Effect of a phosphazene base on the diastereoselectivity of addition of α-sulfonyl carbanions to butyraldehyde and isopropylideneglyceraldehyde

Article abstract of DOI:10.1021/jo9518967

The effect of tBuP4, a strong and cation-free base, on the yield and diastereoselectivity of additions of thus formed "naked" α-sulfonyl carbanions to achiral butyraldehyde and chiral isopropylideneglyceraldehyde was studied. It has been found that with tBuP4 a reasonable yield (～55%) and a slightly better diastereoselectivity (72% of the anti diastreomer) are obtained with achiral and nonfunctionalized butyraldehyde while with isopropylideneglyceraldehyde the use of tBuP4 allowed us to greatly increase the yields (up to 95-100%) and the diastereoselectivities (83-89% of a single diastereomer over the four possible diastereomers). It was also shown that the extra oxygen atom in the α-position plays a determinant role in this effect.

Full text of DOI:10.1021/jo9518967

2
690
J . Org. Chem. 1996, 61, 2690-2694
Effect of a P h osp h a zen e Ba se on th e Dia ster eoselectivity of
Ad d ition of r-Su lfon yl Ca r ba n ion s to Bu tyr a ld eh yd e a n d
Isop r op ylid en eglycer a ld eh yd e
Arlette Solladi e´ -Cavallo* and Didier Roche
Laboratoire de St e´ r e´ ochimie Organom e´ tallique, associ e´ au CNRS, EHICS, 1 rue Blaise Pascal,
6
7008 Strasbourg, France
J ean Fischer and Andr e´ De Cian
Laboratoire de Cristallochimie, associ e´ au CNRS, Universit e´ Louis Pasteur, 4 rue Blaise Pascal,
6
7070 Strasbourg, France
Received October 25, 1995X
The effect of tBuP4, a strong and cation-free base, on the yield and diastereoselectivity of additions
of thus formed “naked” R-sulfonyl carbanions to achiral butyraldehyde and chiral isopropylidene-
glyceraldehyde was studied. It has been found that with tBuP4 a reasonable yield (∼55%) and a
slightly better diastereoselectivity (72% of the anti diastreomer) are obtained with achiral and
nonfunctionalized butyraldehyde while with isopropylideneglyceraldehyde the use of tBuP4 allowed
us to greatly increase the yields (up to 95-100%) and the diastereoselectivities (83-89% of a single
diastereomer over the four possible diastereomers). It was also shown that the extra oxygen atom
in the R-position plays a determinant role in this effect.
Addition of R-sulfonyl carbanions to carbonyls is a well-
Sch em e 1
studied reaction used for the synthesis of trans olefins.1
,2
The R-sulfonyl carbanions are usually generated with
BuLi or EtMgBr, and the diastereoselectivity of the
condensation with aldehydes ranges between 1:1 and
2
-4
3
:1.
We report here the effect of tBuP4, a strong and cation-
5
free base, on the diastereoselectivity of additions of thus
6
formed “naked” R-sulfonyl carbanions to achiral butyral-
dehyde (2) and chiral isopropylideneglyceraldehyde (4).
Ta ble 1. Ad d ition s Eth yl Ben zyl Su lfon e (1a ) to Ach ir a l
Bu tyr a ld eh yd e (2)
base
syn (Rf) I
anti (Rf) II
yield, %
Resu lts
BuLi
3a
3a
3a ′
41 (0.4)a
28 (0.4)
59 (0.24)
72 (0.24)
100
56
72
tBuP4
Ad d ition to Ach ir a l Bu tyr a ld eh yd e (2). Condensa-
tion of ethyl benzyl sulfone (1a ) with butyraldehyde (2)
gave a mixture of the two expected syn and anti diaster-
eomers, Scheme 1.
tBuP4/Me3SiClb
18
c
82
c
a
Et2O/hex 6/4. b Me3SiCl was added to the reaction mixture just
before the workup. c Assigned using the J 12 as compared with the
unprotected compound.
The results are presented in Table 1. Noteworthy was
the quantitative yield obtained upon condensation of the
starting reagents (1a (Li) and 2), probably because of
chelation, Figure 1.
