Asymmetric induction via an intramolecular haloetherification reaction of chiral ene acetals: A novel approach to optically active 1,4- and 1,5-diols

Article abstract of DOI:10.1021/jo960714l

An asymmetric synthesis of chiral 1,4- and 1,5-diols has been developed from the ene acetals 1a and 1c, prepared from the corresponding aldehydes and chiral C₂-symmetric diols, involving remote asymmetric induction as a key step. In the first step, treatment of 1 with I(coll)₂ClO₄ in the presence of an alcohol afforded the macrocyclic acetals (3-5 and 7) in a highly stereoselective manner. Subsequent nucleophilic substitution of iodide followed by a Grignard reaction with complete retention of stereochemistry and a final deprotection of the diphenylethylene or diphenylpropylene unit successfully gave optically active 1,4- and 1,5-diols in good yields.

Full text of DOI:10.1021/jo960714l

J . Org. Chem. 1996, 61, 7309-7315
7309
Asym m etr ic In d u ction via a n In tr a m olecu la r Ha loeth er ifica tion
Rea ction of Ch ir a l En e Aceta ls: A Novel Ap p r oa ch to Op tica lly
Active 1,4- a n d 1,5-Diols
Hiromichi Fujioka,* Hidetoshi Kitagawa, Yasushi Nagatomi, and Yasuyuki Kita*
Faculty of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565, J apan
Received April 18, 1996X
An asymmetric synthesis of chiral 1,4- and 1,5-diols has been developed from the ene acetals 1a
and 1c, prepared from the corresponding aldehydes and chiral C2-symmetric diols, involving remote
asymmetric induction as a key step. In the first step, treatment of 1 with I(coll)2ClO4 in the presence
of an alcohol afforded the macrocyclic acetals (3-5 and 7) in a highly stereoselective manner.
Subsequent nucleophilic substitution of iodide followed by a Grignard reaction with complete
retention of stereochemistry and a final deprotection of the diphenylethylene or diphenylpropylene
unit successfully gave optically active 1,4- and 1,5-diols in good yields.
Sch em e 1
In tr od u ction
Nucleophilic addition to a carbocation or oxonium ion,
formed by C-O bond fission of an acetal, has been
recognized as a useful synthetic tool in organic chemistry,
and many variants have been developed so far. In these
reactions, a Lewis acid is usually used as an initiator to
accelerate the cleavage of an acetal.1 Cationic species,
formed by electrophilic addition of halonium ion to a
double bond, have also been developed as initiators to
cleave an acetal, since Fraser-Reid et al. had recently
reported that a remote double bond can cleave an acetal
under neutral, oxidative conditions through an intramo-
lecular haloetherification reaction.2 On the other hand,
asymmetric synthesis using chiral acetals from C2-
symmetric diols has been vigorously studied as an
important approach to optical active compounds.3 This
transformation involves two types of reactions: (1) an
asymmetric reaction involving cleavage of the C-O bond
of the acetal, which functions as the chiral synthetic
equivalent of a carbonyl group, and (2) asymmetric
induction on a neighboring prochiral center. However,
no report that involves these two types of reactions has
been published. Also, in the type-1 reactions, only a
Lewis acid was used to cleave an acetal, not a carbo-
cation.
cyclic acetal with two newly formed asymmetric centers.
This reaction is unprecedented as it involves two types
of reactions using C2-symmetric acetals (Scheme 1).4
To develop this chemistry, we studied the transforma-
tion of several ene acetals and found that the ene acetal
1a (cf. Table 1) derived from chiral hydrobenzoin in the
case of n ) 1 and the ene acetal 1c (cf. Table 2) derived
from chiral 1,3-diphenyl-1,3-propanediol in the case of n
) 2 were found to be best substrates for affording cyclic
mixed acetals with high diastereoselectvity (Scheme 2,
first step). After substitution of the iodide by the
nucleophile, the alkoxy group of the mixed acetal was
then converted to an alkyl group by Grignard substitution
(Scheme 2, second step). Finally, deprotection of the
diphenylethylene or diphenylpropylene unit gave chiral
1,4- or 1,5-diols, respectively (Scheme 2, third step). We
present here the full details of our results5 and the formal
synthesis of Solenopsin A,6 which is isolated from the
venom secreted by the fire ant Solenopsis invicta, and
the synthesis of a civet constituent.7
It occurred to us that the intramolecular haloetheri-
fication reaction of the ene acetal 1 prepared from a C2-
symmetric diol in the presence of an alcohol could proceed
by the cascade of cationic intermediates i w ii to give a
X Abstract published in Advance ACS Abstracts, September 15, 1996.
(1) For examples, see: (a) Kotsuki, H. Synlett 1992, 97. (b) Mu-
kaiyama, T.; Murakami, M. Synthesis 1987, 1043. (c) Mukaiyama, T.
Org. React. 1982, 28, 203.
(2) For studies of halonium ion mediated neighboring group activa-
tion of acetal cleavage, see: (a) Robert, M.; Udodong, U. E.; Roberts,
C.; Mootoo, D. R.; Konradsson, P.; Fraser-Reid, B. J . Am. Chem. Soc.
1995, 117, 1554. (b) Roberts, C.; Madsen, R.; Fraser-Reid, B. J . Am.
Chem. Soc. 1995, 117, 1546. (c) Madsen, R.; Fraser-Reid, B. J . Org.
Chem. 1995, 60, 772. (d) Fraser-Reid, B.; Udodong, U. E.; Wu, Z.;
Ottosson, J .; Merritt, J . R.; Rao, C. S.; Roberts, C. Synlett 1992, 927.
(e) Zhang, H.; Wilson, P.; Shan, W.; Ruan, Z.; Mootoo, D. R. Tetrahe-
dron Lett. 1995, 36, 649. (f) Wilson, P.; Shan, W. F.; Mootoo, D. R. J .
Carbohydr. Chem. 1994, 13, 133. (g) Elvey, S. P.; Mootoo, D. R. J . Am.
Chem. Soc. 1992, 60, 9685. (h) Mootoo, D. R.; Date, V.; Fraser-Reid,
B. J . Chem. Soc., Chem. Commun. 1987, 1462. References e-h include
the reactions of remote stereocontrol.
(4) For our representative studies using the chiral C2-symmetric
acetals, see: (a) Fujioka, H.; Kitagawa, H.; Yamanaka, T.; Kita, Y.
Chem. Pharm. Bull. 1992, 40, 3118. (b) Fujioka, H.; Annoura, H.;
Murano, K.; Kita, Y.; Tamura, Y. Chem. Pharm. Bull. 1989, 37, 2047.
(c) Tamura, Y. Annoura, H.; Yamamoto, H.; Kondo, H.; Kita, Y. Fujioka,
H. Tetrahedron Lett. 1987, 28, 5709. (d) Tamura, Y. Annoura, Fujioka,
H. Tetrahedron Lett. 1987, 28, 5681. (e) Tamura, Y.; Ko, T.; Kondo,
H.; Annoura, H.; Fuji, M.; Takeuchi, R.; Fujioka, H. Tetrahedron Lett.
