Diastereoselective syntheses of chroman spiroketals via [4 + 2] cycloaddition of enol ethers and o-quinone methides

Article abstract of DOI:10.1021/ol8003244

(Chemical Equation Presented) A variety of chroman spiroketals are synthesized via inverse-demand [4 + 2] cycloaddition of enol ethers and ortho-quinone methides (o-QMs). Low temperature o-QM generation in situ allows for the kinetic, diastereoselective construction of these motifs, providing entry to a number of unusual chroman spiroketal natural products.

Full text of DOI:10.1021/ol8003244

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1477-1480
Diastereoselective Syntheses of
Chroman Spiroketals via [4 2]
Cycloaddition of Enol Ethers and
o-Quinone Methides
+
Maurice A. Marsini, Yaodong Huang, Christopher C. Lindsey, Kun-Liang Wu, and
Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, UniVersity of California at Santa Barbara
Santa Barbara, California 93106-9510
pettus@chem.ucsb.edu
Received February 12, 2008
ABSTRACT
A variety of chroman spiroketals are synthesized via inverse-demand [4
+ 2] cycloaddition of enol ethers and ortho-quinone methides (o-
QMs). Low temperature o-QM generation in situ allows for the kinetic, diastereoselective construction of these motifs, providing entry to a
number of unusual chroman spiroketal natural products.
Aliphatic spiroketals are a common substructure of natural
products isolated in a large variety from both marine and
terrestrial sources.1 Studies aimed at understanding the origins
of their conformational preference have resulted in the
general assumption that the spiroketal carbon corresponds
to the thermodynamically most stable isomer as determined
by stereoelectronic influences. Hence, the biosynthesis of
these fluxional natural products usually results in the
construction of the most stable diastereomer or a mixture
that reflects energy differences between respective diaster-
eomers.
For some time, we have speculated that a rare subset
consisting of chroman spiroketals (1,2 2,3 and 3,4 Figure 1)
may possess features that refute this basic tenet and require
Figure 1. Natural products that contain a chroman spiroketal.
a kinetic assembly. These uniquely robust chroman spiroketal
(1) Perron, F.; Albizati, K. F. Chem. ReV. 1989, 89, 1617.
scaffolds have caused us to consider new methods for their
(2) (a) Puder, C.; Loya, S.; Hizi, A.; Zeeck, A. Eur. J. Org. Chem. 2000,
construction.
729. (b) Brockmann, H.; Lenk, W.; Schwantje, G.; Zeeck, A. Tetrahedron
Lett. 1966, 7, 3525. (c) Brockmann, H.; Lenk, W.; Schwantje, G.; Zeeck,
A. Chem. Ber. 1969, 102, 126. (d) Brockmann, H.; Zeeck, A. Chem. Ber.
1970, 103, 1709.
(3) Stierle, A. A.; Stierle, D. B.; Kelly, K. J. Org. Chem. 2006, 71, 5357.
(4) (a) Namikoshi, M.; Kobayashi, H.; Yoshimoto, T.; Meguro, S. Chem.
Lett. 2000, 308. (b) Namikoshi, M.; Kobayashi, H.; Yoshimoto, T.; Meguro,
S. Chem. Pharm. Bull. 2000, 1452.
Some time ago, we developed a method that enables the
controlled, low-temperature generation of o-quinone methides
(o-QMs) (Figure 2, I).5 The process, which is driven by the
relative stability of sequential anions formed along the
cascade, begins by formation of an alkoxide. This species
10.1021/ol8003244 CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/13/2008