7
lithiosulfone anion 1a (Li) (generated from 1a with BuLi
as base) with butyraldehyde 2 (Table 1, entry 1). Since
these reactions are reversible one must think in terms
of stability of products and one may conclude that the
Li-alcoholate formed, 3a (Li), is more stable than the
When tBuP4 was used as base lower yield (56%) was
obtained (Table 1, compare entries 1 and 2); this reflects
the expected lower stability of the “naked” alcoholate 3a -
(tBu P 4H) as compared with the chelated one, 3a (Li).
1
3
It must be noted that quenching with Me SiCl allowed
X
us to increase the yield to 72% (Table 1, entry 3), thus
Abstract published in Advance ACS Abstracts, March 15, 1996.
(
1) J ulia, M.; Arnould, D. Bull. Soc. Chim. Fr. 1973, 743. J ulia, M.;
Paris, J . M. Tetrahedron Lett. 1973, 4833.
2) Kocienski, P. J .; Lythgoe, B.; Ruston, S. J . Chem. Soc., Perkin
Trans. 1 1978, 829 and references therein.
3) Truce,W. E.; Klinger, T. C. J . Org. Chem. 1970, 35, 1834 and
references therein.
4) Kingsbury, C. A. J . Org. Chem. 1972, 37, 102 and references
therein.
making this reaction synthetically useful.8
It appeared that the anti (threo) isomer was favored
(
4
(Table 1) in accord with literature results and that the
(
diastereoselectivity increased when tBuP4 was used as
base (Table 1, compare entries 1 and 2). More interesting
is the further increase of the diastereoselectivity upon
(
(5) Schwesinger, R. Nachr. Chem. Tech. Lab. 1990, 38, 1214.
quenching the alcoholate formed with Me
3
SiCl (Table 1,
Seebach, D.; Beck, A. K.; Studer, A. Modern Synthetic Methods 1995;
Ernst, B., Leumann, C., Eds.; Verlag Helvetica Chimica Acta: Basel;
VCH: Weinheim, 1995; Vol. 7.
compare entries 2 and 3).8
Ad d ition to Ch ir a l Isop r op ylid en eglycer a ld eh yd e
4) a n d Ald eh yd es 6 a n d 7. The results of the
(
6) “Naked” means cation-free as the plus and minus species are
very probably intimately associated in this solvent.
7) For structure and conformation stability of lithiosulfones, cf.:
(
(
Kaufman, M. J .; Gronert, S.; Bors, D. A.; Streitwieser, A. J . Am. Chem.
Soc. 1987, 109, 602. Gais, H. J .; Hellmann, G.; G u¨ nther, H.; Lopez,
F.; Lindner, H. J .; Braun, S. Angew. Chem., Int. Ed. Engl. 1989, 28,
(8) As the reaction is reversible, the increase in diastereomer II upon
quenching the reaction mixture with Me
3
SiCl (72% II to 82% II)
+
suggests that alcoholate 3a II(tBu P 4H ) is more reactive toward Me
3
-
+
+
1
025.
SiCl than 3a I(tBu P 4H ) and 1a (tBu P 4H ).
0
022-3263/96/1961-2690$12.00/0 © 1996 American Chemical Society

Diastereoselectivity of Addition of R-Sulfonyl Carbanions
J . Org. Chem., Vol. 61, No. 8, 1996 2691
F igu r e 1.
Sch em e 2
Ta ble 2. Ad d ition of Ben zyl Su lfon es 1a -c to Ch ir a l Ald eh yd e 4
R
base
solvent, T, °C
I (Rf)
II (Rf)
III (Rf)
IV (Rf)
yield, %
Et
EtMgBr
LDA
BuLi
THF, 0
THF, -78
THF, -78
5a
5a
5a
5a
5a
5a
5b
5c
5c
60 (0.35)a
7 (0.26)
2
13
14
0
17 (0.17)
16 (0.12)
61
62
90
45
90
43
35
34
75
83
40
39
14
25
17
15
13
38
0
BuLi
THF/TMEDA, -78
THF, -40
tBuP4
tBuP4
tBuP4
BuLi
THF, -78
0
0
95
b
Ph
tBu
THF, -78
87 (0.31)
13 (0.22)
20 (0.26)
0
100
100
100
THF, -78
31 (0.29)c
89
31 (0.19)
11
18 (0.12)
0
tBuP4
THF, -78
a
Et2O/hex 8/2. b Et2O/hex 1/1. c Et2O/hex 4/6.
