol, the use of tert-butyl carbonates being highly
effective in terms of regioselectivity and yields.
A series of compounds, many of them showing strong
biological activities, have been isolated from marine organ-
isms.1 This class of compounds includes the so-called ladder
ether toxins, which exhibit a high degree of structural com-
plexity in regard to stereochemistry, molecular dimension,
and ring size.2,3 On the other hand, polyfunctionalized cyclic
ethers are also the main structural features of a wide range
of substances isolated from different species of Laurencia
red algae.1 These synthetically challenging structures and
potent biological activities have attracted the attention of
numerous synthetic chemists, and a variety of approaches
have been explored.4
Considering the biological origin of the above-mentioned
molecules involving a cascade poly-oxacyclization,5 the two
most attractive basic strategies include the intramolecular
opening of epoxides6 and the trapping of electron-deficient
carbons,7 in both cases using alcohols as nucleophiles. In
this context, the Nicholas reaction8 has proved to be an
excellent way to achieve both the activation of epoxides9
(1) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1-48, and earlier reviews
in the same series.
(2) Yasumoto, T.; Murata, M. Chem. ReV. 1993, 93, 1897-1909.
(3) Representative examples of marine ladder toxins: (a) (brevetoxin-
B): Lin, Y.-Y.; Risk, M.; Ray, S. M., Van Engen, D.; Clardy, J.; Golik, J.;
James, J. C.; Nakanishi, K. J. Am. Chem. Soc, 1981, 103, 6773-6775. (b)
(brevetoxin-A): Shimizu, Y.; Chou, H.-N.; Bando, H.; VanDuyne, G.;
Clardy J. C. J. Am. Chem. Soc, 1986, 108, 514-515. (c) (hemibrevetoxin-
B): Krishna Prasad, A. V.; Shimizu, Y. K. J. Am. Chem. Soc., 1989, 111,
6476-6477. (d) (ciguatoxin): Murata, M.; Legrand, A. M.; Ishibashi, Y.;
Fukui, M.; Yasumoto, T. J. Am. Chem. Soc. 1990, 112, 4380-4386. (e)
(gambieric acids): Nagai, H.; Murata, M.; Torigoe, K.; Satake, M.;
Yasumoto, T. J. Org. Chem., 1992, 57, 5448-5453. (f) (gambierol): Satake,
M.; Murata, M.; Yasumoto, T. J. Am. Chem. Soc. 1993, 115, 361-362. (g)
(prymnesin-2): Igarashi, T.; Satake, M.; Yasumoto, T. J. Am. Chem. Soc.
1996, 118, 479-480. (h) (scaritoxin): Satake, M.; Ishibashi, Y.; Legrand,
A.-M.; Yasumoto, T. Biosci. Biotech. Biochem. 1996, 60, 2103-2105. (i)
(yessotoxin): Satake, M.; Terasawa, K.; Kadowaki, Y.; Yasumoto, T.
Tetrahedron Lett. 1996, 37, 5955-5958. (j) (adriatoxin): Ciminello, P.;
Fattorusso, E.; Forino, M.; Magno, S.; Poletti, R.; Viviani, R. Tetrahedron
Lett. 1998, 39, 8897-8900.
(4) (a) Alvarez, E.; Candenas, M. L.; Pe´rez, R.; Ravelo, J. L.; Mart´ın, J.
D. Chem. ReV. 1995, 95, 1953-1980. (b) Mori, Y. Chem. Eur. J. 1997, 3,
849-852. (c) Hoberg, L. O. Tetrahedron 1998, 54, 12631-12670. (d)
Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S. Angew.
Chem., Int. Ed. 2000, 39, 44-122. (e) Marmsa¨ter, F. P.; West, F. G. Chem.
Eur. J. 2002, 8, 4346-4353.
(5) (a) Nakanishi, K. Toxicon 1985, 23, 473-9. (b) Chou, H.-N.; Shimizu,
Y. J. Am. Chem. Soc. 1987, 109, 2184-2185. (c) Lee, M. S.; Qin, G.-W.;
Nakanishi, K.; Zagorski, M. G. J. Am. Chem. Soc. 1989, 111, 6234-6241.
(6) (a) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K.
J. Am. Chem. Soc. 1989, 111, 5330-5334. (b) Mori, Y.; Yaegeshi, K.;
Furukawa, H. J. Am. Chem. Soc. 1996, 118, 8158-8159.
(7) (a) Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. J. Am. Chem. Soc.
1989, 111, 4136-4137. (b) Nicolaou, K. C.; Tiebes, J.; Theodorakis, E.
A.; Rutjes, F. P. J. T.; Koide, K.; Sato, M.; Untersteller, E. J. Am. Chem.
