Inter- and intramolecular differentiation of enantiotopic dioxane acetals through oxazaborolidinone-mediated enantioselective ring-cleavage reaction: Kinetic resolution of racemic 1,3-alkanediols and asymmetric desymmetrization of meso-1,3-polyols

Article abstract of DOI:10.1021/jo025944g

Acetals derived from racemic 1,3-alkanediols undergo kinetic resolution in chiral oxazaborolidinonemediated ring-cleavage reaction with nucleophiles such as enol silanes and allylic silanes. Enantioselectivity of the reaction is affected by nucleophiles, the N-sulfonyl groups of oxazaborolidinones, and the substituents attached to the acetal carbon. For disubstituted acetals rac-1 and for trisubstituted acetal rac-2, derived from syn-2,4-dimethyl-1,3-pentanediol, satisfactory enantioselectivity is obtained by using methallylsilane 7b,c as a nucleophile in combination with N-mesyloxazaborolidinone 4a. On the other hand, enantioselective reaction of trisubstituted acetal rac-3b, derived from anti-2,4-dimethyl-1,3-pentanediol, is realized by using silyl ketene acetal 5e in combination with N-tosyloxazaborolidinone 4b. The reaction conditions optimized for the kinetic resolution, or enantiomer differentiating reaction, of the racemic acetals are successfully applied to asymmetric desymmetrization of meso-1,3-polyols through intramolecular differentiation of the enantiotopic acetal moieties of the bis-acetal derivatives. The utility of the ring-cleavage reaction as a method for enantioselective terminal differentiation of prochiral polyols is demonstrated in convergent asymmetric synthesis of pentol derivative 35 corresponding to the C(19)-C(27) ansachain of rifamycin S.

Full text of DOI:10.1021/jo025944g

In ter - a n d In tr a m olecu la r Differ en tia tion of En a n tiotop ic Dioxa n e
Aceta ls th r ou gh Oxa za bor olid in on e-Med ia ted En a n tioselective
Rin g-Clea va ge Rea ction : Kin etic Resolu tion of Ra cem ic
1,3-Alk a n ed iols a n d Asym m etr ic Desym m etr iza tion of
Meso-1,3-p olyols
Toshiro Harada,* Takayuki Egusa, Yasuto Igarashi, Motoharu Kinugasa, and Akira Oku
Department of Chemistry, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, J apan
harada@chem.kit.ac.jp
Received May 17, 2002
Acetals derived from racemic 1,3-alkanediols undergo kinetic resolution in chiral oxazaborolidinone-
mediated ring-cleavage reaction with nucleophiles such as enol silanes and allylic silanes.
Enantioselectivity of the reaction is affected by nucleophiles, the N-sulfonyl groups of oxaza-
borolidinones, and the substituents attached to the acetal carbon. For disubstituted acetals rac-1
and for trisubstituted acetal rac-2, derived from syn-2,4-dimethyl-1,3-pentanediol, satisfactory
enantioselectivity is obtained by using methallylsilane 7b,c as a nucleophile in combination with
N-mesyloxazaborolidinone 4a . On the other hand, enantioselective reaction of trisubstituted acetal
rac-3b, derived from anti-2,4-dimethyl-1,3-pentanediol, is realized by using silyl ketene acetal 5e
in combination with N-tosyloxazaborolidinone 4b. The reaction conditions optimized for the kinetic
resolution, or enantiomer differentiating reaction, of the racemic acetals are successfully applied
to asymmetric desymmetrization of meso-1,3-polyols through intramolecular differentiation of the
enantiotopic acetal moieties of the bis-acetal derivatives. The utility of the ring-cleavage reaction
as a method for enantioselective terminal differentiation of prochiral polyols is demonstrated in
convergent asymmetric synthesis of pentol derivative 35 corresponding to the C(19)-C(27) ansa-
chain of rifamycin S.
SCHEME 1
In tr od u ction
Two-direction chain extension and asymmetric desym-
metrization of the resulting meso precursors have re-
cently emerged as an efficient strategy for the construc-
tion of multiple stereogenic centers.1 The meso precursors
can be synthesized in a convergent manner based on the
strategy involving the simultaneous, diastereoselective
extension of chains in two directions. The final terminus
differentiation in an enantioselective manner accom-
plishes the construction of multiple stereogenic centers.
The approach has been successfully employed in asym-
metric syntheses of skipped and polypropionate-derived
1,3-polyols of potential σ-symmetry.1b,2 For the crucial
step of terminus differentiation, enantioselective epoxi-
dation,2a,b allylation,2c,e acetalization,2d,f aldol reaction,2g
Horner-Wardworth-Emmons reaction,2h and enzymatic
esterification2i have been employed.
We recently reported an oxazaborolidinone-mediated
enantioselective ring-cleavage reaction of cyclic acetals
derived from meso-1,2- and 1,3-diols (Scheme 1).3 In this
reaction, the chiral Lewis acid selectively activates one
of the enantiotopic C-O bonds leading to the ring-
cleavage product of high ee. Although there is no prece-
(1) (a) Schreiber, S. L. Chem. Scr. 1987, 27, 563-566. (b) Poss, C.
S.; Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9-17. (b) Magnuson, S.
R.; Tetrahedron 1995, 51, 2167-2213. (c) Willis, M. C. J . Chem. Soc.,
Perkin Trans. 1 1999, 1765-1784.
(2) (a) Schreiber, S. L.; Goulet, M. T.; Schulte, G. J . Am. Chem. Soc.
1987, 109, 4718-4719 (b) Schreiber, S. L.; Goulet, J . Am. Chem. Soc.
1987, 109, 8120-8121. (c) Wang, Z.; Decheˆnes, D. J . Am. Chem. Soc.
1992, 114, 1090-1091. (d) Harada, T.; Kagamihara, T.; Tanaka, S.;
Sakamoto, K.; Oku, A. J . Org. Chem. 1992, 57, 1637-1638. (e) Ward,
D. E.; Liu, Y.; Rhee, C. K. Synlett 1993, 561-563. (f) Harada, T.; Oku,
A. Synlett 1994, 95-104. (g) Oppolzer, W.; Walther, E.; Balado, C. P.;
De Brabander J . Tetrahedron Lett. 1997, 38, 809-812. (h) Tullis, J .
S.; Vares, L.; Kann, N.; Norrby, P.-O. Rein, T. J . Org. Chem. 1998, 63,
8284-8294. (i) Cheˆnevert, R.; Rose, Y. S. J . Org. Chem. 2000, 65,
1707-1709.
(3) (a) Kinugasa, M. Harada, T.; Oku, A. J . Am. Chem. Soc. 1997,
119, 9067-9068. (b) Kinugasa, M.; Harada, T.; Oku, A. Tetrahedron
Lett. 1998, 39, 4523-4526. (c) Harada, T.; Nakamura, T.; Kinugasa,
M.; Oku, A. Tetrahedron Lett. 1999, 40, 503-506. (d) Harada, T.;
Yamanaka, H.; Oku, A. Synlett 2001, 61-64. (e) Harada, T.; Sekiguchi,
K.; Nakamura, T.; Suzuki, J .; Oku, A. Org. Lett. 2001, 3, 3309-3312.
10.1021/jo025944g CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/06/2002
7080
J . Org. Chem. 2002, 67, 7080-7090

Differentiation of Enantiotopic Dioxane Acetals
while rac-2 (R3 ) Me, R3 ) H) and -3 (R3 ) H, R3
)
SCHEME 2
R
â
R
â
Me) correspond to polypropionate-derived polyol deriva-
tives.
SCHEME 3
dent, enantiodifferentiating ring-cleavage of prochiral bis-
acetal derivatives is expected to provide a straightforward
and general method for desymmetrization of meso-1,3-
polyols (Scheme 2). Lewis acid-mediated ring-cleavage of
cyclic acetals derived from 1,3-alkanediols (RCH(OH)CH2-
CH2OH) is known to proceed regioselectively at the less
hindered C-O bond.4,5 For a bis-acetal derived from a
meso-1,3-polyol, selective cleavage of a specific terminal
C-O bond is expected to take place through intra-
molecular differentiation of the enantiotopic acetal moi-
eties by an oxazaborolidinone, leading to the formation
of a desymmetrized product.
We wish to report herein a successful application of
oxazaborolidinone-mediated enantioselective ring-cleav-
age to asymmetric desymmetrization of meso-1,3-polyols.6
In the present work, we first investigated intermolecular
differentiation, or kinetic resolution, of racemic acetals
derived from 1,3-alkanediols (Scheme 3). The optimized
conditions established for the kinetic resolution was then
applied to intramolecular differentiation of prochiral bis-
acetals derived from meso-1,3-polyols.
Ring-cleavage reaction of acetal rac-1a derived from
4-methyl-1,3-pentanediol and benzaldehyde was carried
out with a variety of nucleophiles (5-7) (1.5 equiv) by
using N-mesyloxazaborolidinone 4a (0.5 equiv) as a chiral
Lewis acid in CH2Cl2 at -50 °C (eq 1, Table 1). Because
a part of a ring-cleavage product was obtained as a TMS
ether derivative except for entry 5, the crude mixture was
subsequently hydrolyzed with aqueous acetic acid or with
Bu4NF in THF. Under these conditions, (4S)-1a reacted
selectively, irrespective of the nucleophiles, to give 8a -d
or 9a ,b with high diastereoselectivity (>90% ds)8 and
enantiomerically enriched acetal (4R)-ent-1a was recov-
ered. The selectivity factor s () k1/kent-1) of the reaction
was calculated from the percent conversion and ee of the
recovered acetal.10
Resu lts a n d Discu ssion
Kin etic Resolu tion of Ra cem ic Aceta ls Der ived
fr om 1,3-Alk a n ed iols. To establish optimum reaction
conditions for asymmetric desymmetrization of the bis-
acetals, we first investigated kinetic resolution of three
types of acetals rac-1-3. Acetals rac-1 (R3 , R3â ) H) were
R
chosen as model compounds for skipped polyol derivatives
(4) Choi, V. M.; Elliott, J . D.; J ohnson, W. S. Tetrahedron Lett. 1984,
25, 591-594.
(5) Kinugasa, M.; Harada, T.; Egusa, T.; Fujita, K.; Oku, A. Bull.
