Synthesis of bicyclic ortho esters by epoxy ester rearrangements and study of their ring-opening reactions

Full text of DOI:10.1021/jo005665y

J . Org. Chem. 2001, 66, 337-343
337
Syn th esis of Bicyclic Or th o Ester s by
Ep oxy Ester Rea r r a n gem en ts a n d Stu d y of
Th eir Rin g-Op en in g Rea ction s
Peter Wipf* and Diana C. Aslan
Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
We have recently reported a facile synthesis of 2,7,8-
trioxabicyclo[3.2.1]octanes (ABO-esters) via cationic zir-
conocene-catalyzed rearrangement of epoxy esters (eq
3).2f,7,8 ABO-esters display a higher acid stability com-
pwipf+@pitt.edu
Received September 29, 2000
In tr od u ction
Ortho esters represent a class of masked acid deriva-
tives that greatly modify the reactivity pattern of the
parent carboxylates and permit entry into a much
broader range of nucleophilic and electrophilic transfor-
mations.1 However, ortho esters have found surprisingly
little use in organic synthesis to date, and much of their
chemistry remains to be explored.2 Since ortho esters are
among the few carboxylic acid protective groups that
demonstrate a high level of stability toward strong
nucleophiles and bases, most current applications have
been limited to protective group chemistry.3 While a
broad use of ortho esters may have been complicated by
the difficulty and low yields in their preparation from
acids or nitriles and alcohols, the Pinner reaction, fol-
lowed by ortho ester exchange processes, represents a
useful general strategy (eq 1).4 Corey’s OBO-ester pro-
pared to OBO-esters and are selectively cleaved in the
presence of cationic zirconocene.7 This orthogonal protec-
tive group profile and the possibility to cleave the five-
membered ring preferentially to the six-membered ring
in the [3.2.1] bicyclic framework provide new opportuni-
ties for the use of ortho esters as protective groups and
in synthetic methodology.2f We now report new applica-
tions of the zirconocene-catalyzed epoxy ester rearrange-
ment for the preparation of ortho ester scaffolds as well
as some explorative studies for the selective ring opening
with organometallic reagents.
Resu lts a n d Discu ssion
Acylation of the enantiopure alcohol 2 derived from (S)-
citramalate via triol 19a with hydrocinnamic acid, acetal
hydrolysis, and mesylation of the primary alcohol fol-
lowed by base-induced cyclization provided the epoxy
ester 5 in high overall yield (Scheme 1). Addition of 0.01
equiv of AgClO4 to a solution of 5 and 0.10 equiv of Cp2-
ZrCl2 in CH2Cl2 led to the in situ formation of a cationic
zirconocene species that served as a selective Lewis acid
for the rearrangement of epoxy ester into the ortho ester
moiety.7,8,10,11 Small amounts of the tetrahydrofuran ester
side product formed in this transformation were removed
by exposure of the crude reaction mixture to 1 M LiOH.7
The (1S,5R)-2,7,8-trioxabicyclo[3.2.1]octane 6 was thus
obtained in 24% overall yield from acetal 2.
A shortened route was used for the preparation of
racemic 6 (Scheme 2). Esterification of the commercially
available homoallylic alcohol 7 with hydrocinnamic acid
and epoxidation with m-CPBA led to (()-5, which was
rearranged to ortho ester (()-6 in 82% yield. Since the
latter reaction was performed on considerably larger
scale, the product was formed in higher yield and did not
require the purification by saponification necessary for
optically active 6.
tocol, e.g., the BF3-etherate mediated preparation of the
2,6,7-trioxabicyclo[2.2.2]octane ring system from oxetanyl
esters, allows the conversion of functionalized carboxyl-
ates into ortho esters and has found wide application (eq
2).5,6
(1) For representative recent examples, see: (a) Zhu, J .; Munn, R.
J .; Nantz, M. H. J . A(1).For representative recent examples, see: (a)
Zhu, J .; Munn, R. J .; Nantz, M. H. J . Am. Chem. Soc. 2000, 122, 2645.
(b) Kanoh, S.; Nishimura, T.; Kita, Y.; Ogawa, H.; Motoi, M.; Takani,
M.; Tanaka, T. J . Org. Chem. 2000, 65, 2253. (c) Oku, A.; Numata, M.
J . Org. Chem. 2000, 67, 1899. (d) Andres, J . M.; de Elena, N.; Pedrosa,
R. Tetrahedron 2000, 56, 1523-1531. (e) Ito, H.; Sato, A.; Kusanagi,
T.; Taguchi, T. Tetrahedron Lett. 1999, 40, 3397.
(2) Reviews: (a) DeWolfe, R. H. In Carboxylic Ortho Acid Deriva-
tives; Academic Press: New York, 1970. (b) DeWolfe, R. H. Synthesis
1974, 153. (c) Pindur, U.; Mu¨ller, J .; Flo, C.; Witzel, H. Chem. Soc.
Rev. 1987, 16, 75. (d) Kantlehner, W. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 6, p 485. (e) Scarpati, R.; Iesce, M. R.; Cermola, F.; Guitto,
A. Synlett 1998, 17. (f) Wipf, P.; Tsuchimoto, T.; Takahashi, H. Pure
Appl. Chem. 1999, 71, 415.
(3) (a) Kocienski, P. J . Protecting groups; Thieme Verlag: Stuttgart,
1994. (b) Greene, T. W.; Wuts, P. G. M. Protective groups in organic
synthesis, 3rd ed.; Wiley: New York, 1999.
(4) Voss, G.; Gerlach, H. Helv. Chim. Acta 1983, 66, 2294.
(5) Corey, E. J .; Raju, N. Tetrahedron Lett. 1983, 24, 5571.
(6) (a) Luo, Y.; Blaskovich, M. A.; Lajoie, G. A. J . Org. Chem. 1999,
64, 6106. (b) Fenk, C. J . Tetrahedron Lett. 1999, 40, 7955. (c) Ducray,
P.; Lamotte, H.; Rousseau, B. Synthesis 1997, 404. (d) Charette, A.
B.; Chua, P. Tetrahedron Lett. 1997, 38, 8499. (e) Dube´, D.; Deschenes,
D.; Tweddell, J .; Gagnon, H.; Carlini, R. Tetrahedron Lett. 1995, 36,
1827.
(7) Wipf, P.; Xu, W.; Kim, H.; Takahashi, H. Tetrahedron 1997, 53,
16575.
(8) Wipf, P.; Xu, W. J . J . Org. Chem. 1993, 58, 5880.
(9) (a) Barner, R.; Schmid, M. Helv. Chim. Acta 1979, 62, 2384. (b)
Gill, M.; Smrdel, A. F. Tetrahedron: Asymmetry 1990, 1, 453.
(10) Wipf, P.; Xu, W. J . Org. Chem. 1993, 58, 825.
(11) Suzuki, K. Pure Appl. Chem. 1994, 66, 1557.
