Enantioselective [4 + 2] cycloadditions of o-quinone methides: Total synthesis of (+)-mimosifoliol and formal synthesis of (+)-tolterodine

Article abstract of DOI:10.1021/jo048703c

The first example of an enantioselective cycloaddition of an o-quinone methide (o-QM) with a chiral enol ether is described along with the total synthesis of (+)-mimosifoliol and the formal synthesis of (+)-tolterodine. These syntheses exemplify a three-c

Full text of DOI:10.1021/jo048703c

Enantioselective [4 + 2] Cycloadditions of o-Quinone Methides:
Total Synthesis of (+)-Mimosifoliol and Formal Synthesis of
(+)-Tolterodine
Carolyn Selenski and Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, University of California at Santa Barbara,
Santa Barbara, California 93106-9150
pettus@chem.ucsb.edu
Received July 27, 2004
The first example of an enantioselective cycloaddition of an o-quinone methide (o-QM) with a chiral
enol ether is described along with the total synthesis of (+)-mimosifoliol and the formal synthesis
of (+)-tolterodine. These syntheses exemplify a three-component, one-pot benzopyran approach for
the construction of chiral benzylic junctions. Cycloadditions of various enol ethers and o-QMs are
examined, and diastereoselectivities >95% are obtained with trans-2-phenyl-1-cyclohexanol and
2,2-diphenylcyclopentanol vinyl ethers.
SCHEME 1
Introduction
Due to the ephemeral nature and high reactivity of
most o-quinone methides (o-QMs), their method for
generation determines their ensuing application. Typi-
cally, o-QMs are generated under Lewis acidic or thermal
conditions and result in a mixture of endo and exo
isomers in [4 + 2] cycloadditions.1 The appearance of exo
cycloadducts reflect the thermodynamic conditions needed
for o-QM generation. However, a short time ago, a low-
temperature anionic method for o-QM generation greatly
enhanced the diastereoselectivities of succeeding cycload-
ditions.2 o-QMs generated in this manner undergo re-
markably endo selective [4 + 2] cycloadditions with a
variety of electron-rich dienophiles.3 An asymmetric
format was explored in the synthesis of (+)-mimosifoliol
(2) utilizing a chiral vinyl ether and an o-QM to create a
chiral benzopyran building block.4 To the best of our
knowledge, this is the first reported enantioselective
cycloaddition of an o-QM with an enol ether. This article
describes (1) o-QM formation in greater detail, (2) il-
luminates numerous enol ethers and their syntheses, (3)
reports the diastereoselectivities observed from a series
of enol ethers and o-QMs, and (4) applies the asymmetric
method to (+)-tolterodine (1), a remedy for urinary
incontinence (Scheme 1).
astereoselective reactions unsuitable. For example, Po-
chini heats 2-[hydroxy(phenyl)methyl]phenol and ethyl
vinyl ether (EVE) to 170 °C, and the resulting cycload-
dition proceeds with a 3:1 ratio of endo/exo products.5
Dufresne thermolyzes 2-phenyl-4-ethyl-1,3,2-benzodiox-
aborin with EVE at 300 °C and observes a 1:1 mixture
of endo/exo products.6 Similarly, Chiba uses Lewis acidic
conditions with o-hydroxybenzyl alcohols and enol ethers
to result in a ratio of cycloadducts.7
o-QM Generation
In the past, methods for o-QM generation have been
harsh and cumbersome, thus making subsequent di-
(1) Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58,
5367-5405.
(2) Van De Water, R.; Magdziak, D.; Chau, J.; Pettus, T. R. R. J.
Am. Chem. Soc. 2000, 122, 6502-6503.
(3) Jones, R. M.; Selenski, C.; Pettus, T. R. R. J. Org. Chem. 2002,
67, 6911-6915.
(4) Selenski, C.; Mejorado, L.; Pettus, T. R. R. Synlett 2004, 1101-
1103.
(5) Arduini, A.; Bosi, A.; Pochini, A.; Ungaro, R. Tetrahedron 1985,
41, 3095-3103.
(6) Chambers, J. D.; Crawford, J.; Williams, H. W. R.; Dufresne,
C.; Scheigetz, J.; Bernstein, M. A.; Lau, C. K. Can. J. Chem. 1992, 70,
1717-1732.
10.1021/jo048703c CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/02/2004
9196
J. Org. Chem. 2004, 69, 9196-9203

Enantioselective [4 + 2] Cycloadditions of o-Quinone Methides
FIGURE 1. o-QM cascade.
The following low-temperature, anionic method for
o-QM generation achieves high endo/exo ratios for en-
suing cycloadditions (Figure 1). It has been proposed
o-QM formation results from a series of events called the
o-QM cascade. The cascade begins with the nucleophilic
addition of an organometallic reagent to an o-Boc sali-
cylaldehyde I. The resulting benzyloxy anion II attacks
the -OBoc carbonate to form a cyclic intermediate III,
which collapses to form a more stable phenoxide IV upon
-BOC migration. Under certain circumstances, â-elim-
ination of the -OBoc residue produces an o-QM V.
Cascade incursion is both metal and temperature de-
pendent, presumably reflecting the strength of the oxy-
gen-metal bond and the electrophilicity of the metal
cation. For example, an aluminum reagent proceeds to
intermediate II, whereas a lithium reagent continues to
intermediate IV. Surprisingly, a magnesium reagent
facilitates the final conversion to V, an unfavorable event
which is energetically offset by entropy, the Lewis acidity
of Mg2+, and CO2 expulsion. The resulting geometry of
the o-QM olefin is E unless a large group is located at
the 6-position of the salicylaldehyde.
FIGURE 2. Chiral enol ethers examined.
In 1986, Posner surveyed the diastereoselective cy-
cloadditions of enol ethers 3, 4, 5, and 7 with 3-arene-
sulfonyl-2-pyrone to form [2.2.2]-bicyclic lactone adducts.9
Enol ether 5 was superior in the cycloaddition proceeding
in >90% de and >90% yield. In 1989, Franck reported
the cycloaddition of 9 with an isoquinolinium salt in 91%
yield and 95% de.10 In 1990, Denmark investigated 8 and
9 in tandem cycloadditions with nitroalkenes.11 Enol
ether 8 was designed by Denmark, and over the next
decade 8 and 9 were used in the syntheses of many
alkaloids.12 In 1991, Thornton surveyed the diastereo-
selectivities of enol ethers 4 and 5 in high-pressure
cycloadditions with 3-hydroxylated-2-pyrones resulting
in good yields and a range of diastereoselectivities.13 In
1994, Dujardin investigated the cycloaddition of 6, de-
rived from a Fisher esterification of mandelic acid, with
various oxabutadienes undergoing cycloadditions in >90%
de.14
If an o-QM is generated in the presence of a chiral enol
ether, it is consumed in a diastereoselective [4 + 2]
cycloaddition. The ensuing cycloaddition is governed by
four elements: (1) the olefin geometry of the o-QM, (2)
the facial selectivity of the chiral enol ether, (3) the
transition state between the reacting components, and
(4) the effect of o-QM generation on the product distribu-
tion.