Chem. Soc., J pn. 1996, 69, 3639-3650.
(7) For the stereoselective formation of the dioxane acetals from the
corresponding diols, see: Clode, D. Chem. Rev. 1979, 79, 491-513.
(8) The stereochemical assignment of major diastereomers is tenta-
tive, based on the assumption of the introduction of the nucleophile
with inversion of the acetal carbon.8,3e
(6) For a preliminary communication, see: (a) Harada, T.; Egusa,
T.; Kinugasa, M.; Oku A. Tetrahedron Lett. 1998, 39, 5531-5534. (b)
Harada, T.; Egusa, T. Oku, A. Tetrahedron Lett. 1998, 39, 5535-5536.
J . Org. Chem, Vol. 67, No. 20, 2002 7081

Harada et al.
TABLE 1. Kin etic Resolu tion in Rin g-Clea va ge
TABLE 3. Kin etic Resolu tion in Rin g-Clea va ge
Rea ction of Aceta ls 1a ,g-j w ith Meth a llylsila n es 7b,ca
Rea ction of Aceta l r a c-1a a
time conversion ent-1 ee
entry acetals (h)
yield
product (%)
(%)b
(%)c
s
nucleo- time conversion ent-1a
yield
product (%)
(%)b
ee (%)c
s
1
rac-1a
rac-1g
rac-1h
rac-1i
8
2.5
8
63
41
58
67
69
92
56
67
79
84
10
16
5.6
5.1
5.4
9b
9f
9g
9h
-
nde
32
55
entry phile
(h)
2d
3
1
2
3
4
5
6
7
8
5a
5b
5c
5d
6a
7b
7c
24
24
24
9
24
3
4
8
30
4
49
32
63
60
48
59
56
63
60
44
36
23
68
69
54
77
80
92
88
41
3.2
3.6
4.4
5.3
6.4
7.4
10
10
11
8a
8b
8c
8d
9a
9b
9b
9b
9b
9b
42
28
61
52
39
40
51
ndd
58
ndd
4
5
2.5
57
rac-1j 24
nde
a
Unless otherwise noted, reactions were carried out by using
4a (0.5 equiv) and 7c (1.5 equiv) in CH2Cl2 (1 M) at -50 °C.
b
Based on the recovery of acetals which was determined by GC
analysis using an internal standard. c Determined by GC (Chrom-
9e
10f
pack CP-Cyclodextrin-â-236-M-19, 25 m) for rac-1a ,g,i or HPLC
d
4.7
(Chiracel OD) for rac-1h ,j. 7b (1.5 equiv) was used as a nucleo-
phile. e Not determined.
a
Unless otherwise noted, reactions were carried out by using
4a (0.5 equiv) and a nucleophile (1.5 equiv) in CH2Cl2 (1 M) at
b
TABLE 4. Kin etic Resolu tion in Rin g-Clea va ge
Rea ction of syn -2,4-Dim eth ylp en ta n ed iol-Der ived
Aceta l 2
-50 °C. Based on the recovery of acetals which was determined
by GC analysis using an internal standard. c Determined by GC
d
(Chrompack CP-Cyclodextrin-â-236-M-19, 25 m). Not deter-
mined. e 0.3 equiv of 4a was used. f Oxazaborolidinone 4b (0.5
equiv) was used.
TABLE 2. Kin etic Resolu tion in Rin g-Clea va ge
Rea ction of Aceta ls 1a -f w ith Meth a llylsila n e 7ca
time conversion ent-1
(h)
yield
product (%)
entry acetal
(%)b
ee (%)c
s
1
2
3
4
5
6
rac-1a
rac-1b 10
rac-1c
rac-1d
rac-1e
rac-1f
8
63
38
58
44
58
34
92
45
81
34
76
34
10
10
9.2
3.5
7.6
6.8
9b
9c
9d
-
ndd
35
conversion
(%)b
ent-2
yield
(%)
1.5
0.7
1
54
entry nucleophile
ee (%)c
s
product
ndd
49
9e
-
1
2
3
5a
5e
7b
58
43
41
77
52
55
8.1
9.3
17
10a
10b
11
42
34
38
6
ndd
a
All reactions were carried out by using 4a (0.5 equiv) and 7c
b
a
(1.5 equiv) in CH2Cl2 (1 M) at -50 °C. Based on the recovery of
acetals which was determined by GC analysis using an internal
standard. c Determined by GC (Chrompack CP-Cyclodextrin-â-
236-M-19, 25 m). For ent-1c,d and ent-1f, the GC analyses were
carried out after conversion to an acetonide derivative and ent-
All reactions were carried out by using 4a (1 equiv) and 7b (3
b
equiv) in CH2Cl2 (0.4 M) at -50 °C for 24 h. Based on the
recovery of acetals which was determined by GC analysis using
an internal standard. c Determined by GC (Chrompack CP-
Cyclodextrin-â-236-M-19, 25 m).
d
1e, respectively. Not determined.
was obtained when methallyldimethylphenylsilane (7c)
was used as a nucleophile (entries 7 and 8). Under these
conditions, enantiomerically enriched ent-1a of 92% ee
was recovered at 63% conversion. The amount of ox-
azaborolidinone 4a could be reduced to 0.3 equiv without
lowering the selectivity (entry 9). In the ring-cleavage
reaction of acetals derived from meso-1,2- and -1,3-diols,
N-tosyloxazaborolidinone 4b exhibited higher enantio-
selectivities than N-mesyl derivative 4a .3 However, 4b
did not give a better result for rac-1a (entry 10).
The enantioselectivity (s) varied significantly depend-
ing on the nucleophiles. There is a general trend of higher
selectivity for the less reactive nucleophiles.11 Thus, enol
silyl ethers 5b-d exhibited selectivity higher than silyl
ketene S,O-acetal 5a (entry 1 vs entries 2-4). In com-
parison with acetophenone enol silyl ether 5c (s ) 4.4),
5d with an electron-withdrawing p-chlorophenyl group
exhibited improved selectivity (s ) 5.3). Although the re-
action of allyltrimethylsilane (7a) was sluggish, methallyl-
trimethylsilane (7b) reacted smoothly with superior
selectivity of 7.4 (entry 6). Further improvement (s ) 10)
The effect of aryl substituent attached to the acetal
carbon was studied in the reaction with methallylsilane
7c (Table 2). The reaction rate increased significantly in
going from electron-withdrawing substituents to electron-
donating substituents. Decreased enantioselectivity was
observed for electron-donating groups such as p-meth-
oxyphenyl (PMP) and 2-furyl (entries 4 and 5) while the
electron-withdrawing p-chlorophenyl group in rac-1b did
not improve the selectivity (entry 2). The lower selectivity
(9) Harada, T.; Nakamura, T.; Kinugasa, M.; Oku, A. J . Org. Chem.
1999, 64, 7594-7600.
(10) s ) k1/kent-1 ) ln[(1 - C)(1 - ee)]/ln[(1 - C)(1 + ee)] where C
is the conversion and ee is the enantiomeric excess. Kagan, H. B.;
Fiaud, J . C. Top. Stereochem. 1988, 18, 249-330.
(11) (a) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33,
938-957. (b) Mayr, H.; Kuhn, O.; Gotta, M. F.; Patz, M. J . Phys. Org.
Chem. 1998, 11, 642-654. (c) Burfeindt, J .; Patz, M.; Mu¨ller, M.; Mayr,
H. J . Am. Chem. Soc. 1998, 120, 3629-3634.
7082 J . Org. Chem., Vol. 67, No. 20, 2002

Differentiation of Enantiotopic Dioxane Acetals
TABLE 5. Kin etic Resolu tion in Rin g-Clea va ge Rea ction of a n ti-2,4-Dim eth ylp en ta n ed iol-Der ived
Aceta l 3a ,ba
oxaza-
borolidinone
conversion
(%)b
ent-3
yield
(%)
entry
acetal
nucleophile
ee (%)c
s
productd
1d
2
3
4
5
6
7
8
rac-3a
rac-3b
4c
4a
5a
5a
5e
7b
6b
5a
5e
6b
46
78
68
31
57
47
53
65
6.9
69
74
20
69
53
71
76
1.3
2.7
4.0
3.0
6.2
6.9
9.3
5.1
12a
12b
12c
13
36
55
54
34
52
43
49
58
13
4b
12b
12c
13
a
Unless otherwise noted, reactions were carried out by using an oxazaborolidinone (1 equiv) and a nucleophile (3 equiv) in CH2Cl2 (0.4
M) at -60 °C for 16-17 h. b Based on the recovery of acetals which was determined by GC analysis using an internal standard. c Determined
d
by GC (Chrompack CP-Cyclodextrin-â-236-M-19, 25 m) for ent-3a or by HPLC (Chirapak AD) for ent-3b. The reaction was carried out
by using 0.5 equiv of 4c and 1.5 equiv of 5a at -40 °C.
was observed for sterically more demanding 1-naphthyl
derivative rac-1f (entry 6).
with methallylsilane 7b or with silyl ketene acetal 5a .
This may probably due to the stability of rac-3a with the
three substituents being equatorial.3e The use of more
acidic N-trifluoromethanesulfonyl-oxazaborolidinone 4c5
facilitated the reaction (Table 5, entry 1) but no enantio-
selectivity was observed.
Ring-cleavage reaction of acetals rac-1g-j derived from
the other 1,3-alkanediols and benzaldehyde was exam-
ined by using oxazaborolidinone 4a as a chiral Lewis acid
and methallylsilanes 7b or 7c as a nucleophile (Table
3). The absolute configuration determination of the
recovered acetals, by comparison with an authentic
sample (for ent-1i), or by conversion to the known 1,3-
diols (for ent-1a ,g,j) or its diaceate derivative (for ent-
1h ), revealed a similar sense of enantioselectivity in all
reactions. The degree of enantioselectivity was affected
by the structure of the R2 group. A highly enantioselective
reaction (s ) 16) was observed for 4-tert-butyl derivative
rac-1g with 7b (entry 2). On the other hand, 4-phenyl-
ethyl, -methyl, and -phenyl derivatives rac-1h -j exhib-
ited the reduced selectivities in comparison with rac-1a .
