Strategy for Enantio- and Diastereoselective Syntheses of All Possible Stereoisomers of 1,3-Polyol Arrays Based on a Highly Catalyst-Controlled Epoxidation of α,β-Unsaturated Morpholinyl Amides: Application to Natural Product Synthesis

Article abstract of DOI:10.1002/chem.200305709

We describe a new strategy for enantio- and diastereoselective syntheses of all possible stereoisomers of 1,3-polyol arrays. This strategy relies on a highly catalyst-controlled epoxidation of α,β-unsaturated morpholinyl amides promoted by the Sm-BINOL-Ph

Full text of DOI:10.1002/chem.200305709

FULL PAPER
Strategy for Enantio- and Diastereoselective Syntheses of All Possible
Stereoisomers of 1,3-Polyol Arrays Based on a Highly Catalyst-Controlled
Epoxidation of a,b-Unsaturated Morpholinyl Amides: Application to Natural
Product Synthesis
Shin-ya Tosaki, Yoshihiro Horiuchi, Tetsuhiro Nemoto, Takashi Ohshima, and
Masakatsu Shibasaki*[a]
Abstract: We describe a new strategy
for enantio- and diastereoselective syn-
theses of all possible stereoisomers of
1,3-polyol arrays. This strategy relies
on a highly catalyst-controlled epoxida-
tion of a,b-unsaturated morpholinyl
amides promoted by the Sm BINOL
Ph3As=O (1:1:1) complex, followed by
a conversion of morpholinyl amides
into ketones and diastereoselective
ketone reduction. Highly enantio- (up
to >99% ee) or diastereoselective (up
to >99.5:0.5) epoxidation was ach-
ieved using 5 10 mol% of the Sm com-
plex to afford synthetically very useful,
nearly optically pure a,b-epoxy mor-
pholinyl amides. Stereoselectivity of
the epoxidation was controlled by the
chirality of BINOL with overwhelming
inherent diastereofacial preference for
the substrate. Combination with the
syn- and anti-selective ketone reduc-
tion with the highly catalyst-controlled
epoxidation allowed for an iterative
strategy for the syntheses of all possi-
ble stereoisomers of 1,3-polyol arrays.
Eight possible stereoisomers of 1,3,5,7-
tetraol arrays were synthesized with
high to excellent stereoselectivity.
Moreover, the efficiency of the present
strategy was successfully demonstrated
by enantioselective syntheses of several
1,3-polyol/a-pyrone natural products,
for example, cryptocaryolone diacetate.
Keywords: asymmetric synthesis ¥
diastereoselectivity ¥ epoxidation ¥
morpholinyl amide ¥ polyols
Introduction
catalytic asymmetric epoxidation of allylic alcohols[7] or un-
functionalized olefins,[8] catalytic asymmetric hydrogena-
tion,[9] catalytic asymmetric Mukaiyama type aldol reac-
tion,[10] and catalytic asymmetric dihydroxylation.[11] The
second stage of the synthesis is the elongation of 1,3-polyol
arrays by stereoselective construction of the next chiral
center. Chirality in the vicinity of the substrate reaction site
makes this process very challenging and attractive in terms
of the diversity of diastereocontrol. Thus, organic chemists
have developed a variety of strategies, which can be classi-
fied into three approaches according to the structure rela-
tion between the chiral source and chiral products: a) sub-
strate control synthesis (employing intramolecular chirality
transfer); b) reagent control synthesis (employing stoichio-
metric amounts of the chiral source); and c) catalyst control
synthesis (employing catalytic amounts of the chiral source).
The majority of the strategies use the substrate controlled
asymmetric induction (category a). Many highly stereocon-
trolled 1,3-asymmetric induction reactions[12] have been de-
veloped that mainly rely on 1,3-syn[13]- or anti[14]-selective
ketone reduction using borane reagents, intramolecular ad-
dition of the acetal to olefins,[15] inter- or intramolecular ad-
dition of silyl reagents to olefins such as hydrosilylation,[16]
and intramolecular allylsilylation to carbonyl groups.[17] In
The stereoselective synthesis of 1,3-polyol arrays is one of
the most important topics in organic chemistry because of
the ubiquity of 1,3-polyols in various biologically active nat-
ural products and drugs, such as polyene macrolide antibiot-
ics.[1] Thus, numerous strategies for their synthesis have been
developed with great success.[2] The synthesis of 1,3-polyol
arrays starts with the introduction of the first chiral center
to the molecule. For this purpose, with the majority of chiral
pool strategy,[3] a wide variety of synthetic methods are uti-
lized[4] and the following asymmetric reactions are mainly
used for 1,3-polyol syntheses: chiral auxiliary controlled
aldol reaction,[5] allylboration using chiral borane reagents,[6]
[a] S.-y. Tosaki, Y. Horiuchi, T. Nemoto, Dr. T. Ohshima,
Prof. Dr. M. Shibasaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo, Hongo
Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)-3-5684-5206
E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
contrast to the diversity of asymmetric reactions that are
employed for the introduction of the first chirality, only a
few chiral reagents (category b) or chiral catalysts (catego-
ry c) are applied for stereoselective elongation of 1,3-polyol
arrays due to crucial matched or mismatched effects caused
by the substrate chirality. Among the above-mentioned
asymmetric reactions, chiral auxiliary controlled aldol reac-
tion (category b),[5,18] allyl addition using chiral borane or ti-
tanium reagents (category b),[6,19] and catalytic asymmetric
epoxidation of allylic alcohols (category c)[7,20] are common-
ly used for 1,3-polyol synthesis. Employing these strat-
egies,[21] many polyene macrolide antibiotics, such as ampho-
tericin B,[22] mycoticin A,[23] roxaticin,[24] filipin III,[25] rofla-
mycoin,[26] dermostatin,[27] and 1,3-polyol/a-pyrones[28] were
synthesized in a highly stereocontrolled manner.[29]
selectivity even after improvement using the Pr BINOL
Ph3As=O (1:1:1) complex (up to 86% ee, Scheme 1).[38b]
We recently reported a more general variant of this cata-
lytic asymmetric epoxidation by using simple a,b-unsaturat-
ed amides 8 promoted by Sm BINOL Ph3As=O (1:1:1)
To synthesize not only 1,3-polyol natural products, but
also their analogues, a highly versatile synthetic method that
makes all possible stereoisomers freely accessible with the
same efficiency is required. To address this issue, catalyst-
controlled chiral induction would be more desirable in
terms of accessibility to a variety of stereoisomers. In reality,
however, chiral induction controlled by an asymmetric cata-
lyst results in low selectivity in a mismatched case affected
by the chirality in the vicinity of the reaction site.[30] Crucial
mismatched effects are sometimes observed even in well-es-
tablished Sharpless× catalytic asymmetric epoxidation.[30]
Here, we report a new general strategy for the stereoselec-
tive syntheses of all possible stereoisomers of 1,3-polyol
arrays based on a highly catalyst-controlled epoxidation of
a,b-unsaturated morpholinyl amides and diastereoselective
ketone reduction. Syntheses of all possible stereoisomers of
1,3,5,7-tetraol arrays were achieved by repeating the present
strategy. Moreover, synthetic application to the enantiose-
lective syntheses of several 1,3-polyol/a-pyrone natural
products was successfully demonstrated.
Scheme 1. Catalytic asymmetric epoxidation of a,b-unsaturated carboxyl-
ic acid imidazolides.
complex 9 (Scheme 2).[38] In this case, the corresponding
a,b-epoxy amides 10 were obtained in excellent yield (up to
99%) and in quite high enantiomeric excess (up to >99%)
with broad substrate generality (R1 = alkyl or Ar). For the
synthesis of a chiral 1,3-polyol array, g,d-epoxy b-keto esters
7 are promising intermediates. In fact, both syn- and anti-
3,5-dihydroxy esters were obtained by a regioselective epox-
ide opening reaction of 7, followed by a diastereoselective
ketone reduction (see below). g,d-Epoxy b-keto esters 7 can
also be synthesized from highly optically active a,b-epoxy
amides 10 through esterification by Martin sulfurane.[38b,39]
The requirement for excess amount of the expensive Martin
sulfurane (>3 equiv), however, makes this process difficult
to apply to large-scale synthesis.
Results and Discussion
Catalytic asymmetric epoxidation of a,b-unsaturated
amides: We previously reported a highly enantioselective
catalytic asymmetric epoxidation of a,b-unsaturated carbox-
ylic acid imidazolides 1[31] promoted by the La BINOL -
Ph3As=O (1:1:1) complex 2[32] (Scheme 1). This is the first
example of a general catalytic asymmetric epoxidation of
a,b-unsaturated carboxylic acid derivatives using a 1,4-addi-
tion of hydroperoxide as the initial step. Although a salen
manganese complex[33] or an optically active ketone[34] has
been used for catalytic asymmetric epoxidation of a,b-unsa-
turated esters, our strategy is more desirable in terms of che-
moselectivity.[35] Epoxidation of a,b-unsaturated carboxylic
acid imidazolides afforded stable chiral a,b-epoxy peroxy
esters 3 (up to 94% ee)[36] that were efficiently converted to
the corresponding chiral a,b-epoxy esters 4, a,b-epoxy
amides 5, a,b-epoxy aldehydes 6, and g,d-epoxy b-keto
esters 7. Thus, a,b-epoxy peroxy esters 3 are synthetically
useful versatile intermediates.[37] In contrast to b-aryl-substi-
tuted substrates, epoxidation of b-alkyl-substituted a,b-unsat-
urated carboxylic acid imidazolides 1, however, had lower
Scheme 2. Catalytic asymmetric epoxidation of a,b-unsaturated simple
amides.
From a synthetic point of view, we examined the catalytic
asymmetric epoxidation of a,b-unsaturated Weinreb
amide[40] 13 using 10 mol% of (S)-Sm complex
9
(Scheme 3). Although the reaction proceeded smoothly, it
had exceptionally low enantioselectivity (64% ee). Thus, we
explored other synthetically useful substrates that can take
the place of Weinreb amides. Morpholinyl amides are as
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1,3-Polyol Arrays
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useful as Weinreb amides.[41] A variety of organometallic re-
agents, such as Grignard reagents, alkyllithiums, and metal
hydrides, react with morpholinyl amide through a reaction
mechanism similar to that of the Weinreb amide, affording
the corresponding ketone or aldehyde in good yield. When
a,b-unsaturated morpholinyl amide 15a was used as a sub-
strate, in sharp contrast to the Weinreb amide 13, 10 mol%
of (S)-Sm complex 9 afforded the corresponding a,b-epoxy
morpholinyl amide 16a in quantitative yield and excellent
enantiomeric excess (99% ee). In a multi-gram scale reac-
tion, the use of 5 mol% of the catalyst also gave satisfactory
results (quant., 98% ee).
Figure 1. Proposed mechanism for the catalytic asymmetric epoxidation
promoted by the Ln BINOL Ph3As=O (1:1:1) complex.
Scheme 3. Catalytic asymmetric epoxidation of a,b-unsaturated Weinreb
amide and morpholinyl amide.
Studies towards the selectivity difference between Wein-
reb amide and morpholinyl amide would lead to a better un-
derstanding of the mechanism of the Ln BINOL Ph3As=O
complex-promoted catalytic asymmetric epoxidation. Our
previous studies utilizing X-ray analysis and laser desorp-
tion/ionization time-of-flight mass spectrometry suggest that
the active catalyst of epoxidation is a monomeric species.[32b]
Moreover, the results of all catalytic asymmetric epoxida-
tions of a,b-unsaturated carbonyl compounds are consistent
with our proposed mechanism involving coordination of a
carbonyl oxygen to the lanthanide metal in a syn s cis coor-
dination manner and internal delivery of tert-butyl peroxide
from a lanthanide metal to the b-carbon of an a,b-unsaturat-
ed carbonyl compound (Figure 1, 17!18). When using
Weinreb amide 20 or N-acyloxazolidinone 19,[31,42] there
should be an unfavorable anti coordination, and this biden-
tate coordination might disturb the favorable manner of the
reaction, resulting in unsatisfactory selectivity. On the other
hand, asymmetric epoxidation of morpholinyl amide should
proceed in the favorable syn-s-cis coordination manner 21
Figure 2. Working transition state model for the catalytic asymmetric ep-
oxidation promoted by the Ln BINOL Ph3As=O (1:1:1) complex.
ric epoxidation of a,b-unsaturated morpholinyl amide, fol-
lowed by a conversion of morpholinyl amides into ketones
and diastereoselective ketone reduction (Scheme 4). An im-
portant feature of this epoxidation is that the stereochemical
outcome is very predictable, [e.g., (S)-catalyst gives (2R,3S)-
epoxides without exception].[31,32,38] In addition, the epoxida-
tion exhibits almost perfect enantioselectivity (99% ee) with
high substrate generality. Thus, we expect that even when a
chiral center is in the vicinity of the b-carbon of an a,b-un-
saturated morpholinyl amide, stereoselectivity of the epoxi-
dation will be controlled by the chirality of BINOL with
overwhelming inherent diastereofacial preference for the
substrate. Incorporation of the established syn- and anti-se-
lective ketone reduction with the catalyst controlled epoxi-
dation allows for an iterative strategy for the syntheses of
all possible stereoisomers of 1,3-polyol arrays.
ꢀ
because the rotation of the C N bond to form a bidentate
coordination (21!22) would be prevented by unfavorable
energetics, such as orthogonality of the N-lone pair and the
carbonyl p-orbitals. Enantiomeric induction in the present
system is explained by assuming the transition state shown
in Figure 2.
Syntheses of all possible stereoisomers of 3,5,7,9-tetrahy-
droxy esters based on highly catalyst-controlled epoxidation:
Our strategy for the stereoselective synthesis of the 1,3-
polyol array relies on a highly catalyst-controlled asymmet-
Syntheses of both syn- and anti-5,7-dihydroxy a,b-unsatu-
rated morpholinyl amides are described in Scheme 5. Reac-
tion of epoxy morpholinyl amide 16a with lithium enolate
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M. Shibasaki et al.
FULL PAPER
Scheme 4. New iterative strategy for the syntheses of all possible stereoisomers of 1,3-polyol arrays without stereochemical limitation.
of ethyl acetate at ꢀ788C afforded g,d-epoxy b-keto esters
7a (78%). A regioselective epoxide opening reaction of 7a
was achieved with Na[(PhSe)B(OEt)3],[43] prepared from
PhSeSePh and NaBH4 in ethanol, to afford d-hydroxy b-
keto esters 23a in 79% yield.[44] After the reaction was com-
plete, PhSeSePh was regenerated, easily recovered by silica
gel column chromatography, and reused with the initial effi-
ciency.[43] syn-Selective reduction of 23a was performed with
Et2BOMe and NaBH4 to give the desired syn-diol syn-24a
in 75% isolated yield (syn:anti >20:1).[13,45] anti-Diol anti-
24a was synthesized in 80% isolated yield by anti-selective
amide syn-27a by a DIBAL reduction to aldehyde syn-26a
followed by Masamune Roush-type Horner Wadsworth
Emmons reaction.[49] In the case of acetonide-protected anti-
diol anti-25a, the DIBAL reduction resulted in decomposi-
tion of the substrate. Thus, conversion of anti-25a to alde-
hyde anti-26a was conducted with a LiBH4/B(OMe)3 reduc-
tion[50] followed by TPAP oxidation.
To elongate the 1,3-polyol array stereoselectively,
a
second asymmetric epoxidation was investigated. The results
are summarized in Table 1. As expected, even when using
substrates that have a chirality and several functions in the
vicinity of the reaction site, both the (S)- and (R)-Sm com-
plex promoted the epoxidation with nearly perfect stereose-
lectivity (entries 1 5, 7, 8).[48,51] Only in the reaction of TES
protected (5R,7S)-diol syn-27c with the (R)-Sm complex
was a slightly lower diastereoselectivity observed (92:8)
(entry 6).[45] The stereochemistry of epoxide 30 was con-
firmed by X-ray crystallographic analysis (Figure 3). The
stereochemistry of other epoxides was also determined by
appropriate derivatization.[42] The results indicated that the
47]
reduction with Me4NBH(OAc)3 (syn:anti 1:9).[14,45 Taking
into account the synthetic utility of this strategy, the diols
were protected with three types of protecting groups (aceto-
nide syn-25a, MOM syn-25b, and TES syn-25c). The enan-
tiomeric excesses of syn- and anti-24a were determined
after conversion to acetonides (syn- and anti-25a), and it
was confirmed that no racemization occurred during the
process.[48] Then, the protected diol syn-25a was converted
to the corresponding (E)-a,b-unsaturated morpholinyl
Scheme 5. Syntheses of both syn- and anti-5,7-dihydroxy a,b-unsaturated molpholinyl amides.
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1,3-Polyol Arrays
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good to excellent stereoselectivity (Table 2).[52] Undoubtedly,
enantiomers of all eight stereoisomers can be synthesized by
employing the (R)-Sm complex for the first asymmetric ep-
oxidation. To the best of our knowledge, this is the first
demonstration of the syntheses of all possible stereoisomers
of 1,3,5,7-tetraol arrays with high enantio- and diastereose-
lectivity.[52] The present strategy paves the way for the highly
stereoselective syntheses of all possible stereoisomers of 1,3-
polyols with broad substrate generality.
Figure 3. X-ray structure of 30.
Application to natural product synthesis (1)
Sm BINOL Ph3As=O complex promotes the asymmetric
epoxidation under high catalyst control with overwhelming
inherent diastereofacial preference for the substrate.
Finally, we demonstrated stereoselective conversion of
both syn- and anti-5,7-dihydroxy 2,3-epoxy amides to
3,5,7,9-tetrahydroxy esters. According to the method shown
in Scheme 6, epoxy amides 30, 31, 36, and 37 were success-
fully converted to all eight possible stereoisomers 40 47 in
Triol synthesis:[38b] Having established stereoselective syn-
thesis of 1,3-polyol arrays, we applied the method to enan-
tioselective synthesis of 1,3-polyol/a-pyrone natural prod-
ucts, which are very attractive target natural products be-
cause of their interesting bioactivity, such as antifungal ac-
tivity and antitumor activity.
Compounds 54 and 55 were isolated from the leaves and
bark extract of Ravensara anisata by Hostettmann et al. and
Table 1. The second stereoselective catalytic epoxidation promoted by (S)- or (R)-Sm complex 9.
Entry
1
Substrate
Catalyst
Product
Yield [%][a]
95
Ratio of Diastereoisomers
(S)-Sm 9
30:31 >99:1[c]
2
syn-27a[b]
(R)-Sm 9
quant.
30:31 1:>99[c]
3
4
5
6
(S)-Sm 9
(R)-Sm 9
(S)-Sm 9
(R)-Sm 9
90
87
81
97
32:33 >99.5:0.5[c]
32:33 0.5:>99.5[c]
34:35 >95.5[d]
34:35 8:92[d]
syn-27b[b]
syn-27c[b]
7
8
(S)-Sm 9
(R)-Sm 9
99[f]
36:37 >99:1[g]
36:37 1:>99[g]
anti-27a[e]
89[f]
[a] Isolated yield of the two diastereomers. [b] The diastereomeric ratio of the substrate was >99:1. [c] Determined by HPLC analysis. [d] Determined
1
by H NMR analysis. [e] A mixture of diastereomers (anti:syn 9:1) was used as the substrate. [f] Product included ca. 10% of inseparable C-5 epimer (30
or 31). [g] Determined by HPLC analysis. All possible stereoisomers (30, 31, 36, and 37) were separable on HPLC.
