Chiral 1-(1,3-dithian-2-yl) prop-2-en-1-ols: new scaffolds for enantiopure α-hydroxyaldehydes

Article abstract of DOI:10.1016/j.tet.2015.05.039

Abstract We have demonstrated that chiral 1-(1,3-dithian-2-yl)prop-2-en-1-ols as new scaffolds, obtained by enzyme-catalyzed kinetic resolution, undergo Suzuki-Miyaura cross-couplings and hydroformylation smoothly. Also, we have found that a 1,3-dithianyl group of the products can be removed without any erosion of the enantiopurity under mild conditions. A new access to a variety of enantiopure α-hydroxyaldehydes with ensured absolute configuration is described.

Full text of DOI:10.1016/j.tet.2015.05.039

Accepted Manuscript
Chiral 1-(1,3-Dithian-2-yl) prop-2-en-1-ols: New Scaffolds for Enantiopure α-
Hydroxyaldehydes
Masaru Akehi, Mariko Kawamoto, Tadakatsu Mandai
PII:
S0040-4020(15)00697-3
10.1016/j.tet.2015.05.039
TET 26757
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 April 2015
Revised Date: 8 May 2015
Accepted Date: 11 May 2015
Please cite this article as: Akehi M, Kawamoto M, Mandai T, Chiral 1-(1,3-Dithian-2-yl) prop-2-en-1-ols:
New Scaffolds for Enantiopure α-Hydroxyaldehydes, Tetrahedron (2015), doi: 10.1016/j.tet.2015.05.039.
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ACCEPTED MANUSCRIPT
Abstract
We have demonstrated that chiral 1-(1,3-dithian-2-yl)prop-2-en-1-ols as new scaffolds, obtained
by enzyme-catalyzed kinetic resolution, undergo Suzuki-Miyaura cross-couplings and
hydroformylation smoothly. Also, we have found that a 1,3-dithianyl group of the products can be
removed without any erosion of the enantiopurity under mild conditions. A new access to a variety
of enantiopure α-hydroxyaldehydes with ensured absolute configuration is described.

ACCEPTED MANUSCRIPT
Graphical abstract
Chiral 1-(1,3-Dithian-2-yl) prop-2-en-1-ols:
New Scaffolds forEnantiopure α-Hydroxyaldehydes
MasaruAkehi, Mariko Kawamoto, Tadakatsu Mandai*
Department of LifeScience, Kurashiki University ofScience &theArts
2640 Nishinoura, Tsurajima, Kurashiki 712-8505, Japan
Tel: +81(86)4401080; Fax: +81(86)4401062; E-mail: ted@chem.kusa.ac.jp
Keywords: Scaffold; α-Hydroxyaldehyde; Suzuki-Miyaura cross-coupling; Hydroformylation;
1,3-Dipolar cycloaddition.
1. Introduction
1
Much attention has been paid to the Petasis protocol, which affords an array of β-amino
alcohols in a single step involving a three component coupling reaction of α-hydroxyaldehydes,
amines, and organoboronic acids (Scheme 1). The reaction proceeds in a highly
diastereoselective manner to exclusively furnish anti β-amino alcohols, and hence generally
provides single enantiomers (>98% ee) when enantiopure α-hydroxyaldehydes are engaged.
R2 R3
N
H
R2
R3
R1
N
CHO
OH
R1
R4
OH
OH
B
HO
R4
Scheme 1. Petasis protocol.
1

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Regardless of its high potential utility in organic synthesis, the Petasis protocol has found
somewhat limited use because enantiopureα-hydroxyaldehydes are not easily available. Several
approaches to these valuable intermediates reported to date are based on the derivatization of
natural sources. For example, chiral 2,3-dihydroxy-4-butenals were prepared from D-xylose and
2a
D-ribose, and α-hydroxyesters derived from the corresponding natural α-amino acids were
converted to α-hydroxyaldehydes via protection of the hydroxyl group followed by ester
2b
reduction using DIBAL-H. The stereogenic centers of products obtained by these approaches
are derived directly from the starting materials. Furthermore, chiral 2-hydroxyaldehydes have
2c
been obtained via enzyme-mediated kinetic resolution of the 2-hydroxyaldehyde racemate. In
3
addition, asymmetric synthesis using chiral templates is a powerful and flexible approach for
obtaining higher homologs bearing a longer carbon chains, although strict temperature control
maybe required to obtain a high degree of enantiomericpurity.
4
Asymmetric dihydroxylation (AD) of 2-alkenyl acetals generating 2,3-dihydroxyaldehydes is
of special interest as it provides a more direct approach to α-hydroxyaldehydes through AD of
5
2
-alkenylsulfones (Scheme 2).
Scheme 2. Synthesis of α-hydroxyaldehydes via asymmetric dihydroxylation (AD).
Although these AD methods require great care in the preparation of the starting materials, they
hold promise as reliable strategies because the absolute configuration of the products can easily
be predicted.
Broadening the synthetic utility of α-hydroxyaldehydes requires the development of a new
synthetic method ensuring both high enantiopurity and absolute configuration.We thus devised
1-(1,3-dithian-2-yl) prop-2-en-1-ol (±)-1 as a scaffold for this purpose, and designed a new
strategy leading to a variety ofα-hydroxyaldehydes mentioned above. This strategy involves the
6
combination of an enzyme-catalyzed reaction of racemic (±)-1 and transition metal-catalyzed
7
8
reactions such as Suzuki-Miyaura cross-coupling or hydroformylation (Figure 1). We were
2

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confident that these metal-catalyzed reactions would proceed well with (±)-1 on the basis of
9
encouraging reports using substrates containing the 1,3-dithianyl group suggesting that the
coordinative 1,3-dithianyl group did not interrupt catalytic cycles mediated by a zero-valent
metal species.
Figure1. Synthetic design ofα-hydroxyaldehydes and its precursors.
2
. Results and discussion
We first investigated into lipase-catalyzed kinetic resolution of (±)-1 in an organic solvent
Scheme 3). By simply stirring a solution of (±)-1 and 2-propenyl acetate (2 equiv.) in toluene in
10
(
11
the presence of dried CAL-B [20 mg per 1 mmol of (±)-1] at 50 °C for 65 h, one enantiomer
was predominantly acetylated with excellent enantioselectivity (E>226). Separation by column
12
chromatography gave unreacted alcohol (S)-1 in 49% yield (>98% ee) and the acetate of the
12
enantiomer (R)-1-OAc in 51% yield (96% ee). The absolute configuration of (S)-1 was
10
tentativelyassigned on an empirical basis.
Scheme 3. Lipase-catalyzed kinetic resolution of (±)-1.
To improve the enantiopurity of (R)-1, (R)-1-OAc was subjected to lipase-catalyzed
hydrolysis (Scheme 4). Stirring a solution of (R)-1-OAc in dioxane/phosphate buffer (pH 6.86)
with CAL-B [20 mg per 1 mmol of (R)-1-OAc] at 40 °C for 65 h provided (R)-1 in 81% yield
3

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13
(
>98% ee) after silica gel column chromatography.
Scheme 4. Lipase-catalyzed hydrolysis of (R)-1-OAc.
Enantiopure (S)-1 (>98% ee) and (R)-1 (>98% ee) thus obtained were smoothly converted to
their O-protected derivatives, (S)-2 and (R)-2, respectively, in good yield (Figure 2). For example,
benzyl ether (S)-2a was prepared in 88% yield by treatment of (S)-1 with NaH and benzyl
chloride in dry THF/DMF at room temperature for 2 h. In addition, silyl ethers (S)-2b and (S)-2c
were prepared in high yields by treatment of (S)-1 with the corresponding silyl chlorides (2
equiv.) and imidazole (4 equiv.) as a base in DMF. Acetals (1S)-2d and its diastereomer (1R)-2d
were easily obtained in high yields by treatment with ethyl vinyl ether in the presence of a
catalytic amount of pyridiniump-toluenesulfonate (PPTS)in CH Cl .
2
2
Figure2. Protected2.
With a variety of O-protected derivatives 2 in hand, alkenyl-alkyl cross-coupling reaction was
7
smoothly effected using the Suzuki-Miyaura protocol (Scheme 5). For example, benzyl ether
(S)-2a was reacted with freshly prepared crystalline 9-borabicyclo[3.3.1]nonane dimer
14
(
9-BBN) (2 equiv.) in THF at 40 °C for 1 h. To the resulting alkylborane, iodobenzene (2
15
2
equiv.), 3 M aq. K PO (3 equiv.) and then PdCl (dppf)·CH Cl (5 mol%) were added and the
3
4
2
2
reaction mixture was stirred at 40 °C for 4 h, producing 3a in 87% yield. Also, the
cross-coupling of sily ether (S)-2b with iodobenzene proceeded under the same conditions,
4

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affording 3b in 83% yield. Subsequently, (R)-2c and (1R)-2d were subjected to the
cross-coupling reaction with bromobenzene instead of iodobenzene, providing 3c and 3d in 86
and 93% yield, respectively. Similarly, the reaction of acetal (1S)-2d with methyl
4-bromobenzoate uneventfullyfurnished3e bearing an ester functionalityin 82% yield.
Scheme 5. Suzuki-Miyaura cross-coupling reaction of2 with ArX.
Additionally, the cross-coupling reaction of 2 with 1,2- and 1,4-diiodobenzenes proceeded
effectively, producing several synthetically valuable compounds with bi-functional groups.
(Scheme 6). For example, (R)-2c was treated with 9-BBN (2 eq.) at 40 °C for 1h, then
1
,4-diiodobenzene (0.5 equiv.), 3M aq. K PO (3 equiv.) and PdCl (dppf)·CH Cl (5 mol %)
3
4
2
2
2
were added and the reaction proceeded at 40 °C for2 h. The crude coupling product was treated
with tetrabutylammonium fluoride (TBAF) in THF at room temperature for 5 h, providing diol
3f in 56% isolated yield over two steps. The cross-coupling reaction of (1S)-2d with
1,2-diiodobenzene or 1,4-diiodobenzene was performed under the same reaction conditions to
give diols 3g and 3h in 67% and 75% yields, respectively.
5