It was shown that the ring-cleavage reaction of disub-
In accord with the increased reactivity observed for
acetals rac-1c-e with electron-donating aryl groups,
PMP derivative 3b exhibited an appropriate reactivity
in the reaction using N-mesyloxazaborolidinone 4a at
-60 °C (entries 2-5). Examination of several nucleo-
philes however resulted in unsatisfactory enantioselec-
tivity. Of these, tributylmethallylstannane (6b) exhibited
the highest selectivity of 6.2.13 For the reaction of PMP
derivative 3b, N-tosyloxazaborolidinone 4b was found to
be a better chiral Lewis acid especially when a silyl
ketene acetal was employed as a nucleophile (entries
6-8). Satisfactory enantioselectivity (s ) 9.3) was ob-
tained in the reaction with silyl ketene acetal 5e. Here
again, a similar sense of asymmetric induction was
observed judging from the recovery of (4S,5R) enanti-
omer.12
In the kinetic resolution of the racemic acetals, enan-
tiomers 1-3 always underwent ring-cleavage in prefer-
ence to ent-1-3. According to the previous studies on the
mechanism of ring-cleavage reaction mediated by achiral14
and chiral Lewis acids,9 it is most probable that the
enantiomer differentiating reaction of rac-1-3 proceeds
through an SN1-type stepwise mechanism involving
contact ion pair intermediates 14a ,b (Scheme 4). Thus,
the dissociation of the acetal-oxazaborolidinone complex
13a and subsequent attack of a nucleophile to the
resulting ion pair 14a lead to the formation of the major
ring-cleavage products.
stituted acetals rac-1 (R1 ) Ph, R3R, R3 ) H) can be
â
carried out in an enantioselective manner by using
oxazaborolidinone 4a as a chiral Lewis acid and meth-
allylsilane 7b or 7c as a nucleophile. We then focused
our attention to the kinetic resolution of trisubstituted
acetals rac-2 and -3 derived respectively from syn- and
anti-2,4-dimethyl-1,3-pentanediol.
2-Phenyl derivative rac-2 provided significantly high
enantioselectivity (s ) 17) in the reaction with oxaza-
borolidinone 4a and methallylsilane 7b (Table 4, entry
3). The recovered acetal was enriched with (4S,5S)
enantiomer,12 showing a similar sense of asymmetric
induction. The acetal also exhibited relatively high
selectivity of 8.1 and 9.3 in the reaction with silyl ketene
acetal 5a and 5e, respectively (entries 1 and 2).
In sharp contrast to acetals rac-1 and -2, trisubstituted
acetal rac-3a derived from the anti-1,3-diol and benz-
aldehyde was found to be quite less reactive, not under-
going ring-cleavage by using N-mesyl derivative 4a either
For the reaction of dioxolane acetals derived from meso-
1,2-diols (Scheme 1; R2 ) PhCtC, n ) 0), it was clarified
(13) The reaction of 6b with allyltributylstannane 6a was sluggish.
(14) (a) Denmark, S. E.; Almstead, N. G. J . Am. Chem. Soc. 1991,
113, 8089-8110. (b) Sammakia, T.; Smith, R. S. J . Am. Chem. Soc.
1992, 114, 10998-10999. See also references cited in ref 8.
(12) The absolute structure was determined by conversion to the
known 1,3-diol.
J . Org. Chem, Vol. 67, No. 20, 2002 7083

Harada et al.
SCHEME 4a
SCHEME 5
SCHEME 6
BL* ) 4.
that dissociation to an ion pair is rate-determining step
followed by a rapid reaction of nucleophiles.9 This led us
to propose the selective complexation of one of the
enantiotopic oxygen atoms to the chiral Lewis acid as a
major factor governing the enantioselectivity.9,3e If the
reaction of rac-1-3 also involved a similar mechanistic
profile, the observed enantioselectivity would not be
affected by nucleophiles. The observed effect of nucleo-
philes implies that there is a preequilibrium between
acetal-oxazaborolidinone complexes 13a ,b and ion pairs
14a ,b prior to the attack of nucleophiles. In comparison
with the corresponding five-membered ring contact ion
pair intermediates, six-membered ring ion pairs 14a ,b
might be more stable, resulting in relatively slow reaction
with nucleophiles. The low reactivity observed for rac-
3a of which three substituents are equatorial might be
an extreme case of the phenomenon. Owing to such
mechanistic complexity, it is difficult to rationalize the
selectivity observed in the present enantiomer differen-
tiating ring-cleavage reaction. If we assume that ion pairs
14a and 14b possess comparable reactivity toward nu-
cleophiles, the observed selectivity might be again the
result of enantiodifferentiating complexation by the
oxazaborolidinones to form 13a . Alternatively, it is
conceivable that, in an extreme case, ion pair 14a
produced from less favorable complex 13a undergoes
selective attack by the nucleophiles to give the major
ring-cleavage product.
SCHEME 7
Chelation-controlled reduction15 of 15 stereoselectively
gave syn diol 16 in 90% yield. Protection of the diol moiety
and subsequent reduction of the resulting ester trans-
formed 16 into acetal 17 in 90% yield. Hydrogenolysis of
17 followed by acetalization of the resulting meso-tetrol
with benzaldehyde furnished a crystalline bis-acetal 18a
in 63% yield.
Starting from succinaldehyde derivative 19, homolo-
gous meso-bis-acetal 18b was stereoselectively prepared
by using 1,4-asymmetric induction, developed by Molan-
der et al.,16 as a key reaction (Scheme 6). Thus, treatment
of 19 with allyltributylstannane in the presence of
TMSOTf afforded meso diallylation product 20 (75%)
stereoselectively (meso:dl ) 9:1). The second allylation
presumably proceeded through a cyclic oxonium ion
intermediate 22, leading to the selective formation of
meso 20 (Scheme 7).16 The stereochemistry of the diol was
Asym m etr ic Desym m etr iza tion of P olyols. After
establishing the conditions for kinetic resolution, or
intermolecular differentiation, of racemic acetals, we then
applied them to asymmetric desymmetrization of meso-
polyols through intramolecular differentiation of the
prochiral bis-acetal derivatives.
(15) Chen, K.-M.; Gunderson, K. G.; Hardtmann, G. E.; Prasad, K.;
Repic, O.; Shapiro, M. J . Chem. Lett. 1987, 1923-1926.
(16) Molander, G. A.; Haar, J . P. J . Am. Chem. Soc. 1993, 113, 40-
49.
meso-1,3,5,7-Heptanetetrol bis-acetal 18a was pre-
pared in five steps from hydroxy ester 15 (Scheme 5).
7084 J . Org. Chem., Vol. 67, No. 20, 2002

Differentiation of Enantiotopic Dioxane Acetals
SCHEME 9
confirmed by converting it into cyclic silyl ether 23 (eq
5), whose methyl groups are inequivalent in NMR
analysis. Oxidative cleavage of the double bond and
subsequent reduction of the aldehyde moieties converted
20 into 21 in 69% yield. After deprotection and acetal-
ization of the resulting meso-tetrol with benzaldehyde,
a crystalline bis-acetal 18b was isolated in 67% yield.
Asymmetric desymmetrization of bis-acetals 18a ,b was
successfully achieved by carrying out the ring-cleavage
reaction under the optimized conditions for kinetic
resolution of acetals rac-1. Thus, treatment of 18a with
methallylsilane 7c (1.5 equiv) in the presence of N-
mesyloxazaborolidinone 4a (1.0 equiv) at -50 °C afforded
the mono-cleavage product 24a in 94% yield (Scheme 8).
After protection of the hydroxy group as a pivalate (84%),
removal of the 3-methyl-1-phenyl-3-butenyl group by
oxidative cleavage of the double bond and subsequent
treatment of the resulting â-alkoxy ketone with Na2CO3
in ethanol furnished O-benzylidene pivalate 26a of 88%
ee16 in 75% yield.
To further demonstrate the efficiency of the present
approach, we then applied it to the stereocontrolled
construction of seven contiguous stereogenic centers in
the C(19)-C(27) ansa chain of rifamycin S.20,2d Meso-triol
derivative 28 with seven potential stereogenic centers
was prepared in a convergent manner according to a
method reported previously by us (Scheme 9).2d,h Thus,
hydroboration of diene 27 followed by Swern oxidation
and subsequent crotylboration of the resulting dialdehyde
gave 28 stereoselectively. Ozonolysis of 28 and trans-
acetalization of the resulting tetrol with p-anisaldehyde
dimethyl acetal furnished prochiral bis-acetal 29 in 75%
yield.
SCHEME 8
Ring-cleavage reaction of bis-acetal 29 was carried out
first under the conditions optimized for rac-3b. However,
treatment of 29 with silyl ketene acetal 5e and N-
tosyloxazaborolidinone 4b at -60 °C for 22 h resulted in
the recovery of the bis-acetal. The outside oxygen atom,
O(1) or O(9), might coordinate to the oxazaborolidinone,
and the nucleophile needs to attack the acetal carbon
from the inside of the molecule. The low reactivity of 29
may have arisen from unfavorable interaction between
the nucleophile and the TBS group attached to O(5). We
then examined the ring-cleavage reaction of hydroxy
derivative 30, which was obtained by desilylation of 29
in quantitative yield. Under similar conditions, 30 un-
Under similar conditions, ring-cleavage of bis-acetal
18b afforded the mono-cleavage product 24b (82%)
together with the bis-cleavage product 25 (15%). The
minor enantiomer ent-24b (not shown) with more reactive
(S)-acetal moiety, if formed, would undergo second ring-
cleavage preferentially to give 25. Therefore, the forma-
tion of 25 in relatively large amount suggested a higher
ee of 24b through such sequential kinetic resolution.18
Indeed, transformation of 24b through a similar reaction
sequence gave O-benzylidene pivalate 26b of high ee
(95%)17 in 63% overall yield. The absolute configurations
of 26a and 26b, established by the modified Mosher’s
method,19 were in accord with the anticipated reaction
on the (S)-acetal moiety of 18a ,b.
(20) For the total synthesis of rifamycin S, see; (a) Nagaoka, H.;
Rutsh, W.; Schmid, G.; Iio, H.; J ohnson, M. R.; Kishi, Y. J . Am. Chem.