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M. Shibasaki et al.
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Table 2. Syntheses of all possible stereoisomers of 3,5,7,9-tetrahydroxy esters.
ꢀ
without C C double bond mi-
gration. Diastereoselective
Entry
1[c]
Product
Yield [%][a]
Ratio of diastereoisomers[b]
ketone reduction was achieved
by the reaction of L-Selectide
at ꢀ1008C to afford the desired
alcohol 52 (60%, conv. 97%, b-
OH:a-OH 7:1).[56] Esterification
of 52 with acryloyl chloride pro-
ceeded smoothly, and the re-
sulting acryloyl ester was con-
verted into a-pyranone 53 by
ring-closing metathesis.[57] In
this stage, two diastereomers
were separated. Finally, the
total syntheses of 54 and 55
were achieved for the first time
by removal of the benzylidene
group followed by monoacety-
lation via cyclic ortho ester for-
mation. They were subjected to
further acylation with Ac2O/
DMAP to give diacetate 56.
Spectral data of 54, 55, and 56
on 1H NMR and 13C NMR
were identical with those re-
ported in the literature.[53] The
optical rotation of 54 and 55
([a]2D5 =ꢀ29.7 (c=0.60 in
MeOH)) was opposite to the
85
40:41 >99.5:0.5
2[c]
3[c]
4[c]
5[d]
6[d]
7[d]
8[d]
75
97
40:41 5:>95
42:43 >99:1
42:43 6:94
93
57[e]
44:45 >99:1
44:45 4:96
53
86
46:47 >99.5:0.5
46:47 2:98
90[f]
reported
([a]D =+35
optical
rotation
in
[a] Isolated yield of two diastereomers. [b] Determined by HPLC analysis. [c] Ratio of the first major isomer
and the other isomer of the substrate was >99:1. [d] Ratio of the first major isomer and the other isomer (C-7
epimer) of the substrate was 9:1. [e] Product included 8% inseparable C-7 epimer 40. [f] Product included 7%
inseparable C-7 epimer 43.
(c=0.05
MeOH)).[53] These results indi-
cate that the absolute stereo-
chemistry of the natural prod-
uct was 6R, 2’S, 4’S. Moreover,
anti-3,5-dihydroxy ester anti-
24a was efficiently converted to
Aimi×s intermediate 57 for the
synthesis of strictifolione (58)
in two steps (92%).[58]
Application to natural product
synthesis (2)
Scheme 6. Representative procedure for the stereoselective syntheses of 3,5,7,9-tetrahydroxy esters.
Tetraol synthesis: Cryptocaryo-
lone diacetate (67) was isolated
from the leaves and bark of
exhibit antifungal activity.[53] The synthetic route to 54 and
55 is outlined in Scheme 7. Catalytic asymmetric epoxida-
tion of a,b-unsaturated morpholinyl amide 48 with 10 mol%
Sm (R)-BINOL Ph3As=O complex 9 afforded a,b-epoxy
amide 49 (92%, >99% ee).[48,54] Reaction of epoxy amide
49 with the lithium enolate of the Weinreb amide afforded
g,d-epoxy b-keto amide 50. A regioselective epoxide open-
ing reaction followed by syn-selective reduction and benzyli-
dene protection furnished protected diol amide 51. The
choice of a diol protecting group was crucial for the diaste-
reoselective ketone reduction at a later stage.[55] Treatment
of 51 with allylmagnesium bromide resulted in allyl ketone
Cryptocarya latifolia by Drewes et al.,[59a] and the first total
synthesis of 67 was recently reported by O×Doherty et al.[28e]
Although their synthesis was performed in an enantioselec-
tive manner, the absolute configuration of cryptocaryolone
diacetate (67) remains unclear because O×Doherty et al. did
not report the optical rotation. Thus, to confirm the absolute
configuration and demonstrate the usefulness of the above-
mentioned iterative strategy based on stereoselective epoxi-
dation and diastereoselective reduction, we performed enan-
tioselective synthesis of 67 (Scheme 8). Our synthesis of 67
began with the catalytic asymmetric epoxidation of 59. The
use of 5 mol% of (S)-Sm complex 9 effectively promoted
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1,3-Polyol Arrays
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Scheme 7. First total synthesis of 1,3-polyol/a-pyrone natural products 54 and 55.
Scheme 8. Total synthesis of cryptocaryolone diacetate 67.
the asymmetric epoxidation to afford a,b-epoxy morpholinyl
amide 49 (89%, 98% ee).[60] Reaction of epoxy morpholinyl
amide 60 with the lithium enolate of butyl acetate afforded
g,d-epoxy b-keto ester 61.[61] A regioselective epoxide open-
ing reaction with Na[(PhSe)B(OEt)3] followed by syn-selec-
tive reduction and benzylidene protection furnished protect-
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M. Shibasaki et al.
FULL PAPER
ed 3,5-dihydroxy ester 62.[62] Conversion of 62 to the corre-
sponding (E)-a,b-unsaturated morpholinyl amide 63 was
performed with a procedure similar to that described above.
The second epoxidation of 63 using 10 mol% of (S)-Sm
complex 9 afforded 64 in a highly stereocontrolled manner
(90%, a:b >99.8:0.2).[48] The sequence from the reaction
with the lithium enolate of ethyl acetate to the benzylidene
protection provided the known intermediate 65 for the syn-
theses of 67 and 68. The spectral analysis data and optical
rotation were consistent with the reported values.[28e] After
conversion to aldehyde, a highly Z-selective Wittig reaction
according to Ando×s method[63] provided (Z)-a,b-unsaturat-
ed ester 66 as the sole detectable isomer. Finally, by follow-
ing the procedure of O×Doherty et al., 66 was successfully
converted to cryptocaryolone diacetate (67), which was con-
strated for the first time. Furthermore, enantioselective syn-
theses of several 1,3-polyol/a-pyrone natural products such
as cryptocaryolone diacetate were achieved using the pres-
ent strategy. Further applications of this strategy to stereose-
lective syntheses of 2n-substituted 1,3-polyol arrays by re-
gioselective epoxide opening reaction with various nucleo-
philes are currently in progress.
Experimental Section
General: Infrared (IR) spectra were recorded on a JASCO FT/IR 410
Fourier transform IR spectrophotometer. NMR spectra were recorded
on
a JEOL JNM-LA500 spectrometer, operating at 500 MHz for
1H NMR and 125.65 MHz for 13C NMR. Chemical shifts in CDCl3 were
1
1
firmed by spectral data on H NMR, 13C NMR, H-H COSY,
reported downfield from TMS (=0 ppm) for H NMR or in the scale rel-
ative to CHCl3 (7.26 ppm for 1H NMR) as an internal reference. For 13C
NMR, chemical shifts were reported downfield from TMS (=0 ppm) or
in the scale relative to CHCl3 (77.00 ppm for 13C NMR) as an internal
reference. Chemical shifts in C6D6 were reported in the scale relative to
C6H6 (7.16 ppm for 1H NMR) as an internal reference. For 13C NMR,
chemical shifts were reported in the scale relative to C6H6 (128.00 ppm
for 13C NMR) as an internal reference. Optical rotations were measured
on a JASCO P-1010 polarimeter. EI mass spectra were measured on
JEOL JMS-DX303, JEOL JMS-AX505W or JMS-BU20 GCmate. ESI
mass spectra were measured on Waters micromass ZQ or AB Mariner.
FAB-HRMS spectra were measured on JEOL S-SX102A. EI-HRMS
spectra were measured on JEOL JMS-AX505W. The enantiomeric
excess (ee) was determined by HPLC analysis. HPLC was performed on
JASCO HPLC systems consisting of the following: pump, 880-PU or PU-
980: detector, 875-UV or UV-970. Reactions were carried out in dry sol-
vents under an argon atmosphere, unless otherwise stated. Ln(OiPr)3 was
purchased from Kojundo Chemical Laboratory Co., LTD., 5-1-28, Chiyo-
da, Sakado-shi, Saitama 350-0214, Japan (fax: +(81)-492-84-1351). MS
4 ä (Molecular Sieve UOP type 4 ä, powder) was purchased from
Fluka. Other reagents were purified by the usual methods.
HMQC, IR, and HR-MS. NMR data for C6D6 were consis-
tent with those reported by Drewes et al.[59a] and 13C NMR
data for CDCl3 were consistent with those reported by
O×Doherty et al.[28e] Since there was a magnitude gap of the
optical rotation between synthetic cryptocaryolone diacetate
([a]2D3 =ꢀ18.8 (c=0.35 in CHCl3)), whose purity was eluci-
dated based on 13C NMR analysis,[42] and natural cryptocar-
yolone diacetate ([a]2D3 =ꢀ145 (c=0.27 in CHCl3)),[59a,64] un-
fortunately, we have not succeeded in the determination of
the absolute configuration of cryptocaryolone diacetate.
However, we can conclude that cryptocaryolone diacetate
with 1S,5R,7S,2’S,4’S has the optical rotation ([a]2D3 =ꢀ18.8
(c=0.35 in CHCl3)). Moreover, O×Doherty et al.[28e] suc-
ceeded in synthesizing cryptocarya triacetate (68),[59] using
65 as an intermediate; this indicates that a formal total syn-
thesis of 68 has been also achieved in our group. The abso-
lute configuration of 68 has been unequivocally determined
by the total synthesis.[28b]
Catalytic asymmetric epoxidation of a,b-unsaturated Weinreb amide and
morpholinyl amide
(2R,3S)-2,3-Epoxy-N-methoxy-N-methyl-5-phenylpentanamide (14): pale
yellow oil; [a]2D1 = ꢀ15.1 (c = 1.36, CHCl3, 64% ee); IR (neat): n˜
=
2938, 1672, 1455, 1386, 701 cmꢀ1 1H NMR (CDCl3): d=7.30 7.18 (m,
;
Conclusion
5H), 3.70 3.66 (m, 4H), 3.23 3.20 (m, 4H), 2.81 (m, 2H), 2.00 (m, 2H);
13C NMR (CDCl3): d = 168.3, 140.6, 128.4, 128.2, 126.0, 61.7, 57.3, 51.9,
33.1, 32.4, 31.8, 30.7; HPLC conditions (column: DAICEL CHIRALPAK
AS-H, isopropanol/hexane 1:4, flow rate: 1.0 mLminꢀ1, detector: 254 nm,
tR [(2R,3S)-isomer] = 25.0 min, [(2S,3R)-isomer] = 37.5 min).
In summary, a new strategy for the stereoselective syntheses
of all possible stereoisomers of 1,3-polyol arrays was ach-
ieved using the Sm BINOL Ph3As=O (1:1:1) complex,
which promoted highly enantioselective as well as diastereo-
selective epoxidation of a,b-unsaturated morpholinyl
amides. Even when there is chirality in the vicinity of the b-
carbon of an a,b-unsaturated morpholinyl amide, stereose-
lectivity of the epoxidation can be controlled by the chirality
of BINOL with overwhelming inherent diastereofacial pref-
erence for the substrate. The resulting chiral a,b-epoxy mor-
pholinyl amides are synthetically very useful and versatile
intermediates, that react with a variety of nucleophiles to
afford the corresponding chiral carbonyl compounds such as
g,d-epoxy b-keto esters. The following regioselective epox-
ide opening reaction and syn- or anti-selective ketone reduc-
tion allows for a highly stereoselective 1,3-diol synthesis.
Stereoselective elongation of 1,3-polyol arrays was realized
by repeating the above process. The present strategy paves
the way for highly stereoselective syntheses of all possible
stereoisomers of 1,3-polyol arrays and eight possible stereo-
isomers of 1,3,5,7-tetraol arrays were successfully demon-
4-[(E)-1-Oxo-5-phenyl-2-pentenyl]morpholine (15a): Oxalyl chloride
(3.2 mL, 36.9 mmol) was added at 48C to a solution of 5-phenyl-2-pente-
noic acid (5 g, 28.4 mmol) in dichloromethane (50 mL). After the addi-
tion, the flask was warmed to room temperature and stirred for 2 h. The
reaction mixture was evaporated and then THF(20 mL) was added to
the residue. The resulting acyl chloride solution was dropped into a solu-
tion of morpholine (2.6 mL, 30 mmol) in THF(20 mL) and saturated
aqueous NaHCO3 (7 mL). After stirring for 50 min, the reaction mixture
was evaporated. The residue was taken up with ethyl acetate, and the or-
ganic phase was washed with 1n HCl, and brine. The combined organic
layers were dried over Na2SO4, filtered and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, ethyl acetate)
to afford 15a as pale yellow oil (6.53 g, 94%). It solidified upon standing.
M.p. 428C; IR (neat): n˜ = 2920, 2855, 1620, 1432, 1115 cmꢀ1 1H NMR
;
(CDCl3): d = 2.59 (td, J=7.5, 7.0 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H), 3.71
3.48 (m, 8H), 6.19 (d, J=15.0 Hz, 1H), 6.94 (dt, J=15.0, 7.0 Hz, 1H),
7.23 (m, 3H), 7.34 (m, 2H); 13C NMR (CDCl3): d = 34.2, 34.6, 42.2, 46.0,
66.8, 120.5, 126.0, 128.3, 128.4, 140.9, 145.3, 165.7; HRMS (FAB+): m/z:
calcd for C15H20O2N: 246.1494, found: 246.1499.
4-[(2R,3S)-2,3-Epoxy-1-oxo-5-phenylpentyl]morpholine (16a): Sm(OiPr)3
(6.4 mL, 1.28 mmol, 0.2m solution in THF) at room temperature was
added to a mixture of (S)-BINOL (336 mg, 1.28 mmol), triphenylarsine
1534
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 1527 1544

1,3-Polyol Arrays
1527 1544
oxide (412 mg, 1.28 mmol) and MS 4 ä (25.6 g; MS 4 ä was not dried.
1000 mg per 1 mmol of starting material) in THF(91.6 mL). After stir-
ring for 40 min at the same temperature, tert-butyl hydroperoxide
(TBHP; 6.14 mL, 30.72 mmol, 5m solution in decane) was added. After
10 min, a solution of amide 15a (6.28 g, 25.6 mmol) in THF(30 mL) was
added. After stirring for 8 h, the reaction mixture was filtered and the fil-
trate was diluted with ethyl acetate. The resulting solution was washed
with 2% aqueous citric acid, saturated aqueous sodium thiosulfate and
brine. The combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by column chromatogra-
phy (silica gel, hexane/ethyl acetate 2:1 to 0:1) to afford 16a as yellow oil
(6.7 g, 25.6 mmol, quant., 98% ee). It solidified upon standing. The solid
was recrystallized from diethyl ether to afford 16a with up to 99% ee.
M.p. 668C; [a]2D4 = ꢀ28.7 (c = 1.56, CHCl3, 99% ee); IR (KBr): n˜ =
d = 0.60 (m, 12H), 0.95 (m, 18H), 1.25 (t, J=7.0 Hz, 3H), 1.66 1.88 (m,
4H), 2.42 (dd, J=7.0, 14.5 Hz, 1H), 2.49 (dd, J=7.0, 14.5 Hz, 1H), 2.58
2.72 (m, 2H), 3.82 (tt, J=5.5, 11.5 Hz, 1H), 4.11 (m, 2H), 4.24 (tt, J=6.0,
12.5 Hz, 1H), 7.15 7.20 (m, 3H), 7.26 7.30 (m, 2H); 13C NMR (CDCl3):
d = 4.9, 5.1, 6.8, 6.9, 14.1, 31.4, 39.2, 43.0, 45.0, 60.3, 66.8, 68.9, 125.7,
128.32, 128.36, 142.4, 171.4; HRMS (FAB+): calcd for C27H51O4Si2:
495.3326, found 495.3333.
4-[(2E,5R,7S)-1-Oxo-9-phenyl-5,7-bis(triethylsilyloxy)-2-nonenyl]mor-
pholine (syn-27c): DIBAL-H (2.4 mL, 2.4 mmol, 1.0m in toluene) was
added dropwise at ꢀ788C to a solution of syn-25c (1.0 g, 2.02 mmol) in
toluene (25 mL). After stirring for 3 h at the same temperature, the reac-
tion mixture was quenched with methanol. 20% aqueous potassium
sodium tartrate was added to the solution and the resulting mixture was
extracted with ethyl acetate (3 î). The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatography (silica gel,
hexane/ethyl acetate 30:1) to afford an aldehyde as oil (882 mg,
1
2918, 2852, 1637, 1468, 1249, 1118 cmꢀ1; H NMR (CDCl3): d = 1.92 (m,
2H), 2.82 2.66 (m, 2H), 3.13 (td, J=5.5, 2.0 Hz, 1H), 3.22 (d, J=2.0 Hz,
1H), 3.26 (m, 1H), 3.40 (m, 1H), 3.59 3.48 (m, 6H), 7.14 (m, 3H), 7.22
(m, 2H); 13C NMR (CDCl3): d = 31.7, 33.0, 42.2, 45.1, 53.8, 57.6, 66.6,
126.2, 128.3, 128.5, 140.6, 165.9; HRMS (FAB+): calcd for C15H20O3N:
262.1443, found 262.1423; HPLC conditions (column: DAICEL CHIR-
ALPAK AS-H, isopropanol/hexane 1:4, flow rate: 1.0 mLminꢀ1, detector:
254 nm, tR [(2S,3R)-isomer] = 43.5 min, (16a) = 62.5 min).
1.96 mmol, 97%). To
a stirred mixture of the aldehyde (1.03 g,
2.28 mmol), LiCl (116 mg, 2.74 mmol), 4-(2-diethoxyphosphoryl-1-oxo-
ethyl)morpholine (29; 727 mg, 2.74 mmol) in acetonitrile (13 mL) at
room temperature was added DBU (0.41 mL, 2.74 mmol). After stirring
overnight, The reaction mixture was diluted with ethyl acetate. The re-
sulting mixture was washed with saturated aqueous NH4Cl, brine, dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by column chromatography (silica gel, hexane/ethyl acetate 1:1) to
afford syn-27c as oil (1.2 g, 2.14 mmol, 94%). [a]2D3 = +1.27 (c = 1.10,
Syntheses of all possible stereoisomers of 3,5,7,9-tetrahydroxy esters
based on highly catalyst-controlled epoxidation
Ethyl (4R,5S)-4,5-epoxy-3-oxo-7-phenylheptanoate (7a): Ethyl acetate
(2.2 mL, 23.0 mmol) was added dropwise at ꢀ788C to a mixture of
LHMDS (23.0 mL, 23.0 mmol, 1.0m solution in THF) and THF (45 mL).
After 30 min, 16a (2 g, 7.65 mmol) in THF(20 mL) was added dropwise
and the reaction mixture was stirred for 6 h at ꢀ788C. The reaction was
quenched with saturated aqueous NH4Cl at ꢀ788C and warmed to room
temperature. The resulting mixture was extracted with ethyl acetate (3î).