1986, 27, 2117. (f) Tamura, Y.; Kondo, H.; Annoura, H.; Takeuchi, R.;
Fujioka, H. Tetrahedron Lett. 1986, 27, 81.
(5) The preliminary stereoselective synthesis of optically active 1,4-
diols has been recently communicated: Fujioka, H.; Kitagawa, H.;
Matsunaga, N.; Nagatomi, Y.; Kita, Y. Tetrahedron Lett. 1996, 37,
2245.
(3) For reviews on the asymmetric synthesis using the chiral C2-
symmetric acetals, see: (a) Alexakis, A.; Mangeny, P. Tetrahedron:
Asymmetry 1990, 1, 477. (b) Fujioka, H.; Kita, Y. Studies in Natural
Product Chemistry; Atta-ur-Rahman, Elsevier, Ed.; Amsterdam: 1994;
Vol. 14, p 469.
(6) Solladie´, G.; Huser, N. Recl. Trav. Chim. Pays-Bas 1995, 114,
153 and references therein.
S0022-3263(96)00714-1 CCC: $12.00 © 1996 American Chemical Society

7310 J . Org. Chem., Vol. 61, No. 21, 1996
Fujioka et al.
Ta ble 1. Rea ction of 1a w ith Electr op h ile in th e
P r esen ce of a n Alcoh ol
Sch em e 2
yield, selectivitya
entry electrophile
R
product
%
(a :b:c:d )b
1
2
3
4
NBS
I(Coll)2ClO4 Me
I(Coll)2ClO4 Bn
Me
2 (X ) Br) 95
74:8:18:0
85:3:12:0
90:10c
3 (X ) I)
4 (X ) I)
86
74
90
I(Coll)2ClO4 MeOCH2CH2 5 (X ) I)
86:2:11:1
a
b
Determined by 1H NMR studies and HPLC analysis. For a ,
b, c, and d , see Scheme 5. c The ratio is a + b:c + d . Determined
by converting the product to the corresponding aldehyde by acid
hydrolysis.
Sch em e 3
Resu lts a n d Discu ssion
F ir st Step : Ha loeth er ifica tion Rea ction . Initially,
the haloetherification reaction of 1a which has a chiral
hydrobenzoin8 as an auxiliary was studied. Electrophiles
9
such as NBS and I(coll)2ClO4 gave the cyclic mixed
acetals (2-5) in the presence of ROH. The reaction using
I2 gave the product of addition of I2 to the double bond.
As shown in Table 1, I(coll)2ClO4 proved to be a better
choice than NBS in terms of diastereoselectivity (entry
1 vs 2). Several alcohols were examined in this reaction,
and the stereoselectivities are similar (entries 2-4). The
structures of the major products (a ) were determined by
1H NMR study and conversion to a known compound10
and shown in Table 1 (for the structures of b, c, and d ,
see Scheme 5).11
the acetal oxygen atom and the cation formed on the
double bond in 1b prevents the formation of a bicyclic
cationic intermediate like A in 1a 12 and (2) the 5,6-
membered bicyclic cationic intermediate B′ is more
unstable than the 5,5-membered one A. We then pre-
pared the ene acetal 1c derived from chiral 1,3-diphenyl-
1,3-propanediol,13 hoping that the 6,6-membered bicyclic
intermediate C is more stable and more easily formed
(Scheme 4).14
Furthermore, the reaction of 1b prepared from chiral
hydrobenzoin and 5-hexenal was studied. In this case,
only normal haloetherification reaction products 6 were
obtained with no diastereoselectivity (Scheme 3).
The different reactivity between 1a and 1b might be
rationalized as follows: (1) the longer distance between
Sch em e 4
(7) For previous synthesis of the optically active natural product,
see: (a) Keinan, E.; Seth, K. K.; Lamed, R. J . Am. Chem. Soc. 1986,
108, 3474. (b) Seebach, D.; Pohmakotr, M. Helv. Chim. Acta 1979, 62,
1096. (c) Lichtenthaler, F. W.; Klingler, F. D.; J arglis, P. Carbohydr.
Res. 1984, 132, C1.
(8) Chiral hydrobenzoin is readily available in both enantiomeric
forms by asymmetric synthesis or resolution; for asymmetric synthesis,
see, Wang et al. (Wang, Z. -M.; Sharpless, K. B. J . Org. Chem. 1994,
59, 8302) and for resolution of dl-hydrobenzoin, see Optical Resolution
Procedures for Chemical Compounds; Mewman, P., Optical Information
Center: Manhattan College, Riverdale, NY 1984; Vol. 3, p 353.
(9) Preparation: Lemieux, R. U.; Morgan, A. R. Can. J . Chem. 1965,
43, 2190.
As expected, although a higher temperature (-20 °C)
was necessary compared to 1a (-78 °C) and the selectiv-
ity was slightly reduced, the reaction of 1c proceeded
successfully to give cyclic acetal 7 in good yields (Table
2). In this case, CH3CN is the solvent of choice (entry 1
vs 2), and bis(sym-collidine)iodine hexafluorophosphate
[I(coll)2PF6]15 showed the best stereoselectivity and re-
activity (entry 4). The structure of the major product 7
was determined by conversion to the known compounds
(10) The stereochemistries of the major products a were determined
from the NOE experiment on 8a (Table 3) derived from 5a . The
stereochemistries of the halomethyl substituent were determined by
(12) A similar result was reported by B. Fraser-Reid et al. They
suggested that the formation of the 6-membered oxonium ion was
slower than that of the 5-membered one (see ref 2d).
(13) Optically active 1,3-diphenyl-1,3-propanediol is available in both
enantiomeric forms by asymmetric synthesis or microbial resolution;
for asymmetric synthesis, see, Wang et al. (Wang, Z. -M.; Ito, K.;
Harada, T.; Tai, A. Bull. Chem. Soc. J pn. 1980, 53, 3367) and for
microbial resolution, see: Yamamoto, K.; Ando, H.; Chikamatsu, H.
J . Chem. Soc., Chem. Commun. 1994, 334.
converting 5 to the (R)-enriched-pentane-1,4-diol {[R]23 -10° (c 0.46,
D
MeOH) lit. [R]21D -13.4° (c 1.05, MeOH); Kitahara, T.; Mori, K.; Matsui,
M. Tetrahedron Lett. 1979, 32, 3021} in a three-step sequence: (1)
acid hydrolysis, (2) LiAlH4 reduction, and (3) hydrogenolysis.
(14) There is another possible 6,5-membered bicyclic intermediate
from reaction of the acetal derived from 4-pentenal and 1,3-diphenyl-
1,3-propanediol. We did not feel it necessary to examine its reaction
in order to develop the asymmetric synthesis of 1,4-diols.
(15) Bis(sym-collidine)iodine(I) hexafluorophosphate (I(coll)2PF6) is
also used during halolactonization, see: Simonot, B.; Rousseau, G. J .
Org. Chem. 1994, 59, 5912.
(11) The structures of b, c, and d were postulated from consideration
of the reaction mechanism and the assignment is tentative.