Soc. 1980, 102, 7962-7965. (b) Nagaoka, H.; Kishi, Y. Tetrahedron
1981, 37, 3873. For the synthesis of ansa chain, see: (c) Nakata, M.;
Takao, H.; Ikeyama, Y.; Sakai, T.; Tatsuta, K.; Kinoshita, M. Bull.
Chem. Soc. J pn. 1981, 54, 1749-1756. (d) Masamune, S.; Imperiali,
B.; Garvey, D. S. J . Am. Chem. Soc. 1982, 104, 5528. (e) Hanessian,
S.; Pougny, J .-R.; Bossenkool, I. K. J . Am. Chem. Soc. 1982, 104, 6164-
6166. (f) Still, W. C.; Barrish, J . C. J . Am. Chem. Soc. 1983, 105, 2487-
2489. (g) Fraser-Reid, B.; Magdzinski, L.; Molino, B. J . Am. Chem. Soc.
1984, 106, 731-734. (h) Danishefsky, S. J .; Myles, D. C.; Harvey, D.
F. J . Am. Chem. Soc. 1987, 109, 862-867. (i) Roush, W. R.; Palkowitz,
A. D. J . Am. Chem. Soc. 1987, 109, 953-955. (j) Ziegler, F. E.; Cain,
W. T.; Kneisley, A.; Stirchak, E. P.; Wester, R. T. J . Am. Chem. Soc.
1988, 110, 5442-5452. (k) Katsuki, T.; Hanamota, T.; Yamaguchi, M.
Chem. Lett. 1989, 117-120. (l) Paterson, I.; McClure C. K.; Schumann,
R. C. Tetrahedron Lett. 1989, 30, 1293-1296. (m) Roush, W. R.;
Palkiwitz, A. D.; Ando, K. J . Am. Chem. Soc. 1990, 112, 6348-6359.
(n) Lautens, M.; Belter, R. K. Tetrahedron Lett. 1992, 33, 2617-2620.
(o) Miyashita, M.; Yoshihara, K.; Kawamine, K.; Hoshino, M.; Irie, H.
Tetrahedron Lett. 1993, 34, 6285-6285. (p) Yadav, J . S.; Srinivas Rao,
C.; Chandrasekhar, S.; Rama Rao, A. V. Tetrahedron Lett. 1995, 36,
7717-7720. (q) Hanessian, S.; Wang, W.; Gai, Y.; Oivier, E. J . Am.
Chem. Soc. 1997, 119, 10034-10041. (r) Hunt, K. W.; Grieco, P. A.
Org. Lett. 2001, 3, 481-484.
(17) The ee value was determined by 1H NMR analysis of the MTPA
ester.
(18) (a) Schreiber, S. L.; Schreiber, T. S.; Smith, D. B. J . Am. Chem.
Soc. 1987, 109, 1525-1529. (b) Ward, D. E.; Liu, Y.; How, D. J . Am.
Chem. Soc. 1996, 118, 3025-3026. (c) Ward, D. E.; How, D.; Yadong,
Y. J . Am. Chem. Soc. 1997, 119, 1884-1894.
(19) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092-4096.
J . Org. Chem, Vol. 67, No. 20, 2002 7085

Harada et al.
derwent a smooth ring-cleavage reaction to give 32 (86%)
Con clu sion
as a 7:3 mixture of diastereomers (eq 6).21 To our surprise,
We have shown that oxazaborolidinone-mediated ring-
cleavage reaction can be successfully used in kinetic
resolution of racemic acetals derived from 1,3-alkanediols.
Enantioselectivity of the reaction was most affected by
nucleophiles. For disubstituted acetals rac-1 and for
trisubstituted acetal rac-2, derived from syn-2,4-di-
methyl-1,3-propanediol, satisfactory enantioselectivity (s
) 5.1-17) was obtained by using methallylsilane 7a or
7b as a nucleophile in combination with N-mesyl-
oxazaborolidinone 4a . On the other hand, enantioselec-
tive reaction (s ) 9.3) of trisubstituted acetal rac-3b
derived from an anti-1,3-alkanediol was realized by using
silyl ketene acetal 5e in combination with N-tosyl-
oxazaborolidinone 4b. The reaction conditions optimized
in the enantiomer differentiating ring-cleavage reaction
were successfully applied to asymmetric desymmetriza-
tion of meso-1,3-polyols through intramolecular differ-
entiation of the bis-acetal derivatives. Highly convergent
asymmetric synthesis of the pentol derivative corre-
sponding to the C(19)-C(27) ansa-chain of rifamycin S
demonstrates the utility of the ring-cleavage reaction as
a method for terminal differentiation of the prochiral
polyols.
2D-NMR (H-H, C-H COSEY, and HMBC) analyses
revealed the structure of the major isomer to be that
produced through the cleavage of the inside C-O bond.
Moreover, the major isomer was found to be racemic
(3% ee) by a chiral-phase HMPLC analysis. It is probable
that a Brønsted acid generated through the coordination
of the oxazaborolidinone by the hydroxy group activated
the inner oxygen atoms O(3) and O(7) without selectiv-
ity.22
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, 1H and 13C NMR spectra
were recorded in CDCl3 at 300 and 75.6 MHz, respectively.
Unless otherwise noted, mass spectra were measured using
the EI (70 eV) ionization. All commercially available reagents
were used without further purification. Dichloromethane and
DMF were distilled from calcium hydride. THF and benzene
were distilled from sodium/benzophenone ketyl. Unless other-
wise noted, organic extracts were dried over Na2SO4. Flash
chromatography was conducted on silica gel (Wakogel C-300).
(2R*,3R*)-,23 (2R*,3S*)-2,4-Dimethyl-1,3-pentanediol,24 acetal
1i,5 N-sulfonyl L-phenylalanines,25 enol silanes 5a -e,26 tri-
butylmethallylstannane 6b,27 and methallyltrimethylsilane
7b28 were prepared according to the literature procedures.
(2R*,4R*)-4-Isop r op yl-2-p h en yl-1,3-d ioxa n e (1a ). To a
solution of 5-methyl-1,3-pentanediol (0.945 g, 8.0 mmol) and
benzaldehyde (0.849 g, 8.00 mmol) in benzene (50 mL) was
added and p-toluenesulfonic acid monohydrate (15 mg, 0.08
mmol). The reaction flask was equipped with a Dean-Stark
trap, and the mixture was heated at reflux for 4 h. The mixture
was poured into aq NaHCO3 and extracted twice with hexane.
The organic layers were dried and concentrated in vacuo.
Distillation of the residue (bp 77-79 °C/0.3 mmHg) gave 2.23
g (74%) of 6a : 1H NMR δ 0.95 (3H, d, J ) 6.0 Hz), 1.02 (3H,
d, J ) 6.7 Hz), 1.53 (1H, m), 1.73-1.88, (2H, m), 3.52 (1H,
ddd, J ) 2.4, 6.8, and 11.2 Hz), 3.94 (1H, dt, J ) 2.7 and 12
Hz), 4.29 (1H, ddd, J ) 1.4, 5.0 and 11.3 Hz), 5,0.50 (1H, s),
Protection of the hydroxy group of 30 as a sterically
less demanding methyl ether gave O-methyl derivative
31 in 93% yield. Although the reaction of 31 with silyl
ketene acetal 5e was sluggish, the bis-acetal underwent
smooth ring-cleavage reaction with less bulky ethyl
acetate-derived silyl ketene acetal 5f in the presence of
oxazaborolidinone 4b to give TMS ether 33 (a 9:1 mixture
of diastereomers) and free alcohol 34 (a 9:1 mixture of
diastereomers) in 58% and 31% yield, respectively (Scheme
10). In the attempted conversion of 33 to 34 by treatment
with Bu4NF, removal of the nucleophile derived moiety
leading to diol 35 was also occurred. Taking advantage
of the observation, the ring cleavage products as a
mixture 33 and 34 was treated with Bu4NF at room
temperature for 18 h to give diol 35 in 73% overall yield
from 31. Selective protection of the terminal hydroxy
group as a TBS ether furnished 36 in 96% yield. The
enantiomeric purity of 36 was determined to be 87% ee
by chiral phase HPLC analysis. The absolute structure
determined by the modified Mosher method18 is the one
expected from the study on kinetic resolution of rac-3b.
SCHEME 10
(21) Attempted esterification (Ac2O, pyridine, DMAP and MTPACl,
i-PrNEt2, DMAP) of 32 as a mixture failed, suggesting that that both
isomers possess sterically hindered secondary hydroxy groups.
(22) Ishihara, K.; Kaneeda, M.; Yamamoto, H. J . Am. Chem. Soc.
1994, 116, 11179-11180.
(23) Harada, T.; Matsuda, Y.; Wada, I.; Uchimura, J .; Oku, A. J .
Chem. Soc., Chem. Commun. 1989, 1429-1430.
(24) Montgomery, S. H.; Pirrung, M.; Heathcock, C. H. Organic
Syntheses; Wiley: New York, 1990; Collect. Vol. VII, pp 190-194.
(25) McChesney, E. W.; Wann, J r., W. K. J . Am. Chem. Soc. 1937,
58, 1116.
(26) Kita, Y.; Segawa, J .; Haruta, J .; Yasuda, H.; Tamura, Y. J .
Chem. Soc., Perkin Trans. 1 1982, 1099.
(27) Miura, K.; Saito, H.; Fujisawa, H. Hosomi, A. J . Org. Chem.
2000, 65, 8119-8122.