10.1021/jo005665y CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/13/2000

338 J . Org. Chem., Vol. 66, No. 1, 2001
Notes
Sch em e 1
Sch em e 2
different substituents from carboxylic acid precursors,
disappointingly we isolated 12a -c as racemic mixtures.
While the reasons for the lack of any transfer of
chirality from the enantiomerically pure 6 to the tertiary
alcohol 12 are not completely clear, we speculate that the
addition to twist boat conformer 913 occurs via an acyclic
oxocarbenium ion intermediate14d,15 that does not provide
any 1,5-stereoinduction (Figure 1). We have been unable
to identify Lewis acid/nucleophile conditions that would
lead to the formation of enantioenriched 11.
Our preliminary studies had indicated that ring open-
ing of (()-6 with Grignard reagents occurred stereose-
lectively and a sequential conversion from ortho ester to
the ketal and further to the tertiary alcohol was possible.2f
Indeed, exposure of 6 to an excess of MeMgCl in toluene12
at room temperature provided ketal 9 in 88% yield
(Scheme 3).13 Subsequent titanium tetrachloride assisted
cleavage of 9 with ethyl, isopropyl, and phenyl Grignard
reagents provided diols 11a -c,14,15 which were converted
to the corresponding methyl ketones by treatment with
PCC16 and fragmented to the desired tertiary alcohols
12a -c by â-elimination with piperidine. Ketal 9 is quite
acid sensitive and rearranges to the seven-membered 10.
While this sequence proceeds with good overall yields and
allows for the preparation of tertiary alcohols with three
It is possible that steric hindrance between the two
quaternary centers on twist boat 9 facilitates the ring-
opened, extended intermediate structure 13 that lacks
stereocontrol. Accordingly, we proceeded with the syn-
thesis of ortho ester analogues 14-16 that were either
less substituted or displayed a different substitution
pattern (Figure 2). A common motif of bicycles 14 and
15 was the absence of the methyl group at C(5), which
should decrease the steric hindrance for a complex
formation with a Lewis acid. Fused ring system 16
provided a more rigidified scaffold that should resist
relaxing into a twist boat conformation.
While the preparation of epoxy ester 18 proceeded
uneventfully, we were unable to obtain the kinetically
favored ortho ester 14 in the cationic zirconocene rear-
rangement and isolated the thermodynamically favored
tetrahydrofuran 19 instead in 82% yield (Scheme 4). For
the preparation of 4,4-dimethylated bicycle 15, diol 20
was monoprotected,17,18 oxidized, subjected to a Wittig
chain extension, and deprotected in 65% overall yield
(Scheme 5). After conversion to epoxy ester 22, cationic
zirconocene rearrangement at 0 °C for 30 min led to a
3:1 preference for ortho ester 15 over tetrahydrofuran 23.
If the reaction time was increased, only 23 was detected
in the reaction mixture. Purification of 15 with concomi-
tant removal of 23 was readily accomplished by treat-
ment with 1 M LiOH solution.
(12) Yeh, S.-M.; Lee, G. H.; Wang, Y.; Luh, T.-L. J . Org. Chem. 1997,
62, 8315.
(13) The structure of 9 was assigned based on COSY and NOE
experiments. CDCl3 was filtered through basic alumina in order to
remove HCl impurities that would lead to decomposition of the sample.
(14) For related acetal openings, see: (a) Lindell, S. D.; Elliott, J .
D.; J ohnson, W. S. Tetrahedron Lett. 1984, 25, 3947. (b) Elliott, J . D.;
Steele, J .; J ohnson, W. S. Tetrahedron Lett. 1985, 26, 2535. (c) Alexakis,
A.; Mangeney, P. Tetrahedron Asymmetry 1990, 1, 477. (d) Sammakia,
T.; Smith, R. S. J . Am. Chem. Soc. 1992, 114, 10998. (e) Luh, T. Y.
Synlett 1996, 201 and references therein.
A straightforward reaction sequence was developed for
the preparation of ortho ester 16. After conversion of
(15) For a related tandem cyclization/alkylation process with epoxy
ketones and epoxy esters, see: Fotsch, C. H.; Chamberlin, A. R. J . Org.
Chem. 1991, 56, 4141.
(16) Cisneros, A.; Fernandez, S.; Hernandez, J . E. Synth. Commun.
1982, 12, 833.
(17) McDougal, P. G.; Rico, J . G.; Oh, Y.-I.; Condon, B. D. J . Org.
Chem. 1986, 51, 3388.
(18) Na¨f-Mu¨ller, R.; Pickenhagen, W.; Willhalm, B. Helv. Chim. Acta
1981, 131, 1424.

Notes
J . Org. Chem., Vol. 66, No. 1, 2001 339
Sch em e 3
Sch em e 5
F igu r e 1. Mechanistic hypothesis for TiCl4-(LA)-assisted
opening of ketal 6.
lecular addition through half-chair 28 that display op-
posite facial selectivity.
F igu r e 2. Analogues of bicyclic ortho ester 6 with alternative
substitutions.
In contrast, the much more rigid tricyclic ortho ester
16 does not have the option of ring flipping, and indeed
ketals 31a and 31b were obtained as single diastereo-
mers after treatment with methyl and phenyl Grignard
reagents (Scheme 8). While standard allylation of 31a
with allyl silane in the presence of TiCl4 at -78 °C led to
a 1:1 mixture of diastereomers of 32, intramolecular
transfer of an allylsilane according to Oshima’s protocol20
provided 32 as an 8:1 mixture of diastereomers. The
major isomer was assigned based on transition state
model 33, which is in agreement with the studies by
Oshima and others on the stereochemical course of Lewis
acid-assisted nucleophilic opening of mixed acetals.14
After oxidation of the diol with PCC, â-elimination of the
resulting 2-alkoxymethylene cyclohexenone with piperi-
dine led to the tertiary alcohol 12d .
Sch em e 4
cyclohexanone to the hydroxymethylene ketone 24,19
esterification, Wittig chain extension, and epoxidation led
to ester 26, which smoothly converted to polycyclic 16
under cationic zirconocene conditions (Scheme 6).
With ortho esters 15 and 16 in hand, we explored the
ring opening reactions with Grignard reagents. Surpris-
ingly, treatment of 15 with MeMgBr and PhMgBr
resulted a 2:1 and 4:1 mixture of diastereomeric acetals
29a and 29b, respectively (Scheme 7). The use of cuprate
reagents in place of the organomagnesium derivatives did
not improve the diastereoselectivity of this substitution
reaction. In addition, treatment of 29b with allyl silane
in the presence of TiCl4 led to diol 30 as a 1:1 mixture of
diastereomers. We believe that the mediocre diastereo-
selectivity in the formation of ketal 29 from ortho ester
15 is due to a combination of intramolecular nucleophilic
addition through half-chair conformer 27 and intermo-
Con clu sion s
The formation of ortho esters with three distinctively
different carbon-oxygen bonds provides an attractive
manifold for selective functional group manipulations.