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Scheme 6. Suzuki-Miyaura cross-coupling reaction of2 with diiodobenzenes.
Furthermore, a challenging alkyl-alkyl cross-coupling reaction of (S)-2a with
16
1-bromooctane was executed according to a slightly modified protocol developed by Fu,
furnishing the coupling product3i in 60% yield (Scheme 7).
Scheme 7. Cross-coupling of (S)-2a with 1-bromooctane.
With an array of the cross-coupling products 3 in hand, we then verified that the 1,3-dithianyl
group in (1S)-3d and 3c could be removed without adversely affecting the enantiomeric excess
(Scheme 8). First, (1S)-3d was treated with PPTS (5 mol%) in MeOH to give alcohol (S)-4a,
17
which was exposed to an excess of iodomethane (10 equiv.) in a mixture of MeCN and aq.
5a
NaHCO at room temperature for 24 h, affording an assumedhemiacetal dimer that provided a
3
1
complicated H NMR spectrum. Thus, the crude product was treated with MeONH ·HCl (2
2
equiv.) in MeOH in the presence of pyridine (5 equiv.) to afford a separable 4:1 mixture of
6

ACCEPTED MANUSCRIPT
oximes (S)-4b and (S)-4c.Second, 3c was also converted to (R)-4b and (R)-4c by way of (R)-4a
under the same conditions. We found no discrepancy in the predicted and obtained optical
rotation values and confirmed that the chiral centers of (S)-4a and (R)-4a were not compromised
throughout these transformations.
Scheme 8. Oxime formation from (1S)-3d and 3c.
O-Protected α-hydroxyaldehydes as well as α-hydroxyaldehydes are synthetically valuable
intermediates. We next checked the enantiopurity of O-protected aldehydes formed via
deprotection of the 1,3-dithianyl group (Scheme 9). For example, (S)-3a was treated with an
excess of MeI (10 eq.) to uneventfully afford aldehyde 5a in 94% yield. The enantiomeric
excess was confirmed by converting 5a to benzoate 5a-1 via NaBH reduction and subsequent
4
18
benzoylation.HPLC analysis of 5a-1 revealed that no epimerization occurred throughout the
process. Additionally, deprotection of (S)-3b was effected under the same conditions to give
19
aldehyde 5b, which was converted to dibenzoate 5b-1 in three steps. HPLC analysis of 5b-1
showed that the deprotection step did not adversely affect the enantiopurity. Furthermore, the
absolute configuration of (S)-3b was confirmed to be S by converting to the known dimethoxy
20
derivative6.
7

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Scheme 9. Formation ofO-protected α-hydroxyaldehydes.
In addition to Suzuki-Miyaura cross-coupling, the synthetic utility of the terminal olefin in
(S)-1 and (S)-2 was exemplified by hydroformylation, which allows incorporation of a formyl
group in a highly regioselective fashion (Scheme 10). Initially, we found that hydroformylation
21
of (S)-1 by the catalytic system Rh(acac)(CO) /XANTPHOS produced hemiacetal 7 in 70%
2
yield together with a trace of complex mixture (<1%). Furthermore, (S)-2a, (S)-2b and (S)-2c
gave satisfactoryratios of linear aldehyde8/branched aldehyde 9.
Scheme 10. Hydroformylation of (S)-1 and (S)-2.
8

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In an effort to expand the synthetic utility of (S)-1 and (R)-1, we examined the
22
hydroxyl-directed 1,3-dipolar cycloaddition of nitrile oxides (Scheme 11). Initially, the reaction
of (S)-1 with benzohydroximinoyl chloride (10)using triethylamine as a base furnished 11 with
23
poor diastereoselectivity. Fortunately both the syn-selectivityand the yield of alcohol 11 were
24
dramatically improved using the Kanemasa protocol. The syn/anti ratio of 11 (>98% dr) was
1
25
determined by H NMR (500 MHz) after converting to the corresponding acetate 12. Next, the
26
oxazoline ring of 11 was cleaved by treatment with Zn to furnish diol 13, which was then
27
acetylated by treatment with Ac O/pyridine to afford diacetate 14 as a 2:1 separable mixture.
2
From a synthetic point of view, these results are very significant because scaffold (S)-1 permits
construction of a denselyfunctionalizedα-hydroxyaldehyde in several short steps.
Scheme 11. Hydroxyl-directed 1,3-dipolar cycloaddition of (S)-1
9

ACCEPTED MANUSCRIPT
3. Conclusion
Scaffold (S)-1 and O-protected derivatives (S)-2 are amenable to palladium-catalyzed
Suzuki-Miyaura cross-coupling and rhodium-catalyzedhydroformylation. Also, (S)-1 undergoes
hydroxyl-directed 1,3-dipolar cycloaddition in a highly stereoselective manner, providing a
variety of synthetically valuable intermediates (Scheme 12). Most importantly,
α-hydroxyaldehyde can be generated without any erosion of enantiopurity, definitively
demonstrating the high synthetic value of (S)-2.
S
S
S
S
S
S
S
Ar
Ar
CHO
OPG
S
S
O
OPG
(S)-2
OH
S)-1
OPG
(
HO
N
O
S
Ar
OHC
Ar
CHO
OH
S
S
OH
OPG
Scheme 12.Avarietyof transformations of (S)-1 and (S)-2.
4. Experimental section
4.1 General Procedure
All air- and moisture-sensitive reactions were performed in flame-dried glassware fitted with
rubber septa under a positive pressure of argon, unless otherwise noted. THF and DME were
distilled from sodium benzophenone ketyl. Dichloromethane was washed with water and brine
successively, and dried over 4Å molecular sieves. CAL-B was dried under reduced pressure
(<0.5 mmHg) at room temperature for 8 h. Isopropenyl acetate was freshly distilled before use.
Other commercially available reagents were used as received, unless otherwise noted. TLC
analysis was performed on precoated plates (0.25 mm, silica gel, Merck Kieselgel 60F ).
254
Compounds were visualized by dipping the plates in aq. PMA, ethanolic PMA, or
p-anisaldehyde, followed by heating. Flash column chromatography was performed with silica
gel 60 N (spherical, neutral, 40-50 µm, Kanto Chemical Co., Inc.). IR spectra were recorded on
a varian FTIR 7000 e. High performance liquid chromatography (HPLC) analyses were
performed with Hitachi High-Technologies Co. using Chiralpak IA or Chiralpak IB column
1
0

ACCEPTED MANUSCRIPT
(0.46 cm x 25 cm). Melting points were recorded with a Büchi 510 apparatus and are not
corrected. Optical rotations were measured on a JASCO DIP-1000. Mass spectra were recorded
1
13
on a JEOL JMS-DX 303. H-NMR (500 MHz) and C-NMR (125 MHz) spectra were
1
13
recorded on a JEOL JNM-LA 500. H-NMR (400 MHz) and C-NMR (100 MHz) spectra
were recorded on a JEOL JNM-ECS 400. The chemical shifts are given in δ units relative to
1
13
1
internal tetramethylsilane (0 ppm for H and C), chloroform (7.26 ppm for H, 77.0 ppm for
13
1
13
C), or methanol (3.30 ppm for H, 49.0 ppm for C). Elemental analysis was done using a
Perkin-Elmer 2400 CHN analyzer.
4.1.1. Racemic 1-(1,3-dithian-2-yl)prop-2-en-1-ols [(±)-1].
A solution of 1,3-dithiane (6.01 g, 50 mmol) in THF (100 mL) was cooled to -70 °C and a
solution of n-BuLi (1.56 M in hexane, 33.7 mL, 52.6 mmol) was added dropwise over a period
of 5 min. The reaction mixture was allowed to warm to -30 °C over the next 1.5 h, and then
cooled back down to -70 °C. Acrolein (3.67 mL, 55 mmol) was added dropwise over 2 min.
After stirring at this temperature for 10 min, thereaction was terminated by slow addition of 1M
HCl (60 mL). The aqueous mixture was diluted with brine (100 mL), and extracted into a
mixture of toluene (50 mL) and EtOAc (50 mL). The organic layer was washed with brine (100
mL x 2) and dried over anhydrous MgSO . Filtration and evaporation of the solvent in vacuo
4
1
followed by short-path distillation provided (±)-1 (7.93 g, 90% yield) as a colorless oil; H NMR
(
500 MHz, CDCl ) δ 6.00 (ddd, J = 16.8, 10.7, 5.8 Hz, 1H), 5.44 (dd, J = 17.1, 1.2 Hz, 1H), 5.23
3
(dd, J = 10.4, 1.2 Hz, 1H), 4.40-4.37 (m, 1H), 3.96 (d, J = 6.4 Hz, 1H), 2.98-2.92 (m, 2H),
13
2
.80-2.74 (m, 2H), 2.51 (d, J = 4.0 Hz, 1H), 2.13-2.06 (m, 1H), 2.01-1.94 (m, 1H); C NMR
(
100 MHz, CDCl ) δ 136.6, 117.5, 73.3, 51.7, 28.3, 28.0, 25.4; Anal. Calcd. for C H OS : C,
3
7
12
2
+
+
+
4
7.69; H, 6.86. Found: C, 47.29; H, 6.89; HRMS (FAB , [M+H] ) m/z calcd for [C H OS ] :
7 13 2
177.0408 found: 177.0407.
4
.1.2. Lipase-catalyzed kinetic resolution of (±)-1.
R)-1-(1,3-Dithian-2-yl)allyl acetate[(R)-1-OAc] and (S)-1-(1,3-Dithian-2-yl)prop-2-en-1-ol
(S)-1]
A mixture of (±)-1 (6.63 g, 37.6 mmol), 2-propenyl acetate (4.14 mL, 37.6 mmol) and CAL-B
752 mg, 20 mg/mmol of (±)-1) in toluene (37.6 mL) was stirred at 50 °C for 65 h. The enzyme
(
[
(
was removed by filtration through Celite 545, and washed with toluene (5 mLx 2). The filtrate was
concentrated in vacuo to give a crude oil (7.82 g), which was purified by column chromatography
11