Chiral Enol Ethers
After considering the availability and past performace
of many enol ethers, enol ethers 3-9 were investigated
(Figure 2). At first glance, enol ethers may appear flexible
and would exhibit poor facial selectivity; however, Houk
found the s-trans conformation to be preferred during
inverse-demand Diels-Alder reactions.8 The preference
is explained on the basis of electrostatic interactions and,
to a lesser extent, steric affects. Allylic strain of the vinyl
C-H, aryl C-H, and the chiral center limits the confor-
mations of the enol ether and increases the diastereose-
lectivity during cycloaddition.
Traditionally, the synthesis of enol ether used toxic
reagents, resulted in mediocre yields, and therefore was
unappealing for application in total synthesis. The origi-
nal Watanabe process entails transetherification of n-
(9) Posner, G. H.; Wettlaufer, D. G. Tetrahedron Lett. 1986, 27, 667-
670.
(10) Choudhury, A.; Franck, R. W.; Gupta, R. B. Tetrahedron Lett.
1989, 30, 4921-4924.
(11) Denmark, S. E.; Senanayake, C. B. W.; Ho, G.-D. Tetrahedron
1990, 46, 4857-4876.
(12) The following alkaloids were synthesized: (-)-mesembrine, (+)-
castanospermine, (-)-hastanecine, (+)-casuarine, (-)-rosmarinecine,
(+)-detoxinine, and (+)-australine.
(7) Chiba, K.; Hirano, T.; Kitano, Y.; Tada, M. J. Chem. Soc., Chem.
Commun. 1999, 691-692.
(8) Liu, J.; Niwayama, S.; You, Y.; Houk, K. N. J. Org. Chem. 1998,
63, 1064-1073.
(13) Prapansiri, V.; Thornton, E. R. Tetrahedron Lett. 1991, 32,
3247-3150.
(14) Dujardin, G.; Rossignol, S.; Molato, S.; Brown, E. Tetrahedron
1994, 50, 9037-9050.
J. Org. Chem, Vol. 69, No. 26, 2004 9197

Selenski and Pettus
TABLE 1. Diastereoselective Cycloadditions of o-QMs and Enol Ethers*
*Method A: The aldehyde (0.1 M Et2O) and enol ether (2 equiv) were cooled to -78 °C, the Grignard reagent (1.05 equiv) was added
dropwise, and the reaction was warmed to rt over 3 h. Method B: After the aldehyde (0.1 M Et2O) was cooled to 0 °C the alkyllithium
(1.05 equiv) was added dropwise, and the reaction stirred for 15 min and then cooled to -78 °C. The enol ether (2 equiv) was added,
followed by the addition of MgBr2‚Et2O (1 equiv). The reaction was warmed to rt over 3 h. a Diastereomeric excess. b Yield for all
diastereomers. c Isolated yield for major diastereomer.
SCHEME 2. Enol Ether Synthesisa
step can take up to 1 week for completion. More recently,
Schlaf reported that 4 can be prepared in 83% yield by
using an air-stable palladium catalyst; unfortunately,
hindered alcohols require lengthy reaction times (Scheme
2, method c).17 We find the Ishii method to be vastly
superior due to short reaction times, high yields, and ease
of experimental setup (Scheme 2, method d).18 In our
hands, enol ethers 3 and 4 were readily prepared in 86%
and 95% yields, respectively, by heating vinyl acetate,
the alcohol, Na2CO3, and catalytic [Ir(cod)Cl]2.
a Key: (a) BVE, cat. Hg(OAc)2, R*OH, 75 °C, 6 h; (b) (i) EVE,
CF3CO2H, R*OH, 20 °C, 5d; (ii) NEt3, TMSOTf, 0 °C, CH2Cl2, 12
h; (c) BVE, R*OH, cat. (DPP)Pd(OCOCF3)2, 75 °C, 12 h; (d)
AcOCHdCH2, R*OH, cat. [Ir(Cod)Cl]2, Na2CO3, toluene, 90 °C,
12 h.
butyl vinyl ether (BVE) in the presence of substoichio-
metric mercuric acetate and a chiral alcohol (Scheme 2,
method a).15 Following the Watanabe method, the syn-
theses of 3 and 6 result in 60% and 43% yields, respec-
tively. Dujardin subsequently reported a mercury-free
two-step preparation of 3 and 6 in 75% and 80% yields,
respectively (Scheme 2, method b).16 Though the method
avoids hazardous materials, acetal formation in the first
Results and Discussion
The diastereoselective cycloadditions of enol ethers 3-9
with o-QMs 12-15 were studied (Table 1). o-QMs 12-
(16) Dujardin, G.; Rossignol, S.; Brown, E. Tetrahedron Lett. 1995,
36, 1653-1656.
(17) Bosch, M.; Schlaf, M. J. Org. Chem. 2003, 68, 5225-5227.
(18) Okimoto, Y.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2002,
124, 1590-1591.
(15) Watanabe, W. H.; Conlon, L. E. J. Am. Chem. Soc. 1957, 79,
2828-2833.
9198 J. Org. Chem., Vol. 69, No. 26, 2004

Enantioselective [4 + 2] Cycloadditions of o-Quinone Methides
FIGURE 3. Crystal structures of chromans 22 and 16.
SCHEME 3
15 were generated by the addition of phenyl or methyl
Grignard reagent to o-Boc salicylaldehydes 1019 or 11.20
Enol ethers 3-5 and 7-9 were prepared by the Ishii
method,18 while enol ether 6 was prepared using the
mercury-free procedure16 by Dujardin. In most cases,
method A or B can be used for the syntheses of chromans
16-28. Method B manipulates the metal-dependent
cascade shown in Figure 1 and should be used when an
enol ether contains functionality prone to nucleophilic
attack.
hand, 2,2-diphenylcyclopentanol vinyl ether (8)22 under-
goes cycloaddition with o-QM 12 in 66% yield and 95%
de; however, its five-step synthesis makes it somewhat
unattractive as a chiral building block. The diastereo-
selectivities of trans-2-phenyl-1-cyclohexanol vinyl ether
(9)23 are outstanding for all o-QMs. The isolated yields
of benzopyrans 22, 24, 26, and 28 range from 69 to 88%
all in 95% de. Enol ether 9 is a good choice for application
in total synthesis because of its high diastereoselective
induction, facile construction, and commercial availability
of its corresponding alcohol in both enantiomers.
