An efficient strategy for the synthesis of endocyclic enol ethers and its application to the synthesis of spiroacetals

Article abstract of DOI:10.1021/ol800815t

(Chemical Equation Presented) An efficient strategy for the synthesis of endocyclic enol ethers based on a Suzuki-Miyaura coupling/ring-closing metathesis sequence has been developed. The strategy has successfully been applied to the synthesis of spiroacetals, including cytotoxic marine metabolites attenols A and B.

Full text of DOI:10.1021/ol800815t

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2549-2552
An Efficient Strategy for the Synthesis
of Endocyclic Enol Ethers and Its
Application to the Synthesis of
Spiroacetals
Haruhiko Fuwa* and Makoto Sasaki*
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku
UniVersity, 1-1 Tsutsumidori-amamiya, Aoba-ku, Sendai 981-8555, Japan
hfuwa@bios.tohoku.ac.jp
Received April 10, 2008
ABSTRACT
An efficient strategy for the synthesis of endocyclic enol ethers based on a Suzuki-Miyaura coupling/ring-closing metathesis sequence has
been developed. The strategy has successfully been applied to the synthesis of spiroacetals, including cytotoxic marine metabolites attenols
A and B.
Spiroacetal is a structural motif that is widely found in
biologically active natural products such as insect phero-
mones, steroidal saponins, polyketide antibiotics, and marine
metabolites.1 Utilization of a spiroacetal substructure as a
scaffold in the search for novel biologically functional
molecules has also been investigated.2 The most common
approach to the synthesis of spiroacetals 1 is cyclization of
keto-diols 2 under acidic conditions (Scheme 1). Meanwhile,
spiroacetalization of endocyclic enol ethers 3 under thermo-
dynamically equilibrating conditions also represents a power-
ful strategy for the construction of anomeric spiroacetals.3
A few methods for kinetic spiroacetalization of 3 that appear
to be particularly effective for the synthesis of certain
nonanomeric spiroacetals have also been reported.4 Thus,
Scheme 1. General Plan for the Synthesis of Spiroacetals
(1) For reviews of the synthesis of spiroacetals: (a) Perron, F.; Albizati,
K. F. Chem. ReV. 1989, 89, 1617. (b) Aho, J. E.; Pihko, P. M.; Rissa, T. K.
Chem. ReV. 2005, 105, 4406.
(2) For examples: (a) Barun, O.; Kumar, K.; Sommer, S.; Langerak,
A.; Mayer, T. U.; Mu¨ller, O.; Waldmann, H. Eur. J. Org. Chem. 2005,
4773. (b) Zinzalla, G.; Milroy, L.-G.; Ley, S. V. Org. Biomol. Chem. 2006,
4, 1977. (c) Milroy, L. G.; Zinzalla, G.; Prencipe, G.; Michel, P.; Ley, S. V.;
Gunaratnam, M.; Beltran, M.; Neidle, S. Angew. Chem., Int. Ed. 2007, 46,
2493.
10.1021/ol800815t CCC: $40.75
Published on Web 05/17/2008
2008 American Chemical Society