Asymmetric Induction via Intramolecular Haloetherification
J . Org. Chem., Vol. 61, No. 21, 1996 7311
Ta ble 2. Rea ction of 1c w ith Electr op h ile in th e
P r esen ce of MeOCH2CH2OH
Ta ble 3. Nu cleop h ilic Su bstitu tion of Iod id e
yield,
%
entry
I+
solvent
temp, °C yield, % selectivitya
entry
substr
conditions
product
1
2
3
I(coll)2ClO4 CH2Cl2 -78 °C-rt
I(coll)2ClO4 CH3CN -20 °C-rt
I(coll)2ClO4 CH3CN
57
66
74
76:4:18:2
78:9:14:1
78:11:10:1
1
2
3
5 (n ) 0) LiAlH4, THF
R1 ) H (8a )
72
70
65
5 (n ) 0) NaCN, DMSO R1 ) CN (8b)
0 °C-rt
5 (n ) 0) NaH, CH2-
(CO2Me)2
R1 ) CH(CO2Me)2
4
I(coll)2PF6 CH3CN -20 °C-rt
NIS CH3CN -20 °C-rt
85
41
80:6:12:2
(8c)
4
5
6
7 (n ) 1) LiAlH4, THF
R1 ) H (8d )
79
82
79
5
72:12:15:1
7 (n ) 1) NaCN, DMSO R1 ) CN (8e)
7 (n ) 1) NaH, CH2-
R1 ) CH(CO2Me)2
(8f)
a
Determined by chiral HPLC (Celamospher chiral Ru-1) analy-
(CO2Me)2
sis of the reductive derivative 8d .
(11 and 15) and by postulating that the reaction pro-
ceeded through an SN2-type attack of an alcohol to the
bicyclic oxonium ion C as observed in the reaction of 1a
(see the section Reaction Mechanism).
Rea ction Mech a n ism . The plausible reaction mech-
anism in the case of 1a is shown in Scheme 5. First,
7, involving four stereoisomers respectively, with several
nucleophiles proceeded without any problem by known
procedures. The results are summarized in Table 3. At
this stage, 8a -f were obtained in a pure state and the
yields shown in Table 3 are the yields of pure 8a -f.
We next studied the nucleophilic replacement of the
alkoxy group of 8a and 8d with carbon nucleophiles.
Grignard reagents17 reacted at the acetal carbon and
substitution occurred in good yields with complete reten-
tion of stereochemistry to give 9 (Table 4).18 A long chain
Sch em e 5
Ta ble 4. Gr ign a r d Rea ction of 8
entry
substr
R2
product
yield, %
1
2
3
4
8a (n ) 0)
8a (n ) 0)
8a (n ) 0)
8a (n ) 0)
Me
Et
allyl
9a
9b
9c
9d
96
87
92
86
5
6
7
8
8d (n ) 1)
8d (n ) 1)
8d (n ) 1)
8d (n ) 1)
Me
Et
allyl
9e
9f
9g
9h
90
90
98
97
C
11H23
addition of the halonium ion to the double bond followed
by attack of one of the acetal oxygen atoms forms the
bicyclic oxonium ion intermediate A or A′. Subsequent
SN2-type attack of an alcohol to A or A′ occurs to give
the 8-membered acetal (a > b, c > d ). In view of the
fact that this reaction gives rise exclusively to 8-mem-
bered acetal a as the major product, we think that
intermediate A should be more favorable than A′ (Scheme
5, a + b > c + d ). In the case of 1c, the reaction might
proceed in a similar way through the most stable
intermediate C among the possible bicyclic intermediates
(Scheme 6).16
carbon nucleophile can be introduced without any prob-
lem (entry 8). In these reactions, the methoxyethoxy
group is essential since the derivatives with a methoxy
group or benzyloxy group derived from 3 or 4 by LiAlH4
reduction showed disappointing results (with MeMgI;
(16) We performed MO calculations for all of possible 6,6-membered
bicyclic oxonium ions by SPARTAN (version 3.1.2) using the AM1
Hamiltonian. The results showed that the cis-decalin form intermediate
C is the most stable among the others involving trans-decalin form
intermediates. (The heat of formation of C was 145.71 kcal/mol. The
others were 146.80 kcal/mol for another cis-decalin form intermediate
and 148.79, 151.16 kcal/mol for trans ones.) These calculational results
were consistent with our experimental results. We think that the
stability of bicyclic intermediates has a large influence on the reaction
of 1c. We also performed MO calculations on 5,5-membered bicyclic
intermediates. In these cases, the intermediate A′ was more stable
than A. (The heat of formation of A was 159.30 kcal/mol, and of A′
was 157.18 kcal/mol.) This calculational result did not fit with our
experimental results. It is probable that the repulsion between the
halomethyl substituent and anion species, which should exist on the
convex side of the cation, has a large influence on the reaction of 1a
and makes the formation of A′ undesirable.
Sch em e 6
(17) For the reaction of a Grignard reagent and an acetal, see: Yuan,
T.-M.; Yeh, S.-M.; Hsieh, Y.-T.; Luh, T.-Y. J . Org. Chem. 1994, 59, 8192
and references therein.
Secon d Step : Su bstitu tion of Iod id e a n d Alk oxy
Gr ou p . Substitution of the iodide in compounds 5 and

7312 J . Org. Chem., Vol. 61, No. 21, 1996
Fujioka et al.
43% for the methoxy derivative and 0% for the benzyloxy
derivative). The reason for the good yields and complete
retention of stereochemistry can be attributed to the
formation of complex D. With Lewis acidic conditions
(TiCl4/allyltrimethylsilane/CH2Cl2/-78 °C) the reaction
gave complex mixtures.
Th ir d Step : Dep r otection . As highly stereoselective
construction of compounds 9a -h had been achieved, we
next examined the removal of the chiral auxiliary unit
using catalytic hydrogenolysis or Birch reduction. Both
processes proceeded smoothly and afforded the corre-
sponding optically active 1,4- and 1,5-diols (10, 11) in
good yields, respectively. Since the 1,5-diol (11) had
already been converted to solenopsin A, a constituent of
the venom of the fire ant S. invicta, by G. Solladie´ et
al.,6 a formal synthesis of solenopsin A was achieved
(Scheme 7).
Con clu sion s
A new asymmetric synthesis of chiral 1,4- and 1,5-diols
has been developed on the basis of remote asymmetric
induction as a key step. In the first step, the acetal acts
initially as a nucleophile and then as an electrophile in
a one-pot operation and the two remote stereogenic
centers are built up simultaneously. It is noteworthy
that the formation of a bicyclic cationic intermediate
makes the reaction stereoselective. In the second step,
the conversion of an alkoxy group to alkyl groups has
been achieved in high yields with complete retention of
stereochemistry. The use of a methoxyethoxy functional-
ity is noteworthy. In the third step, the usual deprotec-
tion procedure worked well to give optically active 1,4-
and 1,5-diols. These results suggest that the diphen-
ylethlene or diphenylpropylene unit is a useful protecting
group for diols.