The 2,7,8-trioxabicyclo[3.2.1]octane scaffold offers the
potential for selective cleavage of C-O bonds based on
ring size. We have been able to demonstrate that this
strategy is feasible and can be applied for the preparation
of ketals as single stereoisomers and tertiary ethers in
highly diastereoenriched form. In addition, tertiary al-
(20) Fujita, K.; Inoue, A.; Shinokubo, H.; Oshima, K. Org. Lett. 1999,
1, 917.
(19) Swan, G. A. J . Chem. Soc. 1950, 1539.

340 J . Org. Chem., Vol. 66, No. 1, 2001
Notes
Sch em e 6
Et2O, the organic layer was dried (MgSO4), and the solvent was
evaporated under reduced pressure. The crude residue was
purified by chromatography on SiO2 (CH2Cl2/MeOH, 10:1) to give
pure 2 (1.54 g, 81%) as an oil: IR (neat) 3399, 2919, 1435, 1350,
1255, 1051 cm-1; 1H NMR δ 3.96-3.88 (m, 1 H), 3.84-3.72 (m,
3 H), 2.81 (bs, 1 H), 2.00-1.91 (m, 1 H), 1.77-1.62 (m, 5 H),
1.35 (s, 3 H), 0.91 (t, J ) 7.5 Hz, 3 H), 0.91 (t, J ) 7.5 Hz, 3 H);
13C NMR δ 114.0, 81.0, 75.1, 59.5, 41.2, 29.4, 29.2, 24.8, 8.5, 8.4;
HRMS (EI) calcd. for C10H20O3 188.1412, found 188.1408.
Sch em e 7
3-P h en ylp r op ion ic Acid (4S)-2-(2,2-Dieth yl-4-m eth yl[1,3]-
d ioxola n -4-yl)eth yl Ester (3). A mixture of 2 (1.00 g, 5.32
mmol), hydrocinnamic acid (1.60 g, 10.6 mmol, 2 equiv), and
DMAP (N,N-(dimethylamino)pyridine, 0.19 g, 1.60 mmol, 0.3
equiv) in 25 mL of CH2Cl2 was treated at 0 °C with EDCI (1-
(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.22
g, 6.38 mmol, 1.2 equiv). The reaction mixture was stirred at
room temperature for 15 h, quenched with water, and extracted
with Et2O. The organic layer was washed with 1 N HCl, water,
and brine, dried (Na2SO4), and concentrated under reduced
pressure. Purification of the crude residue by chromatography
on SiO2 (hexanes/Et2O, 2:1) gave pure 3 (1.34 g, 79%) as an oil:
cohols can be obtained from the latter derivatives by a
straightforward oxidation-â-elimination sequence. 2,7,8-
Trioxabicyclo[3.2.1]octanes (ABO-esters) can be readily
obtained by the cationic zirconocene-catalyzed rearrange-
ment of epoxy esters. Since chiral terminal epoxides are
available from the chiral pool or by asymmetric synthe-
sis21 and chirality is cleanly transferred to the ortho ester
carbon in the rearrangement step,2f,7 this strategy also
offers the opportunity for enantioselective ortho ester,
acetal, ether, and alcohol preparations. Ring-inversions
and bond rotations can decrease the facial selectivity of
nucleophilic additions to the cationic intermediates, and
among the various substitution patterns for ortho esters
that we explored, the fused ring system 16 appears to
provide the most effective scaffold for highly stereose-
lective functionalizations.
IR (neat) 2973, 1736, 1168, 1074 cm-1 1H NMR δ 7.27-7.15
;
(m, 5 H), 4.26-4.10 (m, 2 H), 3.75, 3.43 (AB, J ) 8.2 Hz, 2 H),
2.92 (t, J ) 7.7 Hz, 2 H), 2.58 (t, J ) 7.7 Hz, 2 H), 1.95-1.76 (m,
2 H), 1.66-1.56 (m, 4 H), 1.25 (s, 3 H), 0.89 (t, J ) 7.4 Hz, 6 H);
13C NMR δ 172.8, 140.6, 128.7, 128.5, 126.5, 113.4, 79.4, 74.8,
61.3, 38.9, 36.1, 31.1, 29.8, 29.6, 25.2, 8.7; HRMS (EI) calcd for
C
15H18O4 (M - C2H5) 291.1596, found 291.1593.
3-P h en ylp r op ion ic Acid (3S)-3,4-Dih yd r oxy-3-m eth yl-
bu tyl Ester (4). A solution of 3 (4.40 g, 13.7 mmol) in 20 mL of
THF/H2O (9:1) was treated with pTsOH (p-toluenesulfonic acid,
0.261 g, 1.38 mmol, 0.1 equiv) and heated at reflux for 4 h. The
reaction mixture was cooled to room temperature and neutral-
ized with saturated aqueous NaHCO3, the precipitate was
filtered off, and the filtrate was extracted with Et2O. The organic
layer was dried (Na2SO4) and concentrated under reduced
pressure to give 4 (1.97 g, 57%) as a yellow oil: IR (neat) 3409,
2927, 1731, 1161 cm-1; 1H NMR δ 7.32-7.19 (m, 5 H), 4.25 (t, J
) 6.7 Hz, 2 H), 3.45, 3.40 (AB, J ) 11.0 Hz, 2 H), 2.96 (t, J )
7.7 Hz, 2 H), 2.64 (t, J ) 7.8 Hz, 2 H), 2.17 (bs, 2 H), 1.93-1.73
(m, 2 H), 1.18 (s, 3 H); 13C NMR δ 173.0, 140.4, 128.6, 128.3,
126.4, 72.0, 69.9, 61.1, 36.9, 36.0, 31.0, 23.7; HRMS (EI) calcd
for C14H20O4 252.1362, found 252.1360.
Exp er im en ta l P a r t
Gen er a l Meth od s. All reactions with moisture-sensitive
compounds were conducted in oven-dried glassware under an
atmosphere of dry nitrogen. Solvents were dried by distillation
from sodium benzophenone (THF, Et2O) or from CaH2 (CH2Cl2).
n-Butyllithium solution was purchased from Aldrich in Sure-
Seal containers. Starting materials that were commercially
available were used without purification. Melting points are
uncorrected and were determined either using recrystallized
samples or samples which crystallized during concentration of
the chromatography eluents. IR spectra were recorded neat
using NaCl cells. NMR spectra were obtained at 300 MHz/75
MHz (1H/13C) in CDCl3. Analytical thin-layer chromatography
(TLC) was performed on precoated SiO2 60 F-254 plates (particle
size 0.040-0.055 mm, 230-400 mesh) and visualization was
accomplished with a 254 nm UV light or by staining with a basic
KMnO4 solution or anisaldehyde dye.