Sch em e 3
Ta ble 3. Ad d ition of Ben zyl Su lfon e 1a to Ald eh yd es 6
a n d 7
condensation of benzylsulfones 1a -c with (R)-(+)-iso-
propylideneglyceraldehyde (4), Scheme 2, are given in
Table 2.
One must note the high yields (90-100%) obtained
with tBuP4 in contrast with the previous result where
the use of tBuP4 considerably lowered the yield (compare
Table 2, entries 5, 6, 7, and 9 with Table 1, entry 2). It
was reasonable to postulate that the extra oxygen atoms
alde-
hyde base
yield,
%
I (Rf)
II (Rf)
III (Rf) IV (Rf)
EtMgBr 8a 23 (0.33)a 35 (0.33) 23 (0.22) 19 (0.16)
6
6
6
7
7
77
80
100
48
might play an important role by adding extra NC-
BuLi
tBuP4 8a 70
BuLi
tBuP4 9a 30
8a 16
32
2
29
16
23
12
δ+
H
‚‚‚O interactions (which are known to contribute by
9a 34 (0.13)b 34 (0.13) 17 (0.11) 15 (0.11)
9
ca. 4-6 kcal/mol ) between one or both oxygen atoms of
the aldehydic part of the substrate and the conjugated
acid of the phosphazene base (tBuP4H ). Therefore,
34
17
19
62
+
a
Et2O/hexane 7/3. b Et2O/hexane 9/1.
aldehydes 6 and 7 possessing only one oxygen atom either
in the R-position or in the â-position have been examined,
Scheme 3 and Table 3. One may note that the yields
with aldehyde 6 were always higher than with aldehyde
mers over the four possible were observed with aldehyde
(Table 2, entries 5-7 and 9). However, the major
4
diastereomers formed, 5a -cI, are now 1,2-syn (erythro),
Table 5, instead of 1,2-anti (threo) as in the case of
condensation with butyraldehyde 2 having no extra
oxygen (where 3a II was the major compounds, Table 1).
It is worth noting that the use of tBuP4 upon conden-
sation of the benzyl sulfone 1a with aldehyde 6 led also
to an increase in diastereoselectivity, 70% of 8a I, while
with aldehyde 7 there was no change of the diastereo-
selectivity (Table 3, compare entries 1 and 2 with 3 and
7
(Table 3, compare entries 1-3 with 4 and 5) and that
the use of tBuP4 as base again led to higher yields, but
more so with 6 (100%) than with 7 (62%).
It thus appeared that an extra oxygen atom in the
R-position is determinant for the obtention of high yields.
Most important is also the better diastereoselectivity
obtained with tBuP4 as base where only two diastereo-
4
with 5). Obviously the extra oxygen atom in the
(
9) Taylor, R. ; Kennard, O. J . Am. Chem. Soc. 1982, 104, 5063.
R-position is also determinant for obtention of a better
diastereoselectivity.
Mautner, M. J . Am. Chem. Soc. 1983, 105, 4912. Mautner, M.;
Deakyne, C. A. J . Am. Chem. Soc. 1985, 107, 469.

2
692 J . Org. Chem., Vol. 61, No. 8, 1996
Solladi e´ -Cavallo et al.
Ta ble 4. NMR P a r a m eter s of 3a a n d A:
a
P h SO2CH(P h )CH(OH)P h
δ H1b
δ H2b
J 12b
3
3
AI
a I
a II
3.98
4.12
4.19
4.46
4.82
4.67
6.03
5.70
2
9
2.5
10
syn
anti
syn
AII
anti
a
Compounds AI and AII have been resynthesized following ref
. b δ in ppm and J in Hz.
4
Ta ble 5. Ch a r a cter istics of 5a -c a n d 8
Rf
δ H1
δ H2
δ H3
J 12
J 23
1,2
2,3
5
a Ia
a II
0.35 4.47
0.26 4.05
4.70
4.65
4.67
4.35
4.56
∼4.70
4.74
4.52
4.52
4.74
4.62
3.52
4.20
∼3.90
∼3.53
3.54
1.5
3.5
9
10
1.5
9
5
syn
syn
anti
syn
5
5
5
5
5
5
5
5
5
8
8
8
8
b
b
a III 0.17 4.05
a IV 0.12 4.25
bI
bII
cI
cII
cIII 0.19 4.48
cIV 0.12 4.25
a I
3.5 anti anti
1.5 anti syn
9
0.31 4.43
0.22
0.29 4.65
0.26 4.70
syn
anti
c
3.39
3.55
1.5 9.5 syn
10
6.5
4
2
anti
F igu r e 2. ORTEP plot of one molecule of 5a I. Elipsoids are
scaled to enclose 50% of the electronic density.