ACCEPTED MANUSCRIPT
(silica gel, toluene/EtOAc=20/1~5/1) to afford (R)-1-OAc (4.30 g) as a pale yellow oil and (S)-1
(3.26 g) as a pale yellow oil, respectively. Short-pass distillation gave (R)-1-OAc (4.15 g, 50.6%) as
a colorless oil and (S)-1 (3.23 g, 48.7%) as a colorless oil, respectively.
23
1
(
R)-1-OAc: [
.7 Hz, 1H), 5.57 (dd, J = 6.7, 6.7 Hz, 1H), 5.40 (d, J = 17.1 Hz, 1H), 5 33 (d, J = 10.4 Hz, 1H),
.10 (d, J = 6.7 Hz, 1H), 2.96-2.90 (m, 2H), 2.81-2.75 (m, 2H), 2.13 (s, 3H), 2.13-2.08 (m, 1H),
α]D +20.3 (c 1.16, CHCl ); H NMR (500 MHz, CDCl ) δ 5.96 (ddd, J = 17.1, 10.4,
3 3
6
4
13
1
.98-1.92 (m, 1H); C NMR (125 MHz, CDCl ) δ 169.3, 132.9, 118.9, 48.8, 28.4, 28.1, 25.2, 20.7;
3
+
+
+
HRMS (FAB , [M+Na] )m/z calcd for[C H O S Na ] : 241.0333 found: 241.0332.
9
14 2 2
2
4
(
S)-1: [α] -20.1 (c 1.11, CHCl ).
D 3
(
R)-1-OAc was converted to (R)-1 by treatment with K CO (5 mol%) in MeOH at room
2 3
temperature for 2 h. HLC analysis: Chiralpak IA, n-hexane/2-propanol=9/1, 1.0 mL/min, 254 nm.
S)-1: t 10.8 min (>98% ee), (R)-1: t 12.0 min (96% ee).
(
R
R
4
.1.3. Lipase-catalyzed hydrolysis of (R)-1-OAc.
R)-1-(1,3-Dithian-2-yl)prop-2-en-1-ol [(R)-1]
Amixture of (R)-1-OAc (4.07 g, 18.6 mmol, 96% ee) and CAL-B (372 mg, 20 mg/mmol of
R)-1-OAc) in a mixed solution of phosphate buffer (pH 6.86, 1.9 mL) and 1,4-dioxane (18.6
(
(
mL) was stirred at 40 ºC for 65 h. The reaction mixture was passed through Celite 545 and
rinsed with toluene (5 mL x 2). The filtrate was concentrated in vacuo and the residue was
distributed between EtOAc (30 mL) and brine (20 mL). The separated organic layer was
washed with brine (30 mL), dried over anhydrous MgSO . Filtration and evaporation of the
4
solvent
toluene/EtOAc=1/0~15/1~3/1) provided (S)-1-OAc (645 mg, 2.95 mmol) and (R)-1 (2.67 g,
1% yield) as a colorless oil after short-path distillation.
in
vacuo
followed
by
column
chromatography
(silica
gel,
8
2
2
(
R)-1: [α] +21.7 (c 1.15, CHCl ).
D 3
(
S)-1-OAc was converted to (S)-1 by treatment with K CO (5 mol%) in MeOH at room
2 3
temperature for 2h. HPLC analysis: Chiralpak IA (n-hexane/2-propanol=9/1, 1.0 mL/min, 254
nm, (S)-1: t 10.9 min (76%ee), (R)-1: t 12.2 min (>98% ee).
R
R
4
.1.4. General procedurefor benzylation of (S)-1 and (R)-1.
S)-2-(1-(Benzyloxy)allyl)-1,3-dithiane [(S)-2a]
R)-2-(1-(Benzyloxy)allyl)-1,3-dithiane [(R)-2a]
BnCl (0.92 mL, 8.0mmol) was added to a suspensionof NaH (55% in mineral oil, 350 mg, 8
(
(
1
2

ACCEPTED MANUSCRIPT
mmol) in DMF (8 mL) at 5 °C, and then a solution of(S)-1 (705 mg, 4.0 mmol) in THF (5 mL)
was added dropwise over a period of 2 min. The reaction mixture was stirred at room
temperature for 2 h, poured into cold water, and extracted with toluene (20 mL x 2). The
combined extracts were washed successively with water (20 mL) and brine (20 mL). The
organic layer was dried over anhydrous MgSO , filtrated and concentratedin vacuo. Purification
4
of the crude oil by short-path distillation and subsequent column chromatography (silica gel,
21
n-hexane/EtOAc=20/1~10/1) gave (S)-2a (936 mg, 88 % yield) as a colorless oil; [
α
]D +21.1
1
(
c 1.13, CHCl ); H NMR (500 MHz, CDCl ) δ 7.38-7.32 (m, 4H), 7.29-7.26 (m, 1H), 5.88
3
3
(ddd, J = 17.7, 10.4, 8.3 Hz, 1H), 5.40 (d, J = 10.5 Hz, 1H), 5.33 (d, J = 17.5 Hz, 1H), 4.67 (d, J
=
12.0 Hz, 1H), 4.44 (d, J = 12.5 Hz, 1H), 4.24 (d, J = 5.5 Hz, 1H), 3.96 (dd, J = 7.7, 6.4 Hz,
13
1
H), 2.90-2.81 (m, 4H), 2.12-2.07 (m, 1H), 1.94-1.86 (m, 1H); C NMR (500 MHz, CDCl )
3
+
+
δ 137.2, 134.5, 127.7, 127.2, 126.9, 119.4, 81.5, 69.8, ,50.8, 29.3, 29.4; HRMS (EI , [M] ) m/z
+
calcd for [C H OS ] : 266.0799 found: 266.0796.
14
18
2
24
(
R)-2a was obtained from (R)-1 in 85% yield: [α]D -19.1 (c 1.09, CHCl3).
4
.1.5. General procedure for silylation of (S)-1 and (R)-1 with TBDMSCl.
S)-((1-(1,3-Dithian-2-yl)allyl)oxy)(tert-butyl)dimethylsilane[(S)-2b]
R)-((1-(1,3-Dithian-2-yl)allyl)oxy)(tert-butyl)dimethylsilane[(R)-2b]
(
(
TBDMSCl (610 mg, 4.05 mmol) was added to a solution of (S)-1 (353 g, 2.0 mmol) and
imidazole (681 mg, 10.0 mmol) in DMF (5 mL) at room temperature. After stirring for 4 h,
glycerine (2 mL) was added to the reaction mixture, and stirring was continued for an additional
1
h. The reaction mixture was distributed between toluene (30 mL) and water (30 mL). The
organic layer was successively washed with sat. aq. NaHCO (20 mL) and brine (30 mL), dried
3
over anhydrous MgSO Filtration and evaporation of the solvent in vacuo followed by column
4.
22
chromatography (silica gel, n-hexane/EtOAc=15/1) gave (S)-2b (564 mg, 95% yield); [
α
]D
1
-
13.5 (c 0.98, CHCl ); H NMR(500 MHz, CDCl ) δ 5.92 (dd, J = 17.0, 10.5, 6.5 Hz, 1H), 5.28
3
3
(d, J = 17.0 Hz, 1H), 5.22 (d, J = 10.0 Hz, 1H), 4.23 (dd, J = 6.5, 6.0 Hz, 1H), 4.12 (d, J = 6.0 Hz,
1H), 2.88-2.82 (m, 4H), 2.10-2.08 (m, 1H), 1.90-1.85 (m, 1H), 0.92 (s, 9H), 0.12 (s, 3H), 0.07 (s,
13
3
H); C NMR (125 MHz, CDCl ) δ 137.9, 116.6, 76.4, 53.6, 29.7, 28.9, 25.6, 18.0, -4.5, -5.0;
3
+
+
+
HRMS (FAB , [M+H] ) m/z calcd for[C H OS Si ] : 291.1273 found: 291.1267.
13
27
2
22
(
R)-2b was obtained from (R)-1 in 95% yield; [α]D +14.5 (c 1.00, CHCl3).
4.1.6. General procedure for silylation of (S)-1 and (R)-1 with TBDPSCl.
1
3

ACCEPTED MANUSCRIPT
(S)-((1-(1,3-Dithian-2-yl)allyl)oxy)(tert-butyl)diphenylsilane[(S)-2c]
(R)-((1-(1,3-Dithian-2-yl)allyl)oxy)(tert-butyl)diphenylsilane[(R)-2c]
Asolution of TBDPSCl (1.10 g, 4.0 mmol) in DMF (5 mL) was added to a solution of (S)-1
(
353 mg, 2.0 mmol) and imidazole (681 mg, 10.0 mmol) in DMF (5 mL). The reaction mixture
was stirred at room temperature for 12 h. The reaction was quenched by addition of glycerine (2
ml), and stirring was continued for 1 h. The mixture was distributed between toluene (30 mL)
and water (50 mL). The organic layer was washed with sat. aq. NaHCO (20 mL), dried over
3
anhydrous MgSO , filtered and concentrated in vacuo. The residual viscous oil (1.68 g) was
4
purified by column chromatography (silica gel,n-hexane/EtOAc=15/1) to afford (S)-2c (800 mg,
22
9
7% yield) as a white semi-solid; [α]D -59.4 (c 1.01, CHCl ); FTIR (KBr): 2932, 2857, 1588,
3
-1 1
1
473, 1428, 1113, 931, 875, 708 cm ; H NMR (500 MHz, CDCl ) δ 7.77 (d, J = 7.5 Hz, 2H),
3
7.66 (d, J = 7.0 Hz, 2H), 7.46-7.27 (m, 6H), 5.92 (ddd,J = 17.0, 10.5, 6.5 Hz, 1H), 5.11-5.06 (m,
2H), 4.35 (dd, J = 5.5, 5.5 Hz, 1H), 3.40 (d, J = 5.0 Hz, 1H), 2.82-2.61 (m, 4H), 2.04-2.01 (m,
13
1
H), 1.85-1.77 (m, 1H), 1.09 (s, 9H); C NMR(125 MHz, CDCl ) δ 136.5, 135.9, 135.9, 133.7,
3
+
1
33.4, 129.7, 129.6, 127.4, 127.4, 117.4, 76.6, 54.4, 30.4, 30.0, 26.9, 26.2, 19.4; HRMS (FAB ,
+
+
[
M+H] ) m/z calcd for [C H OS Si ] : 415.1586 found: 415.1565.
23 31 2
23
(
R)-2c was obtained from (R)-1 in 95% yield; [α]D +60.3 (c 0.90, CHCl3).
4
.1.7. 2-((1S)-1-(1-Ethoxyethoxy)allyl)-1,3-dithiane [(1S)-2d].
To a solution of (S)-1 (1.06 g, 6.0 mmol) and ethyl vinyl ether (1.15 mL, 12.0 mmol) in
CH Cl (20 mL) was added pyridinium p-toluenesulfonate (PPTS) (75 mg, 0.3 mmol) at room
2
2
temperature. After stirring for 2 h, the reaction was terminated by addition of sat. aq. NaHCO3
solution (20 mL). The organic layer separated was dried over anhydrous MgSO , filtered and
4
concentrated in vacuo. The residue (1.50 g) was purified by column chromatography (silica gel,
23
n-hexane/EtOAc/Et N=100/5/1) to afford (1S)-2d (1.40 g, 94% yield) as a colorless oil; [
α
]D
3
1
+
17.9 (c 1.44, CHCl ); H NMR (500 MHz, CDCl ) δ 6.00-5.78 (m, 1H), 5.40-5.28 (m, 2H),
3
3
4.82-4.75 (m, 1H), 4.30-4.12 (m, 2H), 3.75-3.40 (m, 2H), 2.95-2.80 (m, 4H), 2.15-2.06 (m, 1H),
13
1
.95-1.85 (m, 1H), 1.40-1.30 (m, 3H), 1.24-1.14 (m,3H).; C NMR (125 MHz, CDCl ) δ 135.5,
3
134.6, 118.6, 117.1, 98.7, 96.1, 78.7, 78.3, 59.9, 58.1, 51.1, 50.7, 29.2, 25.2, 19.4, 19.2, 14.6,
+
+
+
1
4.6, 14.3; HRMS (FAB , [M+H] ) m/z calcd for[C H OS Si ] : 415.1586 found: 415.1565.
23 31 2
4.1.8. 2-((1R)-1-(1-Ethoxyethoxy)allyl)-1,3-dithiane [(1R)-2d].
To a solution of (R)-1 (1.76 g, 10.0 mmol) and ethyl vinyl ether (1.92 mL, 20 mmol) in
1
4

