The thiopyran route to polypropionates. Asymmetric synthesis of the building blocks by enantioselective protonation

Article abstract of DOI:10.1016/j.tetasy.2004.06.027

Enantioselective protonation of the s-BuLi derived lithium enolate of (S)-phenyl 1,4-dioxa-8-thia-spiro[4.5]decane-6-carbothioate 14 with N-isopropylephedrine 15 gives 14 as a 10:1 mixture of enantiomers. Recrystallization of nonracemic 14 gives a highly

Full text of DOI:10.1016/j.tetasy.2004.06.027

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2425–2430
The thiopyran route to polypropionates. Asymmetric synthesis of
the building blocks by enantioselective protonation
Dale E. Ward,* Olukayode T. Akinnusi, Idralyn Q. Alarcon, Vishal Jheengut,
Jianheng Shen and J. Wilson Quail
Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, Canada SK S7N 5C9
Received 26 May 2004; accepted 18 June 2004
Available online 28 July 2004
Abstract—Enantioselective protonation of the s-BuLi derived lithium enolate of (S)-phenyl 1,4-dioxa-8-thia-spiro[4.5]decane-6-carbo-
thioate 14 with N-isopropylephedrine 15 gives 14 as a 10:1 mixture of enantiomers. Recrystallization of nonracemic 14 gives a highly
enantioenriched material (>90% ee), which can be converted into 1,4-dioxa-8-thia-spiro[4.5]decane-6-carboxaldehyde 2 without race-
mization. Diastereoselective aldol reactions of tetrahydro-4H-thiopyran-4-one with nonracemic 2 proceed with negligible racemization
to give adducts that are useful building blocks for polypropionate synthesis.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
OH OH OH
tetrapropionate
fragment
We have been investigating the stereoselectivities of
sequential aldol reactions of 1 and 2 as the foundation
of a thiopyran-based synthetic route to polypropionates
(Scheme 1).1–3 The diastereoselectivity of the first aldol
reaction is easily modulated. Three of the four possible
diastereomers from the reaction of 2 with 3 can be pro-
duced stereoselectively simply by varying the mediator
(4as with MeLi, 4ss with TiCl4, 4sa with MgBr2ÆOEt2)1
while the fourth diastereomer can be obtained in good
overall yield by isomerization (4safi4aa).3 The second
aldol reaction is also highly diastereoselective. Using
racemic components, reactions of the Ti(IV) enolates of
4 with 2 occur with considerable mutual kinetic enantio-
selectionꢀ (MKE)4,5 and, in each case, give one of the
eight possible diastereomersꢁ of 5 with high stereoselecti-
vity.2 To gain access to nonracemic diastereomers of 4
and 5 and as a prelude to an investigation of double
stereodifferentiation6,7 in the aldol reactions of 4 with 2,
we required enantioenriched aldehyde 2. Herein we
O
S
O
O
S
HO
O
O
O
O
1st aldol
+
S
4
S
2
1
4 possible diastereomers
OTMS
O
O
O
2nd aldol
S
2
3
S
OH OH OH OH OH
hexapropionate fragment
OH
O
S
HO
O
O
O
O
5
S
S
20 possible diastereomers
(16 chiral, 4 meso)
Scheme 1.
report a simple and efficient synthesis of (+)-2 and (ꢀ)-
2 via enantioselective protonation8,9 and demonstrate
that their conversion into the tetrapropionate synthons
4 occurs without racemization.
*
Corresponding author. Tel.: +306-966-4656; fax: +306-966-4730; e-
mail: dale.ward@usask.ca
ꢀ Also known as mutual kinetic resolution. See Ref. 4 for a discussion
of the relative merits of the terminology.
ꢁ There are 20 possible diastereomers of 5 (16 chiral and 4 meso).
Assuming no isomerization of the ketone, an aldol reaction of any
one racemic diastereomer of 4 with racemic 2 can give eight possible
diastereomers.
2. Results and discussion
Initial attempts to obtain enantioenriched 2 focused on
the resolution of carboxylic acid 7 (Scheme 2). Ketal
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.06.027

2426
D. E. Ward et al. / Tetrahedron: Asymmetry 15 (2004) 2425–2430
Table 1. Enantioselective protonation of enolates from 6, 7, and 13
with (+)-15a
NH2
Ph
O
O
O
O
O
O
O
O
O
NaOH
85%
(R)-8
OH
O(-)
(+)NH3
OMe
Entry Starting ester Base (equiv)
Product % ee
7
S
S
8-14%
S
5b
20
9
6
1
2
6
LDA (3)
(-)-9
s-BuLi (2)c
LDA (2)
s-BuLi (2)
Ph
6
13
(S)-8
3
HCl 90%
7
(S)-7
(R)-10
(R)-2
4
20
33
(4-7%)
5
LDA (2)/n-BuLi (2)d
LDA (2)/n-BuLi (2)d,e 60
O
O
O
6
O
O
O
O
O
Dess-Martin
95%
LiAlH4
90%
7
7
LDA (2)
50
60
71
82
OH
OH
8
s-BuLi (2)
s-BuLi (2)e
s-BuLi (2)f
S
S
S
(S)-2
(S)-10
(R)-7
9
10
Scheme 2.