(28) Ishihara, K.; Mouri, M.; Gao, Q.; Maruyama, T.; Furuta, K.;
Yamamoto, H. J . Am. Chem. Soc. 1993, 115, 11490-111495,
7086 J . Org. Chem., Vol. 67, No. 20, 2002

Differentiation of Enantiotopic Dioxane Acetals
7.31-7.39 (3H, m), 7.48-7.52 (2H, m); 13C NMR δ 17.88, 18.35,
28.24, 32.98, 67.15, 82.22, 100.99, 125.97, 128.12, 128.51,
139.05.
min), ent-1j (100 °C, 10 min and then 5 deg/min, (2R,4S) t1 )
19.31 min, (2S,4R) t2 ) 19.44 min), ent-2 (115 °C, 15 min and
then 2 deg/min, (2R,4S,5S) t1 ) 29.91 min, (2S,4R,5R) t2 )
30.23 min), ent-3a (115 °C, (2R,4S,5R) t1 ) 43.23 min,
(2S,4R,5S) t2 ) 44.57 min). The ee values of ent-1c,d were
determined after converting them to an acetonide derivative
(50 °C, 10 min and then 3 deg/min, (R) t1 ) 15.47 min, (S) t2
) 15.92 min). The ee value of ent-1f was determined after
converting it to 2-furyl derivative ent-1e. The ee values of the
following acetals were determined by a chiral phase HPLC:
ent-1h (Daicel Chiracel OD, 1 mL/min,10% 2-PrOH in hexane)
(2R,4S) t1 ) 4.99 min, (2S,4R) t2 ) 8.10 min), ent-1j (Daicel
Chiracel OD, 1 mL/min, 30% 2-PrOH in hexane) (2R,4R) t1 )
4.58 min, (2S,4S) t2 ) 7.18 min), ent-3b (Daicel Chirapak AD,
1 mL/min,10% 2-PrOH in hexane) (2R,4S,5R) t1 ) 17.64 min,
(2S,4R,5S) t2 ) 19.35 min).
1-Eth oxy-1-(tr im eth ylsilyloxy)eth en e (5f).29 The com-
pound was prepared by the reaction of ethyl acetate with LDA
(1.1 equiv) followed by treatment with chlorotrimethylsilane
1
(1.2 equiv) in THF at -78 to -40 °C. The H NMR analysis of
the crude reaction mixture showed the formation of a 1:1
mixture of 5f and ethyl trimethylsilyl acetate. Concentration
of the crude mixture in vacuo at room temperature and
distillation of the residue under reduced pressure (60 °C/10
mmHg) gave 5f (containing 40% of ethyl trimethylsilyl acetate)
in 30% yield.
Dim eth yl-(2-m eth yl-2-p r op en yl)p h en ylsila n e (7c). The
compound was prepared in 88% yield by the reaction of
methallyl bromide and chlorodimethylphenylsilane with mag-
nesium. 7c: bp 47-48 °C/0.5 mmHg; 1H NMR δ 0.31 (6H, s),
1.62 (3H, m), 1.78 (2H, d, J ) 0.9 Hz), 4.48 (1H, m), 4.60 (1H,
m), 7.37 (3H, m), 7.52 (2H, m).
Gen er a l P r oced u r e for th e P r ep a r a tion of Oxa za bor o-
lid in on es 4a -c. To a solution of an N-sulfonyl amino acid
(0.20 mmol) in CH2Cl2 (2 mL) was added dichlorophenylborane
(26 µL, 0.20 mmol) at room temperature. After being stirred
for 30 min, the mixture was concentrated in vacuo to give 4a -c
as a white solid, which was then dissolved in CH2Cl2 (0.27 mL)
and used in ring-cleavage reactions.
The absolute structures of recovered acetals ent-1a ,g,j, 2,
and 3b were determined by hydrolysis (1N HCl, ethanol,
reflux) of them to the known 1,3-diols. (2R,4R)-1a (88.2% ee,
Table 1, entry 9) gave (R)-4-methyl-1,3-pentanediol: [R]23D 10
(c 0.24, CHCl3), lit.30 12.0 (c 2.43, CHCl3). (2R,4R)-1g (55.6%
ee, Table 3, entry 2) gave (R)-4,4-dimethyl-1,3-pentanediol:
[R]20 8.2 (c 0.27, CHCl3), lit.31 18.0 (c 0.4, CHCl3). (2R,4R)-1j
D
(84.0% ee, Table 3, entry 5) gave (R)-1-phenyl-1,3-pro-
panediol: [R]23 56 (c 1,1, CHCl3), lit.32 ((S)-isomer) -63.8 (c
D
1, CHCl3). (2R,4S,5S)-2 (55.4% ee, Table 4, entry 3) gave
(2S,3S)-2,4-dimethyl-1,3-pentanediol: [R]19D 5.9 (c 0.40, CHCl3),
lit.33 11.3 (c 0.6, CHCl3). (2R,4S,5R)-3b (71% ee, Table 5, entry
Rin g-Clea va ge P r od u ct 9b (Rep r esen ta tive P r oced u r e
for th e Rin g-Clea va ge of Aceta ls; Ta ble 1, en tr y 8). To a
stirred solution of acetal rac-1a (62 mg, 0.30 mmol) and 7c
(86 mg, 0.45 mmol) in CH2Cl2 (0.1 mL) at -50 °C under argon
was added a fleshly prepared CH2Cl2 solution of 4a (0.20 mL,
0.15 mmol). After being stirred for 4 h, the reaction mixture
was quenched by the addition of iso-Pr2NEt (0.1 mL). The
mixture was diluted with ether, poured into aq NaHCO3, and
extracted twice with Et2O. Tetradecane was added to the dried
organic layers as an internal standard. The yield (43.7%) and
ee (79.9%) of ent-1a were determined by GC analyses with an
OV101 (30 m) column and with a CP-Cyclodextrin-â-236-M-
19 (25 m) column (110 °C, 15 min and then 3 deg/min,
(2R,4R)t1 ) 28.52 min, (2S,4S) t2 ) 28.78 min), respectively.
The mixture was then concentrated in vacuo. Because a part
of the ring-cleavage product was obtained as a TMS ether
derivative, the residue was treated with acetic acid-H2O-THF
(volume ratio; 3:3:4) at room temperature for 1 h. The mixture
was poured into water and extracted twice with ether. The
organic layers were washed with aq NaHCO3, dried, and
concentrated in vacuo. Purification of the residue by flash
chromatography (5-10% ethyl acetate in hexane) gave 40.4
mg (51%) of 9b: 1H NMR δ 0.80 (3H, d, J ) 7.0 Hz), 0.91 (3H,
d, J ) 6.9 Hz), 1.44 (1H, m), 1.59 (1H, m), 1.70 (3H, s), 2.09
(1H, m), 2.36 (1H, dd, J ) 6.2 and 13.8 Hz), 2.40 (1H, br), 2.58
(1H, dd, J ) 7.8 and 13.8 Hz), 3.26 (1H, m), 3.54 (1H, m), 4.52
(1H, dd, J ) 6.2 and 7.8 Hz), 4.67 (1H, m), 4.74 (1H, m), 7.25-
7.39 (5H, m);13C NMR δ 15.79, 18.77, 22.90, 28.34, 30.62, 46.43,
61.10, 77.95, 79.35, 113.28, 127.33, 127.93, 128.46, 141.79,
141.96; IR (liquid film) 3400 (br), 1650, 1055, 890, 760, 700
cm-1; MS m/z (relative intensity) 262 (M+. 0.1), 207 (100), 107
(100); HRMS calcd for C17H26O2 262.1933, found; 262.1949.
Anal. Calcd for C17H26O2: C, 77.82; H, 9.99. Found: C, 77.58;
H, 10.22.
7) gave (2R,3S)-2,4-dimethyl-1,3-pentanediol: [R]25 -14.3 (c
D
1,22, CHCl3), lit.34 ((2S,3R)-isomer) 19.6 (c 0.57, CHCl3). The
absolute structure of ent-1h (67.0% ee, Table 3, entry 3) was
determined to be (2R,4S) by converting it to (S)-5-phenyl-1,3-
pentanediyl diacetate ((i) H2, Pd/C, EtOH, (ii) Ac2O, DMAP,
pyridine): [R]23 13.8 (c 0.68, CHCl3), lit.29 18.6 (c 0.474,
D
CHCl3). The absolute structure of ent-1i was determined to
be (2R,4S) by GC analysis of an authentic sample prepared
from (S)-butane-1,3-diol.
m eso-Bis-a ceta l 18a . A mixture of acetal 17 (3.32 g, 9.55
mmol) and 10% Pd/C (66.4 mg) in ethanol (43 mL) was stirred
vigorously under hydrogen atmosphere for 3 days at room
temperature. The mixture was filtered through a pad of
cellulose powder, and the filtrate was concentrated in vacuo.
Acetalization of the crude tetrol with benzaldehyde (2.22 g,
21.0 mmol) was carried out according to a procedure similar
to that described above (benzene reflux, 14 h). Purification of
the crude product with flash chromatography (15% ethyl
acetate in hexane) and recrystallization from benzene and
hexane gave 2.05 g (63% yield) of 18a : mp 91-92 °C; 1H NMR
δ 1.61 (2H, m), 1.79 (1H, td, J ) 5.8 and 14.1 Hz), 1.84-1.98
(2H, m), 2.15 (1H, td, J ) 7.1 and 14.1 Hz), 3.98 (2H, m), 4.12
(2H, m), 4.28 (2H, ddd, J ) 1.3, 5.0, and 11.4 Hz), 5.52 (2H, s)
7.32-7.40 (6H, m), 7.47-7.51 (4H, m); 13C NMR δ 31.14, 41.91,
67.05, 73.52, 101.18, 126.02, 128.22, 128.72, 138.70. Anal.
Calcd for C21H24O4: C, 74.09; H, 7.11. Found: C, 74.26; H,
7.04.
m eso-Bis-a ceta l 18b. A mixture of diol 21 (0.541 g, 1.51
mmol) and 10% Pd/C (106 mg) in ethanol (7 mL) was stirred
vigorously under hydrogen atmosphere for 17 h at room
temperature. The mixture was filtered, and the filtrate was
concentrated in vacuo. Acetalization of the crude tetrol was
carried out by using a mixture of benzaldehyde (384 mg, 3.62
mmol) and benzaldehyde dimethyl acetal (544 mg, 3.62 mmol)
according to a procedure similar to that described above.
The ring-cleavage reactions of other racemic acetals were
carried out according to a procedure similar to that described
above. The ee values of the following acetals were determined
by capillary GC analyses using a Chrompack CP-Cyclodex-
trin-â-236-M-19 (25 m) column: ent-1b (125 °C, 15 min and
then 2.5 deg/min, (2R,4R) t1 ) 37.17 min, (2S,4S) t2 ) 37.38
min), ent-1c (100 °C, 10 min and then 4 deg/min, (2R,4R) t1 )
19.76 min, (2S,4S) t2 ) 20.01 min), ent-1g (100 °C, 10 min
and then 5 deg/min, (2R,4R) t1 ) 22.08 min, (2S,4S) t2 ) 22.26
(30) Harada, T.; Kurokawa, H.; Kagamihara, Y.; Tanaka, S.; Inoue,
A.; Oku, A. J . Org. Chem. 1992, 57, 1412-1421.