(2S)-2-Meth yl-bu ta n e-1,2,4-tr iol (1) was prepared in 72%
yield from (S)-citramalic acid according to a literature proce-
dure.9
(4S)-2-(2,2-Dieth yl-4-m eth yl-[1,3]dioxolan -4-yl)eth an ol (2).
To a solution of triol 1 (1.20 g, 1.00 mmol) in 3-pentanone (20
mL) was added at room temperature P2O5 (2.84 g, 20.0 mmol, 2
equiv). The reaction mixture was stirred at room temperature
for 5 h, another portion of P2O5 (2.84 g, 20.0 mmol, 2 equiv) was
added and stirring was continued for 10 h. The reaction mixture
was neutralized with saturated NaHCO3 and extracted with
3-P h en ylp r op ion ic Acid (2S)-2-(2-Meth yloxir a n yl)eth yl
Ester (5). A solution of diol 4 (2.1 g, 8.3 mmol) in CH2Cl2 was
treated at -10 °C with Et3N (1.7 mL, 9.9 mmol, 1.2 equiv) and
CH3SO2Cl (0.7 mL, 9.1 mmol, 1.1 equiv). After 20 min, the
mixture was diluted with Et2O (40 mL), and the organic layer
was washed with saturated aqueous NaHCO3, 1 N HCl, and
brine, dried (MgSO4), and concentrated under reduced pressure
to give 2.6 g (94%) of mesylated intermediate. A solution of this
compound (0.8 g, 2.7 mmol) in 10 mL of CH2Cl2 was treated at
room temperature with a solution of DBU (1,8-diazabicyclo[5.4.0]-
undec-7-ene, 0.4 mL, 1.1 equiv) in 10 mL of CH2Cl2. The reaction
mixture was stirred at room temperature for 4 h, diluted with
Et2O, and washed with cold (0 °C) 1 N HCl, saturated aqueous
NaHCO3 and brine. The organic layer was dried (Na2SO4) and
purified by chromatography on SiO2 (EtOAc/hexanes, 1:1) to give
1
5 (0.47 g, 82%) as an oil: IR (neat) 2965, 1736, 1163 cm-1; H
NMR δ 7.31-7.19 (m, 5 H), 4.23-4.12 (m, 2 H), 2.96 (t, J ) 7.7
Hz, 2 H), 2.64 (t, J ) 7.7 Hz, 2 H), 2.59, 2.54 (AB, J ) 4.8 Hz,
2 H),1.95-1.79 (m, 2 H), 1.32 (s, 3 H); 13C NMR δ 172.8, 140.5,
128.6, 128.3, 126.4, 61.0, 54.9, 53.6, 35.9, 35.6, 30.9, 21.2; HRMS
(EI) calcd for C14H18O3 234.1256, found 234.1249.
(21) See, for example: (a) Denmark, S. E.; Wu, Z. Synlett 1999, 847.
(b) Tokunaga, M.; Larrow, J . F.; Kakiuchi, F.; J acobsen, E. N. Science
1997, 277, 936.

Notes
J . Org. Chem., Vol. 66, No. 1, 2001 341
Sch em e 8
(1S,5R)-5-Meth yl-1-p h en eth yl-2,7,8-tr ioxa bicyclo[3.2.1]-
5-Met h yl-1-p h en et h yl-2,7,8-t r ioxa b icyclo[3.2.1]oct a n e
((6). Prepared in 82% yield (3.28 g) from (()-5 (4.00 g, 17.1
mmol), Cp2ZrCl2 (0.499 g, 1.71 mmol, 0.1 equiv), and AgClO4
(35.4 mg, 0.171 mmol, 0.01 equiv) according to the procedure
described for 6.
octa n e (6). A solution of epoxy ester 5 (0.23 g, 1.0 mmol) in 20
mL of CH2Cl2 was treated at 0 °C with Cp2ZrCl2 (bicyclopenta-
dienylzirconium dichloride, 29 mg, 0.1 mmol, 0.1 equiv) and after
5 min with AgClO4 (2.0 mg, 0.01 mmol, 0.01 equiv). The reaction
mixture was stirred at 0 °C and monitored by TLC (SiO2, C6H6/
CH2Cl2/EtOAc, 10:2:1), until the formation of the product 6 was
complete (4 h). The reaction mixture was quenched with
saturated aqueous NaHCO3, the aqueous layer was extracted
with Et2O, and the combined organic layers were dried (K2CO3)
and concentrated under reduced pressure. For purification
purposes a solution of the crude ortho ester in 10 mL of THF
was treated with aqueous 1 M LiOH at room temperature for
10 h. The reaction mixture was extracted with Et2O, dried (K2-
CO3), and concentrated under reduced pressure. The crude
residue was eluted on basic alumina with Et2O to give pure 6
(2R,4S)-(2,4-Dim eth yl-2-p h en eth yl[1,3]d ioxa n -4-yl)m eth -
a n ol (9). CH3MgBr (3 M solution in Et2O, 1.0 mL, 3.0 mmol, 3
equiv) was added dropwise at room temperature to a solution
of ortho ester 6 (0.23 g, 1.0 mmol) in 15 mL of toluene. The
reaction mixture was stirred at room temperature until the
starting material was fully consumed (30 min), diluted with Et2O
and quenched with NH4Cl. The aqueous layer was extracted
with Et2O, and the combined organic layers were dried (MgSO4)
and concentrated under reduced pressure. The oily residue was
purified by chromatography on SiO2 (hexanes/EtOAc, 4:1) to give
acetal 9 (0.22 g, 88%) as an oil: IR (neat) 3358, 2936, 1379, 1054
(0.16 g, 70%) as an oil: IR (neat) 2938, 1485, 1372, 1003 cm-1
;
1
cm-1; H NMR δ 7.31-7.19 (m, 5 H), 4.00-3.84 (m, 2 H), 3.39
1H NMR δ 7.30-7.17 (m, 5 H), 4.16-4.04 (m, 2 H), 3.89 (dd, J
) 6.6, 11.4 Hz, 1 H), 3.54 (dd, J ) 2.3, 7.1 Hz, 1 H), 2.84-2.78
(m, 2 H), 2.18-2.00 (m, 3 H), 1.47 (dd, J ) 4.1,13.5 Hz, 1 H),
1.40 (s, 3 H); 13C NMR δ 141.7, 128.3, 125.7, 120.3, 78.7, 73.8,
59.1, 37.2, 33.8, 29.6, 22.0; HRMS (EI) calcd for C14H18O3
234.1256, found 234.1266.
(d, J ) 6.1 Hz, 2 H), 2.73-2.67 (m, 2 H), 2.15-1.99 (m, 4 H),
1.44-1.40 (m, 1 H), 1.43 (s, 3 H), 1.31 (s, 3 H); 13C NMR δ 142.3,
128.5, 128.4, 125.9, 99.5, 72.9, 70.1, 56.3, 41.3, 30.8, 29.5, 26.8,
24.9; HRMS (EI) calcd for C14H19O2 (M-CH3O) 219.1385, found
219.1380. NOESY studies showed a correlation between the
methyl group from position 4 and the methylene from position
2 of the acetal ring suggesting the conformation depicted in
Scheme 3.