Sch em e 7
Exp er im en ta l Section
All melting points are uncorrected. NMR spectra were
measured on 270 MHz and 500 MHz spectrometers with CDCl3
as a solvent and with SiMe4 as an internal standard. Infrared
(IR) absorption spectra were recorded as a KBr pellet. All
solvents were dried and distilled according to standard pro-
cedure.
P r ep a r a tion of En e Aceta ls 1a -c. To a solution of ene
aldehyde (1.0 mmol) and optical active diol (1.0 mmol) in C6H6
(10 mL) was added p-toluenesulfonic acid (0.05 mmol). The
reaction mixture was refluxed for 1 h with azeotropic removal
of water. K2CO3 was added to the mixture at rt. After being
stirred for 15 min, the solution was filtered through Celite and
concentrated in vacuo. The residue was purified by SiO2
column chromatography using hexane-AcOEt (20/1) as an
eluent to give the ene acetal quantitatively.
(4R,5R)-2-(3-Bu ten yl)-4,5-d ip h en yl-1,3-d ioxola n e (1a ):
colorless oil; bp 140-150 °C (bath temperature)/0.2 mmHg;
[R]25D +53° (c 2.4, CHCl3); IR (KBr) 1496, 1452 cm-1; 1H NMR
δ 1.9-2.1 (m, 2H), 2.3-2.5 (m, 2H), 4.7-4.8 (m, 2H), 5.0-5.2
(m, 2H), 5.55 (t, J ) 4.5 Hz, 1H), 5.8-6.0 (m, 2H), 7.2-7.4 (m,
10H). Anal. Calcd for C19H20O2: C, 81.40; H, 7.19. Found:
C, 81.16; H, 7.27.
Syn th esis of a Civet Con stitu en t. We next synthe-
sized (+)-(S,S)-(cis-6-methyltetrahydropyran-2-yl)acetic
acid (15), a civet constituent that was isolated from the
perfume material civet,19 a glandular secretion of the
civet cat Viverra civetta (Scheme 8). Oxidative cleavage
of the olefin of 9g followed by NaBH4 reduction gave the
alcohol 12. Catalytic hydrogenolysis of 12 afforded the
triol 13, which was combined with PhC(OMe)3 to give the
cyclic ether 14.20 Alkaline hydrolysis of 14 followed by
J ones oxidation gave a civet constituent, the cyclic ether
15.
(4S,6S)-2-(4-P en ten yl)-4,6-diph en yl-1,3-dioxan e (1c): col-
orless oil; bp 180-190 °C (bath temperature)/0.2 mmHg; [R]21
D
+69° (c 1.8, CHCl3); IR (KBr) 1495, 1448 cm-1; 1H NMR δ 1.5-
1.8 (m, 4H), 2.0-2.1 (m, 2H), 2.4-2.5 (m, 2H), 4.75 (dd, J )
9.2, 5.0 Hz, 1H), 4.88 (dd, J ) 10.2, 5.3 Hz, 1H), 4.9-5.1 (m,
2H), 5.33 (t, J ) 3.3 Hz, 1H), 5.7-5.9 (m, 1H), 7.2-7.5 (m,
10H). Anal. Calcd for C21H24O2: C, 81.78; H, 7.84. Found:
C, 81.86; H, 7.82.
Sch em e 8
Gen er a l P r oced u r e for th e Rea ction s in Ta ble 1. To a
solution of the ene acetal (1a , 1.0 mmol) and an alcohol (5.0
mmol) in CH2Cl2 (10.0 mL) was added an electrophile (1.5
mmol) at -78 °C under a nitrogen atmosphere. The reaction
mixture was stirred overnight at rt, then quenched with
saturated aqueous Na2S2O3, and extracted with AcOEt. The
extract was washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by SiO2
column chromatography to give the products in yields shown
in Table 1. The products involving four stereoisomers were
used for the next nucleophilic substitution of iodide (Table 3).
The following data for 3a -5a were collected from the
products (3-5) involving four stereoisomers. 1H NMR data
show the signals of the major ones (3a -5a ).
(2R,3R,5S,8R)-5-(Iod om eth yl)-8-m eth oxy-2,3-d ip h en yl-
1,4-d ioxoca n e (3a ). The ratio of four stereoisomers (3a :3b:
(18) The stereochemistry of compounds 9a -h were determined by
X-ray crystallography of the p-nitrobenzoate derivative 16 derived from
9d by hydroboration-oxidation followed by p-nitrobenzoylation. The
author has deposited atomic coordinates for this structure with the
Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, U.K.
(19) (a) van Dorp, D. A.; Word, J . P. Experientia 1981, 37, 917. (b)
Maurer, B.; Tohmmen, W. Ibid. 1979, 62, 1096. (c) Maurer, B.; Grieder,
A.; Tohmmen, W. Helv. Chim. Acta 1979, 62, 44.
(20) (a) Fujioka, H.; Kitagawa, H.; Kondo, M.; Kita, Y. Heterocycles
1994, 37, 743. (b) Fujioka, H.; Kitagawa, H.; Kondo, M.; Matsunaga,
N.; Kitagaki, S.; Kita, Y. Heterocycles 1993, 35, 665.

Asymmetric Induction via Intramolecular Haloetherification
J . Org. Chem., Vol. 61, No. 21, 1996 7313
3c:3d ) 85:3:12:0) was determined by 1H NMR spectra: IR
as an eluent to give 8b (40.5 mg, 70%) in a pure state: colorless
1
(KBr) 1493, 1454 cm-1; H NMR δ 1.9-2.4 (m, 4H), 3.1-3.2
oil; [R]28 +23° (c 1.0, CHCl3); Rf 0.11; IR (KBr) 2249, 1495,
D
(m, 2H), 3.30 (s, 3H), 4.1-4.3 (m, 1H), 4.42 (d, J ) 8.6 Hz,
1H), 4.56 (d, J ) 8.6 Hz, 1H), 5.4-5.5 (dd, J ) 9.5, 4.0 Hz,
1H), 6.9-7.4 (m, 10H); MS (m/ z) 407 (M+ - OMe); HRMS
calcd for C19H20O2I (M+ - OMe) 407.0507, found 407.0514.
(2R ,3R ,5S ,8R )-8-(Be n zyloxy)-5-(iod om e t h yl)-2,3-d i-
p h en yl-1,4-d ioxoca n e (4a ). The ratio of four stereoisomers
(4a + 4b:4c + 4d ) 90:10) was determined by 1H NMR spectra
1454 cm-1; 1H NMR δ 1.7-1.9 (m, 1H), 2.0-2.2 (m, 2H), 2.4-
2.6 (m, 3H), 3.31 (s, 3H), 3.4-3.8 (m, 4H), 4.25-4.35 (m, 1H),
5.29 (dd, J ) 8.1, 5.6 Hz, 1H), 6.9-7.2 (m, 10H). Anal. Calcd
for C23H27NO4: C, 71.52; H, 7.37; N, 3.79. Found: C, 71.46;
H, 7.14; N, 3.65.