Soc. 1994, 116, 9371-9372. (c) Betancort, J. M.; Mart´ın, V. S.; Padro´n, J.
M.; Palazo´n, J. M.; Ram´ırez, M. A.; Soler, M. A. J. Org. Chem. 1997, 62,
4570-4583 and references therein.
(8) Teobald, B. J. Tetrahedron 2002, 58, 4133-4170.
10.1021/ol0363570 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/16/2004

and the generation of cations that could be transformed into
cyclic ethers.10 On the other hand, methodologies making
use of epoxides as nucleophiles in the synthesis of cyclic
ethers have also been reported.11
Scheme 2. Preparation of Co2(CO)6-propargylic Alcohols
Bearing Remote Protected Epoxy Alcohols
Within our program directed toward the development of
strategies for the stereoselective construction of cyclic ether
metabolites, we wish to report on a new methodology based
of the use of the Nicholas reaction, making use of epoxides
as nucleophiles (Scheme 1). To the best of our knowledge,
Scheme 1. Use of Epoxides as Nucleophiles in the
Intramolecular Nicholas Reaction
this is the first report on the use of an epoxide as a nu-
cleophile to trap dicobalt hexacarbonyl-stabilized propargylic
cations. Here we describe the scope and limitations of this
reaction as an alternative method to synthesize oxacycles in
a stereocontrolled manner.
To study the cyclization process, the synthesis of a series
of linear precursors was achieved, in which propargylic
alcohol and an epoxi-alcohol were linked through an alkyl
chain with a variable length (Scheme 2). We were also
interested in verifying the influence that exerted the protect-
ing groups (P) of the primary alcohol on the process of
cyclization.
To perform the synthesis of the necessary lineal precursors,
we used as starting material the suitable diols, that after
monoprotection as THP derivatives were oxidated and treated
with the lithium salt of trimethylsilyl acetylene yielding the
corresponding propargylic alcohols 6. Protection of the
secondary alcohol as a silyl ether, followed by cleavage of
the tetrahydropyranyl ether afforded compounds 7. Oxidation
of the primary alcohol to the aldehyde followed by a
Horner-Wadsworth-Emmons homologation provided the
corresponding R,â-unsaturated esters that after reduction of
the ester yielded the allylic alcohols 8. These were converted
to the corresponding diastereomeric 2,3-epoxy alcohols 9 via
the Katsuki-Sharpless asymmetric epoxidation using (R,R)-
(+)-diethyl tartrate as the chiral auxiliary.12 Protection of
the free alcohol, as a tert-butyl carbonate, acetate or silyl
ether, and cleavage of the secondary silyl groups and further
complexation of the acetylene moiety by direct reaction with
Co2(CO)8, in CH2Cl2, afforded the complexed epoxides 10,
11 and 12. Compound 10c was obtained by a slightly
different sequence (Scheme 2).
Gratifyingly, we found that cyclization took place under
treatment with BF3‚OEt2 providing the corresponding com-
plexed oxacycles.13 However, the products were different,
depending on the protection, length of the chain and reaction
conditions (Table 1). To better analyze the resulting cyclic
products, we performed a sequence of processes, namely
cyclization, acetylation and further oxidative removal of the
cobalt complex. Thus, the endo-tetrahydropyran diacetate 13
was obtained as the main product when 10a (n ) 1, R )
Ac) was submitted to the cyclization conditions at room
temperature for 24 h (entry 2). However, the amount of
tetrahydrofurans 14 and 15 increased substantially when a
shorter reaction time was applied (entry 1). The influence
(9) Mukai, C.; Yamaguchi, S.; Sugimoto, Y.; Miyakoshi, N.; Kasamatsu,
E.; Hanaoka, M J. Org. Chem. 2000, 65, 6761-6765 and references therein.
(10) (a) Kira, K.; Tanda, H.; Hamajima, A.; Baba, T.; Takai, S.; Isobe,
M. Tetrahedron 2002, 58, 6485-6492 and references therein. (b) Betancort,
J. M.; Mart´ın, T.; Palazo´n, J. M.; Mart´ın, V. S. J. Org. Chem. 2003, 68,
3216-3224.
(11) (a) Alvarez, E.; Diaz, M. T.; Perez, R.; Ravelo, J. L.; Regueiro, A.;
Vera, J. A.; Zurita, D.; Martin, J. D. J. Org. Chem. 1994, 59, 2848-2876
and references therein. (b) Tokiwano, T.; Fujiwara, K.; Marai, A. Synlett
2000, 335-338. (c) Bravo, F.; McDonald, F. E.; Neiwert, W. A.; Do, B.;
Hardcastle, K. I. Org. Lett. 2003, 5, 2123-2126 and references therein.