ACCEPTED MANUSCRIPT
CH Cl (20 mL) was added pyridinium p-toluenesulfonate (PPTS) (63 mg, 0.25 mmol) at room
2
2
temperature. After stirring for 3 h, the reaction was terminated by addition of sat. aq. NaHCO3
solution (20 mL). The organic layer separated was dried over anhydrous MgSO , filtered and
4
concentrated in vacuo. The residue (2.46 g) was purified by column chromatography (silica gel,
n-hexane/EtOAc/Et N=100/5/1) to afford (1R)-2d (2.39 g, 96% yield) as a colorless oil;
3
21
1
[α] -17.1 (c 1.50, CHCl ); H NMR (400 MHz, CDCl ) δ 6.00-5.77 (m, 1H), 5.38-5.28 (m,
D 3 3
2H), 4.84-4.75 (m, 1H), 4.28-4.12 (m, 2H), 3.75-3.40 (m, 2H), 2.94-2.80 (m, 4H), 2.15-2.05 (m,
13
1
H), 1.97-1.85 (m, 1H), 1.37-1.32 (m, 3H), 1.23-1.14 (m, 3H).; C NMR (100 MHz, CDCl )
3
δ 135.8, 134.9, 119.2, 117.8, 99.2, 96.6, 79.1, 78.9, 60.5, 58.6, 51.6, 51.3, 29.7, 25.6, 19.8, 19.6,
15.0, 14.7.
4
.1.9. General protocol for Suzuki-Miyaura cross-coupling reaction of (S)-2 and (R)-2 with
bromobenzene and aryl iodides.
.1.9-1. (S)-2-(1-(Benzyloxy)-3-phenylpropyl)-1,3-dithiane [3a].
4
To a solution of (S)-2a (490 mg, 1.84 mmol)in THF (5 mL) was added 9-BBN(449 mg, 3.68
mmol) in one portion and the mixture was stirred at40 °C for 1 h under argon atmosphere. Then,
iodobenzene (0.41 ml, 3.68 mmol), aq. 3M K PO (2 mL, 5.52 mmol) and PdCl (dppf)·CH Cl
3
4
2
2
2
(
75 mg, 0.092 mmol) were added and the mixture waspurged with argon twice. Thedark brown
mixture was heated at 40 °C for 4 h. After coolingto room temperature, ethanolamine (0.44 mL,
.36 mmol) was added to the reaction mixture and stirred for 1 h. The mixture was distributed
between hexane (30 mL) and water (20 mL). The organic layer was washed with brine (20 mLx
7
2
), dried over anhydrous MgSO , filtered, and concentrated in vacuo. Purification of the residue
4
by column chromatography (silica gel, n-hexane/EtOAc=20/1) gave 3a (554 mg, 87% yield) as
22
1
coloress oil; [
α]D -37.1 (c 1.13, CHCl ); H NMR (500 MHz, CDCl ) δ 7.47-7.14 (m, 10H),
3 3
4.76 (d, J = 11.5 Hz, 1H), 4.55 (d, J = 11.5 Hz, 1H), 4.38 (d, J = 5.0 Hz, 1H), 3.64-3.61 (m, 1H),
13
2
.90-2.78 (m, 5H), 2.64-2.59 (m, 1H), 2.13-2.03 (m, 3H), 1.92-1.85 (m, 1H); C NMR (125
MHz, CDCl ) δ 141.5, 137.9, 128.3, 128.2, 127.9, 127.5, 125.6, 80.0, 72.1, 52.0, 33.6, 31.5, 30.4,
3
+
+
+
2
6.1; HRMS (FAB , [M+H] ) m/z calcd for[C H OS ] : 345.1347 found: 345.1353.
20 25 2
4.1.9-2. (S)-(1-(1,3-Dithian-2-yl)-3-phenylpropoxy)(tert-butyl)dimethylsilane [3b].
19
1
Compound 3b was obtained from (S)-2b in 83% yield, [
NMR (500 MHz, CDCl ) δ 7.29-7.16 (m, 5H), 4.22 (d, J = 5.2 Hz, 1H), 3.93-3.89 (m, 1H),
α]D -4.92 (c 1.42, CHCl ); H
3
3
2.87-2.83 (m, 4H), 2.78-2.72 (m, 1H), 2.26-2.61 (m, 1H), 2.12-2.08 (m, 2H), 2.05-1.97 (m, 1H),
1
5

ACCEPTED MANUSCRIPT
13
0
.95 (s, 9H), 0.15 (s, 3H), 0.10 (s, 3H); C NMR (125 MHz, CDCl ) δ 141.9, 128.3, 128.3,
3
+
+
1
25.7, 74.1, 54.2, 36.2, 31.1, 30.5, 30.4, 26.3, 25.9, 18.2, -4.4; HRMS (FAB , [M+H] ) m/z
+
calcd for [C H OS Si ] : 369.1742 found: 369.1734.
19
33
2
4.1.9-3. (R)-(1-(1,3-Dithian-2-yl)-3-phenylpropoxy)(tert-butyl)diphenylsilane [3c].
To a solution of (R)-2c (207 mg, 0.5 mmol) in THF (5 mL) was added 9-BBN (122 mg, 1.0
mmol) and the mixture was stirred at 40 °C for 1 h under argon atmosphere. Then,
bromobenzene (0.11 mL, 1.0 mmol), aq. 3M K PO (1 mL, 3 mmol) and PdCl (dppf)·CH Cl
3
4
2
2
2
(
41 mg, 0.05 mmol) were added and the mixture was purged with argon twice. The dark brown
mixture was heated at 45 °C for 7 h. After coolingto room temperature, ethanolamine (0.18 mL,
.0 mmol) was added to the reaction mixture and stirred for 1 h. The mixture was distributed
between hexane (30 mL) and water (20 mL). The organic layer was washed with brine (20 mLx
3
2
), dried over anhydrous MgSO , filtered, and concentrated in vacuo. Purification of the residue
4
by column chromatography (silica gel, n-hexane/EtOAc=30/1) gave 3c (212 mg, 86% yield) as
22
1
coloress oil; [
H), 7.72 (d, J = 6.7 Hz, 2H), 7.45-7.10 (m, 9H), 6.99 (d, J = 7.3 Hz, 2H), 4.06 (d, J = 4.0 Hz,
H), 4.05-3.97 (m, 1H), 2.82-2.58 (m, 5H), 2.48-2.41 (m, 1H), 2.05-1.75 (m, 4H), 1.11 (s, 9H);
α]D +13.8 (c 1.63, CHCl ); H NMR (500 MHz, CDCl ) δ 7.79 (d, J = 7.0 Hz,
3 3
2
1
13
C NMR (125 MHz, CDCl ) δ 141.6, 136.1, 136.0, 133.9, 133.7, 129.7, 128.2, 128.1, 127.6,
3
+
+
1
27.5, 125.6, 75.0, 55.1, 36.0, 31.9, 30.8, 30.4, 27.0, 26.4, 19.5; HRMS (FAB , [M+H] ) m/z
+
calcd for [C H OS Si ] : 493.2055 found: 493.2039.
29
37
2
4.1.9-4. 2-((1R)-1-(1-Ethoxyethoxy)-3-phenylpropyl)-1,3-dithiane [3d].
22
1
Compound 3d was obtained from (1R)-2d in 93% yield; [
400 MHz, CDCl ) δ 7.30-7.12 (m, 5H), 4.91 (d, J = 5.2 Hz, 0.5H), 4.78 (d, J = 5.2 Hz, 0.5H),
α]D +24.0 (c 1.31, CHCl ); H NMR
3
(
3
4.41 (d, J = 4.8 Hz, 0.5H), 4.32 (d, J = 4.4 Hz, 0.5H), 3.88-3.47 (m, 3H), 2.92-2.57 (m, 6H),
2.14-1.80 (m, 4H), 1.38 (d, J = 5.2 Hz, 1.5H), 1.35 (d, J = 5.2 Hz, 1.5 H), 1.20 (t, J = 6.8 Hz, 1.5
13
H), 1.18 (d, J = 6.8 Hz, 1.5 H); C NMR (100 MHz, CDCl ) δ 141.9, 141.5, 128.4, 128.3, 125.9,
3
125.7, 99.9, 99.7, 78.1, 60.3, 52.8, 52.7, 34.5, 33.2, 31.7, 31.5, 30.9, 30.6, 26.3, 20.2, 20.1, 15.3;
+
+
+
HRMS (FAB , [M+H] ) m/z calcd for[C H O S ] : 327.1452 found: 327.1473.
17
27 2 2
4
.1.9-5. Methyl 4-((3S)-3-(1,3-dithian-2-yl)-3-(1-ethoxyethoxy)propyl)benzoate [3e].
To a solution of (1S)-2d (514 mg, 2.07 mmol) in THF (10 mL) was added 9-BBN (505 mg,
.14 mmol) and the mixture was stirred at 40 °C for 1 h under argon atmosphere. Then, a
4
1
6