a Reactions (ca. 0.1mmol scale) at ꢀ78°C with enolate formation for
30min (LDA, inverse addition) or 5min (s-BuLi) followed by addi-
tion of (+)-15 (5equiv) and after 1h, addition of D2O and work up
(>90% yield).
ester ( )-6 was easily prepared in two steps from com-
mercially available dimethyl 3,30-thiobispropanoate
(>80% yield on 100g scale).1 Hydrolysis of ( )-6 gave
the desired acid ( )-7 in 89% yield. Crystallization of
the salt prepared from ( )-7 and (R)-(+)-8 (1equiv) from
methanol/ether yielded a 3.5–4:1 mixture of diastereo-
b Workup included exposure of the crude product 12 to TFA in
CH2Cl2 to obtain 6.
c Enolate formation and protonation at ꢀ100°C (bath).
d n-BuLi added after enolate formation with LDA; 10equivof (+)- 15
was used.
1
mers (by H NMR) in 30–35% yield. Recrystallization
e Addition of (+)-15 over 2h.
of this salt gave (ꢀ)-9 as a 25:1 mixture of diastereomers
in 8–14% overall yield. The relative configuration of 9
was established by X-ray crystallographic analysis there-
by confirming that (ꢀ)-9 was derived from (R)-7.§
Extraction of an acidified (pH=1) solution of (ꢀ)-9
(de=91%) gave (R)-(ꢀ)-7 in good yield. Similar treat-
ment of the combined mother liquors from the above
crystallizations gave the acid 7 slightly enriched in the
(S)-enantiomer (65% yield, 10–20% ee). The rather poor
yield of recovered 7 stems from the instability of the
mother liquors, which darken considerably on standing.
Resolution of the recovered 7 as carried out above but
using (S)-(ꢀ)-8 gave (S)-(+)-7 (91% ee) in 7–12% yield
(5–8% overall). Reduction of (R)-(ꢀ)-7 with LiAlH4
gave (S)-(ꢀ)-10 (90%) with enantiomeric purity (deter-
mined by 1H NMR of the derived Mosherꢂs ester)
matching the de of precursor 9. Oxidation of (S)-(ꢀ)-
10 with the Dess–Martin periodinane10 gave (S)-(ꢀ)-2
in excellent yield and with enantiomeric purity (deter-
f Addition of (+)-15 at ꢀ100°C followed by warming to ꢀ78°C over
1h.
acid) esters using 15 as the chiral proton source (easily
prepared from ephedrine;12,13 both enantiomers com-
mercially available), we applied this method to various
derivatives of 6 (Table 1). In each case, enolate forma-
tion was confirmed by quenching a control experiment
with D2O to obtain the starting material (>90% yield)
with >90% deuterium incorporation with complete pro-
ton transfer from 15 (5–10equiv) confirmed by adding
D2O prior to work-up to obtain starting material
(>90% yield) with <10% deuterium incorporation.
The lithium enolate from reaction of 6 with LDA at
ꢀ78°C was unstable and underwent elimination and de-
protonation to give the putative alkoxide dienolate dian-
ion 11 and by using excess LDA 12 could be isolated in
90% yield (Scheme 3).14 Brief exposure of 12 to acid
regenerated 6 in excellent yield. Quenching the reaction
of 6 and excess LDA (3equiv) with (+)-15 followed by
treatment with acid gave 6 with <10% ee.– The lithium
enolate from reaction of 6 with s-BuLi (2equiv) was sta-
ble at ꢀ100°C; however, 6 was obtained with only 20%
ee after quenching the enolate at this temperature with
(+)-15. The TDBMS ether derivative 13 was obtained
with <10% ee– on quenching its LDA generated lithium
enolate with (+)-15. In this case, quenching the enolate
with D2O returned the product with only ca. 70% deute-
rium incorporation suggesting the possibility of ꢃinternal
proton returnꢂ.15 Treatment of the enolate with n-BuLi
prior to addition of D2O gave complete deuterium incor-
poration while the addition of (+)-15 (10equiv) in place
of D2O gave 13 with 33% ee (2:1 er). A 60% ee (4:1 er)
could be obtained by slow addition of (+)-15 to the eno-
late at ꢀ78°C but further improvements could not be
1
mined by H NMR in presence of Eu(tfc)3 as a chiral
shift reagent) consistent with that of precursor 10. Using
the same route, (R)-(+)-2 was prepared from (S)-(+)-7.
Despite considerable effort, we were unable to improve
on the efficiency of the resolution of 7. Although this
route provided usable amounts of the desired 2 with rea-
sonable enantiomeric purity, the low overall yields
prompted the investigation of alternative strategies.