(2R,3R,5S,8R)-5-(2′,2′-Bis(m et h oxyca r b on yl)et h yl)-8-
(m eth oxyeth oxy)-2,3-d ip h en yl-1,4-d ioxoca n e (8c). To a
solution of NaH (60% in oil, 8.0 mg, 0.20 mmol, washed with
dry Et2O) in DMF (0.55 mL) was added dimethyl malonate
(0.025 mL, 0.22 mmol) at rt under a nitrogen atmosphere.
After being stirred at rt for 30 min, 5 (26.6 mg, 0.055 mmol)
in THF (0.10 mL) was added to the reaction mixture, and the
mixture was stirred at 100 °C for 3 h. A few drops of MeOH
and saturated aqueous NH4Cl were added to the reaction
mixture successively, and the resulting solution was extracted
with Et2O. The extract was washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified
by SiO2 column chromatography with hexane-Et2O (1/1) as
eluent to give 8c (17.4 mg, 65%) in a pure state: colorless oil;
of the hydrolyzed derivatives of 4: IR (KBr) 1495, 1454 cm-1
;
1H NMR δ 1.9-2.4 (m, 4H), 3.11 (d, J ) 7.0 Hz, 2H), 4.0-4.8
(m, 5H), 5.57 (t, J ) 6.7 Hz, 1H), 6.8-7.2 (m, 15H). Anal.
Calcd for C26H27O3I: C, 60.71; H, 5.29; I, 24.67. Found: C,
60.45; H, 5.29; I, 24.43.
(2R,3R,5S,8R)-5-(Iod om eth yl)-8-(m eth oxyeth oxy)-2,3-
d ip h en yl-1,4-d ioxoca n e (5a ). The ratio of four stereoiso-
mers (5a :5b:5c:5d ) 86:2:11:1) was determined by 1H NMR
spectra and HPLC analysis (5SL packed column, 4.6 mm i.d.
× 250 mm, CH2Cl2/AcOEt ) 9/1, 1.0 mL/min flow rate): IR
(KBr) 1493, 1454, 1200 cm-1; 1H NMR δ 1.9-2.3 (m, 4H), 3.0-
3.2 (m, 2H), 3.29 (s, 3H), 3.4-3.7 (m, 4H), 4.1-4.2 (m, 1H),
4.41 (d, J ) 8.6 Hz, 1H), 4.53 (d, J ) 8.6 Hz, 1H), 5.55 (dd, J
[R]26 +51° (c 3.2, CHCl3); Rf 0.09; IR (KBr) 1751, 1736 cm-1
;
D
1H NMR δ 1.5-1.7 (m, 1H), 1.9-2.2 (m, 4H), 2.2-2.4 (m, 1H),
3.06 (dd, J ) 11.0, 2.8 Hz, 1H), 3.30 (s, 3H), 3.42 (s, 3H), 3.69
(s, 3H), 3.4-3.8 (m, 4H), 3.8-4.0 (m, 1H), 4.42 (d, J ) 8.6 Hz,
1H), 4.50 (d, J ) 8.6 Hz, 1H), 5.57 (dd, J ) 8.7, 5.1 Hz, 1H),
6.8-7.2 (m, 10H). Anal. Calcd for C27H34O8: C, 66.65; H, 7.04.
Found: C, 66.88; H, 7.15.
) 8.6, 4.3 Hz, 1H), 6.9-7.3 (m, 10H); MS (m/ z) 407 (M+
-
OCH2CH2OMe); HRMS calcd for C19H20O2I (M+ - OCH2CH2-
OMe) 407.0507, found 407.0507.
(2S,4S,6R,10R)-6-(Iod om et h yl)-10-(m et h oxyet h oxy)-
2,4-d ip h en yl-1,5-d ioxeca n e (7, Ta ble 2, En tr y 4). To a
solution of the ene acetal (1c, 1.0 mmol) and MeOCH2CH2OH
(3.0 mmol) in CH3CN (20.0 mL) was added I(coll)2PF6 (3.0
mmol) under a nitrogen atmosphere at -20 °C. The resulting
solution was stirred for 2 h at the same temperature and then
warmed to 0 °C. After being stirred for 2 h, the reaction
mixture was quenched with saturated aqueous Na2S2O3 and
extracted with AcOEt. The extract was washed with brine,
dried over MgSO4, and concentrated in vacuo. The residue
was purified by SiO2 column chromatography with hexane-
AcOEt (4/1) as an eluent to give 7 (382 mg) in 75% yield. The
ratio of the diastereoisomers (7a :7b:7c:7d ) 80:6:12:0) was
determined by HPLC analysis (Ceramospher chiral Ru-1,
MeOH, 0.5 mL/min flow rate). The product involving four
stereoisomers were used for the next nucleophilic substitution
of iodide (Table 3): colorless oil; IR (KBr) 1493, 1450 cm-1; 1H
NMR δ 1.5-2.3 (m, 8H), 3.01 (dd, J ) 9.4, 7.7 Hz, 1H), 3.09
(dd, J ) 9.4, 4.7 Hz, 1H), 3.27 (s, 3H), 3.1-3.2 (m, 1H), 3.2-
3.4 (m, 2H), 3.5-3.6 (m, 2H), 4.63 (dd, J ) 6.0, 2.6 Hz, 1H),
4.80 (dd, J ) 9.4, 5.1 Hz, 1H), 4.87 (dd, J ) 9.8, 4.7 Hz, 1H),
7.2-7.4 (m, 10H). Anal. Calcd for C24H31IO4: C, 56.48; H,
6.12; I, 24.86. Found: C, 56.23; H, 6.06; I, 24.56.
(2S,4S,6S,10R)-10-(Meth oxyeth oxy)-6-m eth yl-2,4-diph en -
yl-1,5-d ioxeca n e (8d ). To a solution of 1,4-dioxocane (7, 610
mg, 1.20 mmol) in THF (10.0 mL) was added LiAlH4 (90.8 mg,
2.40 mmol) in THF (2.0 mL) at 0 °C under a nitrogen
atmosphere. After being stirred for 1 h at the same temper-
ature, the reaction mixture was allowed to warm to rt and
stirred for an additional 1 h. AcOEt (0.5 mL), MeOH, and
aqueous NH4Cl were added to the reaction mixture succes-
sively. The resulting solution was extracted with AcOEt. The
extract was washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by SiO2
column chromatography with hexane-AcOEt (10/1) as eluent
to give 8d (362 mg, 79%) in a pure state: colorless oil; [R]22
D
-95° (c 2.4, CHCl3); Rf 0.18; IR (KBr) 1493, 1450 cm-1 1H
;
NMR δ 1.10 (d, J ) 6.3 Hz, 3H), 1.3-1.5 (m, 1H), 1.6-1.8 (m,
3H), 2.0-2.3 (m, 4H), 3.12 (ddd, J ) 10.6, 6.8, 3.8 Hz, 1H),
3.27 (s, 3H), 3.2-3.4 (m, 2H), 3.5-3.7 (m, 2H), 4.59 (dd, J )
5.6, 3.6 Hz, 1H), 4.79 (dd, J ) 10.2, 5.0 Hz, 1H), 4.93 (dd, J )
10.2, 4.6 Hz, 1H), 7.2-7.4 (m, 10H). Anal. Calcd for
C24H32O4: C, 74.97; H, 8.39. Found: C, 74.84; H, 8.40.