1.5 anti syn
5
6
8.5 syn
6 syn
2.5 anti syn
d
d
b
∼4
anti anti
syn
4.08
3.12
3.62
3.20
3.25
syn
anti
syn
Sch em e 4
0.33 4.57
0.33 4.13
e
a II
∼4.6
3.5
10
b
b
a III 0.22 4.05
4.80
a IV 0.16 4.45f
4.45f
anti anti
a
b
Structure determined by X-ray, Overlapped with a CH2.
c
d
e
Not isolated. AB part of an ABX system. Overlapped with a
signal of 8a I. f Degenerated AB part of an ABXY system, with a
small nonequivalence.
It must also be noted that tert-butyl benzyl sulfone (1c)
gave a better diastereoselectivity than ethyl benzyl
sulfone (1a ) (Table 2, entries 6 and 9). A similar trend
had already been observed but in the case of sulfoxides
by Casey and coll.10
4
those of 5a I, 3a I, 3a II, AI, and AII as well as 11 (whose
1
cf. below).
,2-anti/2,3-syn structure was unambiguously assigned,
However, attempts to quench alcoholates 5a I-III-
tBu P 4H) with R SiCl failed, due to the low reactivity
3
(
The 1.5 Hz value of the J 12 coupling constant observed
in 1,2-syn 5a I is consistent with the values observed for
a I-syn and AI-syn, probably because the O-H‚‚‚O S
2
H-bond is stronger than the O-H‚‚‚OC(C) H-bond. It is
thus reasonable to postulate, on the basis of J 12 coupling
constants, that 5a II, -III and -IV are, respectively, 1,2-
syn (J 12 ) 3.5 Hz), 1,2-anti (J 12 ) 9 Hz), and 1,2-anti (J 12
of these alcoholates. As a matter of fact, an attempt to
protect the hydroxyl group of isolated 5a I failed even with
tBuMe SiOTf after 3 days, and only 57% of protection
2
was obtained after 1 day in the case of 5a II.
Str u ctu r es of Com p ou n d s 5a I-IV, 5bI, 5cI-IV,
a n d 8a I-IV. All diastereomers have been numbered (I,
f
II, ...) according to decreasing TLC frontal retentions (R ),
3
)
10 Hz), Table 5.
Tables 4 and 5.
Therefore, 5a I being 1,2-syn/2,3-anti, 5a II is 1,2-syn/
After separation and recrystallization from EtOAc,
diastereomer 5a I was obtained as a single crystal suit-
able for an X-ray diffraction analysis. The structure,
Figure 2, shows that the configuration of the two new
asymmetric carbons created is 3S,4R (according to ORTEP
numbering), that is, 1S,2R (according to the usual
numbering given in Scheme 2), on the basis of the known
R configuration of carbon C5 (ORTEP numbering), that
is C3 (usual numbering, Scheme 2). Diastereomer 5a I is
thus 1,2-syn/ 2,3-anti.
It also appears that (1) the phenyl ring is almost
eclipsed with the CH bond, S-C3-C10-C15 ) 60°, (2)
the R-oxygen atom of the acetal ring is almost trans to
the hydroxyl group, O4-C5-C4-O3 ) 173.5°, and one
of the sulfone oxygens is pushed away from the hydroxyl
groups, O1-S-C3-C4 ) 160° (O2-S-C3-C4 ) 40°).
Structures of diastereomers 5a II, 5a III, and 5a IV have
then been determined using vicinal H-H coupling con-
stants (Table 5, columns 6 and 7) and comparison with
2
,3-syn, Table 5.
The 1,2-anti/2,3-syn structure was assigned to 5a IV
because the coupling constants (10 and 1.5 Hz) are
similar to those (10 and 1.5 Hz) of compound 11 of known
configuration (cf. below). Therefore, 5a III can only be
1
,2-anti/2,3-anti.
The 1,2-syn/2,3-anti configurations of 5bI, 5cI, and 8a I
have then been assigned by direct comparison with 5a I,
and the 1,2-anti/2,3-syn configurations of 5cII and 8a III
have been assigned by comparison with 11 and 5a IV.