3-P h en ylp r op ion ic Acid 3-Meth ylbu t-3-en yl Ester (8). A
mixture of 3-methylbut-3-en-1-ol (7, 0.50 mL, 5.0 mmol), hydro-
cinnamic acid (0.90 g, 6.0 mmol, 1.2 equiv), and DMAP (0.18 g,
1.5 mmol, 0.3 equiv) in 25 mL of CH2Cl2 was treated at 0 °C
with EDCI (1.2 g, 6.0 mmol, 1.2 equiv). The reaction mixture
was stirred at room temperature for 4 h, quenched with water,
and extracted with Et2O. The organic layer was washed with 1
N HCl, water, and brine, dried (Na2SO4), and concentrated under
reduced pressure. Purification of the crude residue by chroma-
tography on SiO2 (hexanes/Et2O, 2:1) gave ester 8 (1.1 g, 96%)
2,5-Dim eth yl-2-p h en eth yl[1,3]-d ioxep a n -5-ol (10). Treat-
ment of acetal 9 (0.10 g, 0.40 mmol) with CDCl3 containing traces
of acid led to 10 (98 mg, 98%) as a 1:1 mixture of two
diastereomers, which were separated by chromatography on SiO2
(Et2O/hexanes, 1:1): IR (neat) 3380, 2936, 1052 cm-1; diastere-
omer A 1H NMR δ 7.29-7.19 (m, 5 H), 3.91-3.73 (m, 4 H), 2.76-
2.70 (m, 2 H), 2.57 (bs, 1 H), 2.00-1.91 (m, 3 H), 1.81-1.73 (m,
1 H), 1.45 (s, 3 H), 1.40 (s, 3 H); 13C NMR δ 141.9, 128.5, 128.3,
125.9, 110.9, 81.4, 75.1, 59.5. 42.1, 41.2, 30.9, 25.0; diastereomer
as an oil: IR (neat) 2968, 1736, 1454, 1162 cm-1 1H NMR δ
;
1
7.33-7.20 (m, 5 H), 4.81 (bs, 1 H), 4.73 (bs, 1 H), 4.21 (t, J ) 6.8
Hz, 2 H), 3.00 (t, J ) 7.8 Hz, 2 H), 2.64 (t, J ) 7.8 Hz, 2 H), 2.33
(t, J ) 6.8 Hz, 2 H), 1.76 (s, 3 H); 13C NMR δ 173.0, 141.8, 140.7,
128.6, 128.4, 126.4, 112.4, 62.8, 36.8, 36.0, 31.1, 22.6; HRMS
(EI) calcd for C14H18O2 234.1307, found 234.1302.
B H NMR δ 7.30-7.20 (m, 5 H), 3.98-3.74 (m, 2 H), 3.91, 3.82
(AB, J ) 8.4 Hz, 2H), 2.77-2.71 (m, 3 H), 2.01-1.95 (m, 3 H),
1.82-1.74 (m, 1 H), 1.45 (s, 3 H), 1.37 (s, 3 H);13C NMR δ 142.0,
128.5, 128.3, 125.9, 110.9, 81.5, 75.0, 59.6. 42.0, 41.3, 30.8, 25.0,
24.8; HRMS (EI) calcd for C14H19O3 (M - CH3) 235.1334, found
235.1338.
3-P h en ylp r op ion ic Acid 2-(2-Meth yloxir a n yl)eth yl Ester
((-5). A solution of ester 8 (1.1 g, 4.2 mmol) in 100 mL of CH2-
Cl2 was treated at 0 °C with m-CPBA (m-chloroperoxybenzoic
acid, 1.1 g, 6.3 mmol, 1.5 equiv). The reaction mixture was
stirred at 0 °C until the ester was consumed (4 h), diluted with
Et2O, washed with saturated aqueous NaHCO3, 10% aqueous
Na2S2O3, and again saturated aqueous NaHCO3, dried (MgSO4),
and concentrated under reduced pressure. Purification of the
crude residue by chromatography on SiO2 (hexanes/Et2O, 1:1)
gave (()-5 (0.90 g, 80%) as an oil.
4-(1-Eth yl-1-m eth yl-3-p h en ylp r op oxy)-2-m eth ylbu ta n e-
1,2-d iol (11a ). TiCl4 (0.22 mL, 2.0 mmol, 2 equiv) was added
dropwise at -78 °C to a solution of acetal 9 (0.25 g, 1.0 mmol)
in 10 mL of CH2Cl2, followed by the dropwise addition of EtMgBr
(1 M solution in Et2O, 4.0 mL). After the starting material was
consumed (15 min), the reaction was quenched with saturated
aqueous NH4Cl and extracted with Et2O. The combined organic
layers were dried (MgSO4), and the solvent was evaporated
under reduced pressure. Purification by chromatography on SiO2

342 J . Org. Chem., Vol. 66, No. 1, 2001
Notes
(hexanes/Et2O, 1:1) gave 11a (0.17 g, 60%) as an oil: IR (neat)
(0.99 g, 4.3 mmol) in 100 mL of CH2Cl2 was treated at 0 °C with
m-CPBA (1.1 g, 6.4 mmol, 1.5 equiv). The reaction mixture was
stirred at 0 °C until the ester was consumed (4 h), diluted with
Et2O, washed with saturated aqueous NaHCO3, 10% aqueous
Na2S2O3, and again saturated aqueous NaHCO3, dried (MgSO4),
and concentrated under reduced pressure. Purification of the
crude residue by chromatography on SiO2 (hexanes/Et2O, 1:1)
gave epoxy ester 22 (0.84 g, 80%) as an oil: IR (neat) 2972, 1735,
3419, 2972, 1366, 1075 cm-1 1H NMR δ 7.31-7.17 (m, 5 H),
;
3.80 (bs, 2 H), 3.70-3.40 (m, 4 H), 2.98 (bs, 2 H), 2.63-2.57 (m,
2 H), 2.01-1.88 (m, 1 H), 1.84-1.55 (m, 5 H), 1.21 (s, 3 H), 1.19
(s, 3 H), 0.90 (t, J ) 7.5 Hz, 3 H); 13C NMR δ 142.5, 128.6, 128.4,
125.9, 78.0, 72.7, 70.3, 57.5, 39.5, 38.2, 30.3, 30.2, 24.5, 22.6,
8.2; HRMS (EI) calcd for C15H23O3 (M - C2H5) 251.1647, found
251.1640.