(2S,4S,6R,10R)-6-(Cya n om eth yl)-10-(m eth oxyeth oxy)-
2,4-d ip h en yl-1,5-d ioxeca n e (8e). To a solution of 7 (74.0
mg, 0.14 mmol) in DMSO (1.4 mL) was added NaCN (14.0 mg,
0.28 mmol) at rt under a nitrogen atmosphere. After being
stirred at 80 °C for 3 h, the mixture was quenched with
saturated aqueous NaHCO3. The resulting solution was
extracted with AcOEt. The extract was washed with brine,
dried over MgSO4, and concentrated in vacuo. The residue
was purified by SiO2 column chromatography with hexane-
AcOEt (4/1) as eluent to give 8e (48.8 mg, 82%) in a pure
state: colorless oil; [R]25D -69° (c 1.0, CHCl3); Rf 0.11; IR (KBr)
(2R ,3R ,5R ,8R )-8-(Me t h oxye t h oxy)-5-m e t h yl-2,3-d i-
p h en yl-1,4-d ioxoca n e (8a ). To a solution of 1,4-dioxocane
(5, 810 mg, 1.68 mmol) in THF (16.8 mL) was added LiAlH4
(127 mg, 3.36 mmol) in THF (2.0 mL) at 0 °C under a nitrogen
atmosphere. The reaction mixture was stirred at the same
temperature for 1 h, then warmed to rt, and stirred for an
additional 1 h. To the mixture were added AcOEt (0.5 mL)
and saturated aqueous NH4Cl successively. The reaction
mixture was extracted with AcOEt. The extract was washed
with brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by SiO2 column chromatography with
CH2Cl2-AcOEt (30/1) as an eluent to give 8a (430 mg, 72%)
1
2249, 1493, 1452 cm-1; H NMR δ 1.6-1.8 (m, 2H), 1.8-1.9
in a pure state: colorless oil; [R]25 +16° (c 1.1, CHCl3); Rf
(m, 2H), 2.0-2.2 (m, 4H), 2.31 (dd, J ) 16.7, 6.4 Hz, 1H), 2.38
(dd, J ) 16.7, 5.5 Hz, 1H), 3.17 (ddd, J ) 10.3, 6.4, 3.9 Hz,
1H), 3.28 (s, 3H), 3.2-3.4 (m, 1H), 3.38 (ddd, J ) 10.3, 6.4,
3.4, Hz 1H), 3.63 (ddd, J ) 11.1, 6.0, 3.4, Hz 1H), 3.6-3.7 (m,
1H), 4.60 (dd, J ) 5.6, 2.1 Hz, 1H), 4.78 (dd, J ) 9.8, 4.7 Hz,
1H), 4.87 (dd, J ) 10.3, 4.3 Hz, 1H), 7.2-7.4 (m, 10H). Anal.
Calcd for C25H31NO4: C, 73.32; H, 7.63; N, 3.42. Found: C,
73.06; H, 7.72; N, 3.31.
D
0.30;IR (KBr) 1452 cm-1; 1H NMR δ 1.10 (d, J ) 6.4 Hz, 3H),
1.5-1.6 (m, 1H), 1.9-2.1 (m, 2H), 2.2-2.4 (m, 1H), 3.31 (s,
3H), 3.4-3.8 (m, 4H), 4.0-4.2 (m, 1H), 4.41 (d, J ) 8.7 Hz,
1H), 4.56 (d, J ) 8.7 Hz, 1H), 5.60 (dd, J ) 9.0, 4.7 Hz, 1H),
6.9-7.2 (m, 10H). Anal. Calcd for C22H28O4: C, 74.13; H, 7.92.
Found: C, 73.86; H, 7.91.
(2R,3R,5S,8R)-5-(Cya n om eth yl)-8-(m eth oxyeth oxy)-2,3-
d ip h en yl-1,4-d ioxoca n e (8b). To a solution of 5 (74.1 mg,
0.15 mmol) in DMSO (1.5 mL) was added NaCN (11.3 mg, 0.23
mmol) at rt under a nitrogen atmosphere. The mixture was
stirred at 80 °C for 3 h. Saturated aqueous NaHCO3 was
added to the reaction mixture. The mixture was extracted
with AcOEt. The extract was washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified
by SiO2 column chromatography with CH2Cl2-AcOEt (30/1)
(2S,4S,6R,10R)-6-(2′,2′-Bis(m eth oxyca r bon yl)eth yl)-10-
(m et h oxyet h oxy)-2,4-d ip h en yl-1,5-d ioxeca n e (8f). To a
solution of NaH (60% in oil, 48.0 mg, 1.20 mmol, washed with
dry Et2O) in DMF (6.0 mL) was added dimethyl malonate (0.14
mL, 0.22 mmol) at rt under a nitrogen atmosphere. After
being stirred for 30 min at rt, to the reaction mixture was
added 7 (343 mg, 0.67 mmol) in THF (1.0 mL). The resulting
solution was stirred at 100 °C for 3 h. The reaction mixture

7314 J . Org. Chem., Vol. 61, No. 21, 1996
Fujioka et al.
was quenched with a few drops of MeOH and aqueous NH4Cl
and then extracted with Et2O. The extract was washed with
brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by SiO2 column chromatography with
hexane-AcOEt (4/1) as eluent to give 8f (273 mg, 79%) in a
pure state: colorless oil; [R]22D -74° (c 1.7, CHCl3); Rf 0.15; IR
1.14 (d, J ) 6.6 Hz, 3H), 1.2-1.8 (m, 24H), 1.9-2.0 (m, 2H),
2.0-2.4 (m, 2H), 3.3-3.5 (m, 1H), 3.5-3.7 (m, 1H), 4.8-5.0
(m, 2H), 7.2-7.5 (m, 10H). Anal. Calcd for C32H48O2: C,
82.70; H, 10.41. Found: C, 82.64; H, 10.33.
(2R,5S)-8-Non en e-2,5-d iol (10). To a solution of Ca (134.5
mg, 3.35 mmol) in liquid NH3 (100 mL) was added a solution
of 9d (281 mg, 0.84 mmol) and EtOH (0.20 mL, 3.35 mmol) in
ether (5.0 mL) at -78 °C under a nitrogen atmosphere. The
reaction mixture was stirred for 20 min at the same temper-
ature and then quenched with saturated aqueous NH4Cl.
After removal of NH3 at rt, the resulting solution was extracted
with AcOEt. The organic phase was washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue was
purified by SiO2 column chromatography with hexane-AcOEt
(KBr) 1753, 1736, 1493, 1452 cm-1 1H NMR δ 1.4-1.5 (m,
;
1H), 1.6-1.7 (m, 2H), 1.7-1.9 (m, 1H), 1.9-2.2 (m, 5H), 2.3-
2.5 (m, 1H), 3.03 (ddd, J ) 10.6, 6.9, 3.8 Hz, 1H), 3.27 (s, 3H),
3.40 (s, 3H), 3.73 (s, 3H), 3.2-3.4 (m, 2H), 3.5-3.6 (m, 2H),
4.52 (dd, J ) 5.6, 3.6 Hz, 1H), 4.75 (d, J ) 9.7, 5.4 Hz, 1H),
4.82 (dd, J ) 9.9, 5.6 Hz, 1H), 7.2-7.4 (m, 10H); MS (m/ z)
514 (M+).