(12) Katsuki, T.; Mart´ın, V. S. In Organic Reactions; Paquette, L. A., et
al., Eds.; John Wiley & Sons: New York, 1996; Vol. 48, pp 1-299.
566
Org. Lett., Vol. 6, No. 4, 2004

To extend the use of the reaction to larger rings we
performed the cyclization over 11a (Scheme 3). However,
Table 1. Intramolecular Trapping of exo-Co2(CO)6-propargylic
Cations by Epoxides Leading to Oxacycles
Scheme 3. Synthesis of Exo-Substituted syn-Tetrahydropyrans
timea
(h)
yield
(%)
entry
10
T (°C)
13/14/15
1
2
3
4
5
6
7
10a
rt
1
24
4
24
1
91
95
70
93
65
73
25
R ) Ac, 50:25:25
R ) Ac, 80:11:9
R ) Boc, 100:0:0
R ) Ac, 92:4:4
R ) TBDPS, 56:44:0
R ) TBDPS, 56:44:0
R ) TBDPS, 0:100:0
10b
10c
-20
rt
4
24
a Time refers to the cyclization step.
in this case the sequence of reactions yielded stereoselectively
the exo-substituted tetrahydropyran 16. The influence of the
protecting group was also significant since the use of the
carbonate 11b, at 0 °C, provided cleanly 17 in excellent yield
as the only detected product.15 Resulting from the cleavage
of the primary carbonate, when the reaction was ran at room
temperature, the process yielded 16.
Although by NOE studies of 16 we verified the syn-
relationship between the two hydrogens vicinal to the
heterocyclic oxygen, we could not clarify the configuration
of the secondary alcohol of the chain. Thus, we decided to
prepare this compound by an alternative way, guaranteeing
the configuration at the carbinol center (Scheme 4). The
epoxy alcohol 1816 was directly converted into the vinyl
of the nature of the protecting group at the primary alcohol
was clearly established when the cyclization of 10c was per-
formed forcing thermodynamic conditions (entry 7), afford-
ing 14 as the only cyclic product, albeit in a poor yield. The
best results in terms of selectivity to afford the six-membered
rings were achieved when the carbonate 10b was treated
under similar acidic conditions at -20 °C, the tetrahydro-
pyran 13 being obtained as the sole product.14 At tempera-
tures lower than -20 °C the reaction is impractical in terms
of conversion. The configuration was established by NOE
studies, coinciding with that present in the ladder toxins.3
(13) Typical Procedure (Preparation of 13, R ) Ac). To a stirred
solution of the hexacarbonyldicobalt complex of 10a (100 mg, 0.21 mmol)
in dry CH2Cl2 (10.5 mL) was added BF3‚OEt2 (31 µL, 0.21 mmol) at room
temperature. The reaction mixture was stirred for 24 h. The mixture was
poured with vigorous stirring into a saturated solution of NaHCO3 at 0 °C
and extracted with CH2Cl2. The combined organic phases were washed
with brine, dried (MgSO4), and concentrated. The crude complex was
dissolved under argon atmosphere in dry CH2Cl2 (2.1 mL) at room
temperature, and acetic anhydride (30 µL, 0.32 mmol) and DMAP (39 mg,
0.32 mmol) were added. The resulting mixture was stirred for 30 min. The
reaction was diluted with CH2Cl2 and washed with HCl aqueous solution
(5% w/v), a saturated aqueous solution of NaHCO3 and brine, dried over
MgSO4, and concentrated. The crude mixture was dissolved in acetone (2.1
mL) at 0 °C. Ceric ammonium nitrate (323 mg, 0.84 mmol) was added in
portions with stirring until evolution of CO ceased and the CAN color
persisted (10 min). The solvent was removed under vacuum, and the pink
solid residue was then partitioned between Et2O and H2O. The aqueous
phase was extracted additionally twice with Et2O. The combined organic
extracts were dried, filtered, concentrated, and subjected to silica gel flash
Scheme 4. Alternative Synthesis of Exo-Substituted
syn-Tetrahydropyrans
chromatography yielding 13, R ) Ac, as an oil (38 mg, 76% yield): [R]25
D
) -44.2 (c 0.52, CHCl3); 1H NMR (400 MHz, C6D6) δ 1.07 (m, 1H), 1.50
(m, 1H), 1.69 (s, 3H), 1.69 (m, 1H), 1.75 (s, 3H), 1.95 (m, 1H), 2.10 (d, J
) 2.1 Hz, 1H), 3.27 (ddd, J ) 2.1, 5.1, 9.8 Hz, 1H), 3.77 (ddd, J ) 2.3,
2.3, 11.5 Hz, 1H), 4.23 (dd, J ) 2.1, 12.1 Hz, 1H), 4.4 (dd, J ) 5.2, 12.0
Hz, 1H), 4.84 (ddd, J ) 4.9, 10.2, 10.6 Hz, 1H); 13C (75 MHz, C6D6) δ
20.0 (q), 20.1 (q), 28.7 (t), 31.3 (t), 62.8 (t), 66.8 (d), 67.5 (d), 72.9 (d),
77.7 (d), 81.9 (s), 168.8 (s), 169.9 (s); IR (cm-1) 3240, 2930, 1736, 1231;
MS m/z (relative intensity) 167 (35), 138 (40), 95 (100), 67 (70). Anal.