The facial selectivities of enol ethers 4 and 9 during
cycloaddition are shown in Table 1. The relative stereo-
chemistries of chromans 16 and 22 were determined by
X-ray crystallography (Figure 3). (Note: the crystal
structures are shown in their opposite enantiomers) The
syn relationship between the phenyl residue of the
benzopyran and the oxygen substituent of the acetal
results from an endo transition state. Taking into account
pseudoallylic strain and Houk’s calculation, the enol
ether reacts in the s-trans conformation. The o-QM
undergoes reaction opposite the methyl residue of enol
ether 4 and opposite the phenyl residue of enol ether 9.
The S-stereocenter of 4 and the 2R-stereocenter of 9
induces the S-configuration of the resulting benzyl junc-
tion. The absolute configuration of the chiral enol ether
determines the absolute configuration of the resulting
benzopyran. The selectivity model was confirmed by the
key cycloadditions of trans-2S-phenyl-1R-cyclohexanol
When o-QM 12 is generated in the presence of menthol
vinyl ether (3)21 a cycloaddition ensues to produce 20 in
45% de and 60% yield for all cycloadducts. Menthol vinyl
ether (3) was the only enol ether to produce exo cyclo-
adducts visible in the crude reaction. The exo adducts
may result from steric interactions corrupting preference
for an endo transition state. Next, we examined o-QM
12 with 1-phenylethanol vinyl ether (4),9 and the result-
ing cycloaddition proceeded in 90% yield with 88% de.
The yield may reflect the compact size of 4, but the
diastereomeric ratio reflects its failure to react exclusively
from one face. Unfortunately, the diastereoselectivities
(50-60%) and yields (77-85%) associated with products
23, 25, and 27 from o-QMs 13-15 were significantly
lower. We anticipated enol ether 59 containing a tert-butyl
residue might prove more selective; however, the reaction
with o-QM 12 results in 63% yield and 11% de. The tert-
butyl group might overpower allylic strain to confer
rigidity of the enol ether in regard to the reacting face
and the chiral center; therefore, butyl mandelate derived
enol ether 621 was examined with a small sp2 carbonyl
group next to the chiral center. While the yield of 18 was
70% the de was a meager 4%; clearly, both o-QM faces
are accessible for cycloaddition. 1-Mesitylethanol vinyl
ether (7)9 was then examined, hoping the large aryl ring
might drastically change the selectivity; however, com-
pound 19 arises in 58% yield and 25% de. On the other
(19) Tuttle, K.; Rodriguez, A. A.; Pettus, T. R. R. Synlett 2003, 2234-
2237.
(20) Jones, R.; Van De Water, R. W.; Lindsey, C.; Hoarau, C.; Ung,
T.; Pettus, T. R. R. J. Org. Chem. 2001, 66, 3435-3441.
(21) Dujardin, G.; Rossignol, S.; Molato, S.; Brown, E. Tetrahedron.
1994, 50, 9037-50.
(22) Denmark, S. E.; Schnute, M. E.; Marcin, L. R.; Thorarensen,
A. J. Org. Chem. 1995, 60, 3205-3220.
(23) Denmark, S. E.; Senanayake, B. W. J. Org. Chem. 1993, 58,
1853-1858.
(24) Reference deleted in proof.
J. Org. Chem, Vol. 69, No. 26, 2004 9199

Selenski and Pettus
SCHEME 4a
a Key: (a) TMS(CH2)2OH (2 equiv), PPh3 (2 equiv), DIAD (2 equiv), 1 M THF, 12 h; (b) BOC2O (1.1 equiv), Hunig’s base (0.5 equiv),
DMAP (cat.), 0.1 M CH2Cl2; (c) PhMgBr (1.05 equiv), (-)-9 (2 equiv), 0.1 M Et2O, -78 °C to rt, 3 h; (d) CSA (0.6 equiv), 0.1 M 1:1 H2O/
CH3CN, 70 °C, 5 h; (e) LiAlH4 (2 equiv), 0 °C, 5 min; (f) CH2N2; (g) PhSeCN (1.05 equiv), PBu3 (1.1 equiv); (h) NaIO4, NaHCO3, 40 °C; (i)
CsF (2 equiv), 0.1 M DMF, 160 °C, 6 h.
vinyl ether (-)-9 with the appropriate o-QMs that
ultimately created R-mimosifoliol (2) and R-tolterodine
(1).
From this model, it was concluded that substituted enol
ether 2923 should also undergo a diastereoselective cy-
cloaddition (Scheme 3). Addition of phenyl Grignard
reagent to aldehyde 1019 in the presence of enol ether 29
affords benzopyran 30, creating three chiral centers, with
a 60% yield and 95% de.
mary alcohol 36 into the corresponding selenide 37 (0.1
M THF, 2 equiv of PhSeCN, 2 equiv of PBu3, rt, 5 h)
followed by oxidation (0.5 M 2:1 MeOH/H2O, 2 equiv of
NaIO4, 2 equiv of NaHCO3, 40 °C), which resulted in
spontaneous syn-elimination to form the terminal olefin
38.27 Finally, cleavage (0.2 M DMF, 2 equiv of CsF, 160
°C, 6 h) of the -O(CH2)2TMS ether afforded synthetic
R-mimosifoliol (2), which is identical in every respect to
(+)-225 isolated from natural sources.
The formal synthesis of(+)-tolterodine (1) was achieved
in three steps and 65% overall yield (Scheme 5). The
synthesis began with o-Boc salicylaldehyde 40 available
from 2-hydroxy-5-methyl benzaldehyde (39) (1 M CH2-
Cl2, 1.1 equiv of BOC2O, 0.5 equiv of Hunig’s base, cat.
DMAP) in 95% yield. Aldehyde 40 was subjected to
PhMgBr (1.05 equiv) in the presence of enol ether (-)-9
(2.0 equiv) at -78 °C and then warmed over 3 h to room
temperature to afford (+)-41 in 90% yield as a single
diastereomer. The cycloadduct (+)-41 (0.1 M 1:1 H2O/
CH3CN, 0.6 equiv of CSA, 70 °C, 6 h) was hydrolyzed to
produce lactol 4228 in 85% yield. This constitutes a formal
synthesis of (+)-tolterodine (1) as application of the
Botteghi reductive amination with 42 yields the urologi-
cal drug in 90% yield.29
To demonstrate the usefulness of this process within
the context of synthesis, (+)-mimosifoliol (2), isolated
from the rootwood of Aeschynomene mimosifolia Vatke
(Leguminosae),25 was constructed in nine steps with a
35% overall yield (Scheme 4). The synthesis began with
the treatment of benzaldehyde 3126 under a Mitsunobu
protocol (1 M THF, 2 equiv of TMS(CH2)2OH, PPh3, and
DIAD) followed by carbonate formation (1 M CH2Cl2, 1.1
equiv BOC2O, 0.5 equiv of Hunig’s base, cat. DMAP)
resulting in the bis-protected aldehyde 32 in 80% yield
over two steps. When 32 (0.1 M Et2O) was subjected to
PhMgBr (1.05 equiv) in the presence of enol ether (-)-9
(2.0 equiv) at -78 °C and warmed over 3 h to room
temperature, adduct (+)-33 arose in 83% yield. Hydroly-
sis of 33 (0.1 M 1:1 H2O/CH3CN, 0.6 equiv of CSA, 70
°C, 6 h) afforded the lactol 34 in 91% yield along with
the chiral alcohol. Reduction of lactol 34 (0.1 M THF, 3
equiv of LiAlH4, 0 °C, 5 min), followed by methylation (3
equiv of CH2N2, 12 h) afforded the primary alcohol (+)-
36 in 74% yield over two steps. Introduction of the desired
alkene was accomplished by the conversion of the pri-
Conclusions
The first examples of enantioselective cycloadditions
of o-QMs with chiral enol ether 9 have been demon-
(27) Bissel, P.; Nazih, A.; Sablong, R.; Lepoittevin, J.-P. Org. Lett.