Gen er a l P r oced u r e for th e Gr ign a r d Rea ction in
Ta ble 4. To a solution of the acetal (8a or 8d , 1.0 mmol) in
toluene (50.0 mL) was added RMgX (5.0 mmol) at rt under a
nitrogen atmosphere. The reaction mixture was stirred for
12 h and then quenched with aqueous NH4Cl. The resulting
solution was extracted with AcOEt. The organic phase was
washed with brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by SiO2 column chromatog-
raphy using hexane-AcOEt as eluent to give 9.
(2R ,3R ,5S ,8R )-5,8-Dim e t h yl-2,3-d ip h e n yl-1,4-d ioxo-
ca n e (9a ): colorless crystal; mp 106-7 °C (hexane); [R]25D +61°
(c 0.56, CHCl3); IR (KBr) 1493, 1452 cm-1; 1H NMR δ 1.11 (d,
J ) 6.0 Hz, 3H), 1.15 (d, J ) 6.0 Hz, 3H), 1.4-1.5 (m, 1H),
1.6-1.8 (m, 2H), 2.3-2.4 (m, 1H), 4.1-4.2 (m, 1H), 4.35 (d, J
) 9.0 Hz, 1H), 4.64 (d, J ) 9.0 Hz, 1H), 4.6-4.8 (m, 1H), 6.9-
7.2 (m, 10H). Anal. Calcd for C20H24O2: C, 81.04; H, 8.16.
Found: C, 80.74; H, 8.13.
(1/1) as eluent to give 10 (122 mg, 92%): colorless oil; [R]25
D
-11° (c 0.47, CHCl3); IR (KBr) 3300, 1641 cm-1
;
1H NMR δ
1.21 (d, J ) 5.9 Hz, 3H), 1.5-1.7 (m, 6H), 2.1-2.3 (m, 4H),
3.6-3.7(m, 1H), 3.8-3.9 (m, 1H), 4.9-5.1 (m, 2H), 5.8-5.9 (m,
1H). Anal. Calcd for C9H18O2: C, 67.91; H, 11.49. Found:
C, 67.79; H, 11.38.
(2S,6S)-2,6-Hep ta d eca n ed iol (11). To a solution of Ca
(114 mg, 2.85 mmol) in liquid NH3 (100 mL) was added a
solution of 9h (264 mg, 0.57 mmol) and EtOH (0.17 mL, 2.85
mmol) in ether (5.7 mL) at -78 °C under a nitrogen atmo-
sphere. The reaction mixture was stirred for 20 min at the
same temperature and then quenched with saturated aqueous
NH4Cl. After removal of NH3 at rt, the resulting solution was
extracted with AcOEt. The organic phase was washed with
brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by SiO2 column chromatography with
hexane-AcOEt (1/1) as eluent to give 11 (118 mg, 76%):
colorless crystal; mp 55-56 °C (hexane/AcOEt); [R]18D +11° (c
1.1, CHCl3) {lit.6 mp 55-56 °C; [R]D +11° (c 1, CHCl3)}. 1H
NMR spectral data of 11 were good agreement with the
reported values6 of (2S,6S)-2,6-heptadecanediol.
(2R,3R,5S,8R)-5-Eth yl-8-m eth yl-2,3-d ip h en yl-1,4-d ioxo-
ca n e (9b): colorless oil; [R]25 +45° (c 1.0, CHCl3); IR (KBr)
D
1493, 1452 cm-1; H NMR δ 0.89 (t, J ) 7.2 Hz, 3H), 1.12 (d,
1
J ) 6.0 Hz, 3H), 1.3-1.8 (m, 5H), 2.3-2.4 (m, 1H), 4.1-4.2
(m, 1H), 4.30 (d, J ) 9.0 Hz, 1H), 4.4-4.5 (m, 1H), 4.68 (d, J
) 9.0 Hz, 1H), 6.9-7.2 (m, 10H). Anal. Calcd for C21H26O2:
C, 81.25; H, 8.44. Found: C, 81.16; H, 8.43.
(3R,7S)-1,3,7-Octa n etr iol (13). To a solution of 9g (73.2
mg, 0.21 mmol) in dioxane-H2O (v/v ) 3/1, 4.0 mL) were added
NaIO4 (89.3 mg, 0.42 mmol) and a catalytic amount of OsO4
at rt. After being stirred for 3 h, the reaction mixture was
extracted with AcOEt. The organic phase was washed with
brine, dried over MgSO4, and concentrated in vacuo. To a
solution of the residue in MeOH (2.0 mL) was added NaBH4
(16.0 mg, 0.42 mmol). After being stirred for 1 h at rt, the
reaction mixture was extracted with AcOEt. The organic
phase was washed with brine, dried over MgSO4, and concen-
trated under reduced pressure. To a solution of the obtained
crude alcohol (12) in EtOH (4.2 mL) was added a catalytic
amount of Pd(OH)2-C at rt under a medium pressure of H2
(4 kgf/cm2). After the completion of the reaction, the product
was purified by SiO2 column chromatography with CH2Cl2-
(2R,3R,5R,8R)-5-Allyl-8-m eth yl-2,3-d ip h en yl-1,4-d ioxo-
ca n e (9c): colorless oil; [R]25 +23° (c 1.5, CHCl3); IR (KBr)
D
1
1637, 1493, 1452 cm-1; H NMR δ 1.11 (d, J ) 6.8 Hz, 3H),
1.4-1.5 (m, 1H), 1.6-1.8 (m, 2H), 2.1-2.2 (m, 2H), 2.3-2.4
(m, 1H), 4.1-4.2 (m, 1H), 4.30 (d, J ) 8.6 Hz, 1H), 4.5-4.6
(m, 1H), 4.66 (d, J ) 8.6 Hz, 1H), 4.9-5.1 (m, 2H), 5.8-5.9
(m, 1H), 6.9-7.2 (m, 10H). Anal. Calcd for C22H26O2: C,
81.95; H, 8.13. Found: C, 81.85; H, 8.15.
(2R,3R,5R,8R)-5-Bu ten yl-8-m eth yl-2,3-d ip h en yl-1,4-d i-
oxoca n e (9d ): colorless oil; [R]27D +32° (c 2.9, CHCl3); IR 1639,
1493, 1454 cm-1; 1H NMR δ 1.16 (d, J ) 6.8 Hz, 3H), 1.4-2.4
(m, 8H), 4.1-4.2 (m, 1H), 4.29 (d, J ) 9.0 Hz, 1H), 4.4-4.6
(m, 1H), 4.65 (d, J ) 9.0 Hz, 1H), 4.9-5.0 (m, 2H), 5.7-5.9
(m, 1H), 6.9-7.2 (m, 10H). Anal. Calcd for C23H28O2: C,
82.10; H, 8.39. Found: C, 82.04; H, 8.48.