1
1160 cm-1; H NMR δ 7.32-7.20 (m, 5 H), 3.96, 3.89 (AB, J )
3-Meth yl-1-p h en ylp en ta n -3-ol (12a ).22 A solution of tertiary
ether 11a (56 mg, 0.20 mmol) in 3 mL of CH2Cl2 was treated at
room temperature with pyridinium chlorochromate (0.34 g, 1.6
mmol, 8 equiv) and 4 Å molecular sieves (0.30 g). After being
stirred at room temperature for 2 h, the reaction mixture was
filtered through SiO2 and eluted with Et2O, and the filtrate was
evaporated to give the corresponding ketone. A solution of the
ketone (0.2 mmol) in 3.6 mL (9 equiv) of 0.5 M solution of
piperidinium acetate in benzene was heated at reflux for 2 h.
After being cooled to room temperature, the reaction mixture
was filtered through SiO2 (hexanes/Et2O, 1:1). The solvent was
removed under reduced pressure, and the crude residue was
purified by chromatography on SiO2 (hexanes/Et2O, 4:1) to give
pure 12a (23 mg, 64%) as an oil: 1H NMR δ 7.31-7.16 (m, 5 H),
2.71-2.65 (m, 2 H), 1.79-1.73 (m, 2 H), 1.57 (q, J ) 7.5 Hz,
2H),1.23 (s, 3 H), 0.94 (t, J ) 7.5 Hz, 3 H).
11.1 Hz, 2 H), 2.98 (t, J ) 7.8 Hz, 2 H), 2.82-2.80 (m, 1 H), 2.68
(t, J ) 7.7 Hz, 2 H), 2.73-2.57 (m, 2 H), 0.90 (s, 3 H), 0.87 (s, 3
H); 13C NMR δ 172.7, 140.5, 128.6, 128.4, 126.4, 70.4, 56.8, 43.7,
35.9, 34.5, 31.0, 20.4, 20.1; HRMS (EI) calcd for C15H20O3
248.1412, found 248.1409.
4,4-Dim e t h yl-1-p h e n e t h yl-2,7,8-t r ioxa b icyclo[3.2.1]-
octa n e (15) a n d 3-P h en ylp r op ion ic Acid 5,5-Dim eth yltet-
r a h yd r ofu r a n -2-yl Ester (23). According to the procedure
described for 6, oily 15 (0.13 g, 50%) and oily 23 (0.04 g, 17%)
were obtained from the epoxy ester 22 (0.25 g, 1.0 mmol). In
this case, the reaction mixture was quenched with 10% aqueous
KOH solution. 15: IR (neat) 3054, 2965, 2900, 1471, 1456, 4265,
1064, 738 cm-1; 1H NMR δ 7.38-7.25 (m, 5 H), 4.21 (d, J ) 7.7
Hz, 1 H), 4.10-4.08 (m, 1 H), 3.86-3.82 (m, 1 H), 3.80 (d, J )
11.1 Hz, 1 H), 3.42 (d, J ) 11.0, 1 H), 2.96-2.90 (m, 2 H), 2.30-
2.24 (m, 2 H), 1.36 (s, 3 H), 0.84 (s, 3 H); 13C NMR δ 142.1, 128.7,
126.1. 119.3, 81.6, 69.9, 66.3, 37.1, 32.2, 30.1, 24.4, 22.1; HRMS
(EI) calcd for C15H20O3 248.1412, found 248.1412. 23: IR (neat)
3-P h en ylp r op ion ic Acid 2-Oxir a n yleth yl Ester (18). A
mixture of but-3-en-1-ol (17, 0.43 mL, 5.0 mmol), hydrocinnamic
acid (0.90 g, 6.0 mmol, 1.2 equiv), and DMAP (0.18 g, 1.5 mmol,
0.3 equiv) in 25 mL of CH2Cl2 was treated at 0 °C with EDCI
(1.2 g, 6.0 mmol, 1.2 equiv). The reaction mixture was stirred
at room temperature for 4 h, quenched with water, and extracted
with Et2O. The organic layer was washed with 1N HCl, water,
and brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure. Purification of the crude residue by chroma-
tography on SiO2 (hexanes/Et2O, 2:1) gave the ester (0.82 g, 80%)
as an oil. A solution of this ester (0.82 g, 4.0 mmol) in 100 mL
of CH2Cl2 was treated at 0 °C with m-CPBA (1.0 g, 6.0 mmol,
1.5 equiv). The reaction mixture was stirred at 0 °C until the
ester was consumed (6 h), diluted with Et2O, washed with
saturated aqueous NaHCO3, 10% aqueous Na2S2O3 and again
with saturated aqueous NaHCO3, dried (MgSO4), and concen-
trated under reduced pressure. Purification of the crude residue
by chromatography on SiO2 (hexanes/Et2O, 1:1) gave epoxy ester
2966, 1736, 1162, 1081 cm-1 1H NMR δ 7.32-7.18 (m, 5 H),
;
4.88 (dd, J ) 2.1, 3.0 Hz, 1 H), 4.20 (dd, J ) 5.0,10.7 Hz, 1 H),
3.65 (dd, J ) 1.8, 8.7 Hz, 1 H), 3.55, 3.56 (AB, J ) 5.6 Hz, 2 H),
2.97 (t, J ) 7.7 Hz, 2 H), 2.68 (t, J ) 7.7 Hz, 2 H), 1.08 (s, 3 H),
0.97 (s, 3 H);13C NMR δ 172.7, 104.5, 128.7, 128.5, 126.6, 80.9,
78.8, 73.4, 42.5, 36.1, 31.1, 25.2, 18.9; HRMS (EI) calcd for
C15H20O3 248.1412, found 248.1413.
3-P h en ylp r op ion ic Acid 2-Oxocycloh exylm eth yl Ester
(25). A mixture of cyclohexanone (25.0 mL, 0.242 mol) and K2-
CO3 (0.502 g, 3.64 mmol, 0.015 equiv) in 50 mL of water was
stirred vigorously at 40 °C while formaldehyde (37.5 mL, 0.460
mol, 1.9 equiv, 37% aqueous solution) was added during 1 h.
Stirring was continued for 1 h; the cooled reaction mixture was
extracted with Et2O, and the organic layer was dried (MgSO4)
and concentrated under reduced pressure. The crude product
was purified by chromatography on SiO2 (EtOAc/hexanes, 1:1)
to give oily R-hydroxymethyl cyclohexanone 2418 (18.6 g, 60%).
A mixture of 24 (1.28 g, 10.0 mmol), hydrocinnamic acid (1.65
g, 11.0 mmol, 1.1 equiv), and DMAP (0.366 g, 3.00 mmol, 0.3
equiv) in 25 mL of CH2Cl2 was treated at 0 °C with EDCI (2.29
g, 12.0 mmol, 1.2 equiv). The reaction mixture was stirred at
room temperature for 15 h, quenched with water, and extracted
with Et2O. The organic layer was washed with 1 N HCl, water,
and brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure. Purification of the crude residue by chroma-
tography on SiO2 (hexanes/Et2O, 2:1) gave 25 (2.29 g, 83%) as
18 (0.70 g, 80%) as an oil: IR (neat) 2934, 1736, 1453, 1159 cm-1
;
1H NMR δ 7.32-7.21 (m, 5 H), 4.23 (t, J ) 6.3 Hz, 2 H), 3.00-
2.95 (m, 3 H), 2.77-2.74 (m, 1 H), 2.66 (t, J ) 7.7 Hz, 2 H),
2.48-2.46 (m, 1 H), 1.93-1.75 (m, 2 H); 13C NMR δ 172.8, 140.5,
128.6, 128.3, 126.4, 61.4, 49.6, 46.9, 35.9, 31.9, 31.0; HRMS (EI)
calcd. for C13H16O3 220.1099, found 220.1099.