Finally 5cIV and 8a II, having coupling constants similar
to those of 5a II, were assigned the 1,2-syn/2,3-syn
structure, and as a consequence, 5cIII and 8a IV must
have the 1,2-anti/2,3-anti structure.
Str u ctu r e of Com p ou n d 11. Since the (1S,2R,3S)
structure of the lactoepoxide 10 was determined through
X-ray diffraction analysis, opening of the epoxide ring
10
3
with EtSH/AlEt (SN2 mecanism) followed by an oxida-
tion step to the sulfone led to (1R,2R,3S)-11, Scheme 4,
of known 1,2-anti/2,3-syn configuration. Because com-
pound 11 (which also possesses an oxygen atom in the
R-position) has a structure close to that of compounds
5a -c, the vicinal coupling constants (J 12 ) 10 Hz and
(
10) Casey, M.; Mukherjee, I.; Trabsa, H. Tetrahedron Lett. 1992,
3, 127.
11) Solladi e´ -Cavallo, A.; Roche, D.; Bold, G.; Acemoglu, F.; Tintel-
not-Blomley, M., in press.
3
(

Diastereoselectivity of Addition of R-Sulfonyl Carbanions
J . Org. Chem., Vol. 61, No. 8, 1996 2693
J
23 ) 1.5 Hz) measured on compound 11 can be used for
organic layers were washed with brine (40 mL), dried over
MgSO
pure aldehyde was purified by flash chromatography to give
a colorless liquid (100 mg, 35%): R O/hexane 50/
4
, and concentrated under reduced pressure at 0 °C. The
the determination of the structures of compounds 5a -c.
f
) 0.16 (Et
2
Con clu sion
1
5
J
3
0); H NMR δ 9.60 (d, J ) 2.5, 1H), 3.92 (AB part of ABX,
AB ) 8.5, J AX ≈ 4.5, J BX ≈ 7.5, ∆ν ) 79, 2H), 3.87 (m, 2H),
Although additions of R-sulfonyl carbanions to alde-
hydes are reversible reactions, the use of tBuP4, known
to generate “naked” anions, led to a satisfying yield with
butyraldehyde (56%) which can be increased to 72% upon
quenching the reaction mixture with Me SiCl. However,
3
the diastereoselectivity, although significantly higher
with tBuP4, remained low (44%-64%).
.05 (m, 1H), 2.16 (m, 2H).
Gen er a l P r oced u r e for th e Syn th esis of â-Hyd r oxy
Su lfon es 5a -c, 8a , a n d 9a . â-Hydroxy sulfones were pre-
pared using EtMgBr, nBuLi, or tBuP4 as base according to
the procedures described below. Ratio and yields in crude
1
products are given in Tables 1-3. The H NMR data used for
analysis of the ratio and assignment of structure are collected
in Tables 4 and 5.
Upon addition of R-sulfonyl carbanions to chiral alde-
hyde 4 having two extra oxygen atoms in the R- and
â-positions, the use of tBuP4 increased the yield and the
diastereoselectivity in favor of the syn/anti isomer (only
two isomers, over the four possible, were observed). It
also appeared that the extra oxygen atom in the R-posi-
tion was determinant for obtention of high yields (90-
Use of EtMgBr a s Ba se. A 1 M solution of ethylmagne-
sium bromide (1.1 equiv, 0.67 mmol) in Et
solution of sulfone (1.1 equiv, 0.67 mmol) in THF (4 mL) at 0
C. After formation of a white precipitate (30 min), the
2
O was added to a
°
mixture was cooled to -78 °C and the desired aldehyde (1
equiv, 0.61 mmol) was added. The reaction was allowed to
warm to rt (2 h) and was monitored by TLC. The mixture
was then quenched with a saturated solution of NH
mL). The aqueous phase was extracted with Et
O (2 × 20 mL),
and the combined organic layers were dried over MgSO and
4
Cl (20
1
00%) and better diastereoselectivities (de 66-78%).
It must be noted that such diastereoselectivities are
2
4
the highest ever obtained for this kind of condensation
and might well be further improved using more hindered
Schwessinger bases.
concentrated. The crude mixture was analyzed by NMR before
and after purification by flash chromatography.