both thermodynamic and kinetic conditions are readily
applicable to spiroacetalization of endocyclic enol ethers,
making them versatile precursors for the synthesis of
spiroacetals. However, limited methods are currently avail-
able for the synthesis of endocyclic enol ethers; the classical
approaches usually involve electrophilic trapping of 2-lithio
dihydropyrans, which often suffer from a narrow substrate
scope due to the use of strong bases.3,4 We describe herein
an efficient strategy for the synthesis of endocyclic enol
ethers based on a Suzuki-Miyaura coupling/ring-closing
metathesis (RCM) sequence, and its application to the
synthesis of a variety of spiroacetals, including cytotoxic
marine metabolites attenols A and B.
Table 1. Synthesis of Endocyclic Enol Ethers Based on a
Suzuki-Miyaura Coupling/RCM Sequencea
We envisioned that endocyclic enol ether 3 could be
synthesized from enol phosphate 5 and alkylborane 6 Via 4
based on a Suzuki-Miyaura coupling/RCM sequence (Scheme
1).5–8 In this way, spiroacetals can be rapidly elaborated from
readily available acyclic precursors. This strategy is espe-
cially useful when the corresponding lactone-derived enol
phosphate is not accessible or does not couple efficiently. A
prerequisite for the success of our strategy was that the
intermolecular Suzuki-Miyaura coupling of 5 and 6 must
be more favored than the possible intramolecular Heck
cyclization of 5, although we previously showed that
R-nitrogen-substituted alkenyl phosphates readily undergo
an intramolecular Heck cyclization.7c We therefore examined
the coupling of enol phosphates 7-9 with alkylboranes
generated from the corresponding olefins 10-13 using
Pd(PPh3)4 as a catalyst and aqueous Cs2CO3 as a base in
DMF at 50 °C (Table 1). Subsequent RCM was ac-
complished by exposure of the resultant enol ethers to
Grubbs’ second-generation catalyst9 in toluene (5 mM),
affording a variety of endocyclic enol ethers 14-19 in good
overall yields. These results clearly indicate that intermo-
lecular Suzuki-Miyaura coupling predominated over the
possible intramolecular Heck cyclization.
a Cross-coupling: 10-13 (1.5 equiv), 9-BBN-H (2.6 equiv), THF, rt;
then aq Cs2CO3 (3 equiv), Pd(PPh3)4 (0.1 equiv), 7-9 (prepared from 1
equiv of the corresponding acetate), DMF, 50 °C. RCM: Grubbs’ second
generation catalyst (0.1 equiv), toluene, 70 °C. The yields are overall from
the respective acetates. b About 10:1 mixture of diastereomers at C4.
Spirocyclization of endocyclic enol ethers 14-19 under
thermodynamic conditions was then examined (Table 2).
After desilylation (TBAF, 81-100%), the resultant alcohol
was exposed to CSA in CH2Cl2 at room temperature for 2 h.
In the case of 14-16, the doubly anomeric isomers 20-22
were exclusively formed in high yields.10 The cyclization
of 17 after desilylation produced a mixture of nonanomeric
spiroacetals 23a,b due to the presence of an unfavorable
steric interaction within the corresponding doubly anomeric
isomer.10 In the case of 18 and 19, the yields of the doubly
anomeric spiroacetals 24 and 25 were poor because of the
competitive Ferrier cyclization (see Supporting Informa-
tion).10 These results indicate that the stereochemistry of the
C4 benzyloxy group strongly influences the course of
cyclization.
We next examined kinetically controlled iodospirocycliza-
tion of 17-19. Thus, treatment of 17, after desilylation, with
NIS in CH2Cl2 at -90 °C4b gave an inseparable 1:3 mixture
of 26a and 26b in 98% yield. In contrast, iodo-spirocycliza-
tion of 18 was highly stereoselective and high-yielding;
doubly anomeric spiroacetal 27 was isolated as a single
stereoisomer in 83% yield.10 In contrast, iodo-spirocycliza-
(3) For examples: (a) Danishefsky, S. J.; Pearson, W. H. J. Org. Chem.
1983, 48, 3865. (b) Ley, S. V.; Lygo, B. Tetrahedron Lett. 1984, 25, 113.
(c) Kocienski, P.; Yeates, C. J. Chem. Soc., Perkin Trans. 1 1985, 1879.
(d) Boeckman, R. K., Jr.; Charette, A. B.; Asberom, T.; Johnston, B. H.
J. Am. Chem. Soc. 1987, 109, 7553. (e) Dubois, E.; Beau, J.-M. Tetrahedron
Lett. 1990, 31, 5165. (f) Friesen, R. W.; Sturino, C. F. J. Org. Chem. 1990,
55, 5808. (g) Crimmins, M. T.; O’Mahony, R. J. Org. Chem. 1990, 55,
5894. (h) Elsley, D. A.; MacLeod, D.; Miller, J. A.; Quayle, P.; Davies,
G. M. Tetrahedron Lett. 1992, 33, 409.
(4) (a) Pothier, N.; Goldstein, S.; Deslongchamps, P. HelV. Chim. Acta
1992, 75, 604. (b) Holson, E. B.; Roush, W. R. Org. Lett. 2002, 4, 3719.
(c) Potuzak, J. S.; Moilanen, S. B.; Tan, D. S. J. Am. Chem. Soc. 2005,
127, 13796. (d) Moilanen, S. B.; Potuzak, J. S.; Tan, D. S. J. Am. Chem.
Soc. 2006, 128, 1792.
(5) For a review of Suzuki-Miyaura coupling: Miyaura, N.; Suzuki, A.
Chem. ReV. 1995, 95, 2457
(6) For a review of olefin metathesis: Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490
.
.
(7) For our successful application of palladium-catalyzed reactions of
enol phosphates, see: (a) Sasaki, M.; Fuwa, H.; Ishikawa, M.; Tachibana,
K. Org. Lett. 1999, 1, 1075. (b) Fuwa, H.; Sasaki, M. Org. Biomol. Chem.
2007, 5, 1849. (c) Fuwa, H.; Sasaki, M. Chem. Commun. 2007, 2876. (d)
Fuwa, H.; Sasaki, M. Org. Lett. 2007, 9, 3347
.
(8) Other examples of the synthesis of endocyclic enol ethers employing
RCM: (a) Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J. Am.
Chem. Soc. 1996, 118, 1565. (b) Rainier, J. D.; Allwein, S. P. J. Org. Chem.
1998, 63, 5310. (c) Calimente, D.; Postema, M. H. D. J. Org. Chem. 1999,
64, 1770. (d) Clark, J. S.; Kimber, M. C.; Robertson, J.; McErlean, C. S. P.;
Wilson, C. Angew. Chem., Int. Ed. 2005, 44, 6157
(9) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
.
(10) For stereochemical assignments of the synthesized spiroacetals, see
the Supporting Information.
2550
Org. Lett., Vol. 10, No. 12, 2008