The combined organic layers were washed with saturated aqueous
NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, hexane/ethyl
CHCl3, 99% ee); IR (neat): n˜ = 2954, 2877, 1737, 1097, 1006 cmꢀ1 1H
;
NMR (CDCl3): d = 0.59 (m, 12H), 0.96 (m, 18H), 1.62 (m, 1H), 1.66
1.75 (m, 2H), 1.80 (m, 1H), 2.31 (ddd, J=6.0, 7.0, 14.5 Hz, 1H), 2.42
(ddd, J=6.0, 7.0, 14.5 Hz, 1H), 2.60 (m, 1H), 2.67 (m, 1H), 3.50 3.73 (br,
8H), 3.83 (tt, J=6.0, 12.0 Hz, 1H), 3.92 (tt, J=6.0, 12.0 Hz, 1H), 6.22
(d, J=15.0 Hz, 1H), 6.87 (dt, J=15.0, 7.0 Hz, 1H), 7.15 7.20 (m, 3H),
7.26 7.30 (m, 2H); 13C NMR (CDCl3): d = 5.0, 5.1, 6.90, 6.95, 31.5, 39.3,
40.8, 42.1, 44.9, 46.0, 66.7, 66.8, 68.5, 69.0, 121.8, 125.7, 128.2, 128.3, 142.3,
143.0, 165.2; HRMS (FAB+): m/z: calcd for C31H56NO4Si2: 562.3748,
found 562.3768.
acetate 4:1) to afford 7a as yellow oil (1.56 g, 5.95 mmol, 78%). [a]D21
=
+22.4 (c = 0.78, CHCl3, 99% ee). The spectral data were identical to
those of an authentic sample.[31b]
4-[(2R,3S,5R,7S)-2,3-Epoxy-1-oxo-9-phenyl-5,7-bis(triethylsilyloxy)no-
nyl]morpholine (34): Sm(OiPr)3 (0.87 mL, 0.174 mmol, 0.2m solution in
THF) was added at room temperature to a mixture of (S)-BINOL
(49.7 mg, 0.174 mmol), triphenylarsine oxide (55.9 mg, 0.174 mmol) and
MS 4 ä (1.74 g; MS 4 ä was not dried. 1000 mg per 1 mmol of starting
material) in THF(4.0 mL). After stirring for 40 min at the same tempera-
ture, TBHP (0.42 mL, 2.08 mmol, 5m solution in decane) was added.
Afer stirring for 10 min, syn-27c (975 mg, 1.74 mmol) in THF(3.8 mL)
was added and stirred for 12 h. The reaction mixture was filtered and the
filtrate was diluted with ethyl acetate. The resulting mixture was washed
with 2% aqueous citric acid, saturated aqueous sodium thiosulfate, and
brine. The combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by column chromatogra-
phy (silica gel, hexane/ethyl acetate 4:1 to 2:3) to afford 34 as yellow oil
(753 mg, 1.3 mmol, 75%). The diastereomeric ratio of 34 and 35 was
over 95:5 (1H NMR analysis). 34:35 >95:5 prepared from syn-27c (99%
ee); [a]2D2 = ꢀ4.0 (c = 1.00, CHCl3); IR (neat): n˜ = 2954, 1661, 1456,
Ethyl
(5S)-5-hydroxy-3-oxo-7-phenylheptanoate
(23a):[65]
NaBH4
(532 mg, 14.07 mmol) was added portionwise to a mixture of PhSeSePh
(2.19 g, 7.03 mmol) in ethanol (20 mL) at room temperature. After
15 min, the reaction mixture was cooled to 08C, and then 7a (1.23 g,
4.69 mmol) in ethanol (5 mL) was added. After stirring for 10 min, the
reaction was quenched with saturated aqueous NH4Cl. The resulting mix-
ture was extracted with ethyl acetate (3î), and the combined organic
layers were washed with brine, dried over Na2SO4, filtered, and concen-
trated in vacuo. The residue was purified by column chromatography
(silica gel, hexane/ethyl acetate 5:1 to 2:1) to afford 23a as yellow oil
(0.98 g, 3.7 mmol, 79%). [a]2D3 = +9.35 (c 1.25, CHCl3, 99% ee).
Ethyl
(3S,5S)-3,5-dihydroxy-7-phenylheptanoate
(syn-24a):[65]
BEt2(OMe) (4.2 mL, 4.16 mmol, 1.0m in THF) was added at ꢀ788C to a
solution of 23a (1 g, 3.78 mmol) in THF(30 mL) and MeOH (10 mL).
After stirring for 1 h, NaBH4 (179 mg, 4.73 mmol) was added portionwise
at ꢀ788C. After 2 h, the reaction was quenched with brine at ꢀ788C and
warmed to room temprature. The resulting mixture was extracted with
ethyl acetate (2î), and the combined organic layers were washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resi-
due was purified by column chromatography (silica gel, hexane/ethyl ace-
tate 5:1 to 2:1) to afford syn-24a as a colorless oil (758 mg, 2.84 mmol,
75%).
1239, 1116 cmꢀ1 1H NMR (CDCl3): d = 0.59 (m, 12H), 0.96 (m, 18H),
;
1.70 1.88 (m, 2H), 2.65 (m, 2H), 3.26 (dt, J=2.5, 5.0 Hz, 1H), 3.73 (d,
J=2.5 Hz, 1H), 3.57 3.75 (br, 8H), 3.89 (tt, J=5.0, 10.5 Hz, 1H), 4.05
(tt, J=6.0, 12.0 Hz, 1H), 7.15 7.20 (m, 3H), 7.26 7.30 (m, 2H); 13C
NMR (CDCl3): d = 4.9, 5.1, 6.90, 6.96, 31.4, 38.9, 39.5, 42.3, 44.0, 45.3,
53.4, 54.8, 66.7, 67.2, 69.0, 125.7, 128.2, 128.3, 142.3, 166.1; HRMS
(FAB+): m/z: calcd for C31H56NO5Si2: 578.3697, found 578.3712.
Ethyl (3S,5S)-7-phenyl-3,5-bis(triethylsilyloxy)heptanoate (syn-25c): Tri-
ethylsilyl chloride (0.99 mL, 5.89 mmol) was added dropwise at room
temperature to a stirred solution of syn-24a (654 mg, 2.46 mmol), imida-
zole (802 mg, 11.79 mmol) and DMAP (catalytic amount) in DMF
(3 mL) and the resulting solution was stirred overnight. The reaction mix-
ture was poured into brine, and extracted with ethyl acetate. The com-
bined organic layers were washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by column chroma-
tography (silica gel, hexane/ethyl acetate 1:0 to 40:1) to afford syn-25c as
an oil (1.22 g, 2.46 mmol, quant.). [a]2D4 = +10.9 (c = 1.00, CHCl3, 99%
4-[(2S,3R,5R,7S)-2,3-Epoxy-1-oxo-9-phenyl-5,7-bis(triethylsilyloxy)no-
nyl]morpholine (35): 34:35=8:92 prepared from syn-27c (99% ee); [a]D24
=
+21.7 (c = 1.02, CHCl3); IR (neat): n˜ = 2954, 1656, 1459, 1238,
1115 cmꢀ1 1H NMR (CDCl3): d = 0.61 (m, 12H), 0.96 (m, 18H), 1.66
;
(m, 2H), 1.70 1.85 (m, 4H), 2.64 (m, 2H), 3.30 (ddd, J=2.5, 6.5, 6.5 Hz,
1H), 3.34 (d, J=2.5 Hz, 1H), 3.55 3.75 (br, 8H), 3.80 (tt, J=5.5, 6.5 Hz,
1H), 4.04 (tt, J=5.5, 6.5 Hz, 1H), 7.15 7.21 (m, 3H), 7.26 7.29 (m, 2H);
13C NMR (CDCl3): d = 4.9, 5.1, 6.8, 6.9, 31.3, 39.4, 39.6, 42.3, 45.3, 54.2,
55.5, 66.6, 67.2, 68.8, 125.7, 128.2, 128.3, 142.2, 165.9; HRMS (FAB+):
m/z: calcd for C31H56NO5Si2: 578.3697, found 578.3691.
ee); IR (neat): n˜ = 2954, 2877, 1737, 1097, 1006 cmꢀ1; H NMR (CDCl3):
1
1535
Chem. Eur. J. 2004, 10, 1527 1544
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

M. Shibasaki et al.
FULL PAPER
Ethyl (3S,5S)-3,5-isopropylidenedioxy-7-phenylheptanoate (syn-25a):
[a]2D3 = ꢀ27.4 (c 1.08, CHCl3, 99% ee); IR (neat): n˜ = 2991, 2940, 1737,
H, hexane/isopropanol 1:1, flow rate: 1.0 mLminꢀ1, detector: 254 nm, tR
(32) = 19.7 min, (33) = 11.8 min).
1
1496, 1455, 1380, 1199, 1167, 1028, 700 cmꢀ1; H NMR (CDCl3): d = 1.25
4-(2S,3R,5R,7S)-2,3-Epoxy-5,7-bis(methoxymethyloxy)-1-oxo-9-phenylno-
nyl]morpholine (33): 32:33=0.5:>99.5 prepared from syn-27b (99% ee);
[a]2D5 = +19.8 (c = 1.00, CHCl3); IR (neat): n˜ = 2926, 1654, 1451, 1240,
(dt, J=0.6, 7.2 Hz, 3H), 1.40 (s, 3H), 1.43 (s, 3H), 1.72 1.54 (m, 3H),
1.787 1.79 (m, 1H), 2.36 (dd, J=6.3, 15.4 Hz, 1H), 2.52 (dd, J=6.9,
15.4 Hz, 1H), 2.65 (ddd, J=8.0, 8.3, 14.0 Hz, 1H), 2.74 (ddd, J=5.2, 9.0,
14.0 Hz, 1H), 3.84 3.78 (m, 1H), 4.18 4.11 (m, 2H), 4.29 4.24 (m, 1H),
7.19 7.17 (m, 2H), 7.29 7.26 (m, 3H); 13C NMR (CDCl3): d = 14.2, 19.7,
30.1, 31.0, 36.5, 37.8, 41.5, 60.4, 66.0, 67.6, 98.8, 125.8, 128.3, 128.5, 141.9,
171.0; ESI-MS (ESI+): m/z: calcd for C18H26O4Na: 329.17288, found:
329.17278 [M+Na+]; HPLC conditions (column: DAICEL CHIRAL-
CEL OJ-H, hexane/isopropanol 99:1, flow rate: 1.0 mLminꢀ1, detector:
254 nm, tR (syn-25a) = 17.7 min, [(3R,5R)-isomer] 14.4 min).
1114, 1031 cmꢀ1 1H NMR (CDCl3): d = 1.68 (m, 1H), 1.78 (m, 1H),
;
1.82 1.92 (m, 3H), 2.00 (m, 1H), 2.62 2.76 (m, 2H), 3.29 (m, 1H), 3.35
(s, 3H), 3.37 (d, J=2.5 Hz, 1H), 3.40 (s, 1H), 3.58 3.74 (m, 9H), 3.90 (m,
1H), 4.62 4.69 (m, 4H), 7.14 7.21 (m, 3H), 7.25 7.31 (m, 2H); 13C NMR
(CDCl3): d = 31.4, 36.3, 37.3, 39.9, 42.3, 45.3, 54.3, 55.5, 55.7, 55.8, 66.7,
72.6, 74.1, 95.4, 95.8, 125.8, 128.2, 128.4, 141.9, 165.8; HRMS (FAB+):
m/z: calcd for C23H36O7N: 438.2492, found 438.2477; HPLC conditions
(column: DAICEL CHIRALPAK AS-H, hexane/isopropanol 1:1, flow
rate: 1.0 mLminꢀ1
11.8 min).
, detector: 254 nm, tR (32) = 19.7 min, (33) =
4-(2E,5R,7S)-5,7-Isopropylidenedioxy-1-oxo-9-phenyl-2-nonenyl]morpho-
line (syn-27a): [a]2D2 = ꢀ15.1 (c = 1.27, CHCl3, 99% ee); IR (neat): n˜ =
2921, 2851, 1660, 1615, 755, 701 cmꢀ1 1H NMR (CDCl3): d = 1.21 (m,
;
Ethyl (4R,5S,7R,9S)-4,5-epoxy-7,9-isopropylidenedioxy-3-oxo-11-phenyl-
undecanoate (38): Prepared from 30 (30:31 >99:1); [a]2D3 = +18.4 (c =
1H), 1.40 (s, 2î3H), 1.53 (m, 1H), 1.68 (m, 1H), 1.83 (m, 1H), 2.30 (m,
1H), 2.43 (m, 1H), 2.76 2.62 (m, 2H), 3.68 3.50 (m, 8H), 3.76 (m, 1H),
3.92 (m, 1H), 6.26 (d, J=15.0 Hz, 1H), 6.84 (dt, J=15.0, 7.5 Hz, 1H),
7.23 7.17 (m, 3H), 7.31 7.24 (m, 2H); 13C NMR (CDCl3): d = 19.8, 30.2,
31.0, 36.7, 27.8, 39.5, 42.2, 46.1, 66.8, 67.6, 67.9, 98.7, 121.8, 125.7, 128.3,
128.5, 141.9, 142.1, 165.4; HRMS (FAB+): m/z: calcd for C21H32O4N:
374.2331, found 374.2335.
1.01, CHCl3); IR (neat): n˜
= 2990, 2918, 1743, 1717, 1653, 1380,
1199 cmꢀ1; H NMR (CDCl3): d = 1.25 1.32 (m, 4H), 1.33 1.50 (m, 8H),
1.70 (m, 1H), 1.76 1.89 (m, 3H), 2.66 (m, 1H), 2.73 (m, 1H), 3.22 3.42
(m, 3H), 3.78 (m, 1H), 3.98 (m, 1H), 4.20 (m, 2H), 7.14 7.20 (m, 3H),
7.23 7.29 (m, 2H); 13C NMR (CDCl3): d = 14.0, 19.7, 30.1, 31.0, 36.4,
37.7, 37.9, 43.7, 55.0, 58.9, 61.5, 66.0, 67.5, 98.7, 125.7, 128.2, 128.5, 141.8,
166.5, 199.9; HRMS (FAB+): m/z: calcd for C22H31O6: 391.2121, found
391.2112.
1
4-[(2R,3S,5R,7S)-2,3-Epoxy-5,7-isopropylidenedioxy-1-oxo-9-phenylno-
nyl]morpholine (30): 30:31 >99:1 prepared from syn-27a (99% ee);
[a]2D3 = ꢀ19.2 (c = 1.54, CHCl3); IR (KBr): n˜ = 3000, 2920, 2851, 1664,
Ethyl (5S,7R,9S)-5-hydroxy-7,9-isopropylidenedioxy-3-oxo-11-phenylun-
decanoate (39): Prepared from 38 mentioned above; [a]2D3 = ꢀ0.4 (c =
1
1467, 1111 cmꢀ1; H NMR (CDCl3): d = 1.38 (s, 3H), 1.40 (s, 3H), 1.89
1.66 (m, 3H), 2.76 2.61 (m, 2H), 3.23 (td, J=5.0, 2.0 Hz, 1H), 3.46 (d,
J=2.0 Hz, 1H), 3.75 3.60 (m, 8H), 3.78 (m, 1H), 3.96 (m, 1H), 7.19 7.15
(m, 3H), 7.29 7.25 (m, 2H); 13C NMR (CDCl3): d = 19.9, 30.2, 31.0,
36.2, 37.2, 37.7, 42.2, 45.2, 53.5, 54.6, 65.4, 66.7, 67.6, 98.6, 125.8, 128.3,
128.5, 141.8, 166.1; HRMS (FAB+): m/z: calcd for C21H32O5N 390.2280,
found 390.2264; HPLC conditions (column: DAICEL CHIRALPAK AS-
H, hexane/isopropanol 3:1, flow rate: 1.2 mLminꢀ1, detector: 254 nm, tR
(30) = 32.2 min, (31) = 22.8 min).
1.06, CHCl3); IR (neat): n˜
= 3502, 2990, 2939, 1742, 1716, 1380,
1092 cmꢀ1; H NMR (CDCl3): d = 1.20 1.29 (m, 4H), 1.38 1.47 (m, 7H),
1.55 1.73 (m, 3H), 1.82 (m, 1H), 2.60 2.67 (m, 2H), 2.70 2.76 (m, 2H),
3.49 (s, 2H), 3.61 (s, 1H), 3.79 (m, 1H), 4.10 (m, 2H), 4.19 (q, J=7.0 Hz,
2H), 4.26 (m, 1H), 7.15 7.21 (m, 3H), 7.25 7.30 (m, 2H); 13C NMR
(CDCl3): d = 14.0, 19.9, 30.1, 30.9, 36.9, 37.7, 42.3, 49.9, 50.0, 61.3, 67.3,
67.5, 69.4, 98.7, 125.7, 128.2, 128.4, 141.8, 167.0, 202.4; HRMS (FAB+):
m/z: calcd for C22H33O6: 393.2277, found 393.2264.
1
Compound 30 was recrystalized from ethyl acetate/hexane at 48C. Color-
less crystal thus obtained was subjected to X-ray crystallographic analysis
to confirm the stereochemistry.
Ethyl (3S,5R,7R,9S)-3,5-dihydroxy-7,9-isopropylidenedioxy-11-phenylun-
decanoate (40): BEt2(OMe) (0.14 mL, 0.14 mmol, 1.0m in THF) was
added at ꢀ788C to a solution of 39 (50 mg, 0.128 mmol) in THF(1.5 mL)
and MeOH (1.5 mL). After stirring for 1 h, NaBH4 (6.1 mg, 0.16 mmol)
was added at ꢀ788C. After 4 h, the reaction was quenched with saturated
aqueous NH4Cl at ꢀ788C and warmed to room temperature. The result-
ing mixture was extracted with ethyl acetate (3î), and the combined or-
ganic layers were washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by column chromatogra-
phy (silica gel, hexane/ethyl acetate 3:1) to afford 40 as oil (43 mg,
0.109 mmol, 85% yield, syn:anti >99.5:0.5).
4-[(2S,3R,5R,7S)-2,3-Epoxy-5,7-isopropylidenedioxy-1-oxo-9-phenylno-
nyl]morpholine (31): 30:31=1:>99 prepared from syn-27a (99% ee);
[a]2D4 = ꢀ4.3 (c = 1.45, CHCl3); IR (KBr): n˜ = 2993, 2937, 2852, 1671,
1
1430, 1114 cmꢀ1; H NMR (CDCl3): d = 1.38 (s, 3H), 1.42 (s, 3H), 1.86
1.63 (m, 3H), 2.75 2.62 (m, 2H), 3.24 (td, J=5.5, 2.0 Hz, 1H), 3.39 (d,
J=2.0 Hz, 1H), 3.75 3.58 (m, 8H), 3.81 (m, 1H), 4.05 (m, 1H), 7.20 7.17
(m, 3H), 7.29 7.24 (m, 2H); 13C NMR (CDCl3): d = 19.9, 30.2, 31.0,
37.2, 37.8, 39.2, 42.3, 45.2, 54.1, 55.4, 66.7, 67.5, 98.7, 125.8, 128.3, 128.5,
141.8, 166.0; HRMS (FAB+): m/z: calcd for C22H32O5N: 390.2280, found
390.2244; HPLC conditions (column: DAICEL CHIRALPAK AS-H,
hexane/isopropanol 3:1, flow rate: 1.2 mLminꢀ1, detector: 254 nm, tR
(30) = 32.2 min, (31) 22.8 min).