eventually be developed into strategies leading to the
construction of the chroman spiroketal natural products 1-3.
Our investigation began with the preparation of known
enol ethers 4,9 5,10 6,11 and 7,12 as well as the unknown enol
ether 8, which we prepared from the known acid 1113 by
sequential acetalization with formaldehyde and methylenation
with Tebbe’s reagent (Scheme 1).
Scheme 1. Known and Readily Available Five-Membered
Ring Enol Ethers Containing Exocyclic Olefins
Figure 2. (I) Cascade leading to o-QMs. (II) Preferred endo
transition state for [4 + 2] cycloaddition with chiral vinyl ether
derivatives. (III) Proposal to examine the effects of R1, R2, R3 on
the reactions of methylene dihydrofurans.
intercepts a neighboring carbonyl of a phenolic carbonate
and thus liberates a phenoxide that subsequently undergoes
â-elimination of a carboxylate and thereby forms a reactive
o-QM species, which captures the first nucleophile that it
subsequently encounters.
This is a useful method for o-QM generation because,
since the reactive o-QM intermediate is generated at low
temperature in low concentrations, it subsequently partici-
pates in very precise, kinetically controlled reactions.6 Using
this procedure, we demonstrated the first examples of
diastereoselective o-QM cycloadditions and found that the
inverse demand [4 + 2] significantly favors an endo
transition state with electron-rich alkenes.7 In further experi-
ments, we showed that chiral enol ethers containing remote
stereocenters, such as those derived from (1S,2R)-2-phenyl-
cyclohexanol, will participate in diastereoselective cycload-
ditions to yield the corresponding chroman acetals with an
R configuration (Figure 2, II).8 On the basis of these findings,
we began to speculate that an assortment of chiral 2-meth-
ylene tetrahydrofurans with R1, R2, and R3 substituents should
also participate in cycloadditions with similar diastereose-
lectivity (Figure 2, III). Detailed analysis of our proposed
transition state allowed us to further speculate that substit-
uents R1 and R3 would have a pronounced effect on the
stereochemical outcome, whereas the R2 residue would not,
allowing it to be tolerated on the same face as the reaction.
Therefore, we began to examine model systems that might
We also prepared enol ethers 9 and 10 in a short sequence.
We began by subjecting the unsaturated lactone 13 (2.4 M
in THF) to lithiated acetonitrile 14, which results in exclusive
1,4-addition. Use of the latter as the nucleophile avoids the
problem of an undesirable proton transfer during the course
of the reaction. Thus, the intermediate enolate undergoes
subsequent C-methylation with methyl iodide and affords
the trans-substituted lactone 15 in 73% yield (>10:1 dr).
Freshly prepared Tebbe reagent14 fails to provide the desired
product and returns 15 unchanged. However, if 15 (0.1 M
in THF) is refluxed with Petasis’ reagent (2.5 equiv, 4 h)
and sequentially treated to a methanol/water workup, the enol
ether 10 arises whereby the nitrile functionality has also been
transformed into a methyl ketone. While investigation of the
1
crude product mixture by H NMR showed compound 10
as the only identifiable product, bulb-to-bulb distillation with
base washed glassware provided only a 20-30% yield. To
the best of our knowledge, the conversion of a nitrile into a
methyl ketone by the Petasis reagent has never before been
reported.15 Doxsee has observed a related transformation with
(9) Okazoe, T.; Takai, K.; Oshima, K.; Utimoto, K. J. Org. Chem. 1987,
52, 4410.
(5) Van de Water, R. W.; Magdziak, D. J.; Chau, J. N.; Pettus, T. R. R.
J. Am. Chem. Soc. 2000, 122, 6502.
(6) Van de Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367.
(7) Jones, R. M.; Selenski, C.; Pettus, T. R. R. J. Org. Chem. 2002, 67,
6911.
(10) Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H. J. Am. Chem.
Soc. 1980, 102, 3270.
(11) Petasis, N. A.; Lu, S. J. Am. Chem. Soc. 1995, 117, 6394.
(12) Diaz-Ortiz, A.; Diez-Barra, E.; de la Hoz, A.; Prieto, P. Synth.
Comm. 1993, 23, 1935.
(8) (a) Selenski, C.; Pettus, T. R. R. J. Org. Chem. 2004, 69, 9196. (b)
Selenski, C.; Mejorado, L. H.; Pettus, T. R. R. Synlett 2004, 6, 1101.
(13) Baltzer, S.; Schoentjes, B.; Van Dorsselaer, V. Fr. Demande 2004,
85.
1478
Org. Lett., Vol. 10, No. 7, 2008