elucidated based on extensive NMR analysis coupled with
the modified Mosher method and later unambiguously
confirmed through total synthesis.12,13 Our synthesis plan is
summarized in Scheme 2. We envisaged that the spiroacetal
Table 2. Synthesis of Spiroacetals under Acid-Catalyzed
Thermodynamic or Electrophile-Driven Kinetic Conditions
Scheme 2. Synthesis Plan for Attenols A and B
domain of 29 could be accessed by acid-catalyzed spirocy-
clization of endocyclic enol ether 31, which in turn could
be derived from enol phosphate 32 and an alkylborane
generated from olefin 33 by the Suzuki-Miyaura coupling/
RCM sequence.
The synthesis of enol phosphate 32 started with regio- and
stereoselective epoxide opening14 of 34 to give diol 35 (93%
yield), which was converted to nitrile 36 in 71% yield in
two steps (Scheme 3). Reduction of 36 followed by Wittig
Scheme 3. Synthesis of Enol Phosphate 32
a Acid-catalyzed spirocyclization: CSA (0.2 equiv), CH2Cl2, rt, 2 h.
b Iodospirocyclization: NIS (1.5 equiv), CH2Cl2, -90 °C, 1.5 h. c Yields
of desilylation step. d Yields of spirocyclization step.
tion of 19 delivered nonanomeric spiroacetal 28 in 90% yield
as a single stereoisomer.10 These results suggest that kineti-
cally controlled spirocyclization of endocyclic enol ethers
is a powerful method for the synthesis of both anomeric and
nonanomeric spiroacetals. Additionally, these results indicate
that the stereochemical outcome of iodo-spiroacetalization
depends on the local structure of enol ethers, although it is
known that activated glycals have a propensity for the axial
addition of electrophiles.4b
methylenation gave alcohol 37, which was acylated to
provide acetate 38 in good yield. Enolization of 38 with
KHMDS in the presence of (PhO)2P(O)Cl afforded 32.
The synthesis of olefin 33 commenced with protection of
homoallylic alcohol 3915 to give MOM ether 40, which was
homologated to enoate 41 via olefin cross-metathesis (Scheme
4). Hydrogenation of 41 followed by reduction afforded
We successfully applied our strategy to the total synthesis
of attenols A and B (29 and 30, respectively), cytotoxic
marine metabolites isolated from the Chinese bivalve Pinna
attenuata by Uemura, Suenaga, and co-workers.11 The
absolute stereochemistry of these natural products was
(12) (a) Suenaga, K.; Araki, K.; Sengoku, T.; Uemura, D. Org. Lett.
2001, 3, 527. (b) Araki, K.; Suenaga, K.; Sengoku, T.; Uemura, D.
Tetrahedron 2002, 58, 1983
.
(13) (a) Van de Weghe, P.; Aoun, D.; Boiteau, J.-G.; Eustache, J. Org.
Lett. 2002, 4, 4105. (b) Enders, D.; Lenzen, A. Synlett 2003, 2185. (c) La
Cruz, T. E.; Rychnovsky, S. D. J. Org. Chem. 2007, 72, 2602
.
(14) Sasaki, M.; Tanino, K.; Miyashita, M. Org. Lett. 2001, 3, 1765.
(15) Kocienski, P. J.; Yeates, C.; Steet, S. D. A.; Campbell, S. F.
J. Chem. Soc., Perkin Trans. 1 1987, 2183.
(11) Takeda, N.; Suenaga, K.; Yamada, K.; Zheng, S.-Z.; Chen, H.-S.;
Uemura, D. Chem. Lett. 1999, 1025.
Org. Lett., Vol. 10, No. 12, 2008
2551