A mixture of 40 and 41 (40:41 >99.5:0.5); [a]D23
=
ꢀ4.5 (c
=
1.01,
1H
CHCl3); IR (neat): n˜
=
3404, 2939, 2912, 1733, 1379, 1094 cmꢀ1
;
NMR (CDCl3): d = 1.21 1.29 (m, 4H), 1.38 1.47 (m, 7H), 1.51 1.59 (m,
2H), 1.60 1.72 (m, 3H), 1.82 (m, 1H), 2.45 (dd, J=5.0, 16.0 Hz, 1H),
2.52 (dd, J=7.5, 16.0 Hz, 1H), 2.64 (m, 1H), 2.73 (m, 1H), 3.79 (m, 1H),
3.94 (brs, 1H), 3.97 (brs, 1H), 4.10 (m, 2H), 4.15 (q, J=7.0 Hz, 2H),
4.26 (m, 1H), 7.15 7.20 (m, 3H), 7.25 7.30 (m, 2H); 13C NMR (CDCl3):
d = 14.1, 19.9, 30.1, 30.9, 37.0, 37.6, 41.7, 42.7, 43.1, 60.5, 67.5, 68.1, 69.7,
71.3, 98.6, 125.7, 128.2, 128.4, 141.8, 172.1; HRMS (FAB+): m/z: calcd
for C22H35O6: 395.2434, found 395.2418; HPLC conditions (column:
YMC-PACK A-003-5-06 S-5 60A SIL 4.6î250 mm, hexane/isopropanol
98:2, flow rate: 1.5 mLminꢀ1, detector: 254 nm, tR (40) = 32.8 min, (41)
= 36.0 min).
4-(2E,5R,7S)-5,7-Bis(methoxymethyloxy)-1-oxo-9-phenyl-2-nonenyl]mor-
pholine (syn-27b): [a]2D5 = ꢀ9.8 (c = 1.33, CHCl3, 99% ee); IR (neat): n˜
= 2926, 1655, 1617, 1436, 1032 cmꢀ1 1H NMR (CDCl3): d = 1.65 (m,
;
1H), 1.78 1.95 (m, 3H), 2.42 (m, 1H), 2.51 (m, 1H), 2.64 (m, 1H), 2.73
(m, 2H), 3.34 (s, 3H), 3.40 (s, 3H), 3.50 3.74 (m, 9H), 3.80 (m, 1H),
4.58 4.68 (m, 2H), 6.26 (d, J=15.0 Hz, 1H), 6.91 (ddd, J=7.5, 15.0,
15.0 Hz, 1H), 7.16 7.21 (m, 3H), 7.25 7.31 (m, 2H); 13C NMR (CDCl3):
d = 31.4, 36.3, 37.8, 39.4, 42.2, 46.0, 55.72, 55.79, 66.7, 66.8, 73.6, 74.2,
95.4, 95.5, 121.9, 125.8, 128.3, 128.4, 142.0, 142.6, 165.1; HRMS (FAB+):
m/z: calcd for C23H36O6N: 422.2543, found 422.2529.
Ethyl (3R,5R,7R,9S)-3,5-dihydroxy-7,9-isopropylidenedioxy-11-phenylun-
decanoate (41): Acetic acid (0.7 mL) was added at room temperature to
4-(2R,3S,5R,7S)-2,3-Epoxy-5,7-bis(methoxymethyloxy)-1-oxo-9-phenylno-
nyl]morpholine (32): 32:33 >99.5:0.5 prepared from syn-27b (99% ee);
[a]2D5 = ꢀ3.4 (c = 1.00, CHCl3); IR (neat): n˜ = 2928, 1654, 1454, 1240,
a
mixture of tetramethylammonium triacetoxyborohydride (249 mg,
1
1114, 1032 cmꢀ1; H NMR (CDCl3): d = 1.78 (m, 2H), 1.86 (m, 2H), 1.99
0.899 mmol) and acetonitrile (0.7 mL). The reaction mixture was stirred
for 30 min and then cooled to ꢀ58C. The solution of 39 (50 mg,
0.128 mmol) in acetonitrile (1 mL) was added. After stirring for 4.5 h, the
reaction mixture was poured into saturated aqueous NaHCO3, and the
resulting mixture was extracted with ethyl acetate (3î). The combined
organic layers were washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by column chromatogra-
(m, 2H), 2.60 2.78 (m, 2H), 3.30 (m, 1H), 3.34 (s, 3H), 3.38 3.40 (m,
4H), 3.57 3.75 (m, 9H), 3.90 (m, 1H), 4.60 4.70 (m, 4H), 7.16 7.21 (m,
3H), 7.25 7.31 (m, 2H); 13C NMR (CDCl3): d = 31.4, 36.2, 36.4, 39.1,
42.3, 45.3, 53.4, 55.1, 55.72, 55.77, 66.7, 72.5, 74.4, 95.5, 95.6, 125.8, 128.3,
128.4, 141.9, 165.9; HRMS (FAB+): m/z: calcd for C23H36O7N: 438.2492,
found 438.2477; HPLC conditions (column: DAICEL CHIRALPAK AS-
1536
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 1527 1544

1,3-Polyol Arrays
1527 1544
phy (silica gel, hexane/ethyl acetate 1:1) to afford 41 as oil (38 mg,
0.096 mmol, 75% yield, anti:syn >95:5).
phy (silica gel, hexane/ethyl acetate 4:1 to 2:1) to afford anti-24a
(682 mg).
A mixture of 40 and 41 (40:41=5:>95); [a]D23
=
ꢀ9.9 (c
=
1.01,
anti-24a (682 mg) was dissolved in 2,2-dimethoxypropane (10 mL) and
TsOH¥H2O (10 mg) was added to the mixture. After stirring for 7 h at
room temperature, the reaction mixture was quenched with saturated
aqueous NaHCO3. After extracting with ethyl acetate (3î), the com-
bined organic layers were washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by column chroma-
tography (silica gel, hexane/ethyl acetate 5:1) to afford anti-25a as oil
(660 mg).
CHCl3); IR (neat): n˜ = 3421, 2990, 2940, 1732, 1716, 1379, 1199, 1162,
1
1095 cmꢀ1; H NMR (CDCl3): d = 1.27 1.30 (m, 4H), 1.39 1.48 (m, 7H),
1.50 1.77 (m, 5H), 1.83 (m, 1H), 2.50 (m, 2H), 2.64 (m, 1H), 2.73 (m,
2H), 3.60 (brs, 1H), 3.80 (m, 1H), 3.84 (brs, 1H), 4.03 4.20 (m, 4H),
4.33 (m, 1H), 7.15 7.21 (m, 3H), 7.23 7.30 (m, 2H); 13C NMR (CDCl3):
d = 14.1, 19.9, 30.1, 30.9, 37.1, 37.6, 41.6, 42.6, 42.8, 60.5, 65.3, 67.5, 68.9,
70.3, 98.7, 125.7, 128.2, 128.4, 141.8, 172.5; HRMS (FAB+): m/z: calcd
for C22H35O6: 395.2434, found 395.2418; HPLC conditions (column:
YMC-PACK A-003-5-06 S-5 60A SIL 4.6î250 mm, hexane/isopropanol
98:2, flow rate: 1.5 mLminꢀ1, detector: 254 nm, tR (40) = 32.8 min, (41)
= 36.0 min).
LiBH4 (84 mg, 3.84 mmol) and trimethoxyborane (0.032 mL, 0.28 mmol)
were added at room temperature to a solution of anti-25a (660 mg) in di-
ethyl ether (30 mL). The reaction mixture was stirred for 1 h at the same
temperature and quenched with saturated aqueous NaHCO3. After ex-
tracting with ethyl acetate (3î), the combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo to afford an alcohol as oil (425 mg).
Ethyl (4S,5R,7R,9S)-4,5-epoxy-7,9-isopropylidenedioxy-3-oxo-11-phenyl-
undecanoate: Prepared from 31 (30:31=1:>99); [a]2D4 = ꢀ30.2 (c
=
1.12, CHCl3); IR (neat): n˜
= 2991, 2940, 1747, 1716, 1652, 1380,
1199 cmꢀ1; H NMR (CDCl3): d = 1.17 1.34 (m, 4H), 1.35 1.54 (m, 9H),
1.69 (m, 1H), 1.77 1.95 (m, 2H), 2.65 (m, 1H), 2.74 (m, 1H), 3.28 (m,
1H), 3.33 (m, 1H), 3.39 (d, J=9.0 Hz, 1H), 3.80 (m, 1H), 4.04 (m, 1H),
4.20 (m, 2H), 7.16 7.20 (m, 3H), 7.25 7.29 (m, 2H); 13C NMR (CDCl3):
d = 14.0, 19.8, 30.1, 30.9, 37.0, 37.7, 39.0, 43.9, 55.3, 59.5, 61.5, 66.4, 67.4,
98.7, 125.7, 128.2, 128.4, 141.8, 166.5, 199.6; HRMS (FAB+): m/z: calcd
for C22H31O6: 391.2121, found 391.2119.
1
MS 4 ä (800 mg; MS 4 ä not dried), N-methylmorpholine-N-oxide
(282 mg, 2.41 mg) and TPAP (28 mg, 0.08 mmol) were added at room
temperature to a solution of the alcohol (425 mg) in acetonitrile (15 mL).
The reaction mixture was stirred for 1 h and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, hexane/ethyl
acetate 6:1) to afford an aldehyde as oil (250 mg).
N,N-Diisopropylethylamine (0.2 mL, 1.14 mmol) was added at room tem-
perature to a stirred mixture of the aldehyde (250 mg, 0.953 mmol), LiCl
(48.3 mg, 1.14 mmol), 4-(2-diethoxyphosphoryl-1-oxoethyl)morpholine
(29; 302 mg, 1.14 mmol) in acetonitrile (8 mL). The reaction mixture was
stirred overnight, and diluted with ethyl acetate. The resulting mixture
was washed with 2% aqueous citric acid, saturated aqueous NaHCO3,
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resi-
due was purified by column chromatography (silica gel, ethyl acetate) to
afford anti-27a as oil (292 mg, 0.78 mmol, 30% yield, 5 steps). The dia-
steromeric ratio of anti:syn acetonide was determined 90:10 by HPLC
analysis.
Ethyl (5R,7R,9S)-5-hydroxy-7,9-isopropylidenedioxy-3-oxo-11-phenylun-
decanoate: [a]2D4 = ꢀ17.0 (c = 1.08, CHCl3); IR (neat): n˜ = 3489, 2991,
2940, 1742, 1714, 1380, 1265, 1200 cmꢀ1 1H NMR (CDCl3): d = 1.25
;
1.35 (m, 4H), 1.37 1.45 (m, 7H), 1.54 (m, 1H), 1.61 1.73 (m, 2H), 1.82
(m, 1H), 2.60 2.76 (m, 4H), 3.22 (d, J=6.0 Hz, 1H), 3.47 (m, 2H), 3.80
(m, 1H), 4.12 (m, 1H), 4.20 (m, 2H), 4.33 (m, 1H), 7.15 7.21 (m, 3H),
7.23 7.28 (m, 2H); 13C NMR (CDCl3): d = 14.0, 19.7, 30.2, 31.0, 36.6,
37.7, 41.9, 49.8, 49.9, 61.3, 64.4, 66.4, 67.7, 98.7, 125.7, 128.2, 128.4, 141.9,
166.9, 203.1; HRMS (FAB+): m/z: calcd for C22H32O6: 393.2277, found
393.2262.
Ethyl (3R,5S,7R,9S)-3,5-dihydroxy-7,9-isopropylidenedioxy-11-phenylun-
decanoate (42): A mixture of 42 and 43 (42:43 >99:1); [a]2D4 = ꢀ7.6 (c
Ethyl (3R,5S)-3,5-isopropylidenedioxy-7-phenylheptanoate (anti-25a):
[a]2D2
=
+17.4 (c = 0.70, CHCl3, 99% ee); IR (neat): n˜ = 2986, 2937,
1738, 1496, 1455, 1380, 1224, 1187, 1025, 700 cmꢀ1 1H NMR (CDCl3): d
;
=
1.00, CHCl3); IR (neat): n˜ = 3421, 2940, 1732, 1379, 1266, 1199,
1
1095 cmꢀ1; H NMR (CDCl3): d = 1.24 1.29 (m, 4H), 1.36 1.44 (m, 7H),
1.52 1.73 (m, 5H), 1.84 (m, 1H), 2.45 (dd, J=4.5, 16.0 Hz, 1H), 2.51 (dd,
J=7.5, 16.0 Hz, 1H), 2.65 (m, 1H), 2.73 (m, 1H), 3.76 3.84 (m, 2H), 3.96
(brs, 1H), 4.12 4.19 (m, 4H), 4.29 (m, 1H), 7.16 7.20 (m, 3H), 7.24 7.30
(m, 2H); 13C NMR (CDCl3): d = 14.1, 19.7, 30.2, 31.0, 36.6, 37.7, 41.7,
42.5, 42.6, 60.6, 66.8, 67.7, 68.7, 68.8, 98.7, 125.7, 128.2, 128.5, 141.9, 172.3;
HRMS (FAB+): m/z: calcd for C22H35O6: 395.2434, found 395.2412;
HPLC conditions (column: YMC-PACK A-003-5-06 S-5 60A SIL 4.6î
= 7.29 7.26 (m, 3H), 7.19 7.16 (m, 2H), 4.29 4.25 (m, 1H), 4.17 4.11
(m, 2H), 3.79 3.75 (m, 1H), 2.77 (ddd, J=5.5, 9.5, 13.8 Hz, 1H), 2.61
(ddd, J=7.2, 8.9, 13.8 Hz, 1H), 2.50 (dd, J=8.3, 15.3 Hz, 1H), 2.41 (dd,
J=5.2, 15.3 Hz, 1H), 1.88 1.82 (m, 1H), 1.76 1.59 (m, 3H), 1.38 (s, 3H),
1.33 (s, 3H), 1.25 (t, J=7.0 Hz, 3H); 13C NMR (CDCl3): d = 170.9,
141.9, 128.4, 128.3, 125.8, 100.6, 65.6, 63.5, 60.4, 40.8, 37.9, 37.4, 31.6, 24.7,
24.6, 14.2; EI-MS m/z: 306 [M +]; HRMS (FAB+): m/z: calcd for
C18H27O4: 307.1904, found 307.1902; HPLC conditions (column:
DAICEL CHIRALCEL OJ-H, hexane/isopropanol 98:2, flow rate:
1.0 mLminꢀ1, detector: 254 nm, tR (anti-25a) = 8.7 min, [(3S,5R)-isomer]
11.6 min).
250 mm, hexane/isopropanol 98:2, flow rate: 1.5 mLminꢀ1
, detector:
254 nm, tR (42) = 33.0 min, (3) = 37.9 min).
Ethyl (3S,5S,7R,9S)-3,5-dihydroxy-7,9-isopropylidenedioxy-11-phenylun-
decanoate (43): A mixture of 42 and 43 (42:43 6:94); [a]2D4 = +1.0 (c =
1.00, CHCl3); IR (neat): n˜ = 3421, 2990, 2940, 1732, 1379, 1266, 1199,
4-[(2E,5S,7S)-5,7-Isopropylidenedioxy-1-oxo-9-phenyl-2-nonenyl]mor-
pholine (anti-27a): A mixture of syn-27a and anti-27a (syn-27a: anti-
27a 1:9); [a]2D2 = +25.5 (c = 0.89, CHCl3); IR (neat): n˜ = 2933, 2857,
1159, 1094 cmꢀ1 1H NMR (CDCl3): d = 1.27 (t, J=7.0 Hz, 1H), 1.36
;
1660, 1619, 1432, 1224, 1115 cmꢀ1 1H NMR (CDCl3): d = 1.33 (s, 3H),
;
1.45 (m, 8H), 1.57 1.64 (m, 3H), 1.64 1.76 (m, 2H), 1.84 (m, 1H), 2.50
(m, 2H), 2.65 (m, 1H), 2.74 (m, 1H), 3.38 (d, J=4.5 Hz, 1H), 3.49 (d,
J=2.5 Hz, 1H), 3.80 (m, 1H), 4.17 (q, J=7.0 Hz, 2H), 4.24 (m, 1H), 4.34
(m, 1H), 7.15 7.20 (m, 3H), 7.25 7.30 (m, 2H); 13C NMR (CDCl3): d =
14.1, 19.7, 30.2, 31.0, 36.3, 37.7, 41.4, 42.0, 42.3, 60.6, 65.6, 67.8, 98.7,
125.7, 128.2, 128.5, 141.9, 172.7; HRMS (FAB+): m/z: calcd for
C22H35O6: 395.2434, found 395.2410; HPLC conditions (column: YMC-
PACK A-003-5-06 S-5 60A SIL 4.6î250 mm, hexane/isopropanol 98:2,
flow rate: 1.5 mLminꢀ1, detector: 254 nm, tR (42) = 33.0 min, (43) =
37.9 min).
1.36 (s, 3H), 1.62 (m, 2H), 1.74 (m, 1H), 1.83 (m, 1H), 2.33 (m, 1H),
2.41 (m, 1H), 2.60 (m, 1H), 2.75 (m, 1H), 3.55 (br, 2H), 3.68 (br, 6H),
3.76 (m, 1H), 3.93 (m,1H), 6.26 (d, J=15.0 Hz, 1H), 6.83 (dt, J=15.0,
7.0 Hz, 1H), 7.16 7.21 (m, 3H), 7.25 7.31 (m, 2H); 13C NMR (CDCl3): d
= 24.8, 24.9, 31.5, 37.3, 38.2, 38.6, 42.2, 46.1, 65.5, 65.6, 66.7, 66.8, 100.5,
121.6, 125.7, 128.2, 128.4, 141.8, 142.3, 165.4; HRMS (FAB+): m/z: calcd
for C22H32O4N: 374.2331, found 374.2346; HPLC conditions (column:
DAICEL CHIRALPAK AS-H, hexane/isopropanol 98:2, flow rate:
1.2 mLminꢀ1, detector: 254 nm, tR (anti-27a) = 98.9 min, (syn-27a) =
115.1 min).