1999, 1, 1283-1285.
(25) Fullas, F.; Kornberg, L. J.; Wani, M. C.; Wall, M. E. J. Nat.
Prod. 1996, 59, 190-192.
(26) Mali, R. S.; Manekar, A. R.; Tilve, S. G. Org. Prep. Proced. Int.
1992, 24, 52-54.
(28) Gage, J. R.; Cabaj, J. E. (Pharmacia & Upjohn Co.). US Patent
5,922,914, 1999.
(29) Botteghi, C.; Corrias, T.; Marchetti, M.; Paganelli, S.; Piccolo,
O. Org. Process Res. Dev. 2002, 6, 379-383.
9200 J. Org. Chem., Vol. 69, No. 26, 2004

Enantioselective [4 + 2] Cycloadditions of o-Quinone Methides
SCHEME 5a
crude mixture was then chromatographed through silica gel,
eluting with petroleum ether/EtOAc (95:5). Method B. A
flame-dried flask equipped with a stir bar and nitrogen line
was charged with an aldehyde (0.1 M Et2O) and then cooled
to 0 °C. The appropriate organolithium reagent (1.05 equiv)
was added dropwise and then stirred for 15 min. The reaction
mixture was cooled to -78 °C, and the enol ether (5 equiv)
was added, followed by MgBr2‚OEt2 (1 equiv). The reaction
mixture was warmed to rt over 3 h, quenched with 1 M
NaHCO3, and extracted with Et2O. The ether layer was
washed with brine, dried over Na2SO4, and concentrated in
vacuo. The crude mixture was then chromatographed through
silica gel, eluting with petroleum ether/EtOAc (95:5).
Compound 16. General Procedure for Chroman Syn-
thesis (Method A). 1H NMR (400 MHz, CDCl3): δ 7.37-7.17
(m, 10H), 6.77 (s, 1H), 6.27 (s, 1H), 5.11-5.06 (q, 1H, J ) 6.6
Hz), 5.03-5.00 (m, 1H), 4.07-4.03 (m, 1H), 3.55 (s, 3H), 2.28-
2.18 (m, 2H), 1.56 (s, 9H), 1.48 (d, 3H, J ) 6.6 Hz). 13C NMR
(100 MHz, CDCl3): δ 151.7, 147.2, 145.5, 144.1, 143.1, 139.7,
128.8, 128.7, 128.6, 127.9, 126.9, 126.6, 123.3, 113.4, 111.6,
96.8, 83.6, 75.3, 56.6, 41.3, 37.5, 27.8, 24.4. IR (CH2Cl2, νmax
cm-1): 3055, 2984, 1761, 1505, 1419, 1371. HRMS (ESI-TOF)
(M+ + Na): m/z calcd for C29H32O6 476.2199, found 476.2204.
Compound 17. General Procedure for Chroman Syn-
thesis (Method A). 1H NMR (400 MHz, CDCl3): δ 7.36-7.17
(m, 10H), 6.32 (s, 1H), 6.03 (s, 1H), 5.29-5.27 (m, 1H), 4.18
(s, 1H), 4.12-4.09 (m, 1H), 3.58 (s, 3H), 2.47-2.42 (m 1H),
2.31-2.25 (m, 1H), 1.55 (s, 9H), 0.78 (s, 9H). 13C NMR (100
MHz, CDCl3): δ 151.6, 146.9, 145.5, 144.5, 140.8, 139.6, 128.7,
128.6, 128.5, 127.3, 127.0, 126.7, 123.0, 113.3, 112.1, 101.2,
91.6, 83.4, 56.7, 40.1, 36.0, 32.1, 27.8, 26.2. IR (CH2Cl2, νmax
cm-1): 3053, 2972, 2870, 1761, 1504, 1452, 1421, 1394, 1364,
1205, 1151, 11261047, 1007. HRMS (EI): m/z calcd for
C32H38O6 518.2668, found 518.2679.
a (a) BOC2O (1.1 equiv), Hunig’s base (0.5 equiv), DMAP (cat.),
0.1 M CH2Cl2; (b) PhMgBr (1.05 equiv), (-)-9 (2 equiv), 0.1 M Et2O,
-78 °C to rt, 3 h; (c) CSA (0.6 equiv), 0.1 M 1:1 H2O/CH3CN, 70
°C, 5 h.
SCHEME 6
Compound 18. General Procedure for Chroman Syn-
thesis (Method B). 1H NMR (400 MHz, CDCl3): δ 7.37-7.23
(m, 10H), 6.72 (s, 1H), 6.34 (s, 1H), 5.33 (s, 1H), 5.23-5.20
(m, 1H), 4.15-3.99 (m, 3H), 3.58 (s, 3H), 2.41-2.35 (m, 2H),
1.56 (s, 9H), 1.53-1.48 (m, 2H), 1.27-1.20 (m, 2H), 0.89-0.83
(m, 3H). 13C NMR (100 MHz, CDCl3): δ 170.5, 151.7, 146.6,
145.9, 144.1, 139.9, 136.0, 128.9, 128.9, 128.8, 128.7, 127.5,
126.9, 123.0, 113.6, 111.7, 97.7, 83.6, 78.9, 65.3, 56.7, 40.5, 36.5,
30.6, 27.8, 19.1, 13.8. IR (CH2Cl2, νmax cm-1) 2962, 2932, 2873,
1755, 1732, 1514, 1504, 1446, 1371, 1150, 1049. HRMS (ESI-
TOF) (M+ + Na): m/z calcd for C33H38O8 585.2567, found
585.2480.