Enantioselective protonation of enol derivatives has
recently emerged as a simple and attractive method to
obtain nonracemic carbonyl derivatives.8,9 Inspired
by the impressive results reported by Fehr et al.11 for
enantioselective protonation of enolates of a-cyclo-
geranic acid (2,6,6-trimethyl-2-cyclohexene-1-carboxylic
§ Crystallographic data (excluding structure factors) for (+)-9 have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 236943. Copies of the
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
– Measured by 1H NMR in the presence of (R)-(ꢀ)-2,2,2-trifluoro-1-(9-
anthryl)ethanol (TFAE) as a chiral solvating agent. The absolute
configuration of the major enantiomer was not determined.

D. E. Ward et al. / Tetrahedron: Asymmetry 15 (2004) 2425–2430
2427
The individual diastereomers 4as, 4ss, 4sa, and 4aa had
eeꢂs of 90–91% (by 1H NMR of the corresponding
MOM ether derivatives in the presence of (ꢀ)-TFAE
as a chiral solvating agent) establishing that the aldol
reactions occurred with negligible racemization of
(R)-2. Analogous results were obtained using (S)-2.
TFA, CH2Cl2
O
S
OLi
OMe
O
O
LDA
LiO
RO
6
OMe
-78 ˚C
90%
11
S
12 R=H
13 R=SiMe2tBu
Cl-SiMe2tBu
90%
1. (COCl)2
2. PhSH, Et3N
O
O
O
O
O
O
1. s-BuLi
3. Conclusion
SPh
SPh
(R)-14
7
2. (+)-15
96%
14
S
S
(see text)
In summary, highly enantiomerically enriched 14 can be
efficiently obtained by protonation of its s-BuLi derived
lithium enolate with 15. Sequential LiAlH4 reduction
and DMP oxidation of 14 gives the corresponding alde-
hyde 2 without racemization. Diastereoselective aldol
reactions of 1 with nonracemic 2 similarly proceeded
with negligible racemization. The aldol adducts 4 are
useful tetrapropionate synthons. We have previously re-
ported the stereoselective reduction1 of individual iso-
mers of 4 to give syn- or anti-1,3-diols that can be
desulfurized16 without loss of stereochemical integrity.
Bisaldols 5 have been prepared by diastereoselective
aldol reactions of 4 with 2.2 Enantiomerically pure and
synthetically useful hexapropionate synthons 5 should
now be available from nonracemic building blocks 2
and 4. Our progress towards this objective will be re-
ported in due course.
LiAlH4
Dess-Martin
94%
Ph
N
(+)-15
OH
(R)-2
(R)-10
95%
Scheme 3.
realized despite considerable experimentation (varying
temperature, stoichiometry, concentration).
In contrast to 6, the LDA derived lithium enolate of 14
was stable at ꢀ78°C while protonation with (+)-15 at
that temperature gave (ꢀ)-14 as a 3:1 mixture of enantio-
mers (50% ee). The lithium enolate from reaction of 14
with s-BuLi (substantial addition to the ester occurred
with n-BuLi) was more convenient to prepare and gave
slightly better results on protonation with (+)-15 (4:1
er, 60% ee). A 6:1 er (71% ee) could be obtained by slow
addition (2h) of (+)-15 to the lithium enolate of 14 at
ꢀ78°C. Control experiments established that protona-
tion of the lithium enolate of 14 with (+)-15 was very
slow at ꢀ100°C and that 14 slowly racemized (ca. 5%/
h) in the presence of the lithium alkoxide of (+)-15 at
ꢀ78°C. Under optimized conditions, (+)-15 was added
at once to the lithium enolate of 14 at ꢀ100°C and the
solution slowly warmed to ꢀ78°C to give (ꢀ)-14 as
a 10:1 mixture of enantiomers (82% ee).– This procedure
can be easily performed on a gram scale and, most
importantly, the enantioenriched 14 could be purified
to high ee by recrystallization (50% yield, >95% ee).
The process is very efficient overall considering that the
mother liquors and the easily recovered (+)-15 can be re-
used directly. Reduction of (ꢀ)-14 with LiAlH4 gave the
previously characterized (+)-10 establishing that (ꢀ)-14
has an (R)-configuration.
4. Experimental
4.1. 1,4-Dioxa-8-thia-spiro[4.5]decane-6-carboxaldehyde 2
A solution of alcohol (S)-(ꢀ)-10 (92% ee; 207mg,
1.09mmol) and water (19lL, 1.06mmol)17 in CH2Cl2
(10.5mL) was added to a stirred solution of Dess–Martin
periodinane (DMP)18 (675mg 1.59mmol) under argon.