(31) Konoike, T.; Hayashi, T.; Araki, Y. Tetrahedron Asymm. 1994,
5, 1559-1566.
(32) Cheˆnevert, R, Genevieˆre, F.; Rhlid, R. B. Tetrahedron 1992,
48, 6769-6776.
(33) Helmchen, G.; Leikauf, U.; Taufer-Knopfel, I. Angew. Chem.,
Int., Ed. Engl. 1985, 24, 874.
(29) Mikami, K.; Matsumoto, S.; Ishida, A.; Takemura, S.; Suenobu,
T.; Fukuzumi, S. J . Am. Chem. Soc. 1995, 117, 11134-11141.
(34) Abiko, A.; Liu, J .-F.; Masamune, S. J . Am. Chem. Soc. 1997,
119, 2586-2587.
J . Org. Chem, Vol. 67, No. 20, 2002 7087

Harada et al.
Purification of the crude products with flash chromatography
(15% ethyl acetate in hexane) and recrystallization from
benzene and hexane gave 0.360 g (67% yield) of 18b: mp 103-
dd, J ) 8.7 and 15.6 Hz), 3.35 (1H,m), 3.76-4.13 (4H, m), 4.27
(1H, m), 4.86 (1H, dd, J ) 4.5 and 8.7 Hz), 5.50 (1H, s), 7.20-
7.55 (10H, m); 13C NMR δ 27.00 27.58, 30.83, 31.21, 33.24,
38.48, 51.80, 61.11, 67.00, 72.57, 75.20, 77.000, 101.14, 126.02,
126.85, 127.93, 128.14, 128.52, 128.62, 138.78, 141.38, 178.25,
206.51; IR (neat film) 1725, 765, 700 cm-1. A solution of the
ketone (28.5 mg, 0.0573 mmol) in ethanol (6 mL) was heated
under reflux for 3 h in the presence of Na2CO3 (56.1 mg). The
reaction mixture was poured into brine and extracted twice
with ether. The organic layers were dried and concentrated
in vacuo. Purification of the residue by flash chromatography
(20% ethyl acetate in hexane) gave 19.1 mg, (95% yield) of
26b: 1H NMR δ 1.18 (9H, s), 1.46-1.93 (8H, m), 2.48 (1H,
br), 3.66 (1H,m), 3.83 (1H, m),3.95 (1H, dt, J ) 2 and 12 Hz),
4.11 (1H, m), 4.23-4.38 (2H, m), 5.50 (1H, s), 7.26-7.48 (5H,
m); 13C NMR δ 27.17, 32.23, 33.19, 33.54, 38.73, 61.60, 67.02,
68.43, 77.46, 101.18, 125.94, 128.22, 128.70, 138.61, 178.94;
1
103.5 °C; H NMR δ 1.50-1.60 (2H, m), 1.68-1.90 (6H, m),
3.84 (2H, m), 3.94 (2H, dt, J ) 2.5 and 11.4 Hz),4.27 (2H, ddd,
J ) 1.1, 5.0, and 11.4 Hz), 5.51 (2H, s), 7.32-7.40 (6H, m),
7.49-7.52 (4H, m); 13C NMR δ 31.41, 31.81, 67.01, 77.33,
101.09, 125.98, 128.15, 128.62, 138.81. Anal. Calcd for
C
22H26O4: C, 74.55; H, 7.39. Found: C, 74.31; H, 7.30.
Rin g-Clea va ge P r od u ct 24b. Ring-cleavage reaction of
bis-acetal 18b (70.0 mg, 0.198 mmol) was carried out according
to a procedure similar to that described above by using meth-
allylsilane 7c (113 mg, 0.593 mmol) and oxazaborolidinone 4a
(0.198 mmol) in CH2Cl2 (0.38 mL) at -50 °C for 8 h. The
reaction mixture was quenched by the addition of iso-Pr2NEt.
Tetrabutylammonium fluoride (1 M in THF, 1 mL) was added,
and the resulting mixture was stirred at room temperature
for 10 min. The mixture was poured into aq NaHCO3 and
extracted twice with ether. The organic layers were dried and
concentrated in vacuo. Purification of the residue by flash
chromatography (10-25% ethyl acetate in hexane) gave 66.4
mg (82% yield) of 24b and 13.8 mg (15% yield) of bis-cleavage
product 25. Because 25 was contaminated with the decomposi-
tion products of 4a , it was isolated as diacetate (Ac2O, 4-(N,N-
dimethylamino)pyridine, pyridine). 24b: 1H NMR δ 1.43-1.90
(11H, m including s (3H) at d 1.69), 2.33 (1H, dd, J ) 6.0 and
14 Hz), 2.55 (1H, dd, J ) 7.9 and 14 Hz), 2.65 (1H, br), 3.49
(1H, m), 3.59 (1H, m), 3.66 (1H, m), 3.95 (1H, dt, J ) 2.5 and
12 Hz), 4.27 (1H, ddd, J ) 1.1, 4.9, and 11.4 Hz), 4.55 (1H, dd,
J ) 6.0 and 7.9 Hz), 4.67 (1H, m), 4.75 (1H, m), 5.51 (1H, s),
7.18-7.55 (10H, m); 13C NMR δ 22.80, 27.22, 30.79, 31.38,
35.81, 46.61, 60.63, 66.97, 74.65, 76.77, 77.74, 101.13, 113.29,
126.00, 127.08, 127.86, 128.16, 128.45, 128.69, 138.78, 141.77,
141.91; MS (CI) m/z (relative intensity) 411 (M++1, 3), 243
(100); HRMS calcd for C20H29O4 (M+ - CH2dC(CH3)CH2)
355.1909, found; 355.1927. 25: 1H NMR δ 1.4-1.8 (16H, m),
2.25-2.60 (4H, m), 3.40-3.80 (6H, m), 4.52 (2H, br t, J ) ca.
7 Hz), 4.71 (2H, m), 4.78 (2H, m), 7.20-7.35 (10H, m).
Dia ceta te of 25: 1H NMR δ 1.5-1.75 (14 H, m, including br
s (6H) at 1.70), 1.85 (6H, s), 2.33 (2H, br dd, J ) 6.4 and 13.4
Hz), 2.54 (2H, br dd, J ) 7.7 and 13.4 Hz), 3.33 (2H, m), 4.00
(4H, m), 4.44 (2H, dd, J ) 6.4 and 7.7 Hz), 4.65 (2H, br s),
4.74 (2H, br s) 7.20-7.35 (10H, m).
IR (liquid film), 3450 (br), 1720, 1160, 1105, 750, 700 cm-1
;
MS (CI) m/z (relative intensity) 333 (M+ + 1 - H2O, 100), 227
(24); HRMS (CI) calcd for C20H29O4 (M+ + 1 - H2O) 333.2066,
found; 333.2055.
Rin g-Clea va ge P r od u ct 24a . The ring-cleavage product
was obtained in 94% yield according to a procedure similar to
that described above. 24a : 1H NMR δ 1.50 (1H, m), 1.64-
1.94 (7H, m including s (3H) at d 1.72), 2.05 (1H, ddd, J )
2.8, 9.4 and 14.4 Hz), 2.34 (1H, dd, J ) 5.7 and 13.9 Hz), 2.55
(1H, ddd, J ) 0.5, 8.2, and 13.9 Hz), 3.48-3.78 (3H, m), 3.85
(1H, m), 3.94 (1H, m), 4.27 (1H, ddd, J ) 1.1, 4.9, and 11.4
Hz), 4.53 (1H, dd, J ) 5.7 and 8.2 Hz), 4.70 (1H, m), 4.77 (1H,
m) 5.43 (1H, s), 7.25-7.43 (10H, m); 13C NMR δ 22.93, 31.84,
36.50, 39.10, 46.24, 60.46, 66.96, 71.83, 73.78, 77.76, 100.82,
113.19, 125.93, 127.25, 127.87, 128.07, 128.40, 128.61, 138.54,
141.70, 142.04; IR (liquid film) 3450 (br), 1650, 915, 760, 745,
700 cm-1; MS m/z (relative intensity) 396 (M+, <1), 341 (100),
235 (40), 217 (95); HRMS calcd for C25H32O4 396.2300, found;
396.2295,
P iva la te of 24a . The compound was prepared in 84% yield
1
according to a procedure similar to that described above. H
NMR δ 0.98 (9H, s), 1.51 (1H, m), 1.64-2.09 (5H, m including
s (3H) at d 1.72), 2.31(1H, dd, J ) 5.8 and 14 Hz), 2.54 (1H,
dd, J ) 7.7 and 14 Hz), 3.58 (1H, m), 3.86-4.31 (5H, m), 4.47
(1H, dd, J ) 5.8 and 7.7 Hz), 4.69 (1H, m), 4.75 (1H, m) 5.44
(1H, s), 7.23-7.44 (10H, m).