Compound 19. General Procedure for Chroman Syn-
thesis (Method A). 1H NMR (400 MHz, CDCl3): δ 7.33-7.17
(m, 5H), 6.82 (s, 2H), 6.75 (s, 1H), 6.29 (s, 1H), 5.58 (q, 1H, J
) 7 Hz), 4.95-4.92 (m, 1H), 4.07-4.03 (m, 1H), 3.56 (s, 3H),
2.35 (s, 6H), 2.26 (s, 3H), 2.24-2.17 (m, 2H), 1.56 (s, 9H), 1.52-
1.50 (d, 3H, J ) 7 Hz). 13C NMR (100 MHz, CDCl3): δ 151.7,
147.3, 145.6, 144.3, 139.7, 137.0, 134.5, 128.8, 128.7, 128.4,
127.0, 123.3, 113.6, 111.6, 96.4, 83.6, 77.5, 71.2, 56.7, 41.2, 37.6,
27.8, 21.0, 20.5, 20.4. IR (CH2Cl2, νmax cm-1): 3004, 2979, 2934,
2971, 1760, 1609, 1505, 1464, 1454, 1416, 1371, 1274. HRMS
(ESI-TOF) (M+ + Na): m/z calcd for C32H38O6 541.2566, found
541.2558.
strated. The cycloadditions of trans-2-phenyl-1-cyclohex-
anol vinyl ether (9) with o-QMs formulate chiral benzylic
junctions in >95% de. The chiral alcohol is recovered by
hydrolysis and the resulting lactol can be transformed
into any number of useful materials as shown by the
syntheses of (+)-tolterodine (1) and (+)-mimosifoliol (2).
We anticipate future asymmetric synthesis of the chiral
chroman bitucarpin A (Scheme 6). This compound was
isolated from the aerial plants of Mediterranean papil-
ionaceaous plants Bituminaria morisiana and B. bitu-
minosa and has antimicrobial activity.30 It is envisioned
to set the 3-stereocenter of the chroman adduct by a
cycloaddition of the corresponding o-QM with a substi-
tuted enol ether.
Compound 20. General Procedure for Chroman Syn-
thesis (Method A). 1H NMR (400 MHz, CDCl3): δ 7.33-7.19
(m, 5H), 6.73 (s, 1H), 6.28 (s, 1H), 5.25-5.22 (m, 1H), 4.18-
4.14 (m, 1H), 3.56 (s, 3H), 3.45-3.43 (m, 1H), 2.36-2.15 (m,
Experimental Section
General Procedure for Chroman Synthesis for Com-
pounds 16-28, 30, 33, and 41. Method A. A flame-dried
flask equipped with stir-bar and nitrogen line was charged
with an aldehyde (0.1 M Et2O) and an enol ether (2 equiv).
The solution was cooled to -78 °C, and a Grignard reagent
(1.05 equiv) was added dropwise. The reaction mixture was
warmed to rt over 3 h, quenched with 1 M NaHCO3, and
extracted with Et2O. The ether layer was washed with brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The
4H), 1.64-1.57 (m, 2H), 1.55 (s, 9H), 1.49-0.74 (m, 14H). 13
C
NMR (100 MHz, CDCl3): δ 147.5, 145.6, 144.2, 139.7, 128.8,
128.7, 127.0, 123.3, 113.4, 111.9, 101.3, 83.6, 81.6, 56.7, 48.6,
43.5, 41.8, 37.9, 34.5, 31.9, 27.8, 25.8, 23.5, 22.5, 21.2, 16.5.
IR (CH2Cl2, νmax cm-1): 2958, 2927, 2870, 1761, 1603, 1505,
1454, 1417, 1371, 1274, 1207. HRMS (EI): m/z calcd for
C31H42O6 510.2980, found 510.2972.
Compound 21. General Procedure for Chroman Syn-
1
thesis (Method A). H NMR (400 MHz, CDCl3): 7.34-7.08
(30) Pistelli, L.; Noccioli, C.; Appendino, G.; Bianchi, F.; Sterner,
O.; Ballero, M. Phytochemistry 2003, 64, 595-598.
(m, 15H), 6.75 (s, 1H), 6.36 (s, 1H), 4.87-4.85 (m, 1H), 4.84-
J. Org. Chem, Vol. 69, No. 26, 2004 9201

Selenski and Pettus
4.78 (m, 1H), 3.93-3.90 (m, 1H), 3.61 (s, 3H), 2.33-1.62 (m,
7H), 1.59 (s, 9H) 1.39-1.37 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 151.8, 147.1, 146.6, 145.5, 145.4, 144.7, 139.7, 128.7,
128.7, 128.5, 128.4, 127.7, 127.2, 126.5, 126.1, 125.7, 122.7,
113.7, 111.9, 100.7, 87.2, 83.6, 60.2, 56.6, 40.3, 36.4, 34.9, 32.1,
27.8, 20.5. IR (CH2Cl2, νmax cm-1): 2975, 2937, 1761, 1600,
1504, 1495, 1447, 1415, 1371, 1278. HRMS (EI): m/z calcd for
C38H40O6 592.2825, found 592.2806.
Compound 22. General Procedure for Chroman Syn-
thesis (Method A). 1H NMR (400 MHz, CDCl3): δ 7.31-7.00
(m, 5H), 6.89-6.59 (m, 2H), 4.46-4.44 (m, 1H), 3.70-3.64 (m,
1H), 2.62-2.50 (m, 2H), 2.23-2.21 (m, 1H), 1.92-1.58 (m, 3H),
1.55 (s, 9H), 1.46-1.21 (m, 7H). 13C NMR (100 MHz, CDCl3):
δ 153.3, 152.2, 150.2, 144.5, 128.3, 128.2, 128.0, 126.5, 125.4,
113.6, 110.2, 100.7, 83.9, 51.7, 35.5, 34.9, 33.0, 29.9, 27.9, 27.8,
26.0, 25.5, 21.4. IR (CH2Cl2, νmax cm-1): 2990, 2930, 2856, 1757,
1609, 1494, 1370, 1253. HRMS (EI): m/z calcd for C27H34O5
438.2406, found 438.2413.
Compound 23. General Procedure for Chroman Syn-
thesis (Method A). 1H NMR (400 MHz, CDCl3): δ 7.39-7.22
(m, 5H), 6.73 (s, 1H), 6.70 (s, 1H), 5.02 (q, 1H, J ) 6 Hz), 4.97-
4.94 (m, 1H), 3.80 (s, 3H), 2.90-2.85 (m, 1H), 2.09-2.04 (m,
1H), 1.79-1.72 (m, 1H), 1.57 (s, 9H), 1.48-1.46 (d, 3H, J ) 6
Hz), 1.40-1.38 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 151.8,
146.2, 145.7, 143.3, 139.4, 128.7, 127.8, 126.7, 125.6, 112.0,
111.6, 96.4, 83.5, 75.1, 56.9, 35.8, 28.3, 27.9, 24.5, 21.8. IR (CH2-
Cl2, νmax cm-1): 2982, 2934, 1759, 1502, 1454, 1416, 1371, 1277,
1252, 1128, 908. HRMS (EI): m/z calcd for C24H30O6 414.2042,
found 414.2058.