After 10min, Et2O (15mL) was added and a white pre-
cipitate formed after 10min. A solution made up of sat-
urated aqueous NaHCO3 (5.9mL) and Na2S2O3 (1.5g)
diluted to 15mL with water was added to the stirred
reaction mixture resulting in two clear layers. The aque-
ous phase was extracted with Et2O and the combined or-
ganic layers dried over Na2SO4 and concentrated to give
(S)-(ꢀ)-2 as
a
light yellow oil {198mg, 97%;
24
D
1
½aŠ ¼ ꢀ130, (c 1.0, C6H6); 91% ee} that was homogene-
With efficient synthetic routes to (+)-2 and (ꢀ)-2 se-
cured, we turned our attention to the preparation of di-
propionate building blocks 4 (Scheme 4). Reactions of 3
with (R)-2 (91% ee) using the procedures previously de-
scribed with ( )-2,1 gave the expected aldol products 4.
ous by H NMR. Spectral data for (S)-(ꢀ)-2 was in ac-
cord with that previously reported for ( )-2.1 Using the
same procedure, (R)-(+)-10 (91% ee; 205mg, 1.08mmol)
gave (R)-(+)-2 as a light yellow oil {188mg, 93%;
24
D
½aŠ ¼ þ130, (c 1.0, C6H6); 91% ee}. The enantiomeric
ratio (er) of 2 (ca. 0.07M in CDCl3) was determined by
1H NMR in the presence of (+)-Eu(hfc)3 (ca. 0.2equiv)
by integration of the peaks at d 10.36 [1H, br s, HC-7,
(S)-2] and d 10.33 [1H, br s, HC-7, (R)-2]. The absolute
configuration of 2 was assigned based on the absolute
configuration of precursor 10.
O
HO
O
HO
O
O
O
O
MeLi then 2
+
+
S
S
S
S
(+)-4as (71%)
(-)-4ss (12%)
3 + (R)-2
O
HO
O
HO
O
O
O
O
4.2. 1,4-Dioxa-8-thiaspiro[4.5]dec-6-ylhydroxymethyl]-
tetrahydro-4H-thiopyran-4-one 4
MgBr2·OEt2
S
S
S
S
(+)-4sa (55%)
(+)-4aa (19%)
Reaction of (R)-2 (91% ee; 82mg, 0.44mmol) with the
lithium enolate of
Scheme 4.
1 prepared from 3 (330mg,

2428
D. E. Ward et al. / Tetrahedron: Asymmetry 15 (2004) 2425–2430
1.76mmol) and MeLi following the reported procedure1
(but using 4equivof enolate to maximize the conver-
99 (100), 86 (45); HRMS m/z calcd for C8H12O4S
204.0457, found 204.0456 (EI). The enantiomeric ratio
24
D
1
(er) of 7 was determined by H NMR (0.2M in CDCl3;
sion), gave (+)-4as {94mg, 71%; ½aŠ ¼ þ39, (c 1.0,
24
CHCl3)} and (ꢀ)-4ss 17mg, 13%; ½aŠ ¼ ꢀ48, (c
resolution is concentration dependent) in the presence of
(R)-8 (1equiv) by integration of the peaks at d 2.87 (1H,
dd, J=4, 11Hz, HC-7, (R)-7) and d 2.80 (1H, dd, J=4,
11Hz, HC-7, (S)-7). Ratios>35:1 were confirmed by
comparison of the minor peak to the 13C satellite
(0.55% assumed) of the major peak. The (S,S) relative
configuration within (+)-9 was established by X-ray
crystallographic analysis; the absolute configuration of
(+)-7 follows because (+)-9 is prepared from (ꢀ)-8,
which is known to be of an (S)-configuration.
D
1.3, CHCl3). Reaction of (R)-2 (91% ee; 68mg,
0.36mmol) with 3 (135mg, 0.72mmol) in the presence
of MgBrÆOEt2 following the published procedure1 gave
24
D
(+)-4sa {60mg, 55%; ½aŠ ¼ þ44, (c 1.0, CHCl3)} and
24
D
(+)-4aa 21mg, 19%; ½aŠ ¼ þ22, (c 1.0, CHCl3).
NMR data for (+)-4as, (ꢀ)-4ss, (+)-4sa, and (+)-4aa
were in accord with that previously reported for the
racemic analogues.1 Eeꢂs for the major diastereomers
(4as and 4sa) were determined to be ca. 90% by 1H
NMR of the corresponding MOM ether derivatives
(prepared in ca. 95% yield by reaction with MOM-Cl,
i-Pr2EtN and Bu4NI)3 in the presence of (R)-(ꢀ)-2,2,2-
trifluoro-1-(9-anthryl)ethanol (TFAE, 5–10equiv) as a
chiral solvating agent. In each case, signals for one of
the protons from the MOM methylene group and or
methyl group were adequately separated for the two
enantiomers. Analogous results were obtained from
the aldol reactions of (S)-(ꢀ)-2.
4.4. 1-Phenylethylammonium 1,4-dioxa-8-thia-spiro[4.5]
decane-6-carboxylate 9
( )-7 (9.6g, 47mmol) was added to a solution of (R)-
(+)-8 (5.7g, 47mmol) in MeOH (15.4mL). The solution
was diluted with Et2O (123mL) and the well-stoppered
vessel allowed to stand at ambient temperature (crystal-
lization could be accelerated by addition of 1–2mg of
seed crystals of (ꢀ)-9 of >25:1 dr). After crystals had be-
gun to precipitate (generally within 1h with seeding), the
mixture was stored at 4°C for 24h. Filtration yielded
4.3. 1,4-Dioxa-8-thia-spiro[4.5]decane-6-carboxylic acid 7
1
From 6. Aqueous NaOH (0.75M; 150mL, 0.11mol) was
added to a stirred solution of 6 (16.01g, 0.073mol) in
MeOH (40mL) at ambient temperature (exothermic).