3-P h en ylpr opion ic Acid Tetr ah ydr ofu r an -3-yl Ester (19).
According to the procedure described for compound 6, oily 19
(0.18 g, 82%) was obtained from the epoxy ester 18 (0.22 g, 1.0
mmol). In this case, no trace of the desired ortho ester 14 was
observed and the reaction was stopped when the epoxy ester 18
was fully converted to 19 (4 h). The crude residue was eluted
on basic alumina with Et2O to give pure 19: IR (neat) 3410,
1
an oil: IR (neat) 2938, 1735, 1164 cm-1; H NMR δ 7.29-7.15
(m, 5 H), 4.41-4.35 (m, 1 H), 4.07-4.01 (m, 1 H), 2.93 (t, J )
7.6 Hz, 2 H), 2.62 (t, J ) 7.6 Hz, 2 H), 2.64-2.56 (m, 1 H), 2.41-
2.23 (m, 2 H), 2.13-1.98 (m, 2 H), 1.85 (bs, 1 H), 1.70-1.60 (m,
2 H), 1.42-1.26 (m, 1 H); 13C NMR δ 210.4, 172.8, 140.5, 128.5,
128.3, 126.3, 63.3, 49.5, 42.1, 35.8, 31.0, 27.7, 24.7; HRMS (EI)
calcd for C16H20O3 260.1412, found 260.1423.
2933, 1733, 1163, 1079 cm-1 1H NMR δ 7.32-7.20 (m, 5 H),
;
5.32-5.27 (m, 1 H), 3.91-3.75 (m, 4 H), 2.96 (t, J ) 7.6 Hz, 2
H), 2.65 (t, J ) 7.5 Hz, 2 H), 2.18-2.08 (m, 1 H), 1.97-1.91 (m,
1 H); 13C NMR δ 172.7, 140.3, 128.6, 128.4, 126.4, 74.9, 73.1,
67.0, 35.9, 32.8, 30.9; HRMS (EI) calcd for C13H16O3 220.1099,
found 220.1099.
3-P h en ylp r op ion ic Acid 1-Oxa sp ir o[2.5]oct-4-ylm eth yl
Ester (26). To a suspension of Ph3PCH3I (1.6 g, 4.4 mmol) in
THF (100 mL) was added dropwise at 0 °C n-BuLi (2.8 mL, 4.4
mmol, 1.6 M in hexanes). The reaction mixture was stirred at 0
°C for 30 min and cooled to -78 °C, and a solution of ketone 25
(1.1 g, 4.0 mmol) in THF (20 mL) was added. After 1 h, the
reaction mixture was warmed to room temperature, quenched
with NH4Cl and extracted with Et2O. The organic layer was
dried (MgSO4) and concentrated under reduced pressure, and
the crude residue was filtered through a layer of SiO2 providing
the crude ester that was used in the next step without further
purification. A solution of this ester (0.65 g, 2.5 mmol) in 100
mL of CH2Cl2 was treated at 0 °C with m-CPBA (0.65 g, 3.8
mmol, 1.5 equiv). The reaction mixture was stirred at 0 °C until
the ester was consumed (4 h), diluted with Et2O, and washed
with saturated aqueous NaHCO3, 10% aqueous Na2S2O3, and
again with saturated aqueous NaHCO3, dried (MgSO4), and
2,2-Dim eth yl-bu t-3-en -1-ol (21). Prepared according to a
literature protocol in 65% yield from diol 20.18
3-P h en ylp r op ion ic Acid 2-Meth yl-2-oxir a n ylp r op yl es-
ter (22). A mixture of 2,2-dimethylbut-3-en-1-ol (21, 0.50 g, 5.0
mmol), hydrocinnamic acid (0.90 g, 6.0 mmol, 1.2 equiv), and
DMAP (0.18 g, 1.5 mmol, 0.3 equiv) in 25 mL of CH2Cl2 was
treated at 0 °C with EDCI (1.2 g, 6.0 mmol, 1.2 equiv). The
reaction mixture was stirred at room temperature for 4 h,
quenched with water and extracted with Et2O. The organic layer
was washed with 1 N HCl, water, and brine, dried (Na2SO4),
filtered and concentrated under reduced pressure. Purification
of the crude residue by chromatography on SiO2 (hexanes/Et2O,
2:1) gave the ester (0.99 g, 85%) as an oil. A solution of this ester
(22) Khalaf, A. A.; Roberts, R. M. J . Org. Chem. 1972, 37, 2384.

Notes
J . Org. Chem., Vol. 66, No. 1, 2001 343
concentrated under reduced pressure. Purification of the crude
residue by chromatography on SiO2 (hexanes/Et2O, 1:1) gave the
epoxy ester 26 (0.62 g, 57% after two steps) as an oil: IR (neat)
tive of 31b, which was used in the next step without purification.
This product (0.10 g, 0.20 mmol) was dissolved in 3 mL of CH2-
Cl2 at -78 °C and a solution of Ti(OiPr)4 (0.26 mL, 0.9 mmol, 4
equiv) and TiCl4 (98 µL, 0.90 mmol, 4 equiv) in 2 mL of CH2Cl2
were added dropwise. After 15 min, the reaction mixture was
quenched with saturated aqueous NH4Cl and worked up as
described for 30 to give 32 (46 mg, 52% from 31b) as a 8:1
mixture of diastereomers. Major isomer: IR (neat) 3424, 2933,
2934, 1736, 1454, 1290 cm-1 1H NMR δ 7.31-7.18 (m, 5 H)
;
4.20-4.14 and 4.01-3.86 (2m, 2 H), 2.94 (t, J ) 7.7 Hz, 2 H),
2.73 (d, J ) 4.5 Hz, 1 H), 2.75-2.55 (m, 2 H), 2.48 (d, J ) 4.4
Hz, 1 H), 1.95-1.42 (m, 9 H);13C NMR δ 173.0, 172.9, 140.6,
128.7, 128.5, 126.5, 64.0, 63.8, 59.2, 59.1, 53.3, 52.4, 40.7, 39.6,
36.1, 33.4, 32.7, 31.2, 27.8, 27.6, 24.9, 24.5, 23.8, 23.0; HRMS
(EI) calcd for C17H22O3 274.1569, found 274.1582.