Compound 24. General Procedure for Chroman Syn-
thesis (Method A). 1H NMR (400 MHz, CDCl3): δ 7.30-7.05
(m, 10H), 6.68-6.51 (m, 2H), 4.51-4.48 (m, 1H), 3.72-3.66
(m, 2H), 2.53-2.33 (m, 2H), 1.91-1.62 (m, 3H), 1.55 (s, 9H),
1.49-1.28 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 154.3, 152.1,
150.5, 144.2, 130.0, 128.8, 128.7, 128.3, 128.3, 126.9, 123.5,
113.7, 110.2, 101.4, 84.5, 83.6, 51.6, 41.1, 36.8, 35.0, 32.7, 27.9,
26.0, 25.5. IR (CH2Cl2, νmax cm-1): 3057, 2934, 2859, 1757,
1653, 1558, 1497, 1414, 1371. HRMS (ESI-TOF) (M+ + Na):
m/z calcd for C32H36O5 523.2460, found 523.2439.
Compound 25. General Procedure for Chroman Syn-
thesis (Method A). 1H NMR (400 MHz, CDCl3): δ 7.37-7.16
(m, 10H), 6.79 (s, 1H), 6.66-6.57 (m, 2H), 5.12 (q, 1H, J ) 6
Hz), 5.10-5.07 (m, 1H), 4.05-4.01 (m, 1H), 2.31-2.18 (m, 2H),
1.57 (s, 9H), 1.51 (d, 3H, J ) 6 Hz). 13C NMR (100 MHz,
CDCl3): δ 154.3, 152.1, 150.6, 144.0, 143.1, 130.1, 128.8, 128.8,
128.7, 128.0, 127.0, 126.7, 123.5, 113.9, 110.2, 97.3, 83.7, 75.6,
41.1, 37.3, 27.9, 24.5. IR (CH2Cl2, νmax cm-1): 3030, 2980, 2934,
1757, 1684, 1599, 1495, 1454, 1371, 1280, 1134, 1043. HRMS
(EI) m/z calcd for C28H30O5 446.2093, found 446.2096.
Compound 26. General Procedure for Chroman Syn-
thesis (Method A). 1H NMR (400 MHz, CDCl3): δ 7.31-7.19
(m, 5H), 6.66 (s, 1H), 6.59 (s, 1H), 4.41-4.39 (m, 1H), 3.77 (s,
3H), 3.65-3.63 (m, 1H), 2.61-2.49 (m, 2H), 2.22-2.20 (m, 1H),
1.91-1.56 (m, 6H), 1.55 (s, 9H), 1.54-1.22 (m, 6H). 13C NMR
(100 MHz, CDCl3): δ 151.8, 146.2, 145.5, 144.5, 139.2, 128.3,
128.2, 126,4, 126.6, 111.8, 111.6, 100.4, 83.8, 83.5, 56.8, 51.7,
35.4, 34.9, 33.0, 28.1, 27.8, 26.0, 25.5, 21.7. IR (CH2Cl2, νmax
cm-1): 2934, 2858, 1759, 1502, 1416, 1371. HRMS (EI): m/z
calcd for C28H36O6 468.2512, found 468.2532.
Compound 27. General Procedure for Chroman Syn-
thesis (Method A). 1H NMR (400 MHz, CDCl3): δ 7.39-7.12
(m, 6H), 6.73-6.70 (m, 2H), 5.07-5.03 (q, 1H, J ) 6 Hz), 5.01-
4.99 (m, 1H), 2.89-2.85 (m, 1H), 2.09-2.05 (m, 1H), 1.79-
1.73 (m, 1H), 1.57 (s, 9H), 1.49-1.47 (d, 3H, J ) 6 Hz), 1.38-
1.37 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 153.2, 152.2,
150.3, 143.2, 128.7, 128.1, 127.9, 126.7, 125.4, 113.8, 110.2,
96.7, 83.6, 75.2, 35.9, 27.9, 27.8, 24.5, 21.6. IR (CH2Cl2, νmax
cm-1): 2982, 2932, 1757, 1614, 1591, 1499, 1371, 1278, 1249,
1026. HRMS (EI): m/z calcd for C23H28O5 384.1937, found
384.1941.
(m, 10H), 6.67 (s, 1H), 6.20 (s, 1H), 4.46-4.43 (m, 1H), 3.75-
3.71 (m, 1H), 3.66-3.65 (m, 1H), 3.53 (s, 3H), 2.47-2.46 (m,
1H), 2.31-2.30 (m, 1H), 1.90 (m, 6H), 1.55 (s, 9H), 1.51-1.27
(m, 3H). 13C NMR (100 MHz, CDCl3): δ 151.8, 147.4, 145.4,
144.3, 144.2, 139.6, 128.8, 128.6, 128.3, 128.3, 126.8, 126.5,
123.3, 113.4, 111.7, 101.0, 84.4, 83.6, 56.6, 51.6, 41.4, 37.1, 34.9,
32.7, 27.8, 25.9, 25.5. IR (CH2Cl2, νmax cm-1): 3029, 2934, 2858,
1761, 1605, 1483, 1450, 1414, 1371, 1342. HRMS (ESI-TOF)
(M+ + Na): m/z calcd for C33H38O6 553.2566, found 553.2562.
Compound 30. General Procedure for Chroman Syn-
thesis (Method A). 1H NMR (400 MHz, CDCl3): δ 7.26-7.00
(m, 10H), 6.68 (s, 1H), 6.09 (s, 1H), 4.39-4.37 (m, 1H), 3.78-
3.74 (m, 1H), 3.50 (s, 3H), 3.35-3.32 (m, 1H), 2.60-2.53 (m,
1H), 2.47-2.44 (m, 1H), 1.88-1.56 (m, 5H), 1.55 (s, 9H), 1.50-
1.31 (m, 3H) 0.18-0.17 (m, 3H). 13C NMR (100 MHz, CDCl3):
δ 151.9, 147.1, 145.5, 144.7, 143.3, 139.5, 129.5, 128.5, 128.4,
128.3, 126.8, 126.4, 124.0, 113.8, 111.4, 105.8, 84.4, 83.5, 56.6,
51.8, 49.6, 40.3, 35.2, 34.2, 27.8, 26.0, 25.5, 14.3. IR (CH2Cl2,
νmax cm-1): 3051, 2984, 2934, 2858, 1761, 1603, 1504, 1454,
1418, 1371, 1140; HRMS (EI) (M+ + Na): m/z calcd for
C34H40O6 544.2825, found 544.2848.