After 1.5h, the mixture was cooled to 0°C, acidified to
pH1 by addition of conc. HCl and extracted with
CH2Cl2. The combined organic layers were dried over
Na2SO4 and concentrated to give ( )-7 as a white solid
(ꢀ)-9 (4.9g, 32%; 3.7:1 dr by H NMR). Recrystalliza-
tion as above but using a 4:1 (v/v) ratio of Et2O and
MeOH, respectively, gave (ꢀ)-9 (1.6g, 10%, 25:1 dr).
The combined mother liquors were diluted with aqueous
HCl (1M) and extracted with CH2Cl2. The combined
organic layers were dried over Na2SO4 and concentrated
to give (S)-(+)-7 (6.0g, 63%; ca. 20% ee). Resolution as
above but using (S)-(ꢀ)-8 gave (+)-9 (0.82g, 8.6%, 5.3%
overall; 23:1 dr). Repeated recrystallization of (+)-9
1
(14.55g, 97%) that was homogeneous by H NMR. Re-
crystallization (CH2Cl2/hexane; 1:15) yielded ( )-7 as
white needles (13.35g, 89%; mp 101–102°C. Anal. Calcd
for C8H12O4S: C, 47.04; H, 5.92. Found: C, 47.03; H,
5.95).
gave a sample with >100:1 dr {mp 148–149°C;
24
½aŠ ¼ þ34, (c 1.0, CHCl3)}: 1H NMR (500MHz,
D
CDCl3) d 7.43–7.35 (5H, m, Ph), 6.65 (3H, br s, H3N),
4.25 (1H, q, J=6.5Hz, HCN), 3.88–3.80 (4H, m,
H2CO·2), 2.97 (1H, dd, J=8, 13.5Hz, HC-7), 2.91
(1H, dd, J=3, 13, 5Hz, HC-7), 2.66–2.63 (3H, m, HC-
6, H2C-9), 2.25–2.22 (1H, m, HC-10), 1.70–1.67 (1H,
m, HC-10), 1.50 (3H, m, J=6.5Hz, H3C); 13C NMR
(125MHz, CDCl3) d 176.0 (s, C@O), 143.3 (s, Ph),
129.1 (d·2, Ph), 128.1 (d, Ph), 126.7 (d·2, Ph), 108.4
(s, C-5), 65.3 (t, C-2/3), 64.7 (t, C-2/3), 52.7 (d, C-6),
51.5 (d, CHN), 36.0 (t, C-10), 30.6 (t, C-7), 27.3 (t, C-
9), 23.4 (q, CH3). The diastereoisomeric ratio (dr) of 9
From 9. A solution of (ꢀ)-9 (1.6g, 4.9mmol; 92% de) in
CH2Cl2 (25mL) was extracted with 1M HCl. The aque-
ous layer was extracted with CH2Cl2 and the combined
organic layers dried over Na2SO4 and concentrated to
give (R)-(ꢀ)-7 as a white solid {902mg, 90%; mp 92–
24
D
93°C; ½aŠ ¼ ꢀ54, (c 1.0, CHCl3); 92% ee)}. The aque-
ous layer was made basic (pH>12) by addition of solid
NaOH (exothermic) and then extracted with CH2Cl2.
The combined organic layers were dried over Na2SO4
concentrated to give (R)-(+)-8 as a light yellow liquid
(591mg, 99%). Using the above procedure, (+)-9
1
was determined by H NMR (0.2M in CDCl3; resolu-
tion is concentration dependent) by integration of the
peaks at d 2.87 (1H, dd, J=4, 11Hz, HC-7, R*R*-dia-
stereomer) and d 2.80 (1H, dd, J=4, 11Hz, HC-7,
R*S*-diastereomer). Ratios >35:1 were confirmed by
comparison of the minor peak to the 13C satellite
(0.55% assumed) of the major peak. The (S,S) relative
configuration within (+)-9 was established by X-ray
crystallographic analysis (CCDC 236493); the absolute
configuration follows because (+)-9 is prepared from
the known (S)-(ꢀ)-8.