9-P h en et h yl-8,10,12-t r ioxa t r icyclo[7.2.1.00,0]d od eca n e
(16). According to the procedure described for 6, 16 (0.24 g, 90%)
was obtained from the epoxy ester 26 (0.27 g, 1.0 mmol) as a
colorless solid: mp 49-50 °C (hexanes); IR (neat) 2936, 1447,
1299, 1180, 1016 cm-1; 1H NMR δ 7.32-7.17 (m, 5 H), 4.27 (dd,
J ) 4.5, 11.3 Hz, 1 H), 4.04 (d, J ) 7.0 Hz, 1 H), 3.52-2.48 (m,
2 H), 2.88-2.82 (m, 2 H), 2.20-2.15 (m, 2 H), 2.10-1.94 (m, 1
H), 1.88-1.42 (m, 6 H), 1.42-1.20 (m, 2 H);13C NMR δ 141.9,
128.5, 128.4, 125.8, 120.5, 80.1, 74.8, 65.0, 38.5, 37.3, 31.9, 29.8,
26.9, 25.2, 22.0; HRMS (EI) calcd for C17H22O3 274.1569, found
274.1570.
1447, 1061 cm-1 1H NMR (500 MHz) δ 7.41-7.38 (m, 4 H),
;
7.33-7.24 (m, 3 H), 7.20-7.08 (m, 3 H), 5.63-5.55 (m, 1 H),
5.31-5.10 (m, 2 H), 3.67 (d, J ) 10.0 Hz, 1 H), 3.46-3.33 (m, 4
H), 2.82-2.72 (m, 2 H), 2.54-2.38 (m, 2 H), 2.29-2.14 (m, 2 H),
1.73-1.54 (m, 6 H), 1.34-1.24 (m, 4 H); 13C NMR δ 142.7, 142.0,
132.9, 128.5, 128.4, 128.3, 127.5, 126.4, 126.0, 118.5, 81.5, 72.6,
70.1, 63.8, 53.5, 42.7, 41.3, 38.2, 35.1, 29.6, 26.3, 25.7, 21.4;
HRMS (EI) calcd for C23H29O3 (M - C3H5) 353.2117, found
353.2104.
(3R)-1,3-Dip h en ylh ex-5-en -3-ol (12d ). A solution of tertiary
ether 32 (20 mg, 51 µmol) in 2 mL of CH2Cl2 was treated at
room temperature with pyridinium chlorochromate (90 mg, 0.41
mmol) and 4 Å molecular sieves (0.10 g). After stirring at room
temperature for 2 h, the reaction mixture was filtered through
SiO2 (Et2O) and the filtrate was evaporated to give the corre-
sponding ketone. A solution of this ketone in 3 mL of toluene
was treated with piperidine (0.05 mL, 0.5 mmol) and was heated
at reflux for 48 h. After being cooled to room temperature, the
reaction mixture was filtered through SiO2 (hexanes/Et2O, 1:1).
The solvent was removed under reduced pressure and the crude
residue was purified by chromatography on SiO2 (hexanes/Et2O,
4:1) to give 12d (6.0 mg, 47%) as an oil: IR (neat) 3559, 3026,
1495, 1446, 701 cm-1; 1H NMR δ 7.58-7.46 (m, 4 H), 7.40-7.21
(m, 6 H), 5.74-5.63 (m, 1 H), 5.30-5.22 (m, 2 H), 2.90-2.78 (m,
2 H), 2.69-2.62 (m, 1 H), 2.54-2.40 (m, 1 H), 2.31-2.22 (m, 3
H);13C NMR δ 145.9, 142.8, 133.6, 128.7, 128.6, 126.9, 126.0,
125.6, 120.2, 76.0, 48.0, 44.9, 30.3; HRMS (EI) calcd for C18H18
(M - H2O) 234.1409, found 234.1414.
3,3-Dim eth yl-4-(1-p h en eth yl-1-p h en ylbu t-3-en yloxy)bu -
ta n e-1,2-d iol (30). A solution of Ti(OiPr)4 (1.2 mL, 4.0 mmol, 4
equiv) and TiCl4 (0.44 mL, 4.0 mmol, 4 equiv) in 10 mL of CH2-
Cl2 was added dropwise at -78 °C to a solution of acetal 29b
(0.33 g, 1.0 mmol) and allyl trimethylsilane (0.59 mL, 3.7 mmol,
3.7 equiv) in 10 mL of CH2Cl2. After the starting material was
consumed (1 h) the reaction mixture was quenched with aqueous
saturated NH4Cl (10 mL), extracted with Et2O, and the com-
bined organic layers were dried (MgSO4). Purification of the
crude residue by chromatography on SiO2 (hexanes/Et2O, 1:1)
gave oily 30 (0.22 g, 60%) as a 1:1 mixture of diastereomers: IR
1
(neat) 3422, 2918, 1458, 1265, 1069, 740, 739 cm-1; H NMR δ
7.43-7.09 (m, 10 H), 5.66-5.57 (m, 1 H), 5.21-5.10 (m, 2 H),
3.67-3.63 (m, 3 H), 3.17-3.10 (m, 2 H), 2.96 (bs, 2 H), 2.79 (d,
J ) 7.0 Hz, 2 H), 2.49-2.40 (m, 2 H), 2.24-2.16 (m, 2 H), 0.98
(s, 3 H), 0.96 (s, 3 H); 13C NMR δ 142.4, 142.0, 133.2, 133.0,
128.5, 128.4, 128.3, 127.4, 126.4, 126.0, 118.4, 80.7, 78.5, 78.2,
70.2, 69.9, 63.1, 63.0, 40.9, 40.7, 38.5, 37.4, 37.3, 29.5, 23.3, 20.4,
20.3; HRMS (EI) calcd for C21H27O3 327.1960, found 327.1971.
1-H yd r oxym et h yl-2-(1-p h en et h yl-1-p h en ylb u t -3-en yl-
oxym eth yl)cycloh exa n ol (32). To a solution of 31b (0.25 g,
0.7 mmol) in CH2Cl2 (20 mL) at room temperature were added
successively imidazole (48 mg, 0.7 mmol, 1 equiv), DMAP (9.0
mg, 0.07 mmol, 0.1 equiv) and dimethylallylchlorosilane (0.13
mL, 0.90 mmol, 1.2 equiv), and the reaction mixture was stirred
at room temperature for 1 h. The solution was quenched with
saturated aqueous NH4Cl and extracted with Et2O. The com-
bined organic layers were dried (MgSO4) and the solvent was
evaporated under reduced pressure to give the silylated deriva-
Ack n ow led gm en t. This work was supported by the
National Science Foundation (CHE-9453461). We thank
Dr. Teruhisa Tsuchimoto for obtaining preliminary data
on the nucleophilic substitution of ortho esters with
Grignard reagents.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
tocols and spectral characterization for 11b,c, 12b,c, 29a ,b,
1
and 31a ,b; H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O005665Y