ACCEPTED MANUSCRIPT
solution of methyl 4-bromobenzoate (890 mg, 4.14 mmol) in THF (5mL), aq. 3M K PO (3 mL,
3
4
9
mmol) and PdCl (dppf)·CH Cl (82 mg, 0.10 mmol) were added and the mixture was purged
2 2 2
with argon twice. The dark brown mixture was heated at 45 °C for 7 h. After cooling to room
temperature, ethanolamine (0.48 mL, 8.0 mmol) was added to the reaction mixture and stirred
for 1 h. The mixture was distributed between hexane (30 mL) and water (20 mL). The organic
layer was washed with brine (20 mL x 2), dried over anhydrous MgSO , filtered, and
4
concentrated in vacuo. Purification of the residue by column chromatography (silica gel,
23
toluene/EtOAc=20/1~10/1) gave 3e (650 mg, 82%) as coloress oil; [
α
]D -22.7 (c 1.45, CHCl3);
1
FTIR (KBr): 3321, 2894, 1718, 1609, 1431, 1280, 1102, 704, 649 cm-1; H NMR (500 MHZ,
CDCl ) δ 7.95 (d, J = 5.8 Hz, 2H), 7.25-7.30 (m, 2H), 4.92 (q,J = 5.5 Hz, 0.5H), 4.79 (q, J = 5.5
3
Hz, 0.5H), 4.44 (d, J = 4.6 Hz, 0.5H), 4.34 (d, J = 4.9 Hz, 0.5H), 3.90 (s, 3H), 3.90-3.51 (m, 3H),
2.95-2.80 (m, 5H), 2.76-2.65 (m, 1H), 2.16-2.03 (m,3H), 1.95-1.82 (m, 1H), 1.39 (d, J = 5.5 Hz,
13
1
.5H), 1.36 (d, J = 5.2 Hz, 1.5H), 1.22 (t, J = 7.1Hz, 1.5H), 1.19 (t, J = 7.0 Hz, 1.5H).; C NMR
125 MHz, CDCl ) δ 167.2, 147.6, 147.2, 130.2, 130.0, 129.9, 129.7, 128.5, 127.9, 127.8, 127.3,
(
3
126.7, 100.0, 99.8, 78.0, 70.9, 60.5, 60.4, 52.8, 52.5, 52.0, 42.0, 34.2, 33.0, 32.1, 31.8, 31.6, 30.9,
+
+
3
0.6, 27.4, 27.2, 26.2, 22.7, 22.0, 20.2, 20.1, 15.4; HRMS (FAB , [M+Na] ) m/z calcd for [C
19
+
H O S Na] : 407.1327 found: 407.1312.
2
8 4 2
4
.1.10. General protocol for Suzuki-Miyaura cross-coupling reaction of (R)-2 and (1S)-2d with
diiodobenzenes.
.1.10-1. (1R,1'R)-3,3'-(1,4-Phenylene)bis(1-(1,3-dithian-2-yl)propan-1-ol)[3f].
4
To a solution of (R)-2c (829 mg, 2.0 mmol) in THF (8 mL) was added 9-BBN (488 mg, 4.0
mmol) in one portion and the mixture was stirred at40 °C for 1 h under argon atmosphere. Then,
1
,4-diiodobenzene (330 mg, 1.0 mmol, 0.5 equiv.), 3M. aq. K PO (3 mL, 9.0 mmol),
3 4
PdCl (dppf)·CH Cl (82 mg, 0.10 mmol) and THF (10 mL) were added to the mixture in this
2
2
2
order. The whole mixture was purged with argon twice. The dark green mixture was heated at
0 °C for 2 h. After cooling to room temperature, ethanolamine (0.48 mL, 8.0 mmol) and
4
toluene (20 mL) were added and the mixture was stirred for 1 h. Hexane (30 mL) and water (30
mL) were added and the organic layer separated was washed with brine (30 mL), dried over
anhydrous MgSO . Filtration and concentrationin vacuo provided a crude oil, a THF solution (4
4
mL) of which was treated with Bu NF (1 M THF solution, 4 mL) for 5 h. The reaction mixture
4
was distributed between toluene (30 mL) and water (20 mL). The organic layer was dried over
anhydrous MgSO , filtered, and concentrated in vacuo. The residue was washed with hot
4
1
7

ACCEPTED MANUSCRIPT
hexane twice, and purified by column chromatography(silica gel, toluene/ EtOAc = 3/1) to give
22
3
f (241 mg, 56%) as a white amorphous solid; [α]D +64.6 (c 1.55, CHCl ); FTIR (KBr): 3427,
3
-1 1
3
229, 2949, 2928, 2899, 2358, 1419, 1278, 1083, 905, 551 cm ; H NMR (500 MHz, CDCl )
3
δ 7.15 (s, 4H), 3.91-3.85 (m, 4H), 2.95-2.83 (m, 6H), 2.76-2.66 (m, 6H), 2.45 (d, J = 2.5 Hz,
13
2
H), 2.20-1.80 (m, 8H).; C NMR (125 MHz, CDCl ) δ 139.1, 128.5, 71.2, 52.1, 35.7, 31.5,
3
+
+
+
2
8.2, 27.7, 25.6; HRMS (FAB , [M+H] ) m/z calcd for [C H O S ] : 431.1207 found:
20 31 2 4
431.1182.
4.1.10-2. (1S,1'S)-3,3'-(1,2-Phenylene)bis(1-(1,3-dithian-2-yl)propan-1-ol)[3g]
To a solution of (1S)-2d (497 mg, 2.0 mmol) in THF (8 mL) was added 9-BBN (488 mg,
4.0 mmol) in one portion and the mixture was stirred at 40 °C for 1 h under argon atmosphere.
To the reaction mixture, 1,2-diiodobenzene (297 mg, 0.9 mmol, 0.45 equiv.), 3 M aq. K PO (3
3
4
mL, 9.0 mmol), PdCl (dppf)·CH Cl (82 mg, 0.1 mmol) and THF (8 mL) were added. The
2
2
2
resulting dark mixture was heated at 40 °C for 3 h. After cooling to room temperature,
ethanolamine (0.48 mL, 8.0 mmol) was added and stirred for 1 h. The mixture was diluted with
toluene (30 mL) and brine (20 mL) and the organic layer separated was washed with brine (30
mL), dried over MgSO , fiiltered and evaporation of the solvent in vacuo. The crude oil was
4
purified by short-path column chromatography (silica gel, n-hexane/EtOAc =10/1~5/1) to afford
a pale yellow oil, which was treated with a catalytic amount of PPTS in MeOH (5 mL) for 1 h.
The reaction mixture was distributed between EtOAc (30 mL) and sat. aq. NaHCO (20 mL).
3
The organic layer was dried over anhydrous MgSO , filtered, and concentrated in vacuo.
4
Purification of the crude oil by column chromatography (silica gel, toluene/EtOAc=3/1) gave3g
23
1
(
260 mg, 67%) as a pale yellow oil; [
α]D -50.0 (c 1.05, CHCl ); H NMR (500 MHz, CDCl )
3 3
δ 7.24-7.15 (m, 4H), 3.95-3.89 (m, 4H), 2.95-2.85 (m, 6H), 2.82-2.68 (m, 8H), 2.20-1.81 (m,
13
8
H), 2.20-1.80 (m, 8H); C NMR (125 MHz, CDCl ) δ 139.5, 129.2, 126.2, 71.5, 52.1, 35.6,
3
+
+
+
2
8.3, 27.8, 25.5; HRMS (FAB , [M+Na] ) m/z calcd for [C H NaO S ] : 453.1026 found:
20 30 2 4
453.1010.
4
.1.10-3. (1S,1'S)-3,3'-(1,4-phenylene)bis(1-(1,3-dithian-2-yl)propan-1-ol)[3h].
To a solution of (1S)-2d (497 mg, 2.0 mmol) in THF (8 mL) was added 9-BBN (488 mg,
.0 mmol) in one portion and the mixture was stirred at 40 °C for 1 h under argon atmosphere.
,4-Diiodobenzene (297 mg, 0.9 mmol, 0.45 equiv.), 3 M aq. K PO (3 ml, 9.0 mmol),
4
1
3
4
PdCl (dppf)·CH Cl (82 mg, 0.1 mmol) and THF (10 mL) were added to the reaction mixture.
2
2
2
1
8

ACCEPTED MANUSCRIPT
The resulting dark mixture was heated at 40 °C for 2.5 h. After cooling to room temperature,
ethanolamine (0.48 mL, 8.0 mmol) and toluene (20 mL) were added and the mixture was stirred
for 1 h. Hexane (30 mL) and water (30 mL) were added to the mixture and the organic layer
separated was washed with brine (30 mL), dried over MgSO . Filtration and concentration in
4
vacuo provided a crude oil, which was treated with a catalytic amount of PPTS in MeOH (5
mL) for 1 h. The reaction mixture was distributed between EtOAc (30 mL) and sat. aq.
NaHCO (20 mL). The organic layer was dried over anhydrous MgSO , filtered and
3
4
concentrated in vacuo. The residue was washed with hot hexane twice, and purified by column
chromatography (silica gel, toluene/EtOAc = 3/1) to give 3h (291 mg, 75%) as a white
22
amorphous solid; [α]D -65.9 (c 1.05, CHCl3).
4
.1.11. (S)-2-(1-(Benzyloxy)undecyl)-1,3-dithiane [3i].
Asolution of (S)-2a (133 mg, 0.50 mmol) and 9-BBN (122 mg, 1.0 mmol) in THF (2.0 mL)
was stirred at room temperature for 2 h. Pd(acac) (8mg, 0.025 mmol), PCy (28 mg, 0.1 mmol),
2
3
CsOH•H O (252 mg, 1.5 mmol) and 1-bromooctane (0.26 mL, 1.5 mmol) were added to the
2
mixture, and purged with argon twice. The mixture was heated at 60 °C for 10 h and cooled to
room temperature. The mixture was diluted with n-hexane (20 mL), washed with brine (20 mL
x 2), dried over anhydrous MgSO and concentrated in vacuo. Purification of the residual oil by
4
column chromatography (silica gel, n-hexane/EtOAc = 25/1) provided 3i (114 mg, 60% yield)
21
1
as a pale yellow oil; [
H), 4.74 (d, J = 11.6 Hz, 1H), 4.56 (d, J = 11.6 Hz, 1H), 4.35 (d, J = 4.9 Hz, 1H), 3.61-3.57 (m,
H), 2.92-2.80 (m, 4H), 2.14-2.10 (m, 1H), 1.94-1.85 (m, 1H), 1.72-1.69 (m, 2H), 1.50-1.45 (m,
α]D -27.4 (c 1.02, CHCl ); H NMR (500 MHz, CDCl ) δ 7.47-7.26 (m,
3 3
5
1
13
1
H), 1.30-1.24 (m, 15H), 0.88 (t, J = 7.0 Hz, 3H). C NMR (125 MHz, CDCl ) δ 138.2, 128.3,
3
128.0, 127.6, 81.0, 72.3, 52.4, 32.1, 31.9, 30.6, 30.59, 29.6, 29.5, 29.3, 26.3, 25.5, 22.7, 14.1;
+
+
+
HRMS (FAB , [M+H] ) m/z calcd for[C H OS ] : 381.2286 found: 381.2296.
22
37
2
4
.1.12. General procedure for oxime formation from3d and 3c.
.1.12-1. (S)-1-(1,3-Dithian-2-yl)-3-phenylpropan-1-ol
R)-1-(1,3-Dithian-2-yl)-3-phenylpropan-1-ol [(R)-4a]
Compound 3d (784 mg, 2.4 mmol) was treated with PPTS (31.4 mg, 0.125 mmol) in
4
[(S)-4a].
and
(
MeOH (5 ml) at room temperature for 1 h. The reaction mixture was distributed between
toluene (20 ml) and sat. aq. NaHCO (10 ml). The organic layer was dried over anhydrous
3
MgSO .Filtration and evaporation of the solvent in vacuo afforded an oil (610 mg), which was
4
1
9