Synthesis of anti-27a from 23a: Acetic acid (10 mL) was added at room
temperature to a mixture of tetramethylammonium triacetoxyborohy-
dride (3.67 g, 13.24 mmol) and acetonitrile (15 mL). After stirring for
30 min, the mixture was cooled to ꢀ108C and the solution of 23a
(700 mg, 2.65 mmol, >99% ee) in acetonitrile (10 mL) was added. After
stirring for 8 h at 08C, the reaction mixture was poured into saturated
aqueous NaHCO3, and extracted with ethyl acetate (3î). The combined
organic layers were washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by column chromatogra-
4-[(2S,3R,5S,7S)-2,3-Epoxy-5,7-isopropylidenedioxy-1-oxo-9-phenylno-
nyl]morpholine (37): A mixture of 37 and 31 (37:31 9:1); [a]2D4 =ꢀ4.3 (c
= 1.45, CHCl3); IR (neat): n˜ = 2921, 2855, 1655, 1379, 1115 cmꢀ1 1H
;
NMR (CDCl3): d = 1.34+1.37 (syn acetonide) +1.38+1.41 (anti aceto-
nide) (s, 2î3H), 1.61 1.79 (m, 3H), 1.80 1.91 (m, 3H), 2.61 (m, 1H),
2.76 (m, 1H), 3.25 (m, 1H), 3.38 (syn, d, J=1.5 Hz, 1H) + 3.45 (anti, d,
J=2.5 Hz, 1H), 3.57 3.81 (m, 9H), 3.99 (m, 1H), 7.14 7.20 (m, 3H),
7.25 7.29 (m, 2H); 13C NMR (CDCl3): d = 24.8, 24.9, 31.5, 36.8, 37.3,
1537
Chem. Eur. J. 2004, 10, 1527 1544
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

M. Shibasaki et al.
FULL PAPER
37.8, 42.2, 45.2, 53.3, 55.0, 63.3, 65.6, 66.7, 100.4, 125.80, 128.3, 128.4,
141.8, 166.0 (for 37); HRMS (FAB+): m/z: calcd for C22H32O5N:
390.2280, found 390.2282; HPLC conditions (column: DAICEL CHIR-
ALPAK AS-H, hexane/isopropanol 4:1, flow rate: 1.0 mLminꢀ1, detec-
tor: 254 nm, tR (31) = 39.6 min, (37) = 32.5 min).
flow rate: 1.0 mLminꢀ1, detector: 254 nm, tR (40) = 30.6 min, (44) =
34.3 min, (45) = 38.5 min).
Ethyl (3R,5R,7S,9S)-3,5-dihydroxy-7,9-isopropylidenedioxy-11-phenylun-
decanoate (45): A mixture of 44 and 45 (44:45 4:96); [a]2D2 = +5.9 (c =
1.15, CHCl3); IR (neat): n˜
= 3421, 2985, 2938, 1732, 1379, 1223,
4-[(2R,3S,5S,7S)-2,3-Epoxy-5,7-isopropylidenedioxy-1-oxo-9-phenylno-
nyl]morpholine (36): A mixture of 36 and 30 (36:30 9:1); [a]2D2 = +8.2
1163 cmꢀ1 1H NMR (CDCl3): d = 1.27 (t, J=7.0 Hz, 3H), 1.33 (s, 3H),
;
1.38 (s, 3H), 1.58 (m, 1H), 1.63 (m, 3H), 1.69 1.78 (m, 3H), 1.84 (m,
1H), 2.50 2.53 (m, 2H), 2.62 (m, 1H), 2.76 (m, 1H), 3.26 (d, J=5.0 Hz,
1H), 3.46 (d, J=4.0 Hz, 1H), 3.77 (m, 1H), 4.07 4.23 (m, 4H), 4.34 (m,
1H), 7.14 7.20 (m, 3H), 7.26 7.29 (m, 2H); 13C NMR (CDCl3): d = 14.1,
24.80, 24.89, 31.6, 37.4, 37.9, 41.4, 41.6, 42.3, 60.6, 64.4, 65.6, 65.8, 65.9,
100.5, 125.7, 128.3, 128.4, 141.8, 172.7; HRMS (FAB+): m/z: calcd for
C22H35O6: 395.2434, found 395.2394; HPLC conditions (column: SHISEI-
DO SILICA SG80 4.6 mm1î250 mm, hexane/isopropanol 98:2, flow
(c
= 1.00, CHCl3); IR (neat): n˜ = 2984, 2920, 2857, 1653, 1240,
1114 cmꢀ1; H NMR (CDCl3): d = 1.25 1.40 (m, 7H), 1.52 1.90 (m, 5H),
2.62 (m, 1H), 2.76 (m, 1H), 3.24 (m, 1H), 3.37 (anti acetonide) + 3.46
(syn acetonide) (m, 1H), 3.55 3.83 (m, 9H), 3.96 (syn acetonide) + 4.06
(anti acetonide) (m, 1H), 7.16 7.22 (m, 3H), 7.25 7.31 (m, 2H); 13C
NMR (CDCl3): d = 24.8, 24.9, 31.5, 37.3, 38.4, 38.5, 42.3, 45.2, 54.2, 55.6,
64.0, 65.6, 66.7, 100.5, 125.7, 128.2, 128.4, 141.8, 165.9; HRMS (FAB+):
m/z: calcd for C22H32O5N: 390.2280, found 390.2278; HPLC conditions
(column: DAICEL CHIRALPAK AS-H, hexane/isopropanol 4:1, flow
1
rate: 1.0 mLminꢀ1
38.5 min).
, detector: 254 nm, tR (44) = 34.3 min, (45) =
rate: 1.0 mLminꢀ1
40.8 min).
, detector: 254 nm, tR (30) = 55.3 min, (36) =
Ethyl (3R,5S,7S,9S)-3,5-dihydroxy-7,9-isopropylidenedioxy-11-phenylun-
decanoate (46): A mixture of 46:47 (46:47 >99.5:0.5); [a]2D3 = +11.7 (c
1.30, CHCl3); IR (neat): n˜
= 3445, 2985, 2938, 1732, 1379, 1223,
Ethyl (4S,5R,7S,9S)-4,5-epoxy-7,9-isopropylidenedioxy-3-oxo-11-phenyl-
undecanoate: Prepared from a mixture of 37 and 31 (37:31 9:1); [a]D23
ꢀ14.6 (c = 1.04, CHCl3); IR (neat): n˜ = 2986, 2937, 1743, 1720, 1380,
1224, 1029 cmꢀ1 1H NMR (CDCl3): d = 1.25 1.31 (m, 3H), 1.32 1.44
(m, 6H), 1.60 1.92 (m, 6H), 2.62 (m, 1H), 2.75 (m, 1H), 3.17 3.42 (m,
4H), 3.78 (m, 1H), 3.98 (m, 1H), 4.19 (m, 2H), 7.16 7.21 (m, 3H), 7.26
7.30 (m, 2H); 13C NMR (CDCl3): d = 14.0, 24.6, 24.7, 31.5, 37.2, 37.3,
37.9, 43.7, 55.3, 58.7, 61.5, 63.7, 65.5, 100.5, 125.7, 128.2, 128.4, 141.8,
165.5, 199.8; HRMS (FAB+): m/z: calcd for C22H31O6: 391.2121, found
391.2119.
1161 cmꢀ1 1H NMR (CDCl3): d = 1.26 (t, J=7.0 Hz, 3H), 1.33 (s, 3H),
;
=
1.41 (s, 3H), 1.50 1.66 (m, 6H), 1.73 (m, 1H), 1.84 (m, 1H), 2.44 (dd, J=
4.9, 15.9 Hz, 1H), 2.52 (dd, J=7.7, 15.9 Hz, 1H), 2.60 (m, 1H), 2.75 (m,
1H), 3.77 (m, 1H), 3.94 (s, 2H), 4.04 4.13 (m, 2H), 4.16 (q, J=7.0 Hz,
2H), 4.27 (m, 1H), 7.15 7.20 (m, 3H), 7.25 7.30 (m, 2H); 13C NMR
(CDCl3): d = 14.1, 24.7, 25.0, 31.5, 37.3, 38.6, 41.8, 42.6, 42.8, 60.5, 65.6,
67.6, 68.1, 71.8, 100.6, 125.8, 128.3, 128.4, 141.8, 172.2; HRMS (FAB+):
m/z: calcd for C22H35O6: 395.2434, found 395.2409; HPLC conditions
(column: SHISEIDO SILICA SG80 4.6 mm1î250 mm, hexane/isopro-
panol 98:2, flow rate: 1.0 mLminꢀ1, detector: 254 nm, tR (46) = 30.2 min,
(47) = 34.0 min).
;
Ethyl (4R,5S,7S,9S)-4,5-epoxy-7,9-isopropylidenedioxy-3-oxo-11-phenyl-
undecanoate: Prepared from a mixture of 36 and 30 (36:30 9:1); [a]D22
=
Ethyl (3S,5S,7S,9S)-3,5-dihydroxy-7,9-isopropylidenedioxy-11-phenylun-
+37.9 (c = 1.14, CHCl3); IR (neat): n˜ = 2986, 2937, 1745, 1719, 1380,
decanoate (47): A mixture of 47, 46 and 43 (47:46:43 92:1:7); [a]D23
=
1
1224 cmꢀ1; H NMR (CDCl3): d = 1.25 1.45 (m, 9H), 1.56 1.93 (m, 6H),
+22.8 (c = 1.30, CHCl3); IR (neat): n˜ = 3425, 2984, 2938, 1733, 1379,
2.62 (m, 1H), 2.76 (m, 1H), 3.13 3.45 (m, 4H), 3.78 (m, 1H), 4.05 (m,
1H), 4.22 (m, 2H), 7.16 7.22 (m, 3H), 7.26 7.32 (m, 2H); 13C NMR
(CDCl3): d = 14.0, 24.7, 24.8, 31.5, 37.3, 38.2, 38.4, 43.8, 100.6, 125.8,
128.3, 128.4, 141.8, 166.5, 199.7; HRMS (FAB+): m/z: calcd for
C22H32O6: 391.2121, found 391.2219.
1223, 1161 cmꢀ1 1H NMR (CDCl3): d = 1.26 (t, J=7.0 Hz, 3H), 1.33 (s,
;
3H), 1.41 (s, 3H), 1.54 1.68 (m, 6H), 1.74 (m, 1H), 1.85 (m, 1H), 2.51
(m, 2H), 2.62 (m, 1H), 2.76 (m, 1H), 3.60 (m, 1H), 3.75 3.82 (m, 2H),
4.07 4.19 (m, 4H), 4.34 (m, 1H), 7.14 7.22 (m, 3H), 7.26 7.32 (m, 2H);
13C NMR (CDCl3): d = 14.1, 24.7, 25.0, 31.5, 37.3, 38.7, 41.7, 42.2, 42.6,
60.5, 65.3, 65.6, 68.0, 69.4, 100.6, 125.8, 128.3, 128.4, 141.7, 172.5; HRMS
(FAB+): m/z: calcd for C22H35O6: 395.2434, found 395.2408; HPLC con-
ditions (column: SHISEIDO SILICA SG80 4.6 mm1î250 mm, hexane/
isopropanol 98:2, flow rate: 1.0 mLminꢀ1, detector: 254 nm, tR (43) =
36.4 min, (46) = 30.2 min, (47) = 34.0 min).
Ethyl (5S,7S,9S)-5-hydroxy-7,9-isopropylidenedioxy-3-oxo-11-phenylun-
decanoate: A mixture of (7S,9S)-isomer and (7R,9S)-isomer ((7S,9S)-iso-
mer:(7R,9S)-isomer 9:1); [a]D21 = +30.0 (c 1.06, CHCl3); IR (neat): n˜ =
3446, 2985, 2938, 1741, 1715, 1380, 1223 cmꢀ1 1H NMR (CDCl3): d =
;
1.26 1.44 (m, 10H), 1.55 1.78 (m, 4H), 1.84 (m, 1H), 2.62 (m, 1H), 2.71
2.80 (m, 3H), 3.16 (d, J=4.0 Hz, 1H), 3.46 3.50 (m, 2H), 3.76 (m, 1H),
4.10 4.24 (m, 1H), 4.30 (m, 1H), 7.16 7.22 (m, 3H), 7.26 7.29 (m, 2H);
13C NMR (CDCl3): d = 14.0, 24.80, 24.83, 31.6, 37.4, 38.1, 41.4, 49.7, 49.9,
61.4, 63.8, 64.7, 65.8, 100.5, 125.7, 128.2, 128.4, 141.8, 166.9, 203.1; HRMS
(FAB+): m/z: calcd for C22H33O6: 393.2277, found 393.2262.
Application to natural product synthesis (1): Triol
4-[(E)-1-Oxo-7-phenyl-2-heptenyl]morpholine (48): Pale yellow oil; IR
(neat): n˜ = 2926, 2855, 1658, 1620, 1432, 1268, 1230, 1116, 975, 749,
701 cmꢀ1 1H NMR (CDCl3): d = 7.29 7.26 (m, 2H), 7.19 7.15 (m, 3H),
;
6.89 (dt, J=15.0, 7.0 Hz, 1H), 6.17 (d, J=15.0 Hz, 1H), 3.67 3.39 (m,
8H), 2.62 (t, J=7.5 Hz, 2H), 2.25 2.21 (m, 2H), 1.68 1.62 (m, 2H), 1.54
1.48 (m, 2H); 13C NMR (CDCl3): d = 165.6, 146.9, 142.2, 128.3, 128.2,
125.7, 119.5, 66.8, 46.0, 42.2, 36.7, 32.4, 31.0, 27.8; LRMS (EI+): m/z:
273 [M +]; HRMS (FAB+): m/z: calcd for C17H24O2N: 274.1807, found
274.1805.
Ethyl (5R,7S,9S)-5-hydroxy-7,9-isopropylidenedioxy-3-oxo-11-phenylun-
decanoate: A mixture of (7S,9S)-isomer and (7R,9S)-isomer ((7S,9S)-iso-
mer:(7R,9S)-isomer 9:1); [a]D24 = +11.3 (c = 1.15, CHCl3); IR (neat): n˜
= 3461, 2985, 2938, 1742, 1715, 1380, 1224 cmꢀ1 1H NMR (CDCl3): d =
;
1.27 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 1.40 (s, 3H), 1.59 1.76 (m, 5H), 1.83
(m, 1H), 2.61 (m, 2H), 2.74 (m, 2H), 3.49 (s, 2H), 3.60 (s, 1H), 3.76 (m,
1H), 4.10 (m, 1H), 4.19 (q, J=7.0 Hz, 2H), 4.25 (m, 1H), 7.16 7.20 (m,
3H), 7.26 7.30 (m, 2H); 13C NMR (CDCl3): d = 14.0, 24.7, 24.9, 31.5,
37.3, 38.5, 41.8, 49.8, 50.1, 61.3, 65.6, 67.0, 67.6, 100.6, 127.7, 128.3, 128.4,
167.0, 202.3; HRMS (FAB+): m/z: calcd for C22H31O6: 391.2121, found
391.2119.
(2S,3R)-2,3-Epoxy-1-oxo-7-phenylheptyl]morpholine (49): colorless oil;
[a]2D4
=
+20.0 (c = 0.79, CHCl3, 99% ee); IR (neat): n˜ = 2928, 2857,
1659, 1465, 1274, 1239, 749, 701 cmꢀ1 1H NMR (CDCl3): d = 7.29 7.26
;
(m, 2H), 7.19 7.16 (m, 3H), 3.69 3.56 (m, 8H), 3.33 (d, J=2.1 Hz, 1H),
3.15 (ddd, J=6.4, 4.6, 2.1 Hz, 1H), 2.63 (t, J=7.6 Hz, 2H), 1.72 1.48 (m,
6H); 13C NMR (CDCl3): d = 166.1, 142.1, 128.3, 128.3, 125.8, 66.7, 58.2,
53.9, 45.3, 42.3, 35.7, 31.4, 31.0, 25.4; LRMS (EI+): m/z: 289 [M +];
HRMS (FAB+): m/z: calcd for C17H24O3N 290.1756, found 290.1758;
HPLC conditions (column: DAICEL CHIRALPAK AS-H, isopropanol/
hexane 1:4, flow rate: 1.0 mLminꢀ1, detector: 254 nm, tR [(2S,3R)-isomer]
= 32.3 min, [(2R,3S)-isomer] = 58.1 min).
Ethyl (3S,5R,7S,9S)-3,5-dihydroxy-7,9-isopropylidenedioxy-11-phenylun-
decanoate (44): A mixture of 44, 45 and 40 (44:45:40 91:1:8); [a]2D3 = +
15.9 (c = 1.50, CHCl3); IR (neat): n˜ = 3421, 2985, 2938, 1733, 1379,
1223, 1161 cmꢀ1 1H NMR (CDCl3): d = 1.27 (t, J=7.0 Hz, 3H), 1.33 (s,
;
3H), 1.39 (s, 3H), 1.54 1.70 (m, 6H), 1.74 (m, 1H), 1.85 (m, 1H), 2.45
(dd, J=4.6, 16.2 Hz, 1H), 2.51 (dd, J=8.1, 16.2 Hz, 1H), 2.61 (m, 1H),
2.76 (m, 1H), 3.69 (s, 1H), 3.77 (m, 1H), 3.93 (s, 1H), 4.05 4.20 (m, 4H),
4.28 (m, 1H), 7.16 7.19 (m, 3H), 7.24 7.29 (m, 2H); 13C NMR (CDCl3):
d = 14.1, 24.8, 24.9, 31.6, 37.4, 38.1, 41.8, 42.1, 42.4, 60.6, 64.1, 65.8, 68.7,
69.1, 100.5, 125.7, 128.3, 128.4, 141.8, 172.3; HRMS (FAB+): m/z: calcd
for C22H35O6: 395.2434, found 395.2393; HPLC conditions (column: SHI-
SEIDO SILICA SG80 4.6 mm1î250 mm, hexane/isopropanol 98:2,
(4S,5R)-4,5-Epoxy-N-methoxy-N-methyl-3-oxo-9-phenylnonanamide
(50): LHMDS (0.25 mL, 0.25 mmol, 1.0m solution in THF) was added at
ꢀ788C to a stirred solution of N-methoxy-N-methylacetoamide (28 mL,
0.263 mmol) in THF(0.75 mL). After stirring for 20 min, a THFsolution
of 49 (30.5 mg, 0.105 mmol in 0.4 mL THF) was added to the reaction
mixture at the same temperature. The reaction was slowly warmed to
1538
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 1527 1544

1,3-Polyol Arrays
1527 1544
ꢀ508C over a period of 1 h and stirred for 70 h. The reaction was
quenched with saturated aqueous NH4Cl. The aqueous layer was extract-
ed with ethyl acetate (2î5 mL) and the combined organic layers were
washed with brine, and dried over Na2SO4. After concentration in vacuo,
the residue was purified by flash column chromatography (silica gel,
hexane/ethyl acetate 3:1) to give 50 [19.3 mg, 60% (conv. 85%)] as a
pale yellow oil, with recovery of 49 (8.7 mg, 29%). [a]2D6 = ꢀ21.1 (c =
0.87, CHCl3, 99% ee); IR (neat): n˜ =2936, 2858, 1724, 1643, 1454, 1359,
centration in vacuo, the residue was purified by flash column chromatog-
raphy (silica gel, hexane/ethyl acetate 20:1) to give the title compound
(64.2 mg, 87%) as colorless oil. [a]3D0 = ꢀ2.1 (c 1.36, CHCl3, 99% ee); IR
(neat): n˜ = 2934, 2857, 1715, 1454, 1346, 1128, 1026, 921, 752, 699 cmꢀ1
;
1H NMR (CDCl3): d = 7.45 (m, 2H), 7.37 7.29 (m, 5H), 7.18 (m, 3H),
5.92 (ddt, 17.5, 10.5, 7 Hz, 1H), 5.53 (s, 1H), 5.20 (dd, J=10.5, 1.5 Hz,
1H), 5.14 (dd, J=17.5, 1.5 Hz, 1H), 4.32 (m, 1H), 3.83 (m, 1H), 3.24
(ddd, J=7, 1.5, 1.5 Hz, 2H), 2.89 (dd, J=16, 6.5 Hz, 1H), 2.63 (t, J=
7.5 Hz, 2H), 2.57 (dd, J=16, 6 Hz, 1H), 1.72 1.35 (m, 8H); 13C NMR
(CDCl3): d = 206.4, 142.5, 138.5, 130.1, 128.6, 128.4, 128.2, 128.1, 126.0,
125.6, 119.1, 100.5, 76.6, 73.0, 48.8, 48.2, 36.7, 35.8, 35.6, 31.4, 24.6; LRMS
(EI+): m/z: 378 [M +]; HRMS (FAB+): m/z: calcd for C25H31O3:
379.2273, found 379.2276.