Tebbe’s reagent in the presence of DMAP and trimethyl
phosphine.16 If the amount of THF is limited, however, to
the minimal amount required for solubility (toluene/THF,
3:2), the reaction affords the enol ether 9 (4:1 ratio of 9/10)
in a 40-50% yield after flash chromatography and distilla-
tion.
Table 1. Cycloadditions of Methylene-1,3-dioxolanes
With these enol ethers in hand, we began examining their
reactivity with o-QMs. When the known benzyl alcohol 1617
(0.1 M in toluene, -78 °C, 2-4 equiv of the 1,3-dihy-
droisobenzofuran enol ether 4) is treated with t-BuMgCl, an
endo-selective cycloaddition proceeds as the reaction mixture
slowly warms to room temperature (Scheme 2). The reaction
cleanly produces the chroman spiroketal 17 in 60% isolated
Scheme 2. Some [4 + 2] Cycloadditions of Benzofurans and
an o-QM
speculate that the product 21 has the stereochemistry shown,
which reflects a reaction proceeding through an endo
orientation on the face opposite of phenyl residues at R1 and
R3. Next, we examined the corresponding reaction of enol
ether 7 and benzyl alcohol 2019 using similar conditions.
Again, 1H NMR revealed formation of 22 as a single
diastereomer (>20:1). This result suggested to us that the
presence of an R1 substituent was sufficient to control the
diastereoselectivity of the reaction. Thus, we were not
altogether surprised that use of the enol ether 8, which
expresses a substituted aryl ring, undergoes a diastereose-
lective reaction with the o-QM derived from 16 in compa-
rable ratio and yield.
1
yield (>8:1 dr by crude H NMR). This transformation,
therefore, serves as a practical model for an eventual
synthetic strategy aimed toward (+)-paecilospirone (3).
We next examined a similar cycloaddition using the enol
ether 5. The 2-methylbenzofuran 18 is produced along with
a small amount of the desired chroman spiroketal 19 in 10%
yield. Presumably, the fragile 2,3-dihydrobenzofuran enol
ether 5 succumbs to isomerization under these conditions.18
Therefore, due to the low yield for this transformation, we
sought an alternative strategy for the construction of 1 by
investigating o-QM cycloadditions with the enol ethers 6-8.
The starting benzyl alcohol 16 (0.1 M in Et2O at -78 °C,
2 equiv of 6) was subjected again to t-BuMgCl (Table 1). A
cycloaddition occurs as the mixture slowly warms to room
temperature, affording a single diastereomer as determined
With the chroman spiroketal 23 in hand, we paused to
investigate its reformulation into the corresponding benzo-
furan spiro-adduct (Scheme 3). The benzyl ether in 23 (0.5
Scheme 3. Failed Attempts to Effect Trans-Ketalization
1
by crude H NMR (45% isolated yield of 21). On the basis
of our extensive experience with these cycloadditions, we
(14) Payack, J. F.; Hughes, D. L.; Cai, D.; Cottrell, I. F.; Verhoeven, T.
R. Org. Synth. 2002, 79, 19.
M in 95% EtOH) was cleaved in nearly quantitative yield
by exposure of the heterogeneous mixture containing 5%
Pd/C to a hydrogen atmosphere to provide phenol 24.
Subsequent treatment of 24 with various proton sources, as
well as a cadre of Lewis acids, failed to afford the desired
spiro-adduct 26 (via 25). In most instances, the starting
material remained unchanged or suffered decomposition.
The resiliency of the chroman spiroketal 24 and related
structures is appreciated through an understanding of reso-
nance effects. The lone pair of electrons on the chroman
oxygen is delocalized throughout the adjoining aromatic ring.
Therefore, it is difficult for the lone pair of electrons to assist
(15) For reactions of the Petasis reagent with nitriles, see: (a) Petasis,
N. A.; Fu, D.-K. Organometallics 1993, 12, 3776. (b) Barluenga, J.; del
Poso Lasada, C.; Olano, B. Tetrahedron Lett. 1992, 33, 7579. (c) Treatment
of phenylacetonitrile with Petasis’ reagent smoothly affords 1-phenylacetone
in 75% yield. Thus, this mild nitrile-to-ketone transformation appears general
and proceeds in better yields with less complicated examples.
(16) (a) Doxsee, K. M.; Farahi, J. B. J. Am. Chem. Soc. 1988, 110, 7239.
(b) Takeda, T. Bull. Chem. Soc. Jpn. 2005, 78, 195. (c) Doxsee, K. M.;
Farahi, J. B. J. Chem. Soc., Chem. Commun. 1990, 20, 1452.
(17) (a) Marsini, M. A.; Huang, Y.; Van De Water, R. W.; Pettus, T. R.
R. Org. Lett. 2007, 7, 3229. (b) Lindsey, C. C.; Pettus, T. R. R. Tetrahedron
Lett. 2006, 47, 201.
(18) (a) Zhou, G.; Zheng, D.; Da, S.; Xie, Z.; Li, Y. Tetrahedron Lett.
2006, 47, 3349.
(19) Hoarau, C.; Pettus, T. R. R. Org. Lett. 2006, 8, 2843.
Org. Lett., Vol. 10, No. 7, 2008
1479