ACCEPTED MANUSCRIPT
purified by column chromatography (silica gel, n-hexane/EtOAc=5/1~4/1) to afford (S)-4a (586
21
D
mg, 96% yield) as a colorless oil; [α] -50.7 (c 1.33, CHCl ); FTIR (KBr): 3308, 3246, 3024,
3
1
2
907, 2364, 1653, 1597, 1496, 1453, 1278, 1070, 750, 698 cm-1; H NMR(500 MHz, CDCl ) δ
3
7.35-7.15 (m, 5H), 3.92-3.85(m, 2H), 2.95-2.84 (m, 3H), 2.76-2.68 (m, 3H), 2.48 (d, J = 2.2 Hz,
13
1
H), 2.20-1.84 (m, 4H); C NMR(125 MHz, CDCl ) δ 141.6, 128.4, 125.7, 71.1, 52.1, 35.6,
3
+
+
+
3
1.8, 28.1, 27.7, 25.5; HRMS (FAB , [M+H] ) m/z calcd for [C H OS ] : 255.0877 found:
13 19 2
255.0849.
(R)-4a was obtained from 3c in 90% by treatment with TBAF in THF followed by column
24
D
chromatography(silica gel, n-hexane/EtOAc=5/1~4/1); [α] +50.8 (c 1.38, CHCl ).
3
4.1.12-2.
(S,
E)-2-Hydroxy-4-phenylbutanal
O-methyl
oxime
[(S)-4b],
(S,
Z)-2-Hydroxy-4-phenylbutanal O-methyl oxime [(S)-4c], (R, E)-2-Hydroxy-4-phenylbutanal
O-methyl oxime[(R)-4b], and (R, Z)-2-Hydroxy-4-phenylbutanal O-methyl oxime[(R)-4c].
The alcohol (S)-4a (592 mg, 2.33 mmol) was treated with MeI (1.50 mL, 24 mmol) and
NaHCO (3.02 g, 36 mmol) in MeCN/H O (12 mL/3 mL) at room temperature for 24 h. The
3
2
solvent was evaporated and sat. aq. Na SO (10 mL) was added to the residue. The aqueous
2
3
phase was extracted with CHCl (20 mLx 2) and the combined extracts were washedwith brine
3
(
20 mL), dried over anhydrous MgSO . Filtration and concentration in vacuo provided an oil
4
(
428 mg), to which pyridine (1 mL), MeOH (5 mL) andMeONH ·HCl (418 mg, 5 mmol) were
2
added. The reaction mixture was stirred at room temperature for 12 h, and distributed with
CHCl (30 mL) and water (20 mL). The organic layer was washed with brine (20 mL), dried
3
over anhydrous MgSO . Filtration and evaporation of the solvent gave a mixture of oxime
4
alcohols (380 mg) as an oil, which were purified by column chromatography (silica gel,
toluene/EtOAc = 5/1~4/1) to give (S)-4b (211 mg, 47%) and (S)-4c (54 mg, 12%), respectively.
22
D
1
(
S)-4b: R = 0.37 (toluene/EtOAc = 5/1), [α]
+19.2 (C 1.35, CHCl ), H NMR(400 MHz,
f
3
CDCl ) δ 7.39 (d, J = 4.8 Hz, 1H), 4.31-4.26 (m, 1H), 3.86 (s, 3H), 2.36 (d, J = 4.0 Hz, 1H),
3
13
2
.00-1.85 (m, 2H).; C NMR(100 MHz, CDCl ) δ 151.3, 141.2, 128.4, 125.9, 68.4, 61.6, 36.7,
3
+
+
+
3
1.0; HRMS (FAB , [M+H] ) m/z calcd for[C H NO ] : 194.1181 found: 194.1177.
11 16 2
2
1
1
(
S)-4c: R=0.27(toluene/EtOAc = 5/1), [α] -51.1 (C 0.80, CHCl ), H NMR(400 MHz,
f D 3
CDCl ) δ 7.39 (d, J = 4.8 Hz, 1H), 4.31-4.26 (m, 1H), 3.86 (s, 3H), 2.36 (d, J = 4.0 Hz, 1H),
3
13
2
.00-1.85 (m, 2H); C NMR(100 MHz, CDCl ) δ 151.3, 141.2, 128.4, 125.9, 68.4, 61.6, 36.7,
3
31.0.
21
(
R)-4b was obtained from (R)-4a in 44% yield; [α]D -18.7 (c1.27, CHCl3).
2
0

ACCEPTED MANUSCRIPT
21
(
R)-4c was obtained from (R)-4a in 11% yield; [α]D +52.5 (c 0.54, CHCl3).
4.1.13. (S)-2-(Benzyloxy)-4-phenylbutanal [5a].
MeI (0.75 mL, 12.0 mmol) was added to a mixture of (S)-3a (414 mg, 1.20 mmol) and
NaHCO (1.26 g, 15.0 mmol) in an aqueous MeCN/water (10 mL/2 mL) at room temperature
3
and the resulting mixture was stirred for 24 h. Thereaction mixture was diluted with EtOAc (30
mL), washed with sat. aq. Na S O (15 mL) and brine (20 mL x 2). Drying over MgSO and
2
2
3
4
22
concentration in vacuo provided 5a (288 mg, 94% yield) as an colorless oil; [α]D -80.1 (c 1.50,
1
CHCl ): H NMR(500 MHz, CDCl ) δ 9.65 (bs, 1H), 7.45-7.15 (m, 10H), 4.68 (d, J = 11.6 Hz,
3
3
1H), 4.54 (d, J = 11.6 Hz, 1H), 3.76 (t, J = 5.8 Hz, 1H), 2.85-2.68 (m, 2H), 2.10-1.95 (m, 2H).;
13
C NMR (125 MHz, CDCl ) δ 203.4, 140.8, 137.2, 128.5, 128.4, 128.0, 126.1, 82.5, 72.5, 31.6,
3
+
+
+
3
0.8; HRMS (FAB , [M+Na] ) m/z calcd for[C H NaO ] : 277.1204 found: 277.1215.
17 18 2
4.1.14. (S)-2-(Benzyloxy)-4-phenylbutyl benzoate [5a-1].
Aldehyde 5a (288 mg) was reduced with NaBH (43 mg, 1.13 mmol) in MeOH (3 mL) at
4
room temperature for 10 min. The reaction mixture was extracted with toluene (20 mL) and
water (10 mL). Drying over anhydrous MgSO , filtration, and evaporation of the solvent gave
4
alcohol, which was treated with benzoyl chloride (0.35 mL, 422 mg, 3.0 mmol) /pyridine (1
mL) at room temperature for 2 h. The reaction mixture was distributed between toluene (20 mL)
and sat. aq. NaHCO (20 mL). The organic layer was washed with brine (10 mLx 2), dried over
3
anhydrous MgSO , filtered, and concentrated in vacuo, affording a crude benzoate, which was
4
purified bycolumn chromatography(silica gel,n-hexane/EtOAc=12/1) to provide5a-1 (345 mg,
21
1
8
0% yield) as a colorless oil. [
d, J = 7.6 Hz, 2H), 7.60-7.16 (m, 8H), 4.74 (d, J = 11.6 Hz, 1H), 4.60 (d, J = 11.6 Hz, 1H), 4.49
dd, J = 11.6, 4.0 Hz, 1H), 4.37 (dd,J = 11.6, 5.8 Hz, 1H), 3.79-3.74 (m, 1H), 2.87-2.81(m, 1H),
α]D -11.7 (c 1.04, CHCl ); H NMR (500 MHz, CDCl ) δ 8.04
3 3
(
(
13
2
.74-2.68 (m, 1H), 2.05-1.92 (m, 2H); C NMR (125 MHz, CDCl ) δ 166.3, 141.6, 138.2,
3
+
+
1
32.9, 129.9, 129.5, 128.3, 127.8, 127.6, 125.8, 76.0, 66.2, 33.6, 31.4; HRMS (FAB , [M+H] )
+
m/z calcd for[C H O ] : 361.1804 found: 361.1802.
2
4 25 3
Chiral HPLC: Chiralpak IB, (254 nm, n-hexane/2-propanol=100/1, 0.6 ml/min, 254 nm,
racemate; t 14.2 min and t 15.4 min). 5a-1: t 14.2 min, >98% ee
R
R
R
4.1.15. (S)-2-((tert-Butyldimethylsilyl)oxy)-4-phenylbutanal [5b].
MeI (0.62 mL, 10.0 mmol) was added to a mixture of (S)-3b (369 mg, 1.0 mmol) and
2
1