1
1185, 1009, 749, 701 cmꢀ1; H NMR (CDCl3): d = 7.27 (m, 2H), 7.17 (m,
3H), 3.66 (s, 3H), 3.59 (d, J=16 Hz, 1H), 3.41 (d, J=16 Hz, 1H), 3.30
(d, J=1.5 Hz, 1H), 3.20 (s, 3H), 3.15 (m, 1H), 2.62 (t, J=7.5 Hz, 2H),
1.74 1.46 (m, 6H); 13C NMR (CDCl3): d = 200.9, 167.6, 142.0, 128.34,
128.29, 125.8, 61.3, 59.6, 58.1, 42.3, 35.6, 32.1, 31.6, 30.9, 25.3; LRMS
(EI+): m/z: 305 [M +]; HRMS (FAB+): m/z: calcd for C17H24O4N:
306.1705, found 306.1718.
(aS,2R,4S,6R)-2-Phenyl-6-(4-phenylbutyl)-a-2-propenyl-1,3-dioxane-4-
ethanol (52): L-Selectride (0.117 mL, 0.117 mmol, 1.0m solution in THF)
was added at ꢀ1008C to a stirred solution of the allylketone prepared
above (22.2 mg, 0.0586 mmol) in THF(0.6 mL). After stirring for 2 h at
the same temperature, the reaction was quenched with H2O2 (30 wt.%
solution in water) and 1m NaOH. The mixture was allowed to warm to
room temperature and diluted with Et2O. The aqueous layer was extract-
ed with Et2O (2î3 mL) and the combined organic layers were washed
with 2% aqueous Na2S2O3, brine, and then dried over Na2SO4. After con-
centration in vacuo, the residue was purified by flash column chromatog-
raphy (silica gel, hexane/ethyl acetate 10:1) to give 52 [13.3 mg, 60%
(conv. 97%), inseparable mixture of syn,syn- and syn,anti-diastereomer
(7:1)] as colorless oil. [a]D23 = ꢀ0.93 (c = 1.40, CHCl3, 99% ee, 7:1 mix-
ture of syn,syn- and syn,anti-diastereomer); IR (neat): n˜ = 3522, 2935,
(5R)-5-Hydroxy-N-methoxy-N-methyl-3-oxo-9-phenylnonanamide: PhSe-
SePh (936 mg, 3.00 mmol) was added at 08C to a stirred suspension of
NaBH4 (227 mg, 6.00 mmol) in EtOH (5 mL). The reaction was allowed
to warm to room temperature, and then stirred for 20 min. A solution of
50 (305 mg, 1.00 mmol) in EtOH (3 mL) was added to the reaction mix-
ture. After stirring for 10 min, the reaction was diluted with ethyl acetate
and poured into water. The aqueous layer was extracted with ethyl ace-
tate (2î10 mL) and the combined organic layers were washed with
brine, and then dried over Na2SO4. After concentration in vacuo, the resi-
due was purified by flash column chromatography (silica gel, hexane/
ethyl acetate 1:2) to give the title compound (259 mg, 84%) as a pale
yellow oil. [a]2D7 = ꢀ18.8 (c = 1.21, CHCl3, 99% ee); IR (neat): n˜
=
3429, 2934, 1715, 1650, 1454, 1194, 749, 701 cmꢀ1; H NMR (CDCl3): d =
7.28 (m, 2H), 7.18 (m, 3H), 4.08 (m, 1H), 3.68 (s, 3H), 3.61 (s, 2H), 3.22
(s, 3H), 2.72 2.62 (m, 4H), 1.68 1.39 (m, 6H); 13C NMR (CDCl3): d =
204.8, 167.8, 142.5, 128.3, 128.2, 125.6, 67.5, 61.4, 49.8, 48.2, 36.3, 35.8,
32.0, 31.3, 25.1; LRMS (EI+): m/z: 307 [M +]; HRMS (FAB+): m/z:
calcd for C17H26O4N: 308.1862, found 308.1874.
2857, 1454, 1342, 1104, 1026, 914, 752, 698 cmꢀ1 1H NMR (CDCl3):
;
1
syn,syn-diastereomer: d = 7.46 (m, 2H), 7.36 7.27 (m, 5H), 7.18 (m,
3H), 5.84 (ddt, J=17.5, 10.5, 7 Hz), 5.55 (s, 1H), 5.12 (m, 2H), 4.08 (m,
1H), 3.97 (m, 1H), 3.82 (m, 1H), 2.63 (t, J=7.5 Hz, 2H), 2.26 (m, 2H),
1.80 1.43 (m, 10H); 13C NMR (CDCl3): syn,syn-diastereomer: d = 142.5,
138.3, 134.7, 128.7, 128.4, 128.3, 128.2, 126.0, 125.6, 117.6, 100.6, 77.3,
76.8, 70.4, 42.0, 37.1, 35.8, 35.6, 31.4, 24.6; LRMS (EI+): m/z: 380 [M +];
HRMS (FAB+): m/z: calcd for C25H33O3: 381.2430, found 381.2428.
(2R,4R,6R)-N-Methoxy-N-methyl-2-phenyl-6-(4-phenylbutyl)-1,3-diox-
ane-4-acetamide (51): BEt2(OMe) (0.45 mL, 0.45 mmol, 1.0m solution in
THF) was added at ꢀ788C to a stirred solution of (5R)-5-hydroxy-N-me-
thoxy-N-methyl-3-oxo-9-phenylnonanamide (69.1 mg, 0.225 mmol) in
(S)-1-[[(2R,4R,6R)-2-Phenyl-6-(4-phenylbutyl)-1,3-dioxan-4-yl]methyl]-
3-butenyl 2-propenoate: Acryloyl chloride (9.0 mL, 0.11 mmol) and
iPr2NEt (20 mL, 0.115 mmol) were added at 08C to a stirred solution of
52 (21.1 mg, 0.0554 mmol) in CH2Cl2 (0.55 mL). The mixture was allowed
to warm to room temperature and stirred for 3 h. The reaction was dilut-
ed with Et2O and poured into saturated aqueous NaHCO3. The aqueous
layer was extracted with ether and the combined organic layers were
washed with brine, and then dried over Na2SO4. After concentration in
vacuo, the residue was purified by flash column chromatography (silica
gel, hexane/ethyl acetate 25:1) to give the title compound (21.8 mg, 91%,
inseparable mixture of syn,syn- and syn,anti-diastereomer) as a colorless
oil. [a]2D3 = +4.6 (c = 1.09, CHCl3, 99% ee, mixture of syn,syn- and syn,-
anti-diastereomer). IR (neat):n˜ = 2934, 2857, 1721, 1404, 1194, 1026,
THF(1.3 mL) and MeOH (0.44 mL). After stirring for 15 min, NaBH
4
(30 mg, 0.79 mmol) was added and stirred for 5 h at the same tempera-
ture. The reaction was quenched with water and the aqueous layer was
extracted with ethyl acetate (2î10 mL). The combined organic layers
were washed with brine, and then dried over Na2SO4. After concentra-
tion in vacuo, the residue was azeotroped a few times with MeOH to
give crude diol. To a solution of the crude diol in toluene (1.0 mL) was
added benzaldehyde dimethyl acetal (0.084 mL, 0.563 mmol) and PPTS
(2.8 mg, 0.011 mmol) at room temperature, and then the mixture was
heated to reflux. After stirring for 10 h, the reaction was diluted with
ether and poured into saturated aqueous NaHCO3. The aqueous layer
was extracted with diethyl ether (2î5 mL) and the combined organic
layers were washed with brine, and then dried over Na2SO4. After con-
centration in vacuo, the residue was purified by flash column chromatog-
raphy (silica gel, hexane/ethyl acetate 5:1) to give 51 (66.2 mg, 74% in 2
699 cmꢀ1 1H NMR (CDCl3): syn,syn-diastereomer: d = 7.40 (m, 2H),
;
7.28 7.18 (m, 5H), 7.10 (m, 3H), 6.30 (dd, J=17.5, 1.5 Hz, 1H), 6.01 (dd,
J=17.5, 10.5 Hz, 1H), 5.73 (dd, J=10.5, 1.5 Hz, 1H), 5.70 (ddt, J=17.5,
10.5, 7 Hz, 1H), 5.40 (s, 1H), 5.14 (m, 1H), 5.02 (m, 2H), 3.83 (m, 1H),
3.70 (m, 1H), 2.55 (t, J=7.5 Hz, 2H), 2.00 (m, 1H), 1.70 (m, 1H), 1.63
1.29 (m, 8H); 13C NMR (CDCl3): syn,syn-diastereomer: d = 165.7, 142.6,
138.7, 133.2, 130.7, 128.6, 128.5, 128.4, 128.2, 128.1, 126.1, 125.6, 118.2,
100.6, 76.6, 74.0, 70.4, 39.8, 38.9, 36.8, 35.8, 35.7, 31.4, 24.7; LRMS (EI+):
m/z: 434 [M +]; HRMS (FAB+): m/z: calcd for C28H35O4: 435.2535,
found 435.2526.
steps) as yellow oil. [a]D27
(neat): n˜ = 2936, 2857, 1661, 1454, 1343, 1120, 1026, 752, 700 cmꢀ1
=
+21.8 (c
=
0.92, CHCl3, 99% ee); IR
;
1H
NMR (CDCl3): d = 7.48 (m, 2H), 7.36 7.27 (m, 5H), 7.18 (m, 3H), 5.56
(s, 1H), 4.38 (m, 1H), 3.85 (m, 1H), 3.68 (s, 3H), 3.20 (s, 3H), 2.98 (dd,
J=17.5, 5.5 Hz, 1H), 2.63 (t, J=7.5 Hz, 2H), 2.55 (dd, J=17.5, 6 Hz,
1H), 1.81 1.40 (m, 8H); 13C NMR (CDCl3): d = 171.4, 142.6, 138.7,
128.5, 128.4, 128.2, 128.1, 126.1, 125.6, 100.6, 76.6, 73.5, 61.4, 38.2, 37.0,
35.8, 35.7, 32.0, 31.4, 24.7; LRMS (EI+): m/z: 397 [M +]; HRMS (FAB+):
m/z: calcd for C17H24O4N: 398.2331, found 398.2321; HPLC conditions
(column: DAICEL CHIRALPAK AD-H, iPrOH/hexane 1:9, flow rate:
1.0 mLminꢀ1, detector 254 nm, tR [(4S,6S)-isomer] = 7.9 min, [(4R,6R)-
isomer] =) = 10.0 min).
(6S)-5,6-Dihydro-6-[[(2R,4R,6R)-2-phenyl-6-(4-phenylbutyl)-1,3-dioxan-
4-yl]methyl]-2H-pyran-2-one (53): The acryloyl ester prepared above
(19.9 mg, 0.0458 mmol) was dissolved in CH2Cl2 (6.5 mL). After degass-
ing, Grubbs× catalyst (1.5 mg, 1.8 mmol) was added to the mixture at
room temperature. The reaction was heated to reflux for 9 h. After the
solvent being removed, the resulting residue was purified by flash
column chromatography (silica gel, hexane/ethyl acetate 4:1) to give 53
(15.7 mg, 84%, a separable mixture of 53 and 6-epi-53) as a colorless oil.
The mixture was purified by preparative thin-layer chromatography and
53 and 6-epi-53 were isolated as a colorless oil (53: 13.0 mg, 70%; 6-epi-
53: 1.5 mg, 8%). 53: [a]2D7 = ꢀ47.6 (c 1.21, CHCl3, 99% ee); IR (neat): n˜
1-[(2R,4R,6R)-2-Phenyl-6-(4-phenylbutyl)-1,3-dioxan-4-yl]-4-penten-2-
one: Allylmagnesium bromide (0.39 mL, 0.39 mmol, 1.0m solution in
Et2O) was added at 08C to a stirred solution of 51 (77.9 mg, 0.196 mmol)
in THF(1.6 mL). After stirring for 30 min at the same temperature, the
reaction was quenched with saturated aqueous NH4Cl. The aqueous layer
was extracted with ethyl acetate (2î4 mL) and the combined organic
layers were washed with brine, and then dried over Na2SO4. After con-
= 2929, 2857, 1730, 1245, 1119, 1026, 699 cmꢀ1 1H NMR (CDCl3): d =
;
7.46 (m, 2H), 7.38 7.24 (m, 5H), 7.18 (m, 3H), 6.90 (m, 1H), 6.04 (dd,
1539
Chem. Eur. J. 2004, 10, 1527 1544
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

M. Shibasaki et al.
FULL PAPER
J=10, 1.5 Hz, 1H), 5.52 (s, 1H), 4.68 (m, 1H), 4.16 (m, 1H), 3.83 (m,
1H), 2.63 (t, J=7.5 Hz, 2H), 2.55 2.39 (m, 2H), 2.22 (m, 1H), 1.92 (m,
1H), 1.73 1.43 (m, 8H); 13C NMR (CDCl3): d = 164.3, 145.3, 142.5,
138.6, 128.6, 128.4, 128.2, 128.1, 126.0, 125.6, 121.2, 100.5, 77.2, 74.6, 72.5,
40.3, 36.5, 35.8, 35.7, 31.4, 29.3, 24.7; LRMS (EI+): m/z: 406 [M +];
HRMS (FAB+): m/z: calcd for C26H31O4: 407.2222, found 407.2220.
(6R)-6-[(2R,4R)-2,4-Diacetoxy-8-phenyloctyl]-5,6-dihydro-2H-pyran-2-
one (6-epi-56): [a]2D2 = +17.8 (c = 0.18, CHCl3, 99% ee); IR (neat): n˜
= 2931, 1731, 1373, 1240, 1023 cmꢀ1 1H NMR (CDCl3): d = 7.27 (m,
;
2H), 7.19 (m, 3H), 6.85 (ddd, J=10, 5.5, 3 Hz, 1H), 6.02 (dd, J=10,
1.5 Hz, 1H), 5.14 (m, 1H), 4.92 (m, 1H), 4.48 (m, 1H), 2.60 (t, J=7.5 Hz,
2H), 2.35 2.31 (m, 2H), 2.10 1.78 (m, 4H), 2.04 (s, 3H), 2.04 (s, 3H),
1.60 (m, 4H), 1.32 (m, 2H); 13C NMR (CDCl3): d = 170.8, 170.3, 163.6,
144.5, 142.3, 128.4, 128.3, 125.7, 121.6, 74.5, 70.7, 68.0, 39.4, 38.8, 35.7,
34.0, 31.1, 29.6, 24.7, 21.2, 21.2; LRMS (EI+): m/z: 402 [M +]; HRMS
(FAB+): m/z: calcd for C23H31O6: 403.2121, found 403.2108.
(6S)-6-[(2R,4R)-2-Acetoxy-4-hydroxy-8-phenyloctyl]-5,6-dihydro-2H-
pyran-2-one (54), (6S)-6-[(2R,4R)-4-acetoxy-2-hydroxy-8-phenyloctyl]-
5,6-dihydro-2H-pyran-2-one (55): Compound 53 (9.0 mg, 0.022 mmol)
was dissolved in an 80% solution of AcOH (0.5 mL) and the solution
was heated to 608C. After stirring for 5 h, the reaction was diluted with
ethyl acetate and then poured into saturated aqueous NaHCO3. The
aqueous layer was extracted with ethyl acetate and the combined organic
layers were washed with brine, and then dried over Na2SO4. After con-
centration in vacuo, crude diol was obtained. To a stirred solution of the
crude diol in CH2Cl2 (0.2 mL) was added triethyl orthoacetate (10 mL,
0.055 mmol) and PPTS (0.5 mg, 2 mmol) at room temperature. After the
reaction being stirred until all of the starting material was consumed
(1 h), water (1 mL) was added to the reaction and the mixture was stirred
for 1 h. The reaction mixture was directly purified by flash column chro-
matography (silica gel, hexane/ethyl acetate 1:1) to give a mixture of 54
and 55 (6.0 mg, 76% in 2 steps) as a yellow oil. [a]2D6 = ꢀ29.7 (c = 0.60,
MeOH, 99% ee, a mixture of synthetic 54 and 55) (lit.[53]: [a]D = +35 (c
= 0.05, MeOH) for 54 and [a]D = +35 (c = 0.05, MeOH) for 55); IR
(3S,5S)-3,5-Isopropylidenedioxy-7-phenyl-1-heptanol (57): TsOH¥H2O
(1.6 mg, 0.008 mmol) was added at room temperature to a stirred solu-
tion of anti-24a (22.8 mg, 0.086 mmol) in dimethoxypropane (0.6 mL).
After 2 h, the reaction was diluted with ethyl acetate (10 mL). The solu-
tion was washed with saturated aqueous NaHCO3 and brine, and then
dried over Na2SO4. After concentration in vacuo, the residue was purified
by flash column chromatography (silica gel, hexane/ethyl acetate 30:1) to
give anti-25a (25.2 mg, 96%). To a suspension of lithium aluminum hy-
dride (6.6 mg, 0.175 mmol) in THF(0.3 mL) was added a solution of
anti-25a (22.4 mg, 0.073 mmol) in THF(0.7 mL) at 0 8C. After stirring
for 1 h, the reaction was quenched with excess MeOH, and diluted with
ethyl acetate. The mixture was washed with 0.1n aqueous HCl, saturated
aqueous NaHCO3, brine, and then dried over Na2SO4. After concentra-
tion in vacuo, the residue was purified by flash column chromatography
(silica gel, hexane/ethyl acetate 2:1) to give alcohol 57 as a colorless oil
(18.6 mg, 96%).