(820mg, 2.5mmol; 92% de) gave (S)-(+)-7 as a white
24
D
CHCl3); 92% ee}. A sample of (S)-(+)-7 obtained
solid {424mg, 82%; mp 93–94°C; ½aŠ ¼ þ54, (c 1.0,
24
from (+)-9 (>98% de) had ½aŠ ¼ þ60 (c 1.0,
D
CHCl3): IR mmax 3197 (br), 1710cmꢀ1
;
1H NMR
(500MHz, CDCl3) d 4.04–3.99 (4H, m, H2CO·2),
3.11 (1H, ap dd, J=9, 14Hz, HC-7), 3.02–2.96 (2H,
m, HC-6, HC-7), 2.79 (1H, J=3.5, 9, 13Hz, HC-9),
2.71 (1H, dddd, J=1, 3.5, 7, 13Hz, HC-9), 2.22 (1H,
ddd, J=3.5, 7, 13.5Hz, HC-10), 1.86 (1H, ddd, J=3.5,
9, 13.5Hz, HC-10); 13C NMR (75MHz, CDCl3) d
176.1 (s), 107.4 (s), 65.3 (t), 64.8 (t), 51.0 (d), 35.8 (t),
29.6 (t), 26.9 (t); LRMS (EI), m/z (relative intensity):
204 ([M]+, 50), 176 (43), 159 (19), 132 (62), 113 (17),
4.5. 1,4-Dioxa-8-thia-spiro[4.5]dec-6-ylmethanol 10
From 7. A solution of (R)-(ꢀ)-7 (91% ee; 719mg,
3.5mmol) in THF (2mL) was added dropwise via

D. E. Ward et al. / Tetrahedron: Asymmetry 15 (2004) 2425–2430
2429
syringe over 10min to a stirred suspension of LiAlH4
(200mg, 5.3mmol) in THF (15mL) at 0°C. The solution
was removed from the ice bath and, after 1h, heated un-
der reflux for 45min. After the mixture had cooled to
room temperature, ether (15mL), water (0.2mL), 15%
aqueous NaOH (0.2mL), and water (0.6mL) were
added sequentially. The resulting mixture was stirred
for 1h, during which time a white precipitate formed.
The mixture was filtered through Celiteꢁ and the com-
bined filtrate and ether washings dried over Na2SO4,
concentrated, and fractionated by FCC (50% ethyl ace-
tate in hexane) to give (S)-(ꢀ)-10 as a colorless oil
centrated, and fractionated by FCC (50% EtOAc in hex-
ane) to yield the titled compound as a light yellow oil
(1.37g, 94%): IR mmax 3435, 1731, 1666cmꢀ1
;
1H
NMR (500MHz, C6D6) d 4.42 (1H, dd, J=3.5, 4.5Hz,
HC-5), 3.68–3.42 (4H, m, H2CO·2), 3.25 (3H, s,
H3CO), 3.16 (1H, dd, J=4.5, 5Hz, HC-3), 2.94 (1H,
dd, J=5, 13.5Hz, HC-2), 2.90 (1H, br d, J=16.5Hz,
HC-6), 2.75 (1H, dd, J=4.5, 16.5Hz, HC-6), 2.50 (1H,
dd, J=4.5, 13.5Hz, HC-2); 13C NMR (125MHz,
C6D6) d 172.2, 152.7, 96.4, 68.9, 60.9, 52.3, 45.9, 28.5,
25.1; LRMS (EI), m/z (relative intensity): 218 ([M]+,
13), 190 (10), 173 (100), 158 (19), 140 (46), 115 (37), 99
(31), 86 (9); HRMS m/z calcd for C9H14O4S 218.0613,
found 218.0611.
{618mg, 92%; ½aŠ ¼ ꢀ22, (c 1.0, CHCl3)}. This mate-
D
rial was determined to be 90% ee by analysis of the de-
rived Mosherꢂs ester. Spectral data for (S)-(ꢀ)-10 was in
accord with that previously reported for ( )-10.1 Fol-
lowing the same procedure (S)-(+)-7 (91% ee; 408mg,
3.5mmol) was converted into (R)-(+)-10 {346mg, 91%;
4.7. Methyl 3,6-dihydro-4-[2-(dimethyl(1,1-dimethylethyl)
silyloxy)ethoxy]-2H-thiopyran-3-carboxylate 13
½aŠ ¼ þ23, (c 1.0, CHCl3); 91% ee}.
t-BuMe2SiCl (802mg, 5.17mmol), Et3N (1.4mL,
10mmol), and DMAP (29mg, 0.24mmol) were sequen-
tially added to a stirred solution of the hydroxy ester
12 (1.02g, 4.70mmol) in CH2Cl2 (20mL) under argon.