ACCEPTED MANUSCRIPT
NaHCO (1.26 g, 15.0 mmol) in an aqueous MeCN/water (10 mL/2 mL) at room temperature
3
and the resulting mixture was stirred for 24 h. Thereaction mixture was diluted with EtOAc (30
mL), washed with sat. aq. Na S O (15 mL) and brine (20 mL x 2). Drying over MgSO and
2
2
3
4
concentration in vacuo provided a crude aldehyde, which was purified by short-path column
23
chromatography (silica gel, toluene) to afford 5b (223 mg, 80%); [
α
]D -15.0 (c 1.37, CHCl3);
1
H NMR (500 MHz, CDCl ) δ 9.60 (bs, 1H), 7.35-7.20 (m, 5H), 4.03-4.00 (m, 1H), 2.75-2.65
3
13
(
m, 2H), 2.05-1.90 (m, 2H), 0.95(s, 9H), 0.11 (s, 6Η); C NMR (125 MHz, CDCl ) δ 203.8,
3
+
+
1
41.1, 128.3, 126.0, 77.0, 34.4, 30.7, 25.8, 18.1, -4.70, -5.0; HRMS (FAB , [M+H] ) m/z calcd
+
for[C H O Si] : 279.1780 found: 279.1761.
1
6 27 2
4.1.16. (S)-4-Phenylbutane-1,2-diyl dibenzoate [5b-1].
The aldehyde 5b (220 mg, 0.79 mmol) was then reduced with NaBH (38 mg, 1.0 mmol) in
4
EtOH (5.0 mL) at room temperature for 10 min. The reaction mixture was distributed between
toluene (15 mL) and water (30 mL). The organic layer was washed with brine (30 mL) and
dried over anhydrous MgSO . Filtration and evaporation of the solvent in vacuo gave a mixture
4
of alcohols (primary and secondary alcohols), whichwas treated with TBAF (1.0 M in THF, 2.0
mL, 2.0 mmol) at room temperature for 30 min. The mixture was distributed between EtOAc
(15 mL) and brine (20 mL). The organic layer was washed with brine (20 mL), dried over
anhydrous MgSO , filtered and concentrated in vacuo furnished 1,2-diol (118 mg, 0.71 mmol),
4
which was treated with BzCl (0.56 mL, 4.84 mmol) in pyridine (3.0 mL) at 5 ºC. The mixture
was stirred at room temperature for 0.5 h, distributed between EtOAC (20 mL) and water (30
mL). The extract was sequentiallywashed with 1 M HCl (15 mLx 2), sat. aq. NaHCO (15 mL)
3
and brine (15 mL), dried over anhydrous MgSO and concentrated in vacuo. The residue was
4
purified by short-path distillation (150 ºC/1 mmHg)to afford 1,2-dibenzoate 5b-1(239 mg, 90%
21
1
yield) as a colorless oil: [α] -12.4º (c 1.58, CHCl ); H NMR (500 MHz, CDCl ) δ 8.06 (d, J =
D 3 3
7.9 Hz, 2H), 8.00 (d, J = 7.6 Hz, 2H), 7.59-7.53 (m, 2H), 7.46-7.40 (m, 4H), 7.30-7.27 (m, 2H),
7.26-7.17 (m, 3H), 5.55-5.51 (m, 1H), 4.60-4.56 (m, 1H), 4.52-4.48 (m, 1H), 2.86-2.74 (m, 2H),
13
2
.26-2.18 (m, 1H), 2.15-2.09 (m, 1H); C NMR (125 MHz, CDCl ) δ 166.1, 166.0, 140.8,
3
+
+
1
33.0, 130.0, 129.6, 128.4, 128.3, 126.1, 71.6, 65.5, 32.6, 31.5; HRMS (FAB , [M+H] ) m/z
+
calcd for [C H O ] : 375.1596 found: 375.1589.
2
4 23 4
Chiral HPLC: Chiralpak IA, (254 nm, n-hexane/2-propanol=50/1, 1.0 ml/min, racemate; t 9.1
R
min and t 11.4 min). 5b-1: t 9.09 min, >98% ee
R
R
2
2

ACCEPTED MANUSCRIPT
4.1.17. (S)-(3,4-Dimethoxybutyl)benzene [6].
Dibenzoate 5b-1 was converted to dimethyl ether 6 via alkaline hydrolysis followed by
1
etherification with MeI/NaH/DMF in good yield; H NMR (500 MHz, CDCl ) δ 7.35-7.25 (m,
3
5H), 3.43 (d, J=5.5 Hz, 1H), 3.42 (s, 3H), 3.37 (s, 3H), 3.35-3.32 (m, 1H), 2.77-2.63 (m, 2H),
20
25
1
.86-1.81 (m, 2H); [
α]D + 5.62 (c 0.83, CHCl ); [(R)-6: lit [α]D -4.73 (c 1.14, CHCl3)(Ref:
3
Vikhe,Y. S.; Hande, S. M.; Kawai, N.; Uenishi, J.J. Org. Chem. 2009, 74, 5174–5180.)
4.1.18. (5S)-5-(1,3-Dithian-2-yl)tetrahydrofuran-2-ol [7].
In an autoclave, a mixture of (S)-1 (942 mg, 5.34 mmol), Rh(acac)(CO) (28 mg, 0.11
2
mmol) and XANTPHOS (124 mg, 0.214 mmol) in toluene(10 mL) was heated at 50 °C for 4 h
2
under a pressure of H /CO (1:1)(5 kg/cm ). After cooling to room temperature, the yellow-green
2
mixture was passed through florisil pad. The filtrate was concentratedin vacuo to afford a brown
oil (976 mg), which was purified by short column chromatography (silica gel,
n-hexane/EtOAc=2/1~1/1 containing 1% Et N) provided hemiacetal 7 (767 mg, 70% yield)
3
24
accompanied by a small amount of complex mixtures (<0.3%): [α]D +28.5 (c 1.09, CHCl3);
-1 1
FTIR (KBr): 3417, 2901, 2820, 1774, 1463, 1076, 1054, 981, 781, 648 cm ; H NMR (500
MHz, CDCl ) δ 5.64 (bs, 0.6H), 5.53 (bs, 0.4H), 4.50-4.45 (m, 0.6H), 4.29-4.22 (m, 0.4H), 4.17
3
(d, J = 7.3 Hz, 0.4H), 4.11 (d, J = 5.8 Hz, 0.6H), 2.93-2.82 (m, 4H), 2.75 (bs, 0.4H), 2.54 (bs,
13
0
.6H), 2.27-1.89 (m, 6H); C NMR (125 MHz, CDCl ) δ 98.8, 98.4, 81.0, 79.4, 77.8, 52.0, 51.3,
3
+
+
3
3.5, 32.7, 29.4, 29.3, 28.8, 28.7, 27.7, 27.2, 25.8, 25.7; HRMS (FAB , [M-OH] ) m/z calcd for
+
[
C H OS ] : 189.0408 found: 189.0415.
8 13 2
4.1.19. General protocol for hydroformylation of (S)-2.
4.1.19-1. (S)-4-(Benzyloxy)-4-(1,3-dithian-2-yl)butanal [8a].
In an autoclave, a mixture of (S)-2a (1.0 mmol), Rh(acac)(CO) (5 mg, 0.02 mmol) and
2
XANTPHOS (23 mg, 0.04 mmol) in toluene (5 mL) was heated at 50 °C for 20 h under a
2
pressure of H /CO (1:1)(5 kg/cm ). Upon cooling to room temperature, evaporation of the
2
solvent gave a dark oil, which was purified by column chromatography (silica gel,
n-hexane/EtOAc = 5/1) to furnish linear aldehyde 8a (228 mg, 77% yield) as a pale yellow oil:
22
1
[α]D -45.0 (c 1.46, CHCl ); H NMR (500 MHz, CDCl ) δ 9.69 (bs, 1H), 7.38-7.25 (m, 5H),
3 3
4.75 (d, J = 11.5 Hz, 1H), 4.50 (d, J = 11.0 Hz, 1H), 4.37 (d, J = 5.0 Hz, 1H) 3.67-3.49 (m, 1H),
13
2
.92-2.83 (m, 4H), 2.57-2.44 (m, 2H), 2.15-2.02 (m, 3H), 1.94-1.87 (m, 1H); C NMR (125
MHz, CDCl ) δ 201.6, 137.5, 128.2, 128.0, 126.7, 79.4, 72.2, 51.6, 39.7, 30.3, 26.0, 24.7;
3
2
3

ACCEPTED MANUSCRIPT
+
+
+
HRMS (FAB , [M+H] ) m/z calcd for[C H O S ] : 297.0983 found: 297.0983.
1
5 21 2 2
Branched aldehyde 9a (<3%) was observed as a diastereomeric mixture by NMR analysis,
which was contaminated with inseparable unidentified compounds.
4.1.19-2. (S)-4-((tert-Butyldimethylsilyl)oxy)-4-(1,3-dithian-2-yl)butanal [8b].
Synthesis of8b was carried out starting from (S)-2b (145 mg, 0.50 mmol) as described for8a:
Purified by column chromatography (silica gel, n-hexane/EtOAc=10/1-7/1) to give 8b (116 mg,
25
1
7
3% yield) as a colorless oil; [
α]D -18.1 (c 1.28, CHCl ); H NMR (500 MHz, CDCl ) δ 9.78
3 3
(bs, 1H), 4.15 (d, J = 5.5 Hz, 1H), 3.94-3.91 (m, 1H), 2.89-2.79 (m, 4H), 2.60-2.50 (m, 2H),
13
2
.12-2.01 (m, 3H), 1.90-1.84 (m, 1H), 0.91 (s, 9H), 0.15 (s, 3H), 0.08 (s, 3H); C NMR (125
+
MHz, CDCl ) δ 201.9, 73.2, 53.9, 39.3, 30.5, 30.3, 26.7, 26.2, 25.8, 18.1, -4.5; HRMS (FAB ,
3
+
+
[
M+H] ) m/z calcd for [C H O S Si] : 321.1378 found: 321.1384
14 29 2 2
4
.1.19-3. (S)-4-((tert-Butyldiphenylsilyl)oxy)-4-(1,3-dithian-2-yl)butanal [8c].
Synthesis of 8c was carried out starting from (S)-2c (414 mg, 1.0 mmol) as described for 8a:
Purification by column chromatography (silica gel, n-hexane/EtOAc=10/1-7/1) gave 8c (361
22
1
mg, 81% yield) as a pale yellow viscous oil; [α] -40.2 (c 1.27, CHCl ); H NMR (500 MHz,
D 3
CDCl ) δ 9.56 (bs, 1H), 7.77 (d, J = 7.0 Hz, 2H), 7.68 (d, J = 6.8 Hz, 2H), 7.47-7.38 (m, 6H),
3
4.00-3.97 (m, 2H), 2.81 (d, J = 14.1 Hz, 1H), 2.70 (d, J = 14.0 Hz, 1H), 2.63-2.48 (m, 3H),
13
2
.40-2.34 (m, 1H), 1.98-1.94 (m, 3H), 1.84-1.76 (m, 1H), 1.09 (s, 9H); C NMR (125 MHz,
CDCl ) δ 201.0, 135.8, 135.6, 133.3, 133.0, 129.6, 127.4, 127.3, 73.9, 54.5, 39.5, 30.5, 30.0,
3
+
+
+
2
6.8, 26.3, 26.0, 19.2; HRMS (FAB , [M+H] ) m/z calcd for [C H O S Si] : 445.1691 found:
24 33 2 2
445.1713.
Branched aldehyde 9c (<4%) was observed as a diastereomeric mixture by NMR analysis,
which was contaminated with inseparable unidentified compounds.
4.1.20. (S)-(1,3-Dithian-2-yl)((R)-3-phenyl-4,5-dihydroisoxazol-5-yl)methanol [11].
Asolution of EtMgBr (3.0 M in Et O, 8.6 ml, 25.8 mmol) was added to a solution of (S)-1
2
(
1.516 g, 8.6 mmol) and isopropanol (2.17 mL, 28.4 mmol) in CH Cl (50 mL) at 5 ºC. After
2 2
stirring for 10 min, a solution of benzohydroximinoyl chloride (10) (2.0 g, 12.9 mmol) in
CH Cl (30 mL) was added to the reaction mixture at 5 °C over a period of 0.5 h, and then
2
2
allowed to warm to room temperature over the next 22 h. The reaction was terminated by
addition of sat. aq. NH Cl (100 mL). The organic layer was washed with brine (30 mL x 2),
4
2
4