Compound 32. (a) A flame-dried flask equipped with stir-
bar and nitrogen line was charged with PPh3 (2 equiv, 0.5 M
THF). The reaction mixture was cooled to 0 °C, and DIAD (2
equiv) was added dropwise. After 20 min, the solution solidified
and the phenol 31 (1 equiv) and 2-trimethylsiylethanol (2
equiv) were added. The reaction mixture was stirred overnight
at room temperature. Silica gel was added to the reaction
mixture and concentrated in vacuo. The reaction mixture was
chromatographed with petroleum ether/EtOAc (8:2). 1H NMR
(400 MHz, CDCl3): δ 11.41 (s, 1H), 9.69 (s, 1H), 6.99 (s, 1H),
6.44 (s, 1H), 4.20-4.16 (m, 2H), 3.86 (s, 3H), 1.25-1.22 (m,
2H), 0.09 (s, 9H). HRMS (EI): m/z calcd for C13H20O4Si
268.113, found 268.1125. (b) A flame-dried flask equipped with
a stir-bar and a nitrogen line containing the phenol (0.1 M
CH2Cl2) obtained above, Hunig’s Base (0.6 equiv), DMAP (0.05
equiv), and BOC2O (1.2 equiv) was stirred overnight. The
reaction was quenched with 1 M NH4Cl and extracted twice
with CH2Cl2. The organic layer was washed with water and
brine, dried over MgSO4, and concentrated in vacuo. The crude
mixture was then chromatographed on silica gel, eluting with
1
petroleum ether/EtOAc (9:1). H NMR (400 MHz, CDCl3): δ
10.06 (s, 1H), 7.32 (s, 1H), 6.69 (s, 1H), 4.19 (t, J ) 8.4 Hz,
2H), 3.91 (s, 3H), 1.59 (s, 9H), 1.25 (t, J ) 8.4 Hz, 2H), 0.10 (s,
9H). 13C NMR (100 MHz, CDCl3): δ 187.2, 154.5, 151.9, 148.3,
147.7, 120.6, 109.7, 106.6, 84.7, 67.3, 56.4, 27.9, 17.7, -1.3.
IR (CH2Cl2, νmax cm-1): 2956, 2933, 2857, 1761, 1681, 1607,
1512.1, 1275. LRMS (EI): m/z calcd for C18H28O6Si 368, found
368.
Compound 33. General Procedure for Chroman Syn-
thesis (Method A). [R]D ) +15 (c ) 0.6, CHCl3). 1H NMR
(400 MHz, CDCl3): δ 7.26-7.21 (m, 10H), 6.37 (s, 1H), 6.11
(s, 1H), 4.47-4.45 (m, 1H), 4.09-4.05 (t, J ) 8.3 Hz, 2H), 3.74-
3.56 (m, 2H), 3.54 (s, 3H), 2.51-2.45 (m, 1H), 2.35-2.23 (m,
1H), 1.91-1.19 (m, 11H), 0.09 (s, 9H). 13C NMR (100 MHz,
CDCl3): δ 148.2, 147.5, 144.9, 144.2, 143.7, 128.7, 128.4, 128.2,
127.4, 126.6, 126.4, 115.8, 112.7, 102.2, 101.1, 84.3, 66.3, 56.5,
51.6, 41.0, 37.4, 35.0, 32.7, 25.9, 25.4, 17.9, -1.3. IR (CH2Cl2,
νmax cm-1): 2934, 2858, 1618, 1600, 1504, 1494, 1407, 1252.
HRMS (EI): m/z calcd for C33H42O4Si 530.7697, found 530.2835.
General Procedure for Chroman Hydrolysis for Syn-
thesis of Compounds 34 and 42. A flask containing a stir
bar was charged with a chroman (0.1 M 1:1 CH3CN/H2O) and
CSA (0.6 equiv). While the reaction mixture stirred, THF was
added dropwise until the solution became translucent. A
water-jacketed reflux condenser open to the atmosphere was
connected and the reaction heated to 100 °C for 6 h. The
reaction mixture was cooled, quenched with 1 M HCl, and
extracted with chloroform. The organic layer was washed with
brine, dried over MgSO4, and concentrated in vacuo.
Compound 28. General Procedure for Chroman Syn-
Compound 34. General Procedure for Chroman Hy-
1
thesis (Method A). 1H NMR (400 MHz, CDCl3): δ 7.31-7.07
drolysis. H NMR (400 MHz, CDCl3): δ 7.34-7.20 (m, 5H),
9202 J. Org. Chem., Vol. 69, No. 26, 2004

Enantioselective [4 + 2] Cycloadditions of o-Quinone Methides
6.43 (s, 1H), 6.26 (s, 1H), 5.60-5.58 (m, 1H), 4.27-4.23 (m,
1H), 4.08 (t, J ) 8.5 Hz, 2H), 3.59 (s, 3H), 2.29-2.23 (m, 1H),
2.17-2.06 (m, 1H), 1.23-1.21 (t, J ) 8.5 Hz, 2H), 0.07 (s, 2H).
HRMS (EI): m/z calcd for C21H28O4Si 372.1760, found 372.1767.
Compound 35. The lactol 34 (0.1 M THF) was added to a
flame-dried flask equipped with a stir bar and cooled to 0 °C.
LiAlH4 (2 equiv) was added to the reaction mixture and stirred
for 10 min. The reaction was quenched with 1 M HCl, extracted
with chloroform, washed with brine, and dried with Mg2SO4.
1H NMR (400 MHz, CDCl3): δ 7.34-7.20 (m, 5H), 6.47 (s, 1H),
6.43 (s, 1H), 4.53-4.49 (m, 1H), 4.09-4.04 (m, 2H), 3.87-3.82
(s, 1H), 3.66 (s, 3H), 3.57-3.51 (m, 1H), 2.42-2.34 (m, 1H),
2.17-2.06 (m, 1H), 1.26-1.18 (m, 2H), 0.07 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ 148.2, 147.8, 144.2, 144.0, 128.7, 128.3,
126.6, 121.3, 112.8, 103.0, 66.4, 60.9, 56.9, 38.6, 36.7, 18.0,
-1.3. IR (CH2Cl2, νmax cm-1): 3591, 3319, 2955, 2898, 1618,
1507, 1466, 1450, 1411. HRMS (EI): m/z calcd for C21H30O4Si
374.1910, found 374.1907.
Compound 36. The diol 35 was added to a flask containing
a stir bar and freshly prepared CH2N2 (10 equiv, 0.43 M Et2O)
open to the atmosphere. The reaction was monitored by thin-
layer chromatography, and CH2N2 was added until the reac-
tion was complete (∼12 h). The reaction mixture was concen-
trated in vacuo and chromatographed on silica gel with
petroleum ether/EtOAc (9:1). [R]D ) +41 (c ) 0.37, CHCl3).
1H NMR (400 MHz, CDCl3): δ 7.44-7.16 (m, 5H), 6.68 (s, 1H),
6.47 (s, 1H), 4.53-4.49 (m, 1H), 4.14-4.13 (m, 2H), 3.74 (s,
3H), 3.72 (s, 3H), 2.90-2.87 (m, 2H), 2.45-2.39 (m, 2H), 1.24-
1.21 (m, 2H), 0.12 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 151.4,
147.5, 144.9, 128.5, 128.2, 126.2, 124.7, 113.2, 100.0, 76.7, 66.9,
61.3, 57.1, 57.0, 38.8, 37.9, 18.1, -1.2. IR (CH2Cl2, νmax cm-1):
3688, 3053, 2955, 2933, 1607, 1506, 1274. HRMS (EI): m/z
calcd for C22H32O4Si 388.5726, found 388.2083.