After 18h, MeOH (5mL) was added and the mixture
washed with brine. The aqueous layer was extracted
with CH2Cl2 and the combined CH2Cl2 layers dried
over Na2SO4, concentrated, and the residue passed
through a short silica pad eluting with 30% EtOAc in
hexane to afford the titled compound as a light yellow
D
From 14. A solution of (R)-(ꢀ)-14 (355mg, 1.20mmol)
in THF (5mL) was added dropwise via syringe over
5min to a stirred suspension of LiAlH4 (90mg,
2.4mmol) in THF (30mL) at 0°C under argon. The
reaction mixture was allowed to warm to room temper-
ature and after 1.5h, was quenched by addition of 15%
aqueous NaOH (ca. 0.5mL). After 30min, the mixture
was filtered through a short pad of Celiteꢁ, Al2O3,
and Na2SO4 (in three layers, top to bottom) and the
combined filtrate and DCM washings concentrated to
give (R)-(+)-10 as a colorless oil that was homogeneous
1
oil (1.46g, 94%): IR mmax 1743, 1671cmꢀ1; H NMR
(500MHz, C6D6) d 4.53 (1H, dd, J=4, 4Hz, HC-5),
3.73–3.63 (2H, m, H2CO), 3.56–3.50 (2H, m, H2CO),
3.39 (3H, s, H3CO), 3.34 (1H, dd, J=4.5, 5.5Hz, HC-
3), 2.98 (1H, dd, J=5.5, 13.5Hz, HC-2), 2.92–2.84
(2H, m, HC-6), 2.58 (1H, dd, J=4.5, 13.5Hz, HC-2);
13C NMR (125MHz, C6D6) d 171.58 (s, CO), 153.63
(s, C-4), 95.51 (d, C-5), 68.90 (t, C-30), 62.35 (t, C-20),
52.02 (q, CH3O), 46.31 (d, C-3), 29.02 (t, C-2), 26.44
(q·3, (CH3)3C), 25.20 (t, C-6), 18.88 (s, C(CH3)3),
ꢀ4.79 (q, CH3Si), ꢀ4.84 (q, CH3Si); LRMS (EI), m/z
(relative intensity): 317 ([MꢀCH3]+, 3), 275
([MꢀC4H9]+, 19), 257 (19), 229 (22), 213 (11), 173
(33), 89 (33), 73 (100); HRMS m/z calcd for C15H28O4S-
Si 332.1478 (275.0773 for MꢀC4H9), found 275.0767
(MꢀC4H9).
by TLC and 1H NMR {215mg, 94%; ½aŠ ¼ þ24, (c 1.0,
D
CHCl3); 95% ee}. The ee of 10 was determined by
reaction of a small sample (5–10mg) with the acid
chloride prepared from (R)-Mosherꢂs acid (1.5equiv) in
the presence of Et3N and DMAP as previously
described19 gave the crude Mosherꢂs ester;20 the absence
of 10 was confirmed by 1H NMR. The de of the
Mosherꢂs ester (and by implication the ee of the
starting 10) was determined by integration of the peaks
at d 4.64 (1H, dd, J=4, 11Hz, HCO-MTPA, S,R-dia-
stereomer) and d 4.58 (1H, dd, J=4, 11Hz, HCO-
MTPA, R,R-diastereomer). Ratios >35:1 were
confirmed by comparison of the minor peak to the 13C
satellite (0.55% assumed) of the major peak. (+)-10 is
assigned the (R)-configuration because LiAlH4
reduction of (+)-7 gave (+)-10 and the absolute configu-
ration of (S)-(+)-7 was established by X-ray crystallo-
graphic analysis of its ammonium salt with (S)-(ꢀ)-8
[i.e. (+)-9].
4.8. (S)-Phenyl 1,4-Dioxa-8-thia-spiro[4.5]decane-6-carbo-
thioate 14
From ( )-7: Oxalyl chloride (5.4mL, 62mmol) was
added dropwise to a stirred solution of ( )-7 (8.42g,
41.2mmol) in benzene (80mL) at room temperature un-
der argon. After 3h, the mixture was concentrated and
thiophenol (4.50mL, 43.7mmol) and Et3N (11.5mL,
83.7mmol) added sequentially to a stirred solution of
the residue in THF (130mL) (a white precipitate
formed). After 15min, the mixture was filtered through
a mixture of basic Al2O3 and Celite and the combined
filtrate and washings concentrated to give ( )-14 as a
4.6. Methyl 3,6-dihydro-4-(2-hydroxyethoxy)-2H-thiopy-
ran-3-carboxylate 12
LDA was prepared by addition of BuLi (2.5M in hexa-
nes; 8.4mL, 21mmol) to a stirred solution of i-Pr2NH
(2.33g, 23mmol) in THF (65mL) at 0°C under argon.
The mixture was cooled to ꢀ78°C and a solution of
the ketal ester 6 (1.46g, 6.72mmol) in THF (2mL)
added dropwise via syringe. After 30min, the reaction
was quenched by addition of H2O (10mL) and the mix-
ture diluted with brine and extracted with CH2Cl2. The
combined organic layers were dried over Na2SO4, con-
1
white solid (11.8g, 96%) that was homogeneous by H
NMR. Recrystallization from ether gave analytically
pure ( )-14 (10.5g, 86%; mp 80–82°C. Anal. Calcd for
C14H16O3S2: C, 56.73; H, 5.44. Found: C, 56.79; H,
1
5.59): IR mmax 1690cmꢀ1; H NMR (500MHz, CDCl3)

2430
D. E. Ward et al. / Tetrahedron: Asymmetry 15 (2004) 2425–2430
d 7.40 (5H, s, Ph), 4.03–3.93 (4H, m, H2CO·2), 3.28–
3.22 (2H, m, HC-6, HC-7), 2.93–2.86 (2H, m, HC-7,
HC-9), 2.63 (1H, dddd, J=2, 3.5, 5.5, 13.5Hz, HC-9),
2.15 (1H, ddd, J=3, 5.5, 13.5Hz, HC-10), 1.87 (1H,
ddd, J=3.5, 11.5, 13.5Hz, HC-10); 13C NMR
(125MHz, CDCl3) d 195.6 (s), 134.5 (d·2), 129.5 (d),
129.3 (d·2), 127.9 (s), 107.7 (s), 65.4 (t), 65.2 (t), 59.7
(d), 37.4 (t), 30.1 (t), 26.8 (t); LRMS (EI), m/z (relative
intensity): 296 (13), 187 (68), 159 (20), 109 (12), 99
(100), 55 (25); HRMS m/z calcd for C14H16O3S2
296.0541, found 296.0543.