ACCEPTED MANUSCRIPT
dried over MgSO , filtered and concentrated in vacuo to give a crude solid, which was washed
4
20
with toluene to give 11 (1.94g, 76%) as a white solid. mp 189.7-189.9 ºC, [α]D -151.6 (c 1.10,
-1 1
CHCl ); FTIR (KBr): 3520, 2953, 2907, 1598, 1420, 1092, 912, 764, 543 cm ; H NMR (500
3
MHz, CDCl ) δ 7.69-7.67 (m, 2H), 7.41-7.39 (m, 3H), 5.24-5.20 (m, 1H), 4.21 (d, J = 8.6 Hz,
3
1H), 3.89-3.86 (m, 1H), 3.53-3.86 (m, 2H), 2.99-2.92 (m, 2H), 2.81-2.73 (m, 2H), 2.68 (d, J =
13
6
.1 Hz, 1H), 2.12-2.09 (m, 1H), 2.05-2.01 (m, 1H); C NMR (125 MHz, CDCl ) δ 157.0, 130.2,
3
1
29.2, 128.7, 126.8, 79.5, 73.2, 47.8, 37.7, 28.0, 27.5, 25.4; Anal. Calcd. for C H NO S : C,
14
17
2 2
+
+
5
6.92; H, 5.80; N, 4.74; Found: C, 56.67; H, 5.65; N, 4.45; HRMS (FAB , [M+H] ) m/z calcd
+
for[C H NO S ] : 296.0779 found: 296.0789.
14
18
2 2
4.1.21. (S)-(1,3-Dithian-2-yl)((R)-3-phenyl-4,5-dihydroisoxazol-5-yl)methyl acetate [12].
The alcohol 11 (98.6 mg, 0.334 mmol) was treated with pyridine/Ac O (0.5 mL each) at
2
room temperature for 1 h, and the reaction was quenched by addition of sat. aq. NaHCO (20
3
mL). After stirring for 30 min, the mixture was distributed between toluene (30 mL) and sat. aq.
NaHCO (20 ml). The organic layer was sequentially washed with 1 N HCl (20 mL), sat. aq.
3
NaHCO (20 mL) and brine (20 mL). Drying over anyhydrous MgSO and evaporation of the
3
4
22
solvent in vacuo afforded 12 (113 mg, 97%) as a white solid. mp 110.2-110.8 °C, [
α
]D -93.3 (c
1
1
.56, CHCl ); H NMR (500 MHz, CDCl ) δ 7.66-7.65 (m, 2H), 7.42-7.40 (m, 3H), 5.51-5.47
3
3
(m, 1H), 5.43 (d, J = 11.5 Hz, 1H), 4.12 (d, J = 10.1 Hz, 1H), 3.52 (dd, J = 16.8, 11.3 Hz, 1H),
3.09 (dd, J = 16.8, 6.8 Hz, 1H), 3.02-2.96 (m, 2H), 2.73-2.69 (m, 1H), 2.62-2.58 (m, 1H),
13
2
.07-2.02 (m, 5H); C NMR (125 MHz, CDCl ) δ 170.8, 156.2, 130.1, 129.0, 128.6, 126.5,
3
+
+
7
8.2, 72.7, 43.4, 37.3, 26.5, 26.3, 25.0, 20.6; HRMS (FAB , [M+H] ) m/z calcd for
+
[
C H NO S ] : 338.0885 found: 338.0875.
16 20 3 2
4.1.22. (1S,2R)-4-Amino-1-(1,3-dithian-2-yl)-4-phenylbutane-1,2-diol [13].
Amixture of 11 (1.94 g, 6.57 mmol) and zinc powder (10.6 g, 162 mmol) in a 50% aqueous
acetic acid (20 mL) was heated at 60 ºC for 3h. Themixture was filtered through Celite 545 and
the filtrate was concentratedin vacuo. The residue was distributed between CH Cl (50 mL) and
2
2
1
M NaOH (30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous
MgSO , filtered and concentrated in vacuo, providing 13 (1.39 g, 71%) as a mixture of two
4
23
1
diastereomers. [
.28-7.26 (m, 2H), 4.44-4.42 (m, 0.3H), 4.36 (d, J = 9.5 Hz, 0.6H), 4.25 (d, J = 8.2 Hz, 0.6H),
.18-4.08 (m, 1.3H), 3.65 (d, J = 7.6 Hz, 0.3H), 3.60 (d, J = 7.9 Hz, 0.6H), 2.93-2.70 (m, 4H),
α]D +6.84 (c 1.13, CHCl ); H NMR (500 MHz, CDCl ) δ 7.38-7.35 (m, 3H),
3 3
7
4
2
5

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13
2
.12-1.80 (m, 4H); C NMR (125 MHz, CDCl ) δ 146.3, 145.2, 128.8, 128.5, 127.2, 127.1,
3
125.9, 125.4, 74.6, 74.3, 70.5, 67.9, 55.6, 53.0, 49.2, 49.0, 41.6, 40.9, 28.7, 28.4, 28.3, 28.0, 25.7,
+
+
+
2
5.6; HRMS (FAB , [M+H] ) m/z calcd for[C H NO S ] : 300.1092 found: 300.1094.
14 22 2 2
4.1.23. (1S,2R)-4-Acetamido-1-(1,3-dithian-2-yl)-4-phenylbutane-1,2-diyl diacetate[14].
Compound 13 (448 mg, 1.50 mmol) was treated with Ac O/pyridine (2 mL each) in the
2
presence of DMAP(10 mg) at room temperature for 2h. The reaction mixture was concentrated
in vacuo and the residue was distributed between toluene (30 mL) and sat. aq. NaHCO (20 mL).
3
The organic layer was sequentially washed with 1 N HCl (10 mL x 2), sat. aq. NaHCO (20
3
mL) and brine (20 mL). Drying over anhydrous MgSO followed by concentration in vacuo
4
gave 14 (553 mg) as a brown oil, which was purified by column chromatography (silica gel,
toluene/EtOAc=1/2~1/4) to give less polar fraction (369 mg, 58%) as white foam and polar
fraction (191 mg, 30 %) as a colorless oil.
22
Less polar fraction: R=0.47 (toluene/EtOAc=1/2), [α]D -26.7 (c 1.12, CHCl ); FTIR (KBr):
3
f
-1 1
3
297,2938, 1741, 1653, 1540, 1373, 1224, 1027, 702 cm ; H NMR (500 MHz, CDCl ) δ
3
7.47-7.20 (m, 5H), 6.07 (d, J = 8.6 Hz, 1H), 5.84 (d, J = 9.8 Hz, 1H), 5.53-5.50 (m, 1H),
5.28-5.20 (m, 1H), 3.67 (d, J = 9.8 Hz, 1H), 3.20-3.00 (m, 2H), 2.60-2.49 (m, 2H), 2.16 (s, 3H),
13
2
.11-1.90 (m, 4H), 2.04 (s, 3H), 2.02 (s, 3H). C NMR (125 MHz, CDCl ) δ 170.6, 170.3,
3
169.5, 141.5, 128.6, 127.4, 126.1, 70.5, 70.2, 49.2, 42.4, 37.9, 25.5, 24.8, 23.2, 20.9, 20.7;
+
+
+
HRMS (FAB , [M+H] ) m/z calcd for[C H NO S ] : 426.1409 found: 426.1414.
20
27
5 2
24
1
Polar fraction: R = 0.30 (toluene/EtOAc=1/2); [α]D +59.9 (c 1.15, CHCl ); H NMR (500
3
f
MHz, CDCl ) δ 7.40−7.26 (m, 5Η), 6.21 (d, J = 7.7 Hz, 1H), 5.43-5.41 (m, 1H), 5.31 (d, J = 9.5
3
Hz, 1H), 5.14-5.09 (m, 1H), 3.64 (d, J = 9.5 Hz, 1H), 2.88-2.83 (m, 1H), 2.53-2.41 (m, 3H),
2.25-2.20 (m, 1H), 2.25 (s, 3H), 2.14-2.08 (m, 1H), 2.03 (s, 3H), 2.01 (s, 3H), 1.95-1.91 (m,
13
2
H).; C NMR (125 MHz, CDCl ) δ 170.8, 170.3, 169.3, 140.5, 128.8, 127.6, 126.6, 71.6, 69.9,
3
50.2, 43.2, 36.6, 26.2, 25.6, 24.9, 23.2, 20.8.
Acknowledgements
This work was assisted financiallybya research grant from Nippon ChemipharInc.
Supplementary data
Supplementarydata related to this article canbe found at
2
6

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1
1
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1
2. The compound (R)-1-OAc was transesterified (cat. K CO /MeOH) to the corresponding
2 3
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R
R
13. HPLC analysis: Chiralpak IA (n-hexane/2-propanol=9/1, 1.0 mL/min, 254 nm), (S)-1: tR
1
0.9 min (76% ee) and (R)-1: t 12.2 min (>98% ee).
R
1
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1
1
1
1
1
R
R
R
19. HPLC analysis: Chiralpak IA (n-hexane/2-propanol=50/1, 1.0 mL/min, 254 nm),
racemate: t 9.10 min and t 11.4 min, 5b-1: t 9.10 min (>98% ee).
R
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R
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2
8