δ 151.4, 147.6, 143.8, 143.5, 140.8, 128.7, 128.3, 126.2, 123.6,
116.2, 114.1, 100.1, 66.7, 57.0, 57.0, 47.4, 18.1, -1.2. IR (CH2-
Cl2, νmax cm-1): 3053, 2956, 2905, 1608, 1506, 1465, 1448, 1340,
1312, 1250, 1209, 1180. HRMS (EI): m/z calcd for C22H3003Si
370.1960, found 370.1953.
(R)-(+)-Mimosifoliol (2). The ether 38 (0.1 M DMF) was
added to a flame-dried flask equipped with a stir bar and CsF
(2 equiv). The reaction was stirred at 100 °C for 6 h. The
reaction was diluted with H2O, extracted with Et2O, washed
with brine, and dried with MgSO4. [R]D ) +20 (c ) 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): δ 7.29-7.17 (m, 5H), 6.64 (s, 1H),
6.57 (s, 1H), 6.31-6.24 (m, 1H), 5.56 (s, 1H), 5.21-5.20 (m,
1H), 5.11-5.09 (m, 1H), 4.94-4.90 (m, 1H), 3.79 (s, 3H), 3.69
(s, 3H).
Compound 40. A flame-dried flask equipped with a stir
bar and a nitrogen line containing phenol 39 (0.1 M CH2Cl2),
Hunig’s Base (0.6 equiv), DMAP (0.05 equiv), and BOC2O (1.2
equiv) was stirred overnight. The reaction was quenched with
1 M NH4Cl and extracted twice with CH2Cl2. The organic layer
was washed with water and brine, dried over MgSO4, and
concentrated in vacuo. The crude mixture was then chromato-
graphed on silica gel, eluting with petroleum ether/EtOAc (9:
1
1). H NMR (400 MHz, CDCl3): δ 10.15 (s, 1H), 7.68 (s, 1H),
7.43 (d, 1H, J ) 8 Hz), 7.15 (d, 1H, J ) 8 Hz), 2.18 (s, 3H),
1.58 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 189.1, 151.7, 150.2,
136.6, 136.2, 131.0, 128.0, 123.0, 84.6, 27.9, 20.9. IR (CH2Cl2,
νmax cm-1): 2980, 2932, 2868, 1761, 1695, 1607, 1585, 1495,
1396, 1371, 1283, 1236, 1148. HRMS (EI) (M+ + H): m/z calcd
for C13H17O4 237.1049, found 237.1121.
Compound 41. General Procedure for Chroman Syn-
thesis (Method A). 1H NMR (400 MHz, CDCl3): δ 7.32-7.07
(m, 10H), 6.90 (d, 1H, J ) 8 Hz), 6.74 (d, 1H, J ) 8 Hz), 4.50-
4.48 (m, 1H), 3.77-3.66 (m, 2H), 2.51-2.34 (m, 2H), 2.10 (s,
3H), 1.90-1.27 (m, H). 13C NMR (100 MHz, CDCl3): δ 151.5,
144.7, 144.4, 129.9, 129.7, 128.9, 128.5, 128.3, 128.3, 126.6,
126.5, 125.6, 117.1, 101.0, 84.3, 51.6, 41.3, 37.2, 35.0, 32.8, 26.0,
25.5, 20.7. IR (CH2Cl2, νmax cm-1): 3050, 2910, 2805, 1501,
1409. HRMS (EI): m/z calcd for C28H30O2 398.2246, found
398.2234.
Compound 37. The alcohol 36 (0.1 M) was added to a
flame-dried round-bottom flask equipped with a stir bar.
PhSeCN (1.05 equiv) and BBu3 (1.1 equiv) were added to the
reaction mixture and allowed to stir for 2 h. The reaction
mixture was concentrated in vacuo and chromatographed in
1
petroleum ether/EtOAc (9:1). H NMR (400 MHz, CDCl3): δ
7.44-7.16 (m, 10H), 6.68 (s, 1H), 6.47 (s, 1H), 4.47-4.45 (m,
1H), 4.12-4.08 (m, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 2.86-2.82
(m, 2H), 2.39-2.37 (m, 2H), 1.21-1.17 (m, 2H), 0.077 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 151.6, 147.5, 144.4, 143.9,
132.5, 130.6, 129.2, 128.5, 128.2, 126.8, 126.2, 124.3, 112.9,
100.0, 66.9, 57.1, 56.7, 43.4, 35.8, 26.1, 18.1, -1.22. IR (CH2-
Cl2, νmax cm-1): 2954, 2904, 1609, 1580, 1507, 1494, 1478, 1466,
1449, 1438, 1400, 1314, 1273, 1250, 1181, 1130. HRMS (EI):
m/z calcd for C28H36O3SeSi 528.1599, found Se76 524.1630.
Compound 38. The selenide 37 (0.5 M 1:1/H2O:MeOH) was
added to a flask equipped with a stir bar, NaIO4 (1.05 equiv),
and NaHCO3 (2 equiv). THF was added dropwise until the
reaction became transparent. The reaction was then stirred
at 70 °C for 8 h. The reaction was extracted with Et2O and
Compound 42. General Procedure for Chroman Hy-
1
drolysis. H NMR (400 MHz, CDCl3): δ 7.36-7.19 (m, 5H),
6.94 (d, 1H, J ) 8 Hz), 6.77 (d, 1H, J ) 8 Hz), 6.58 (s, 1H),
5.63 (bs, H), 2.05 (s, 3H). IR (CH2Cl2, νmax cm-1): 3410, 3020,
2925, 1605, 1498, 1447, 1205, 1010. HRMS (EI): m/z calcd for
C16H16O2 240.1150, found 240.1140.
Acknowledgment. A research grant from the Na-
tional Science Foundation (Career-0135031) is greatly
appreciated.
Supporting Information Available: General methods
are provided along with full spectral data (1H and 13C NMR,
IR, and HRMS) for compounds 16-33, 35-38, 40 and 41; 1H
1
chromatographed in petroleum ether/EtOAc (95:5). H NMR
1
NMR and HRMS for 34 and 42; and H NMR spectral data
(400 MHz, CDCl3): δ 7.29-7.19 (m, 5H), 6.69 (s, 1H), 6.52 (s,
1H), 6.32-6.25 (m, 1H), 5.22-5.19 (m, 1H), 5.11-5.09 (m, 1H),
4.95-4.91 (s, 1H), 4.14-4.10 (m, 2H), 3.76 (s, 3H), 3.71 (s, 3H),
1.26-1.19 (m, 2H), 0.08 (s, 9H). 13C NMR (100 MHz, CDCl3):
for 1. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO048703C
J. Org. Chem, Vol. 69, No. 26, 2004 9203