Scheme 4
.
Synthesis of Olefin 33
Scheme 5. Completion of the Total Synthesis
alcohol 42. Routine protective group manipulations gave diol
43, which was directly converted to epoxide 44 by 1-(p-
toluenesulfonyl)imidazole/NaH16 in 100% yield. Exposure
of 44 to dimethylsulfonium ylide17 followed by silylation
furnished 33 in 96% yield (two steps).
With requisite fragments 32 and 33 in hand, our attention
turned to the fragment assembly process and the completion
of the synthesis (Scheme 5). Hydroboration of 33 with
9-BBN-H generated an alkylborane, which was in situ
coupled with 32 [Pd(PPh3)4, aqueous Cs2CO3, DMF, 50 °C].
Subsequent RCM delivered endocyclic enol ether 31 in 76%
yield from 33.18 Desilylation followed by acid treatment
furnished spiroacetal 45 as a single stereoisomer in 70%
yield.10 Oxidation of the remaining hydroxy group and
subsequent methylenation gave olefin 46 in 100% yield.
Debenzylation provided alcohol 47, which was oxidized and
then allylated13a to give a separable mixture of alcohols
48a,b. Finally, removal of the protective groups furnished
(-)-attenol A (29) along with (+)-attenol B (30). The
spectroscopic data of synthetic 29 and 30 were in full
accordance with those of natural 29 and 30, respectively.
In conclusion, we have developed an efficient strategy for
the synthesis of endocyclic enol ethers based on the
Suzuki-Miyaura coupling/RCM sequence. Coupled with
thermodynamic and kinetic spiroacetalizations, the present
strategy allows for rapid access to structurally diverse
spiroacetals from a small set of readily available acyclic
precursors. Furthermore, the present strategy has been
successfully applied to the synthesis of cytotoxic marine
metabolites attenols A and B.
Acknowledgment. We thank Professor K. Suenaga (Keio
University) for his helpful comments. This work was
supported in part by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science,
and Technology (MEXT), Japan.
(16) Hong, C. H.; Kishi, Y. J. Am. Chem. Soc. 1991, 113, 9693.
(17) Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall,
T.; Shin, D.-S.; Flack, J. R. Tetrahedron Lett. 1994, 35, 5449.
(18) We have also examined the synthesis of enol ether 31 by a
Suzuki-Miyaura coupling of an alkylborane generated from 33 and a
lactone-derived enol phosphate under the identical conditions, albeit in
moderate yield (53% from 33). Moreover, we recently experienced
difficulties in preparing enol phosphates or triflates from certain ꢀ-alkoxy
lactones. These problems can be circumvented by using the Suzuki-Miyaura
coupling/RCM strategy.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of 1H and 13C NMR
spectra for all new compounds, and stereochemical assign-
ment of synthesized spiroacetals. This material is available
free of charge via the Internet at http://pubs.acs.org.
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