MeOH (20/1) as eluent to give 13 (20.1 mg, 60%): colorless
1
oil; [R]18 +2.3° (c 1.0, MeOH); IR (KBr) 3325 cm-1; H NMR
D
(2S,4S,6S,10S)-6,10-Dim et h yl-2,4-d ip h en yl-1,5-d ioxe-
δ 1.20 (d, J ) 6.3 Hz, 3H), 1.4-1.8 (m, 8H), 2.5-3.4 (brs, 2H),
3.7-4.0 (m, 4H); MS (m/ z) 163 (M+ + H); HRMS calcd for
C8H18O3 (M+) 162.1257, found 162.1267.
ca n e (9e): colorless crystal; mp 108-9 °C (hexane); [R]21
D
-142° (c 1.0, CHCl3); IR (KBr) 1491, 1450 cm-1
;
1H NMR δ
1.15 (d, J ) 6.8 Hz, 3H), 1.3-1.4 (m, 2H), 1.6-1.8 (m, 2H),
1.9-2.0 (m, 2H), 2.2-2.3 (m, 2H), 3.5-3.7 (m, 1H), 4.88 (t, J
) 9.0 Hz, 2H), 7.2-7.5 (m, 10H). Anal. Calcd for C22H28O2:
C, 81.12; H, 8.56. Found: C, 81.41; H, 8.62.
(2S,6S)-2-(2-(Ben zyloxy)eth yl)-6-m eth yltetr a h yd r op y-
r a n (14). To a solution of 13 (18.0 mg, 0.12 mmol) in CH2-
Cl2-MeOH (v/v ) 3/1, 1.2 mL) were added PhC(OMe)3 (0.03
mL, 0.18 mmol) and a catalytic amount of trifluoromethansul-
fonic acid at 0 °C. After being stirred for 12 h, the reaction
mixture was extracted with AcOEt. The organic phase was
washed with brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by SiO2 column chromatog-
raphy with hexane-AcOEt (20/1) to give 14 (26.0 mg, 94%):
(2S,4S,6S,10S)-6-E t h yl-10-m et h yl-2,4-d ip h en yl-1,5-d i-
oxeca n e (9f): colorless crystal; mp 66-67 °C (hexane); [R]21
D
-147° (c 1.1, CHCl3); IR (KBr) 1491, 1450 cm-1
;
1H NMR δ
0.81 (t, J ) 7.3 Hz, 3H), 1.13 (d, J ) 6.0 Hz, 3H), 1.2-1.7 (m,
6H), 1.9-2.0 (m, 2H), 2.2-2.4 (m, 2H), 3.3-3.4 (m, 1H), 3.5-
3.7 (m, 1H), 4.8-4.9 (m, 2H), 7.2-7.4 (m, 10H). Anal. Calcd
for C21H26O2: C, 81.61; H, 8.93. Found: C, 81.71; H, 8.94.
(2S,4S,6R,10S)-6-Allyl-10-m eth yl-2,4-d ip h en yl-1,5-d iox-
colorless oil; [R]25 +39° (c 0.85, CHCl3); IR (KBr) 1720 cm-1
;
D
1H NMR δ 1.16 (d, J ) 6.3 Hz, 3H), 1.1-1.3 (m, 2H), 1.5-1.7
(m, 3H), 1.8-2.0 (m, 3H), 3.4-3.6 (m, 2H), 4.44 (t, J ) 6.6 Hz,
2H), 7.44 (t, J ) 7.3 Hz, 2H), 7.55 (t, J ) 7.3 Hz, 1H), 8.05 (d,
J ) 7.3 Hz, 2H). Anal. Calcd for C15H20O3: C, 72.55; H, 8.12.
Found: C, 72.49; H, 8.22.
eca n e (9g): colorless crystal; mp 73.5-74.5 °C (hexane); [R]23
D
-124° (c 1.3, CHCl3); IR (KBr) 1641, 1491, 1450 cm-1; 1H NMR
δ 1.13 (d, J ) 6.3 Hz, 3H), 1.3-1.5 (m, 2H), 1.6-1.8 (m, 2H),
1.9-2.0 (m, 2H), 2.2-2.4 (m, 4H), 3.4-3.7 (m, 2H), 4.8-5.0
(m, 4H), 5.6-5.8 (m, 1H), 7.2-7.4 (m, 10H). Anal. Calcd for
C24H32O2: C, 82.24; H, 8.63. Found: C, 82.29; H, 8.68.
(2S,4S,6S,10S)-10-Met h yl-2,4-d ip h en yl-6-u n d ecyl-1,5-
(2S,6S)-2-(6-Met h ylt et r a h yd r op yr a n -2-yl)a cet ic Acid
(15). To a solution of 14 (8.8 mg, 0.035 mmol) in MeOH (1.0
mL) was added 10% aqueous NaOH (1.0 mL). After being
stirred for 15 min, the reaction mixture was extracted with
AcOEt. The organic phase was washed with brine, dried over
MgSO4, and concentrated in vacuo. To the resulting crude
d ioxeca n e (9h ): colorless oil; [R]20 -87° (c 1.2, CHCl3); IR
D
(KBr) 1493, 1450 cm-1; H NMR δ 0.88 (t, J ) 6.6 Hz, 3H),
1

Asymmetric Induction via Intramolecular Haloetherification
J . Org. Chem., Vol. 61, No. 21, 1996 7315
alcohol in acetone (1.5 mL) was added J ones reagent (5 equiv).
After being stirred for 30 min, NaHSO3 (excess) was added to
the reaction mixture. The resulting mixture was extracted
with Et2O. The organic phase was washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue was
purified by SiO2 column chromatography with CH2Cl2-Et2O
(3/1) to give 15 (3.8 mg, 68%). 1H NMR spectral data of 15
were good agreement with the reported values7a of (2S,6S)-2-
(6-methyltetrahydropyran-2-yl)acetic acid: [R]25D +26° (c 0.18,
CHCl3); [R]23 +36° (c 0.14, C6H6) {lit.7a [R]22 +18.6° (c 2.77,
Ack n ow led gm en t. We are grateful to Takasago
International Co. for the generous gift of (1S,3S)-1,3-
diphenyl-1,3-propanediol. This research was supported
by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Science and Culture, J apan.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
5, 7, 8a , 8d , 9a , 9d , 9g, and 9h and DIFNOE spectra of 8a .
X-ray experimental data of 16. Cartesian coordinates of
optimized geometries of the intermediate C and the others (25
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
D
D
CHCl3); [R]22 +43.85° (c 2.52, C6H6), lit.7b [R]22 +32.86° (c
D
D
1.05, C6H6), lit.7c [R]22 +35° (c 0.5, CHCl3)}.21
D
(21) The discrepancies of the values are clear although the acid 15
in each citation is optically pure. We think the variation in the optical
rotations is due to concentration differences.
J O960714L