in the departure of the aliphatic ether, which results in the
formation of the oxonium 25. Conversely, the lone pair of
electrons belonging to the chroman oxygen is also difficult
to protonate, which would lead to the cleavage of the
corresponding aryl ether. These facts also account for the
unusual stability of MOM-aryl ethers as compared to the
corresponding aliphatic variety. On the basis of these results,
we abandoned an o-QM strategy for 1 and devised an
alternative method for the construction of naphthoquinone
spiroketals.20
Our attention now turned toward the chroman spiroketal
framework found in the natural product 2. Similar treatment
of 27 and 9 with t-BuMgCl affords 29 along with its
diastereomer in a 61% yield as an inseparable 3:1 ratio (Table
2). We assumed that the R1 substituent (-Me), which is
the reaction of 28 and the enol ether 10, which provides
further evidence for the mildness of this method and its
compatibility with a variety of functional groups. The lower
diastereoselectivity compared with that in Table 1 may
indicate that the steric bulk of R1 (Figure 2) plays a
substantial role in the stereochemical outcome of the reaction.
While we are confident of our structural assignments based
upon analysis of coupling data and NOE effects, we wished
to unequivocally establish the relative stereochemistry of
adducts 17, 21-23, and 29-32. Unfortunately, our attempts
to crystallize these materials failed. We therefore decided
to cleave the Boc group from compound 31, in hope that
the phenol 33 would crystallize. This task was accomplished
by short exposure to 1 N LiOH. Crystallization from CH2-
Cl2/MeOH (1:1) provided X-ray quality crystals of 33 (Figure
3). The resulting structure determination proved 31 arises
Table 2. Cycloadditions of Some Exocyclic Furan Enol Ethers
Figure 3. X-ray crystal structure of 33.
from reaction of the enol ether in endo orientation on the
face opposite the R1 substituent and on the same side as the
R3 substituent.
In conclusion, we provide the first example of kinetically
controlled, diastereoselective construction of chiral chroman
spiroketals using enol ethers and o-QMs. This versatile
method, due to its stereocontrol and functional group
compatibility, seems applicable for subsequent stereoselective
synthetic routes toward chroman spiroketal-containing natural
products (Scheme 1). These results will be reported in due
course.
closer to the site of bond formation, exerted greater stereo-
control than the R2 substituent (-CH2CN), as the latter is
further removed from the site of reaction. Nevertheless, the
ratio was disappointing and we decided to examine the effects
of electronics within the o-QM on the stereoselectivity for
the reaction. Upon exchange of the -OBn for a more electron
deficient -OBoc residue, the reaction of the o-QM derived
from 20 exhibits a small increase in selectivity (3.5:1)
favoring the chroman spiroketal 30. Unfortunately, the
diastereomers again prove inseparable by chromatography
(77% combined yield). Introduction of a bromine atom results
in a higher yield and better selectivity (4.5:1) for 31.21
Moreover, the bromine atom assists in the subsequent
separation of diastereomers by chromatography. Similar
findings were observed for the ketone 32 that arises from
Acknowledgment. Support from the University of Cali-
fornia, Cancer Research Coordinating Committee for inves-
tigations leading to the synthesis of 1 and 2 is greatly
appreciated. We applaud Neil Schore (UC Davis) for his
oversight of this important program.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data (1H NMR, 13C NMR, FT-
IR, HRMS) for compounds 8-12, 15, 17, 19, 21-24, 27,
and 29-33. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) (a) Wu, K.-L.; Wilkinson, S.; Reich, N. O.; Pettus, T. R. R. Org.
Lett. 2007, 9, 5537. (b) Lindsey, C. C.; Wu, K.-L.; Pettus, T. R. R. Org.
Lett. 2006, 8, 2365.
(21) Mejorado, L. H.; Hoarau, C.; Pettus, T. R. R. Org. Lett. 2004, 6,
1535.
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