(neat): n˜ = 3453, 2933, 1730, 1375, 1246, 1035 cmꢀ1 1H NMR (CDCl3):
;
54: d = 7.27 (m, 2H), 7.18 (m, 3H), 6.89 (m, 1H), 6.02 (d, J=9.5 Hz,
1H), 4.95 (m, 1H), 4.65 (m, 1H), 3.89 (m, 1H), 2.61 (t, J=7.5 Hz, 2H),
2.41 (m, 2H), 2.20 1.31 (m, 10H), 2.04 (s, 3H); 13C NMR (CDCl3): 54: d
= 171.3, 163.8, 145.2, 142.3, 128.4, 128.3, 125.7, 121.3, 76.7, 72.4, 67.1,
42.3, 41.7, 35.7, 34.6, 31.1, 29.4, 24.8, 21.3; 1H NMR (CDCl3): 55: d =
7.27 (m, 2H), 7.18 (m, 3H), 6.89 (m, 1H), 6.02 (d, J=9.5 Hz, 1H), 5.23
(m, 1H), 4.51 (m, 1H), 3.70 (m, 1H), 2.62 (t, J=7.5 Hz, 2H), 2.42 2.22
(m, 2H), 2.20 1.31 (m, 10H), 2.06 (s, 3H); 13C NMR (CDCl3): 55: d =
171.3, 163.8, 144.7, 142.3, 128.4, 128.3, 125.7, 121.4, 75.1, 69.2, 69.0, 41.7,
39.3, 37.7, 35.8, 31.3, 29.2, 25.0, 21.3; LRMS (EI+): m/z: 360 [M +];
HRMS (FAB+): m/z: calcd for C21H28O5: 361.2015, found 361.2019.
The spectral data were identical to the reported data.[58] [a]D23
= +23.1
(c = 1.07, CHCl3, 99% ee) (lit.[58] [a]D25 = +24.9 (c = 1.70, CHCl3)).
Application to natural product synthesis (2): Tetraol
4-[(2R,3S)-2,3-Epoxy-1-oxobutyl]morpholine (60): Sm(OiPr)3 (2.1 mL,
0.42 mmol, 0.2m in THF) was added at room temperature to a mixture of
(S)-BINOL (120 mg, 0.42 mmol), triphenylarsine oxide (135 mg,
0.42 mmol) and MS 4 ä (8.38 g; MS 4 ä was not dried. 1000 mg per
1 mmol of starting material) in THF(32 mL). After stirring for 40 min at
the same temperature, TBHP (2.0 mL, 10.1 mmol, 5m in decane) was
added. After 10 min, 59 (1.3 g, 8.38 mmol) in THF(8 mL) was added.
The reaction mixture was stirred for 8 h at the same temperature, and
the reaction mixture was filtered and the filtrate was diluted with ethyl
acetate (80 mL). The resulting mixture was washed with 2% aqueous
citric acid, saturated aqueous sodium thiosulfate and brine. The com-
bined organic layers were dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by column chromatography (silica gel,
hexane/ethyl acetate 1:1 to 0:1) to afford 60 as white foam (1.28 g,
7.47 mmol, 89%). [a]2D2 = ꢀ15.9 (c = 0.98, CHCl3, 98% ee); IR (neat):
(6S)-6-[(2R,4R)-2,4-Diacetoxy-8-phenyloctyl]-5,6-dihydro-2H-pyran-2-
one (56): Ac2O (2.5 mL, 0.027 mmol) and catalytic amount of DMAP
were added to a stirred solution of a mixture of 54 and 55 (2.4 mg,
6.7 mmol) in pyridine (0.1 mL). After stirring for 30 min, the reaction
mixture was diluted with ethyl acetate and the solution was quenched
with saturated aqueous NaHCO3. The aqueous layer was extracted with
ethyl acetate and the combined organic layers were washed with 1n HCl,
brine, and then dried over Na2SO4. After concentration in vacuo, the resi-
due was purified by preparative thin-layer chromatography (silica gel,
hexane/ethyl acetate 1:2) to give 56 (2.4 mg, 89%) as a yellow oil. [a]D22
= ꢀ31.5 (c = 0.33, CHCl3, 99% ee); IR (neat): n˜ = 2931, 1730, 1372,
n˜ = 2860, 1650, 1244, 1113 cmꢀ1 1H NMR (CDCl3): d = 1.41 (d, J=
;
5.1 Hz, 3H), 3.24 (dq, J=2.2, 5.1 Hz, 1H), 3.31 (d, J=2.2 Hz, 1H), 3.19
3.76 (m, 8H); 13C NMR (CDCl3): d = 17.2, 42.3, 45.4, 54.3, 54.9, 66.7,
166.0; HRMS (EI+): m/z: calcd for C8H13O3N: 171.0895, found
171.0894.
1
1240, 1038 cmꢀ1; H NMR (CDCl3): d = 7.27 (m, 2H), 7.18 (m, 3H), 6.88
(m, 1H), 6.01 (dd, J=9.75, 2 Hz, 1H), 5.04 (m, 1H), 4.93 (m, 1H), 4.48
(m, 1H), 2.60 (t, J=7.5 Hz, 2H), 2.45 2.27 (m, 2H), 2.06 (s, 3H), 2.04 (s,
3H), 2.16 1.78 (m, 4H), 1.62 (m, 4H), 1.34 (m, 2H); 13C NMR (CDCl3):
d = 170.8, 170.7, 163.8, 144.7, 142.3, 128.4, 128.3, 125.7, 121.4, 74.9, 70.8,
67.9, 39.0, 39.0, 35.7, 34.1, 31.1, 29.1, 24.7, 21.2, 21.2; LRMS (EI+): m/z:
402 [M +]; HRMS (FAB+): m/z: calcd for C23H31O6: 403.2121, found
403.2108.
4-[(2S,3R)-2,3-Epoxy-1-oxobutyl]morpholine (ent-60): [a]2D2 = +13.8 (c
= 1.09, CHCl3, 99% ee); IR (neat): n˜ = 2862, 1643, 1246, 1111 cmꢀ1 1H
;
NMR (CDCl3): d = 1.41 (d, J=5.1 Hz, 3H), 3.24 (dq, J=2.2, 5.1 Hz,
1H), 3.31 (d, J=2.2 Hz, 1H), 3.19 3.76 (m, 8H); 13C NMR (CDCl3): d =
17.2, 42.3, 45.4, 54.3, 54.9, 66.7, 166.0; HRMS (EI+): m/z: calcd for
C8H13O3N: 171.0895, found 171.0897.
(3R,4S)-3,4-Epoxy-1-phenyl-2-pentanone: Benzylmagnesium chloride
(0.23 mL, 2m in THF) was added dropwise at 48C to a solution of 60
(40 mg, 0.233 mmol) in THF(3 mL). The reaction mixture was quenched
with saturated aqueous NH4Cl. After extracting with ethyl acetate (3î),
the combined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/ethyl acetate 8:1) to afford the benzyl
ketone as oil (25 mg, 0.142 mmol, 60% yield, 98% ee). [a]2D2 = +53.5 (c
In confirmation of the stereochemistry, minor isomer 6-epi-53 was also
converted to the corresponding diacetate 6-epi-56 by the same proce-
dure.
(6R)-5,6-Dihydro-6-[[(2R,4R,6R)-2-phenyl-6-(4-phenylbutyl)-1,3-dioxan-
4-yl]methyl]-2H-pyran-2-one (6-epi-53): [a]2D7 = ꢀ2.1 (c = 0.28, CHCl3,
1
99% ee); IR (neat): n˜ = 2930, 2857, 1724, 1248, 1120, 1026, 699 cmꢀ1; H
NMR (CDCl3): d = 7.46 (m, 2H), 7.37 7.27 (m, 5H), 7.19 (m, 3H), 6.88
(ddd, J=10, 5.5, 3 Hz, 1H), 6.03 (dd, J=10, 1.5 Hz, 1H), 5.50 (s, 1H),
4.80 (m, 1H), 4.23 (m, 1H), 3.82 (m, 1H), 2.63 (t, J=7.5 Hz, 2H), 2.36
(m, 2H), 1.94 (m, 1H), 1.86 (m, 1H), 1.73 1.37 (m, 8H); 13C NMR
(CDCl3): d = 164.4, 145.1, 142.6, 138.7, 128.6, 128.4, 128.3, 128.2, 126.1,
125.6, 121.4, 100.4, 76.7, 74.0, 72.0, 41.6, 37.2, 35.8, 35.7, 31.4, 30.0, 24.7;
LRMS (EI+): m/z: 406 [M +]; HRMS (FAB+): m/z: calcd for C26H30O4:
407.2222, found 407.2213.
=
0.77, CHCl3, 98% ee); IR (neat): n˜ = ;
1718, 1420 cmꢀ1 1H NMR
(CDCl3): d=1.37 (d, J=5.2 Hz, 3H), 3.12 (dq, J=1.9, 5.2 Hz, 1H), 3.24
(d, J=1.9 Hz, 1H), 3.63 (d, J=15.5 Hz, 1H), 3.72 (d, J=15.5 Hz, 1H),
7.20 (m, 2H), 7.26 (m, 1H), 7.32 (m, 2H); 13C NMR (CDCl3): d = 17.4,
44.2, 54.5, 60.3, 127.1, 128.6, 129.5, 132.8, 204.6; HRMS (EI+): m/z:
calcd for C11H12O2: 176.0837, found 176.0830; HPLC conditions (column:
DAICEL CHIRALPAK AD-H, hexane/isopropanol 99:1, flow rate:
1540
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 1527 1544

1,3-Polyol Arrays
1527 1544
0.8 mLminꢀ1, detector: 254 nm, tR [(3R,4S)]
33.5 min).
=
28.5 min, [(3S,4R)]
=
To a mixture of the alcohol (260 mg), MS 4 ä (400 mg; MS 4 ä not
dried), N-methylmorpholine-N-oxide (193 mg, 1.65 mmol) and dichloro-
methane (20 mL) at room temperature was added TPAP (19 mg,
0.055 mmol). The reaction mixture was stirred for 1 h and concentrated
in vacuo. The resulting residue was purified by column chromatography
(silica gel, hexane/ethyl acetate 3:1) to afford an aldehyde as oil
(180 mg).
Butyl (4R,5S)-4,5-epoxy-3-oxohexanoate (61): n-Butyl acetate (1.45 mL,
11.0 mmol) was added dropwise at ꢀ788C to a mixture of LHMDS
(11.0 mL, 10.6 mmol, 1.0m solution in THF) and THF (50 mL). After stir-
ring for 30 min, a solution of 60 (628 mg, 3.67 mmol) in THF(10 mL)
was added dropwise and the reaction mixture was stirred for 6 h at
ꢀ788C. The reaction was quenched with saturated aqueous NH4Cl at
ꢀ788C and warmed to room temperature. The aqueous layer was extract-
ed with ethyl acetate (3î) and the combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, hexane/ethyl
acetate 9:1) to afford 61 as colorless oil (644 mg, 3.2 mmol, 88%). [a]D21
To a stirred mixture of the aldehyde (156 mg, 0.708 mmol), LiCl (36 mg,
0.85 mmol), 4-(2-diethoxyphosphoryl-1-oxoethyl)morpholine (29; 225 mg,
0.85 mmol) in acetonitrile (45 mL) at room temperature was added N,N-
diisopropylethylamine (0.15 mL, 0.85 mmol). After stirring overnight, the
reaction mixture was diluted with ethyl acetate. The resulting mixture
was washed with 2% aqueous citric acid, saturated aqueous NaHCO3,
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resi-
due was purified by column chromatography (silica gel, ethyl acetate) to
afford 63 as oil (230 mg, 0.69 mmol, 74%, 3 steps).
=
+54.9 (c
= 0.99, CHCl3, 98% ee); IR (neat): n˜ = 2961, 1742,
1718 cmꢀ1 1H NMR (CDCl3): d = 0.92 (t, J=7.3 Hz, 3H), 1.38 (tq, J=
;
7.6, 7.3 Hz, 2H), 1.42 (d, J=4.9 Hz, 3H), 1.62 (tt, J=6.4, 7.6 Hz, 2H),
3.23 (m, 1H), 3.26 (s, 2H), 3.37 (s, 3H), 4.13 (t, J=6.4 Hz, 2H); 13C
NMR (CDCl3): d = 13.5, 17.2, 18.9, 30.3, 43.6, 54.3, 60.4, 65.3, 166.6,
200.1; HRMS (FAB+): m/z: calcd for C10H17O4: 201.1127, found
201.1139.
4-[(E)-4-[(2S,4R,6S)-6-Methyl-2-phenyl-1,3-dioxan-4-yl]-1-oxo-2-bute-
nyl]morpholine (63): [a]2D1 = +8.4 (c 1.00, CHCl3, 98% ee); IR (neat): n˜
1
= 2854, 1659, 1617, 1434, 1113 cmꢀ1; H NMR (CDCl3): d = 1.31 (d, J=
6.1 Hz, 3H), 1.42 (ddd, J=11.3, 11.3, 12.8 Hz, 1H), 1.65 (ddd, J=2.1, 2.3,
12.8 Hz, 1H), 2.44 (ddd, J=7.3, 7.3, 10.4 Hz, 1H), 2.58 (ddd, J=7.3, 7.3,
14.5 Hz, 1H), 3.50 3.75 (br, 8H), 3.96 (m, 2H), 5.51 (s, 1H), 6.30 (d, J=
15.3 Hz, 1H), 6.89 (dt, J=15.3, 7.3 Hz, 1H), 7.29 7.38 (m, 3H), 7.46 7.51
(m, 2H); 13C NMR (CDCl3): d = 21.6, 38.2, 38.8, 42.1, 46.1, 66.6, 66.8,
72.8, 75.3, 100.7, 122.4, 126.1, 128.1, 128.6, 138.5, 141.4, 165.4; HRMS
(FAB+): m/z: calcd for C19H26O4N1: 332.1862, found 332.1872.
Butyl (S)-5-hydroxy-3-oxohexanoate: NaBH4 (387 mg, 10.24 mmol) was
added portionwise at room temperature to a mixture of PhSeSePh (1.6 g,
5.12 mmol) in ethanol (8 mL). After stirring for 15 min, the reaction mix-
ture was cooled to 08C, and then a solution of 61 (644 mg, 3.2 mmol) in
ethanol (5 mL) was added. After stirring for 5 min at the same tempera-
ture, the reaction was quenched with saturated aqueous NH4Cl. The re-
sulting mixture was extracted with ethyl acetate (3î), and the combined
organic layers were washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by column chromatogra-
phy (silica gel, hexane/ethyl acetate 20:1, 10:1, 2:1 to 1:1) to afford the
4-[(2S,3R)-2,3-Epoxy-4-[(2S,4R,6S)-6-methyl-2-phenyl-1,3-dioxan-4-yl]-1-
oxobutyl]morpholine (64’): A mixture of 64’ and 64 (64’:64 >99:1) pre-
pared from 63 (98% ee); [a]2D2 = +29.3 (c = 1.50, CHCl3); IR (neat): n˜
=
2856, 1654, 1240, 1116 cmꢀ1 1H NMR (CDCl3): d
; = 1.30 (d, J=
ketoester as yellow oil (574 mg, 2.83 mmol, 89%). [a]D22
=
+36.0 (c =
;
6.4 Hz, 3H), 1.46 (ddd, J=12.2, 13.1, 24.1 Hz, 1H), 1.65 (ddd, J=2.1, 2.3,
13.1 Hz, 1H), 1.79 (ddd, J=6.8, 10.0, 14.2 Hz, 1H), 1.98 (ddd, J=2.8, 4.1,
14.2 Hz, 1H), 3.10 3.30 (m, 4H), 3.35 3.44 (m, 2H), 3.46 3.65 (m, 4H),
3.98 (m, 1H), 4.07 (m, 1H), 5.51 (s, 1H), 7.34 7.40 (m, 3H), 7.46 7.49
(m, 2H); 13C NMR (CDCl3): d = 21.5, 38.7, 38.8, 42.2, 44.9, 54.1, 55.4,
66.2, 66.5, 72.9, 73.7, 101.3, 126.4, 128.3, 129.1, 138.5, 165.9; HRMS
(FAB+): m/z: calcd for C19H26O5N1: 348.1811, found 348.1811; HPLC
conditions (column: AS-H(DAICEL), hexane/isopropanol 3:1, flow rate:
1.0 mLminꢀ1, detector: 254 nm, tR (64’) = 68.9 min, (64) = 91.6 min).
1.15, CHCl3, 98% ee); IR (neat): n˜ = 2964, 1738, 1713 cmꢀ1
1H NMR
(CDCl3): d = 0.93 (t, J=6.9 Hz, 3H), 1.21 (d, J=5.8 Hz, 3H), 1.37 (m,
2H), 1.63 (m, 2H), 2.65 (dd, J=8.5, 17.4 Hz, 1H), 2.73 (d, J=17.4 Hz,
1H), 2.81 (s, 3H), 3.46 (s, 2H), 4.14 (t, J=6.4 Hz, 2H), 4.26 (m, 1H); 13C
NMR (CDCl3): d = 13.5, 18.9, 22.3, 30.3, 49.7, 51.0, 63.6, 65.3, 166.9,
203.5; LRMS (FAB+): m/z: calcd for C10H19O4: 203, found 203; HRMS
(FAB+): m/z: calcd for C10H19O4: 203.1283, found 203.1287.
Butyl
(2S,4S,6S)-6-methyl-2-phenyl-1,3-dioxane-4-acetate
(62):
BEt2(OMe) (3.11 mL, 3.11 mmol, 1.0m in THF) was added at ꢀ788C to a
solution of the d-hydroxy b-ketoester (574 mg, 2.83 mmol) in THF
(4 mL) and MeOH (4 mL). After stirring for 1 h, NaBH4 (134 mg,
3.54 mmol) was added and stirred for 5.5 h at the same temperature. The
reaction mixture was quenched with saturated aqueous NH4Cl at ꢀ788C
and then warmed to room temperature. The resulting mixture was ex-
tracted with ethyl acetate (3î), and the combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. To the obtained residue (653 mg) in toluene (20 mL) at room tem-
perature was added benzaldehyde dimethyl acetal (0.85 mL, 5.66 mmol)
and TsOH¥H2O (10 mg). After stirring overnight, the reaction mixture
was quenched with saturated aqueous NaHCO3. The resulting mixture
was extracted with ethyl acetate (3î), and the combined organic layers
were washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatography (silica gel,
hexane/ethyl acetate 30:1, 10:1 to 4:1) to afford 62 as yellow oil (496 mg,
1.7 mmol, 60%). [a]2D2 = +11.3 (c 1.15, CHCl3, 98% ee); IR (neat): n˜ =
4-[(2R,3S)-2,3-Epoxy-4-[(2S,4R,6S)-6-methyl-2-phenyl-1,3-dioxan-4-yl]-1-
oxobutyl]morpholine (64): Sm(OiPr)3 (0.62 mL, 0.124 mmol, 0.2m in
THF) was added at room temperature to a mixture of (S)-BINOL
(35.5 mg, 0.124 mmol), triphenylarsine oxide (39.9 mg, 0.124 mmol) and
MS 4 ä (1.24 g; MS 4 ä was not dried. 1000 mg per 1 mmol of starting
material) in THF(2.5 mL). After stirring for 30 min, TBHP (2.0 mL,
10.1 mmol, 5m in decane) was added. After stirring for 10 min, 63
(412 mg, 1.24 mmol) in THF(3 mL) was added and the reaction mixture
was stirred for 8 h at the same temprerature. The reaction mixture was
filtered and the filtrate was diluted with ethyl acetate (40 mL). The re-
sulting mixture was washed with 2% aqueous citric acid, saturated aque-
ous sodium thiosulfate, and brine. The combined organic layers were
dried over Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography (silica gel, hexane/ethyl acetate 3:1
to 0:1) to afford 64 as yellow oil (387 mg, 1.11 mmol, 90%).