the derived Mosherꢂs ester (see above under 10). (ꢀ)-14
is assigned the (R)-configuration because LiAlH4 reduc-
tion of (ꢀ)-14 gave (R)-(+)-10 of established absolute
configuration (see above under 10).
References and notes
1. Ward, D. E.; Sales, M.; Man, C. C.; Shen, J.; Sasmal, P.
K.; Guo, C. J. Org. Chem. 2002, 67, 1618–1629.
2. Ward, D. E.; Guo, C.; Sasmal, P. K.; Man, C. C.; Sales,
M. Org. Lett. 2000, 2, 1325–1328.
Enantioselective protonation: s-BuLi (1.1M in hexanes;
6.2mL, 6.8mmol) was added dropwise via syringe over
5min to a stirred solution of ( )-14 (1.02g, 3.44mmol)
in THF (165mL) at ꢀ78°C under argon. After 15min,
the mixture was cooled to ꢀ100°C and after 15min, a
solution of (1S,2R)-(+)-N-isopropylephedrine (+)-
1511,12 (3.4g, 18.9mmol) in THF (5mL) was added at
once via syringe. The mixture was allowed to warm
slowly to ꢀ78°C over 40min and after 2h at that tem-
perature, the reaction quenched by addition of water
(5mL). The cooling bath was removed and after
15min, the mixture was diluted with aqueous HCl
(2M) and extracted with CH2Cl2. The combined organic
layers were dried over Na2SO4, concentrated, and fract-
3. Ward, D. E.; Sales, M.; Sasmal, P. K. J. Org. Chem. 2004,
69, 4808–4815.
4. Oare, D. A.; Heathcock, C. H. Top. Stereochem. 1989, 19,
227–407.
5. Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18,
249–330.
6. Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R.
Angew. Chem., Int. Ed. Eng. 1985, 24, 1–30.
7. Kolodiazhnyi, O. I. Tetrahedron 2003, 59, 5953–6018.
8. Fehr, C. Angew. Chem., Int. Ed. Eng. 1996, 35, 2567–2587.
9. Eames, J.; Weerasooriya, N. Tetrahedron: Asymmetry
2001, 12, 1–24.
10. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7287.
11. Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1042–1044.
12. Fehr, C.; Galindo, J. J. Am. Chem. Soc. 1988, 110,
6909–6911.
13. Page, P. C. B.; Heaney, H.; Rassias, G. A.; Reignier, S.;
Sampler, E. P.; Talib, S. Synlett 2000, 104–106.
14. Kato, K.; Suemune, H.; Sakai, K. Tetrahedron 1994, 50,
3315–3326.
15. Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27,
1624–1654.
16. Ward, D. E.; Man, C. C.; Guo, C. Tetrahedron Lett. 1997,
38, 2201–2202.
17. Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59,
7549–7552.
18. Boeckman, R. K., Jr.; Shao, P.; Mullins, J. J. Org. Synth.
2000, 77, 141–152.
19. Ward, D. E.; Rhee, C. K. Tetrahedron Lett. 1991, 32,
7165–7166.
20. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969,
34, 2543–2549.
ionated by FCC (50% EtOAc in hexane) to give (ꢀ)-14
24
as a white solid {1.01g, 99%; ½aŠ ¼ ꢀ14, (c 1.0,
D
CHCl3); 82% ee}. Recrystallization (2·) of this sample
from ether gave (ꢀ)-14 {0.516mg, 51%; mp 76–78°C;
24
½aŠ ¼ ꢀ18, (c 1.0, CHCl3); 95% ee}. A sample of (ꢀ)-
24
D
14 with >98% ee was obtained by further crystallization
{mp 78–79°C; ½aŠ ¼ ꢀ19, (c 1.0, CHCl3). Anal. Calcd
D
for C14H16O3S2: C, 56.73; H, 5.44. Found: C, 56.73; H,
5.64}. The mother liquors from above were combined
and concentrated to give (ꢀ)-14 (0.490g, 48%; ca. 65%
ee). To recover (+)-15, the aqueous phase was made
basic (pH ca. 12) by addition of 30% aqueous NaOH
and then extracted with CH2Cl2. The combined organic
layers were dried over Na2SO4, concentrated, and the
reddish-brown residue subjected to bulb-to-bulb distilla-
tion (150°C, 0.4 mbar) to afford (+)-15 as a pale yellow
24
oil {3.2 g, 94%; ½aŠ ¼ þ2:5, (c 6.0, CHCl3)}. Reduction
D
of 14 gave 10 whose ee was determined by H NMR of
1