P iva la te 26a . The compound was prepared in 75% yield
P iva la te 26b. To a solution of 24b (35.0 mg, 0.0865 mmol)
and pyridine (0.36 mL) in CH2Cl2 (0.1 mL) was added pivaloyl
chloride (11.1 µL, 0.130 mmol) and 4-(N,N-dimethylamino)-
pyridine (ca. 2 mg) at room temperature. After being stirred
for 11 h, the reaction mixture was poured into water and
extracted twice with ether. The organic layers were dried and
concentrated in vacuo. Purification of the residue by flash
chromatography (5-20% ethyl acetate in hexane) gave 29.8
mg, (70% yield) of the corresponding pivaloyl ester: 1H NMR
δ 1.03 (9H, s)1.40-1.90 (11H, m), 2.28 (1H, dd, J ) 6.4 and
13.7 Hz), 2.53 (1H, dd, J ) 7.5 and 13.7 Hz), 3.35 (1H,m), 3.78
(1H,m), 3.87-4.26 (3H, m), 4.26 (1H, br dd, J ) 4.2 and 11.4
Hz), 4.55 (1H, m), 4.63 (1H, m), 4.70 (1H, m), 5.49 (1H, s),
7.20-7.40 (8H, m), 7.48-7.52 (2H, m); IR (neat film) 1725,
890, 755, 700 cm-1. The ester (29.8 mg, 0.0602 mmol) was
dissolved in 0.83 mL of acetone and 0.20 mL of water. To this
was added a 50 wt % solution of N-methylmorpholine oxide
in water (30 mL) and a 2.5 wt % solution of OsO4 in tert-butyl
alcohol (39 mL, 3.0 mmol), and the reaction mixture was
stirred for 12 h. A solution of NaIO4 (39.3 mg, 0.181 mmol) in
water (0.25 mL) was added, and the resulting solution was
stirred further for 1 h during which time a white precipitate
formed. The mixture was diluted with water and extracted
twice with ether. The organic layers were washed twice with
0.5 M Na2S2O3 and then with brine, dried, and concentrated
in vacuo. Purification of the residue by flash chromatography
(10% ethyl acetate in hexane) gave 28.5 mg (95%) of the
corresponding ketone: 1H NMR δ 1.03 (9H, s)1.40-1.90 (8H,
m), 2.21 (3H, s), 2.55 (1H, dd, J ) 4.5 and 15.6 Hz), 2.99 (1H,
according to a procedure similar to that described above. [R]21
D
) -33.7 (c 1.65, CHCl3); 1H NMR δ 1.18 (9H, s), 1.53 (1H, m),
1.65-1.95 (5H, m), 3.26 (1H, br), 3.94-4.02 (2H, m), 4.08-
4.29 (4H, m), 5.54 (1H, s), 7.26-7.46 (5H, m); 13C NMR δ 27.14,
31.34, 36.43, 38.67, 42.70, 61.12, 66.91, 67.67, 77.40, 101.16,
125.89, 128.25, 128.87, 138.12, 178.66; IR (liquid film) 3520
(br), 1725, 755, 700 cm-1; MS m/z (relative intensity) 336 (M+,
43), 335 (42), 105 (100); HRMS calcd for C19H28O5 336.1937,
found; 336.1932.
m eso-Bis-a ceta l 29. Ozone was introduced into a stirred
solution of diol 282d (639.4 mg, 1.74 mmol) in 80 mL of
methanol at -78°C until the blue color persisted. The excess
ozone was removed by allowing nitrogen to bubble through
the solution at -78 °C. To this at -78 °C was added dimethyl
sulfide (5 mL). The reaction mixture was allowed to warm to
room temperature during 0.5 h. To the resulting mixture was
added NaBH4 (1.31 g, 34.6 mmol). After being stirred for 1.5
h at 0 °C, the mixture was concentrated in vacuo, poured into
brine, and extracted four times with ethyl acetate. The organic
layers were dried and concentrated in vacuo. To a solution of
the resulting crude tetrol in benzene (64 mL) was added
p-anisaldehyde dimethyl acetal (1.77 g, 10.4 mmol), p-tolu-
enesulfonic acid monohydrate (19 mg, 0.17 mmol), and 4-A
molecular sieves (500 mg), and the mixture was stirred at room
temperature for 40 h. After removal of the molecular sieves
by filtration, the filtrate was poured into aq NaHCO3 and
extracted twice with ethyl acetate. The organic layers were
dried and concentrated in vacuo. Purification of the residue
7088 J . Org. Chem., Vol. 67, No. 20, 2002

Differentiation of Enantiotopic Dioxane Acetals
by flash chromatography (10-15% ethyl acetate in hexane)
gave 789 mg (74% overall yield) of 29: 1H NMR (500 MHz,
benzene-d6) δ 0.23 (6H, s), 0.59 (6H, d, J ) 7.0 Hz), 1.10 (9H,
s), 1.31 (6H, J ) 7.0 Hz), 2.01 (2H, m), 2.18 (2H, m), 3.37 (6H,
s), 3.41 (2H, t, J ) 11.0 Hz), 3.79 (2H, d, J ) 10.0 Hz), 3.91
(1H, J ) 5.5 Hz), 4.08 (2H, dd, J ) 4.5 and 11.0 Hz), 5.62 (2H,
s), 6.98 (4H, m), 7.76 (4H, m). 13C NMR (125.8 MHz, benzene-
d6) δ -4.02, 9.97, 12.34, 18.28, 26.22, 30.99, 54.40, 73.04, 77.72,
81.86, 101.26, 113.41, 128.02, 132.23, 160.09; MS m/z (relative
intensity) 614 (M+, 1), 557 (32), 207 (100), 121 (97); HRMS
calcd for C35H54O7Si 614.3639, found; 614.3632,
Bis-a ceta l 30. Bis-acetal 29 (105 mg, 0.171 mmol) was
treated with tetrabutylammonium fluoride (1M in THF) (1.7
mL, 1.7 mmol) at room temperature for 2.5 h. The mixture
was poured into water and extracted twice with ethyl acetate.
The organic layers were dried and concentrated in vacuo.
Purification of the residue by flash chromatography (20-30%
ethyl acetate in hexane) gave 74.4 mg (87% yield) of 30: 1H
NMR (500 MHz, benzene-d6) δ 0.55 (6H, d, J ) 6.7 Hz), 1.21
(6H, d, J ) 7.0 Hz), 1.45 (1H, br), 1.92-2.18 (4H, m), 3.32-
3.40 (8H, m, including s (3H) at 3.36), 3.98 (1H, m), 4.08 (2H,
dd, J ) 4.7 and 11.1 Hz), 4.15 (2H, dd, J ) 1.2 and 11.1 Hz),
5.60 (2H, s), 6.91 (4H, m), 7.69 (4H, m); 13C NMR (125.8 MHz,
benzene-d6) δ 10.99, 11.58, 30.14, 35.74, 54.42, 72.88, 75.72,
82.46, 101.24, 113.58, 125.81, 131.73, 160.15; MS m/z (relative
intensity) 500 (M+, 16), 265 (30), 207 (86), 137 (100); HRMS
calcd for C29H40O7 500.2774, found; 500.2778.
Bis-a ceta l 31. To a solution of 30 (488 mg, 0.975 mmol) in
THF (8.5 mL) at 0 °C was added KHMDS (0.5 M in toluene)
(3.0 mL, 1.5 mmol), and the mixture was stirred at this
temperature for 30 min. To the resulting mixture of the
alkoxide at 0 °C was added iodomethane (0.28 g, 2.0 mmol).
After being stirred for 15 h at room temperature, the mixture
was poured into brine and extracted twice with ether. The
organic layers were dried (MgSO4) and concentrated in vacuo.
Purification of the residue by flash chromatography (10-20%
ethyl acetate in hexane) gave 469 mg (93% yield) of 31: mp
103-104.5 °C (recrystallized from benzene and hexane); 1H
NMR (500 MHz, benzene-d6) δ 0.57 (6H, d, J ) 6.7 Hz), 1.22
(6H, d, J ) 7.1 Hz), 2.12 (4H, m), 3.37 (6H, s), 3.39 (1H, t, J
) 3.5 Hz), 3.40 (2H, t, J ) 11.0 Hz), 3.61 (3H, s), 3.89 (2H, dd,
J ) 1.5 and 10.1 Hz), 4.10 (2H, dd, J ) 4.8 and 11.1 Hz), 5.64
(2H, s), 6.95 (4H, m), 7.79 (4H, m); 13C NMR (125.8 MHz,
benzene-d6) δ 11.61, 11.99, 30.68, 37.19, 54.42, 60.93, 73.10,
82.26, 85.68, 101.07, 113.47, 125.81, 132. 31, 160.00; MS m/z
(relative intensity) 514 (M+, 12), 281 (26), 207 (100); HRMS
calcd for C30H42O7 514.2922, found; 514.2930. Anal. Calcd for
) 2.1 and 8.4 Hz), 3.94 (1H, dd, J ) 3.8 and 8.4 Hz), 4.07 (1H,
m), 4.14 (1H, dd, J ) 4.7 and 10.9 Hz), 4.22 (1H, m), 4.33-
4.43 (3H, m), 4.91 (1H, s), 5.86 (1H, s), 6.94 (2H, m), 6.98 (2H,
m), 7.35 (2H, m), 7.44 (2H, m)]; 13C NMR (125.8 MHz, benzene-
d6) δ 9.27 (CH3CH), 10.94 (CH3CH), 11.57 (CH3CH), 13.00
(CH3CH), 14.13 (CH3CH2O), 18.74 (CH3C-2′), 22.66 (CH3C-2′),
29.89 (CH3CH), 30.08 (CH3CH), 36.35 (CH3CH), 39.25 (CH3CH),
48.10 (C2′), 54.37 (CH3O), 54.45 (CH3O), 60.07 (C-3 or C-5),
70.14 (CH3CH2O), 70.63 (C-1), 72.79 (C-9), 77.27 (C-3 or C-5),
81.35 (C-7), 85.85 (C-1′), 101.49 (O-CH-O), 113.38 (Ar-C),
113.47 (Ar-C), 125.81 (Ar-C), 128.26 (Ar-C), 130.82 (Ar-C),
132.23 (Ar-C), 159.55 (Ar-C), 160.10 (Ar-C), 175.89 (CdO). The
ee value was determined by a chiral phase HPLC (Daicel
Chirapak AD, 1 mL/min, 2% 2-PrOH in hexane) (minor
enantiomer) t1 ) 22.90 min, (major enantiomer) t2 ) 35.05
min).