Calcd for C12H16O5: C, 59.99; H, 6.71. Found: C, 59.98; H, 7.19.
(14) For the influence of temperature to control the stereochemistry in
cobalt induced cyclizations, see: (a) Liu, T.-Z.; Isobe, M. Tetrahedron 2000,
56, 5391-5404. (b) Takase, M.; Morikawa, T.; Abe, H.; Inouye, M. Org.
Lett. 2003, 5, 625-628. (c) Reference 10b.
Org. Lett., Vol. 6, No. 4, 2004
567

carbinol 19 by treatment with bis(cyclopentadienyl)titanium-
(III) chloride.17 Then complexation of the acetylene with Co2-
(CO)8 and cyclization induced by Lewis acid yielded the
corresponding syn-tetrahydropyran 20 as recognized by NOE
analysis.10b,18 Stereoselective dihydroxylation using both AD-
mix-R and AD-mix-â afforded the respective diols 21 and
22.19 Removal of the TMS group and full acetylation
established the equivalence of 16 with the diacetate of 21.
Considering the different behavior in the opening reactions
regarding the length of the chain and the nature of the
protecting group at the primary alcohol, we propose a vicinal
participation of this functionality in the ring formation
(Scheme 5).20 Thus, for the smaller chain the concomitant
Scheme 6. Temperature dependence in the stereoselective
ynthesis of substituted oxepanes
Scheme 5. Mechanistic Proposal in the Cyclization of Epoxy
Propargylic Cations Depending on the Carbon Chain Length
(Scheme 6). Thus, the treatment of the acetate 12a at different
temperatures yielded tiny amounts of exo-cyclic products.
Much better results were obtained when the corresponding
carbonate 12b was submitted to the cyclization conditions.
In this case, a significant amount of the oxepanes 25 was
produced. Also in this case the stereochemistry was highly
sensitive to the temperature, almost exchanging the syn-anti
ratio from -20 °C to room temperature.
In summary, we present a new, highly stereoselective use
of the intramolecular Nicholas reaction using epoxides as
nucleophiles leading to substituted 6 and seven-membered
oxacycles in good yield. Regioselectivity in the cyclization
relies on the distance between the epoxide and the propar-
gylic cation, nature of the protecting group at the primary
alcohol and reaction conditions. The stereochemistry of the
reaction is controlled by the temperature and reaction time.
Further application of the developed methodology addressed
to the synthesis of marine natural products is currently
underway.
attack of the carbonyl group of the protecting group on the
C3 carbon and the oxygen of the epoxide to the propargylic
cation, produce the endo-tetrahydropyran with inversion at
the configuration of the C3 center. However for larger chains
such carbonyl attack takes place at the C2 carbon, opening
the epoxide and yielding the ring by nucleophilic attack of
the resulting alcohol.
We observed the same influence of the protecting group
at the primary alcohol when the carbon chain was elongated
Acknowledgment. This research was supported by the
Ministerio de Ciencia y Tecnolog´ıa of Spain (PPQ2002-
04361-C04-02) and the Canary Islands Government. F.R.P.C.
thanks CajaCanarias for a FPI fellowship. T.M. thanks the
Spanish MCYT-FSE for a Ramo´n y Cajal contract.
(15) For the use of electronically enriched carbonyl derivatives in
cyclization reactions using 2,3-epoxy alcohols, see ref 11c.
(16) Obtained by a similar sequence to that shown in Scheme 1 using a
methyl ether as the protecting group at the secondary carbinol.
(17) Yadav, J. S.; Shekharam, T.; Gadgil, V. R. J. Chem. Soc., Chem.
Commun. 1990, 843-844.
(18) Palazo´n, J. M.; Mart´ın, V. S. Tetrahedron Lett. 1995, 36, 3549-
3552.
(19) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768-2771.
(20) To clarify the scheme the enantiomers of reactants and products
were drawn.
Supporting Information Available: 1H NMR and 13C
NMR spectra for the new compounds and NOE studies of
compounds 13-15, 17, 20, and 25. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0363570
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Org. Lett., Vol. 6, No. 4, 2004