A mixture of 64 and 64’ (64:64’ 99.8:0.2) prepared from 63 (98% ee);
[a]2D4 = ꢀ3.0 (c = 1.11, CHCl3); IR (neat): n˜ = 2856, 1655, 1240, 1115,
2960, 1735, 1176, 1025 cmꢀ1 1H NMR (CDCl3): d = 0.91 (t, J=7.3 Hz,
;
1
1017 cmꢀ1; H NMR (CDCl3): d = 1.32 (d, J=6.1 Hz, 3H), 1.52 (m, 1H),
3H), 1.31 (d, J=6.1 Hz, 1H), 1.36 (tq, J=7.6, 7.3 Hz, 2H), 1.44 (ddd, J=
11.3, 12.0, 12.8 Hz, 1H), 1.61 (tt, J=6.8, 7.6 Hz, 2H), 1.73 (ddd, J=2.2,
2.3, 12.8 Hz, 1H), 2.50 (dd, J=6.1, 15.5 Hz, 1H), 2.72 (dd, J=7.3,
15.5 Hz, 1H), 3.99 (m, 1H), 4.10 (t, J=6.8 Hz, 2H), 4.30 (m, 1H), 5.55 (s,
1H), 7.29 7.37 (m, 3H), 7.48 7.52 (m, 2H); 13C NMR (CDCl3): d = 13.6,
19.0, 21.5, 30.5, 38.1, 40.9, 64.4, 72.7, 73.2, 100.7, 126.0, 128.1, 128.5, 138.4,
170.8; HRMS (EI+): m/z: calcd for C17H24O4: 292.1675, found 292.1680.
1.64 (ddd, J=2.2, 2.4, 13.2 Hz, 1H), 2.00 (ddd, J=4.1, 4.3, 15.0 Hz, 1H),
2.12 (ddd, J=4.6, 5.8, 15.0 Hz, 1H), 3.23 3.33 (m, 3H), 3.37 (m, 2H),
3.50 3.63 (m, 5H), 3.98 (m, 2H), 5.51 (s, 1H), 7.32 7.38 (m, 3H), 7.45
7.49 (m, 2H); 13C NMR (CDCl3): d = 21.4, 36.3, 37.5, 42.0, 44.9, 53.3,
54.2, 66.2, 66.4, 72.4, 72.9, 100.7, 126.0, 128.1, 128.8, 138.3, 165.9; HRMS
(FAB+): m/z: calcd for C19H26O5N1: 348.1811, found 348.1813; HPLC
conditions (column: DAICEL CHIRALPAK AS-H, hexane/isopropanol
3:1, flow rate: 1.0 mLminꢀ1, detector: 254 nm, tR (64’) = 68.9 min, (64)
= 91.6 min).
Synthetic route to 63: LiBH4 (26 mg, 1.19 mmol) and trimethoxyborane
(0.013 mL, 0.119 mmol) were added successively at room temperature to
a solution of 62 (316 mg) in diethyl ether (20 mL). After stirring for 1 h,
the reaction mixture was quenched with saturated aqueous NaHCO3 and
the resulting mixture was extracted with ethyl acetate (3î). The com-
bined organic layers were washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo to afford an alcohol as oil (260 mg).
Ethyl (4R,5S)-4,5-epoxy-6-[(2S,4R,6S)-6-methyl-2-phenyl-1,3-dioxan-4-
yl]-3-oxohexanoate: Ethyl acetate (0.31 mL, 3.2 mmol) was added drop-
wise at ꢀ788C to a mixture of LHMDS (3.2 mL, 3.2 mmol, 1.0m solution
in THF) and THF (4 mL). After stirring for 25 min at the same tempera-
1541
Chem. Eur. J. 2004, 10, 1527 1544
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

M. Shibasaki et al.
FULL PAPER
ture, a solution of 64 (370 mg, 1.07 mmol) in THF(4 mL) was added
dropwise and the reaction mixture was stirred for 4 h at ꢀ788C. The re-
action was quenched with saturated aqueous NH4Cl at ꢀ788C and
warmed to room temperature. After extracting with ethyl acetate (3î),
the combined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/ethyl acetate 4:1 to 3:1) to afford the
epoxy ketoester as pale yellow oil (328 mg, 0.94 mmol, 88%). The title
compound was prepared from 64 (a mixture of 64:64’ (64:64’ 99.8:0.2));
the reaction mixture was quenched with saturated aqueous sodium hy-
drogen carbonate. The resulting mixture was extracted with ethyl acetate
twice, and the combined organic layers were dried over Na2SO4, filtered,
and concentrated in vacuo to afford an alcohol.
To a mixture of the alcohol, and N-methylmorpholine-N-oxide (32 mg,
0.27 mmol) and MS 4 ä (80 mg; MS 4 ä not dried) in dichloromethane
(1 mL) at room temperature was added TPAP (3.2 mg, 0.009 mmol).
After stirring for 30 min at the same temperature, the reaction mixture
was concentrated in vacuo. The residue was purified by column chroma-
tography (silica gel, hexane/ethyl acetate 4:1) to afford an aldehyde as oil
(46 mg, 0.116 mmol, 64%).
[a]2D1
1118 cmꢀ1
=
+50.6 (c = 1.04, CHCl3); IR (neat): n˜ = 2976, 1742, 1718,
;
1H NMR (CDCl3): d = 1.25 (d, J=7.3 Hz, 3H), 1.33 (d, J=
6.4 Hz, 3H), 1.55 1.68 (m, 2H), 1.92 2.05 (m, 2H), 3.30 3.45 (m, 4H),
4.00 (m, 2H), 4.15 4.24 (m, 2H), 5.54 (s, 1H), 7.31 7.38 (m, 3H), 7.44
7.53 (m, 2H); 13C NMR (CDCl3): d = 14.0, 21.5, 37.6, 37.9, 43.8, 55.0,
59.0, 61.5, 72.9, 73.5, 100.7, 126.1, 128.2, 128.7, 138.3, 166.5, 199.8; HRMS
(FAB+): m/z: calcd for C19H25O6: 349.1651, found 349.1641.
To a stirred solution of di-o-tolylphosphonoacetic acid ethyl ester (35 mg,
0.1 mmol) in THF(1 mL) at ꢀ788C was added dropwise KHMDS
(0.2 mL, 0.1 mmol, 0.5m in toluene). After stirring for 1 h at the same
temperature, a solution of the aldehyde (25 mg, 0.063 mmol) in THF
(1 mL) was added dropwise and the resulting solution was stirred for 1 h.
The reaction mixture was quenched with saturated aqueous NH4Cl and
the resulting mixture was extracted with ethyl acetate 311times. The com-
bined organic layers were washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by column chroma-
tography (silica gel, hexane/ethyl acetate 1:0 to 4:1) to afford 66 as oil
(22 mg, 0.047 mmol, 75%). [a]D24 = +27.8 (c 1.10, CHCl3); IR (neat): n˜
Ethyl (S)-5-hydroxy-6-[(2S,4R,6S)-6-methyl-2-phenyl-1,3-dioxan-4-yl]-3-
oxohexanoate: NaBH4 (114 mg, 3.0 mmol) was added portionwise at
room temperature to a mixture of PhSeSePh (311 mg, 1.0 mmol) in etha-
nol (4 mL). After stirring for 5 min, the epoxy ketoester (328 mg,
0.94 mmol) prepared above in ethanol (4 mL) was added. After stirring
for 5 min at the same temperature, the reaction mixture was quenched
with saturated aqueous NH4Cl. After extracting with ethyl acetate (3î),
the combined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/ethyl acetate 4:1, 2:1 to 2:3) to afford
= 2865, 1715, 1340, 1189, 1118, 1025 cmꢀ1 1H NMR (CDCl3): d = 1.29
;
(t, J=7.0 Hz, 3H), 1.32 (d, J=6.4 Hz, 3H), 1.45 1.59 (m, 2H), 1.66 1.77
(m, 3H), 2.14 (ddd, J=7.0, 7.2, 14.0 Hz, 1H), 2.91 (ddd, J=7.0, 14.0,
15.9 Hz, 1H), 3.10 (m, 1H), 3.98 (m, 2H), 4.09 (m, 2H), 4.18 (q, J=
7.0 Hz, 2H), 5.53 (s, 1H), 5.54 (s, 1H), 5.88 (d, J=11.6 Hz, 1H), 6.46
(ddd, J=7.0, 7.2, 11.6 Hz, 1H), 7.31 7.41 (m, 6H), 7.49 7.55 (m, 4H);
13C NMR (CDCl3): d = 14.2, 21.6, 35.0, 36.3, 38.5, 41.7, 59.8, 72.9, 73.0,
73.1, 75.9, 100.6, 100.7, 121.3, 126.0, 126.1, 128.16, 128.19, 128.61, 128.64,
138.65, 138.79, 145.35, 166.31; HRMS (FAB+): m/z: calcd for C28H35O6:
467.2434, found 467.2436.
the hydroxy ketoester as yellow oil (252 mg, 0.72 mmol, 77%). [a]D24
+27.1 (c = 1.07, CHCl3); IR (neat): n˜ = 3447, 2974, 1740, 1715, 1111,
1025 cmꢀ1 1H NMR (CDCl3): d = 1.26 (d, J=7.0 Hz, 3H), 1.31 (d, J=
=
;
6.1 Hz, 3H), 1.46 (ddd, J=10.9, 11.3, 13.1 Hz, 1H), 1.64 (ddd, J=2.3, 2.4,
13.1 Hz, 1H), 1.72 (ddd, J=3.5, 3.7, 14.4 Hz, 1H), 1.84 (ddd, J=8.9, 8.9,
14.4 Hz, 1H), 2.65 (dd, J=4.6, 16.8 Hz, 1H), 2.78 (dd, J=7.7, 16.8 Hz,
1H), 3.37 (d, J=1.9 Hz, 1H), 3.47 (s, 2H), 3.98 (m, 1H), 4.11 4.22 (m,
3H), 4.37 (m, 1H), 5.55 (s, 1H), 7.30 7.37 (m, 3H), 7.44 7.48 (m, 2H);
13C NMR (CDCl3): d = 14.0, 21.5, 38.4, 41.8, 49.7, 49.9, 61.3, 66.6, 72.9,
76.1, 100.8, 126.0, 128.2, 128.7, 138.2, 166.9, 202.6; HRMS (FAB+): m/z:
calcd for C19H27O6: 351.1808, found 351.1818.
Cryprocaryolone diacetate (67): Compound 66 (20 mg, 0.0428 mmol) was
dissolved in 80% aq. acetic acid (1.5 mL) and the solution was heated to
608C. After stirring for 80 min at the same temperature, the reaction
mixture was cooled to room temperature. The resulting solution was
dried over Na2SO4, filtered, and concentrated in vacuo. To a solution of
the crude product in benzene (1 mL) was added TsOH¥H2O (3 mg), and
the resulting mixture was stirred at room temperature for 36 h. The reac-
tion mixture was neutralized with saturated aqueous NaHCO3 and dilut-
ed with ethyl acetate. The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. To a solution of the crude
product in dichloromethane (1 mL) at room temperature were added
pyridine (5 mL), DMAP (1 mg) and Ac2O (50 mL). After stirring for 5 h
at the same temperature, the reaction mixture was quenched with satu-
rated aqueous sodium hydrogen carbonate. The resulting mixture was ex-
tracted with ethyl acetate, and the combined organic layers were dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by column chromatography (silica gel, hexane/ethyl acetate 2:1, 1:1
to 1:2) to afford 67 as oil (7 mg, 0.021 mmol, 50% yield, three steps).
Ethyl (2S,4S,6S)-6-[[(2S,4S,6S)-6-methyl-2-phenyl-1,3-dioxan-4-yl]meth-
yl]-2-phenyl-1,3-dioxane-4-acetate (65): To a solution of the d-hydroxy b-
ketoester (252 mg, 0.72 mmol) prepared above, in methanol (1 mL) and
THF(3 mL) at ꢀ788C was added dropwise Et2B(OMe) (0.79 mL, 1.0m
in THF). After stirring for 1 h, NaBH4 (34 mg, 0.9 mmol) was added one
portion. The resulting mixture was stirred for 6 h at ꢀ788C and then for
2 h at ꢀ408C. The reaction was quenched with saturated aqueous NH4Cl
at ꢀ408C. The resulting mixture was extracted with ethyl acetate (3î).
The combined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo to give a crude product. To a solution
of the crude product in toluene (10 mL) at room temperature were
added benzaldehyde dimethyl acetal (0.16 mL, 1.08 mmol) and
TsOH¥H2O (10 mg). After stirring overnight at the same temperature,
the reaction mixture was quenched with saturated aqueous NaHCO3.
The resulting mixture was extracted with ethyl acetate (3î), and the
combined organic layers were washed with brine, dried over Na2SO4, fil-
tered, and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/ethyl acetate 10:1 to 4:1) to afford 65
as colorless oil (246 mg, 0.56 mmol, 78%). [a]2D6 = +7.9 (c 1.06, CHCl3),
[a]2D5 = +17.9 (c 0.98, EtOH) (lit.[28e] [a]2D1 = +15.7 (c 0.99, EtOH)); IR
[a]2D3
=
ꢀ18.8 (c
=
0.35, CHCl3) (lit.[59a] [a]D23
=
ꢀ145 (c
= 0.27,
CHCl3)); IR (neat): n˜ = 2924, 1732, 1240, 1075 cmꢀ1
;
1H NMR (CDCl3):
d = 1.22 (d, J=6.4 Hz, 3H, H-5’), 1.56 (ddd, J=2.1, 14.0, 15.2 Hz, 1H,
H-8a), 1.67 (ddd, J=4.3, 5.5, 14.4 Hz, 1H, H-1a’), 1.72 (ddd, J=5.5, 5.8,
14.4 Hz, 1H, H-3a’), 1.85 (dd, J=7.4, 14.7 Hz, 1H, H-1’b), 1.85 2.40 (m,
10H, H-9a, H-9b, H-3’b, H-8b, 2.01, 2.02 (2s, 2î3H, 2AcO), 2.75 (dd,
J=5.2, 19.3 Hz, 1H, H-4a), 2.86 (d, J=19.3 Hz, 1H, H-4b), 3.88 (ddd,
J=4.3, 7.6, 15.2 Hz, 1H, H-7), 4.32 (m, 1H, H-5), 4.87 (m, 1H, H-1), 4.95
(dq, J=14.4, 6.4 Hz, 1H, H-4’), 5.08 (ddd, J=5.5, 7.4, 12.7 Hz, 1H, H-2’);
13C NMR (CDCl3): d = 20.0 (C-5’), 21.2 (CH3CO-), 21.3 (CH3CO-), 29.3
(C-9), 36.3 (C-4), 37.0 (C-8), 40.0 (C-1’), 40.4 (C-3’), 63.2 (C-7), 66.0 (C-
5), 67.7 (C-4’), 68.2 (C-2’), 72.1 (C-1), 168.0, 169.7, 169.8; 1H NMR
(C6D6): d = 0.94 0.99 (m, 2H, H-8a, H-9a), 1.12 (d, J=6.1 Hz, 3H, H-
5’), 1.14 (m, 1H, H-9b), 1.35 (ddd, J=4.9, 4.9, 14.1 Hz, 1H, H-1’a), 1.51
(ddd, J=5.5, 5.8, 14.1 Hz, 1H, H-3’a), 1.55 (m, 1H, H-8b), 1.67 1.76 (m,
7H, H-1’b, 1.68, 1.71 (2s, 2î3H, 2AcO), 1.84 (ddd, J=7.3, 7.3, 14.1 Hz,
1H, H-3’b), 2.09 (dd, J=5.2, 18.9 Hz, 1H, H-4a), 2.63 (d, J=18.9 Hz,
1H, H-4b), 3.56 (brs, 1H, H-5), 3.80 (ddd, J=4.0, 11.3, 14.1 Hz, 1H, H-
7), 4.11 (brs, 1H, H-1), 5.11 (dq, J=5.8, 6.1 Hz, 1H, H-4’), 5.20 (dddd,
J=4.9, 5.3, 7.3, 12.8 Hz, 1H, H-2’); 13C NMR (C6D6): d = 20.1 (C-5’),
20.6 (CH3CO-), 20.8 (CH3CO-), 29.6 (C-9), 36.1 (C-4), 36.9 (C-8), 39.7
1
(neat): n˜ = 1734, 1375, 1341, 1113, 1025, 755 cmꢀ1; H NMR (CDCl3): d
= 1.26 (t, J=7.0 Hz, 3H), 1.32 (d, J=6.1 Hz, 3H), 1.45 1.57 (m, 2H),
1.68 (d, J=13.1 Hz, 1H), 1.73 1.81 (m, 2H), 2.14 (ddd, J=7.0, 7.0,
14.0 Hz, 1H), 2.52 (dd, J=6.5, 15.5 Hz, 1H), 2.73 (dd, J=7.0, 15.5 Hz,
1H), 3.97 (m, 1H), 4.05 4.15 (m, 2H), 4.16 (q, J=7.0 Hz, 2H), 4.33 (m,
1H), 5.53 (s, 1H), 5.57 (s, 1H), 7.30 7.39 (m, 6H), 7.44 7.52 (m, 4H); 13C
NMR (CDCl3): d = 14.1, 21.6, 36.3, 38.4, 41.0, 41.6, 60.5, 72.9, 73.0, 73.2,
100.5, 100.7, 126.0, 126.1, 128.1, 128.2, 128.64, 128.66, 138.4, 138.7, 170.6;
HRMS (FAB+): m/z: calcd for C26H33O6: 441.2277, found 441.2274.
Ethyl (Z)-4-[(2R,4R,6R)-6-[[(2S,4S,6S)-6-methyl-2-phenyl-1,3-dioxan-4-
yl]methyl]-2-phenyl-1,3-dioxan-4-yl]-2-butenoate (66): LiBH4 (4.4 mg,
0.198 mmol) and trimethoxyborane (2.2 mL, 0.02 mmol) were added suc-
cessively at room temperature to a solution of 65 (80 mg, 0.18 mmol) in
diethyl ether (2 mL). After stirring for 20 min at the same temperature,
1542
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 1527 1544

1,3-Polyol Arrays
1527 1544
(C-1’), 39.9 (C-3’), 63.0 (C-7), 65.8 (C-5), 67.8 (C-4’), 68.3 (C-2’), 72.8 (C-
1), 169.4, 170.44, 170.47; HRMS (FAB+): m/z: calcd for C16H25O7:
329.1600, found 329.1588.
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CCDC-223952 contains the supplementary crystallographic data for this
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Acknowledgement
This work was supported by RFTF and Grant-in-Aid for Encourage-
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M. Shibasaki et al.
FULL PAPER
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For details, see Supporting Information.
ꢀ
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1
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Received: November 12, 2003 [F5709]
1544
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Chem. Eur. J. 2004, 10, 1527 1544