Rin g-Clea va ge P r od u cts 33 a n d 34. Ring-cleavage reac-
tion of bis-acetal 31 (65.4 mg, 0.127 mmol) was carried out
according to a procedure similar to that described above by
using 5f (92 mg, containing 40% of ethyl trimethylsilyl acetate,
0.57 mmol) and oxazaborolidinone 4b (0.26 mmol) in CH2Cl2
(0.51 mL) at -60 °C for 24 h. Purification of the crude product
by flash chromatography (5-30% ethyl acetate in hexane)
gave, in the order of elution, 49.8 mg (58% yield) of 33 (R )
TMS) (a 9:1 mixture of diastereomers) and 23.7 mg (31% yield)
of 34 (R ) H) (a 9:1 mixture of diastereomers). 33: 1H NMR
(500 MHz, benzene-d6) δ 0.18 (9H, s), 0.64 (3H, d, J ) 7.0 Hz),
0.98-1.03 (9H, m), 1.35 (3H, d, J ) 7.5 Hz), 1.95 (1H, m), 2.0-
2.2 (3H, m), 2.91 (1H, dd, J ) 7.5 and 14.8 Hz), 3.27-3.35
(3H, m), 3.40 (3H, s), 3.44 (3H, s), 3.48 (1H, t, J ) 11.0 Hz),
3.77 (2H, m), 3.79 (3H, s), 3.95-4.10 (3H, m), 4.14 (1H, dd, J
) 4.5 and 11.0 Hz), 5.54 (1H, t, J ) 7.5 Hz), 5.70 (1H, s), 6.92
(2H, m), 6.98 (2H, m), 7.55 (2H, m), 7.79 (2H, m) [a minor
diastereomer resonated at 1.22 (3H, d, J ) 7.5 Hz), 1.27 (3H,
d, J ) 7.0 Hz), 2.76 (1H, dd, J ) 6.5 and 14.8 Hz), 5.37 (1H,
t, J ) 6.5 Hz), 5.64 (1H, s), 7.51 (2H, m), 7.75 (2H, m)]. 34; 1H
NMR (500 MHz, benzene-d6) δ 0.56 (3H, d. J ) 7.0 Hz), 0.84
(3H, d, J ) 7.0 Hz), 0.92 (3H, d, J ) 7.0 Hz), 1.08 (3H, t, J )
7.0 Hz), 1.31 (3H, d, J ) 7.0 Hz), 1.66 (1H, m), 1.89 (1H, m),
1.94 (1H, m), 2.05 (1H, m), 2.78 (1H, dd, J ) 6.0 and 14.0 Hz),
2.84 (1H, br), 3.13 (1H, dd, J ) 8.5 and 14.0 Hz), 3.27 (1H, dd,
J ) 2.5 and 10.0 Hz), 3.39 (6H, s), 3.46 (1H, t, J ) 11.0 Hz),
3.55-3.64 (2H, m), 3.74 (3H, s), 3.94-4.18 (5H, m), 5.62 (1H,
br t, J ) ca. 6 Hz), 5.68 (1H, s), 6.90 (2H, m), 6.97 (2H, m),
7.55 (2H, m), 7.78 (2H, m) [a minor diastereomer resonated
at 0.97 (3H, d, J ) 7.0 Hz), 1.13 (3H, d, J ) 7.0 Hz), 1.14 (3H,
d, J ) 7.0 Hz), 1.22 (3H, d, J ) 7.0 Hz), 5.33 (1H, br t, J ) ca.
6 Hz), and 5.65 (1H, s)]; 13C NMR (125.8 MHz, benzene d6) δ
10.45, 11.84, 13.82, 13.89, 15.20, 30.19, 36.30, 39.45, 41.48,
42.82, 54.37, 54.47, 60.02, 61.36, 65.50, 73.05, 75.58, 77.30,
81.69, 85.94, 101.17, 113.35, 113.61, 125.82, 128.27, 129.79,
132.38, 159.79, 160.15, 170.40; MS m/z (relative intensity) 602
(M+, <1), 556 (<1), 207 (100); HRMS calcd for C34H50O9
602.3455, found; 602.3448.
C
30H42O7: C, 70.01; H, 8.23. Found: C, 70.27; H, 8.19.
Rin g-Clea va ge P r od u ct 32. The ring-cleavage reaction of
bis-acetal 30 (40.4 mg, 0.0807 mmol) was carried out according
to a procedure similar to that described above by using 5e (18
mg, 0.097 mmol) and oxazaborolidinone 4b (0.081 mmol) in
CH2Cl2 (0.65 mL) at -60 °C for 19 h. Purification of the crude
product by flash chromatography (5-20% ethyl acetate in
hexane) gave 42.2 mg (86% yield) of 32 (a 7:3 mixture of
diastereomers). The major isomer was separated by repeated
flash chromatography. 32: 1H NMR (500 MHz, benzene-d6)
of the major isomer δ 0.47 (3H, CH3, d, J ) 6.7 Hz), 0.93 (3H,
CH3, d, J ) 7.0 Hz), 1.03 (6H, CH3 x 2, br d, J ) ca. 7 Hz),
1.20 (3H, t, CH3CH2O, J ) 7.2 Hz), 1.25 (3H, CH3, s), 1.48
(2H, OH, br), 1.52 (3H, CH3, s), 1.92 (1H, CH, m), 2.03-2.13
(3H, CH x, 3 m), 3.35 (1H, H-9R, t, J ) 11.1 Hz), 3.38 (3H,
CH3O, s), 3.41 (3H, CH3O, s), 3.70 (1H, H-1, dd, J ) 2.3 and
8.6 Hz), 3.95 (1H, H-1, dd, J ) 5.9 and 8.6 Hz), 4.05 (1H, H-9â,
dd, J ) 4.7 and 11.1 Hz), 4.16-4.30 (5H, CH3CH2O-, H-3, H-5,
and H-9, m), 4.97 (1H, H-1′, s), 5.80 (1H, O-CH-O, s), 6.92
(2H, Ar-H, m), 6.97 (2H, Ar-H, m), 7.41 (4H, Ar-H, m) [the
minor isomer resonated at δ 0.79 (3H, d, J ) 6.8 Hz), 0.94
(3H, d, J ) 6.7 Hz), 1.02-1.08 (6H, m), 1.17 (3H, d, J ) 6.9
Hz), 1.18 (3H, s), 1.45 (3H, s), 1.75-1.83 (3H, m, including br
s (2H) at 1.76), 2.13 (1H, m), 2.22 (1H, m), 2.40 (1H, m), 3.39
(3H, s), 3.46 (3H, s), 3.47 (1H, s, J ) 11.1 Hz), 3.65 (3H, dd, J
Diol 35. TMS ether 33 (36.2 mg, 0.0538 mmol) was treated
with a tetrabutylammonium fluoride (1M in THF) (1.0 mL,
1.0 mmol) at room temperature for 18 h. The mixture was
poured into water and extracted twice with ethyl acetate. The
organic layers were dried and concentrated in vacuo. Purifica-
tion of the residue by flash chromatography (50% ethyl acetate
in hexane) gave 17.2 mg (86% yield) of 34: 1H NMR (500 MHz,
benzene-d6) δ 0.48 (3H, d, J ) 6.7 Hz), 0.65 (3H, d, J ) 6.9
Hz), 0.88 (3H, d, J ) 7.0 Hz), 1.08 (3H, d, J ) 7.1 Hz), 1.76
(1H, br s), 2.00-2.16 (4H, m), 3.29 (3H, s), 3.37 (3H, s), 3.38
(1H, t, J ) 11.0 Hz), 3.38 (1H, dd, J ) 1.9 and ca. 10 Hz), 3.75
(1H, dd, J ) 1.8 and 10.1 Hz), 3.89 (1H, dd, J ) 3.6 and 10.7
Hz), 3.94-4.05 (2H, m), 4.08 (1H, dd, J ) 4.7 and 11.1 Hz),
4.36 (1H, br), 5.54 (1H, s), 6.97 (2H, m), 7.71 (2H, m); 13C NMR
(125.8 MHz, benzene-d6) δ 9.77, 11.29, 11.35, 13.11, 30.20,
34.53, 36.48, 37.69, 54.48, 61.88, 68.80, 73.00, 76.81, 81.45,
101.25, 113.45, 125.81, 131.97, 160.22; MS m/z (relative
J . Org. Chem, Vol. 67, No. 20, 2002 7089

Harada et al.
intensity) 396 (M+, 18), 281 (32), 207 (100); HRMS calcd for
88.43, 101.29, 113.57, 125.87, 132.11, 160.22; MS m/z (relative
intensity) 510 (M+, <1), 453 (17), 207 (100); HRMS calcd for
C28H50O6Si 510.3376, found; 510.3378; ee determination (HPLC,
Daicel Chirapak AD, 1 mL/min, 1-9% 2-PrOH in hexane)
(major) t1 ) 7.16 min, (minor) t2 ) 14.32 min).
C
22H36O6 396.2511, found; 396.2513.
TBS Eth er 36. A mixture of diol 35 (14.6 mg, 0.0369 mmol),
TBSCl (7.7 mg, 0.051 mmol), and imidazole (4.0 mg, 0.059
mmol) in DMF (0.4 mL) was stirred at room temperature for
18 h. The mixture was diluted with ether, poured into water,
and extracted twice with ether. The organic layers were dried
(MgSO4) and concentrated in vacuo. Purification of the residue
by flash chromatography (10% ethyl acetate in hexane) gave
18.0 mg (96% yield) of 36: 1H NMR (500 MHz, benzene-d6) δ
0.23 (3H, s), 0.27 (3H, s), 0.56 (3H, d, J ) 6.7 Hz), 0.98 (3H, d,
J ) 7.0 Hz), 1.04 (3H, d, J ) 7.0 Hz), 1.14 (9H, s), 1.14 (3H, d,
J ) 6.8 Hz), 1.20 (1H, br), 1.90 (1H, m), 1,98 (1H, m), 2.09
(1H, m), 2.24 (1H, m), 3.33 (3H, s), 3.37 (3H, s), 3.39 (1H, t, J
) 11.0 Hz), 3.45 (1H, dd, J ) 2.0 and 10.3 Hz), 3.81 (1H, dd,
J ) 1.7 and 10.1 Hz), 3.97 (1H, br s), 4.06 (2H, m), 5.56 (1H,
s), 6.96 (2H, m), 7.71 (2H, m); 13C NMR (125.8 MHz, benzene-
d6) δ -5.50, -5.36, 9.80, 11.06, 11.39, 13.31, 25.97, 29.95,
30.33, 34.16, 36.64, 39.09, 54.51, 61.87, 65.05, 73.08, 81.65,
Ack n ow led gm en t. This work was supported par-
tially by Grant-in-Aid for Scientific Research from
Ministry of Education, Culture, Sports, Science and
Technology.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
1
products, H NMR spectra for determination of enantiomeric
excess, and detailed experimental procedures and spectral data
for products. This material is available free for charge via the
Internet at http://pubs.acs.org.
J O025944G
7090 J . Org. Chem., Vol. 67, No. 20, 2002