Use of n Bu Li a s Ba se. A 1.6 M solution of nBuLi in
hexane (1 equiv, 1.08 mmol) was added to a solution of sulfone
(
1 equiv, 1.08 mmol) in THF (5 mL) at -78 °C. The stirring
Exp er im en ta l Section
was maintained for 30 min before addition of the desired
aldehyde (1 equiv, 1.08 mmol). The reaction was allowed to
warm to -50 °C (3 h) and was followed by TLC. The mixture
was then quenched with water (20 mL). The aqueous phase
3
Infrared spectra were obtained using CHCl as solvent, and
-
1
1
13
peaks are reported in cm
.
H (200 MHz) and C (50 MHz)
as solvent unless
NMR spectra were obtained using CDCl
3
otherwise specified (δ in ppm refered to TMS, ∆ν and J in Hz,
sign of J not given). Melting points were determined on a
microscope and are uncorrected. Flash chromatography was
performed using Merck silica gel 70-230 mesh, and Kieselgel
was extracted with Et
organic layers were dried over MgSO
crude mixture was analyzed by NMR before and after purifica-
tion by flash chromatography.
Use of tBu P 4 a s Ba se. A 1 M solution of tBuP4 in hexane
(1 equiv, 0.1 mmol) was added to a suspension of sulfone (1
equiv, 0.1 mmol) in THF (1 mL) at -78 °C. The resulting
yellow solution was further stirred for 15 min before addition
of the desired aldehyde (1.2 equiv, 0.12 mmol). After 15-30
min, the mixture was quenched with a 10% HCl solution (5
2
O (2 × 50 mL), and the combined
4
and concentrated. The
6
0 F254 were used for TLC. All the solvents were distilled
before use: THF over Na/benzophenone, Et
2
O over LiAlH
4
1
,
2
CH Cl over calcium hydride. Sulfones 1a (mp 80-82 °C (lit.
2
2
1
3
mp 84 °C), 1b (mp 141-143 °C (lit. mp 144 °C), and 1c (mp
1
4
1
22-123 °C (lit. mp 126-127 °C) were prepared according
to known procedures. The X-ray diffraction experiments are
available as supporting information.
mL). The aqueous phase was extracted with CH
mL), and the combined organic layers were washed with a 10%
2
Cl
2
(2 × 10
P r ep a r a tion of Ch ir a l Ald eh yd es 4, 6, a n d 7. (R)-2,3-
Isopropylideneglyceraldehyde (4) was prepared from D-man-
nitol as described in refs 15 and 16. (S)-2-(Benzyloxy)propanal
HCl solution (2 × 10 mL) and with brine (10 mL), dried over
4
MgSO , and concentrated. The crude mixture was analyzed
(
6) was prepared from commercialy available (S)-ethyl lactate
as described in ref 17.
()-3-Car bom eth oxytetr ah ydr ofu r an . A solution of com-
by NMR before and after purification by flash chromatography.
1-(Eth ylsu lfon yl)-1-p h en ylp en ta n -2-ol, 3a . 3a I: white
(
powder; R
f
) 0.40 (Et O/hexane 60/40); mp 94-96 °C; IR 3550;
2
1
mercially available tetrahydrofuroic acid (0.54 g, 4.65 mmol)
and p-toluenesulfonic acid (catalytic) in MeOH (10 mL) was
stirred under reflux for 3 h. After evaporation of MeOH, the
H NMR δ 7.57 (m, 2H), 7.45 (m, 3H), 4.82 (dq, J ) 2, 3, 3, 3,
1H), 3.98 (d, J ) 2, 1H), 3.07 (d, J ) 3, OH), 2.75 (q, 2H), 1.40
(m, 4H), 1.22 (t, 3H), 0.87 (t, 3H); 13C NMR δ 130.9, 130.1,
129.3, 128.9, 71.4, 68.4, 46.3, 36.9, 18.9, 13.8, 6.2. Anal. Calcd
2
resulting colorless liquid was dissolved in Et O (50 mL),
washed with water (2 × 40 mL), dried over MgSO
4
, and
for C13
3a II: white powder; R
78 °C; H NMR δ 7.36 (m, 5H), 4.67 (tdd, J ) 2.5, 2.5, 6.5, 9,
1H), 4.12 (d, J ) 9, 1H), 3.66 (d, J ) 2.5, OH), 2.87 (AB part
of ABX
H
20
O
3
S: C, 60.90; H, 7.86. Found: C, 60.65; H, 7.82.
1
concentrated to give a colorless liquid (0.537 g, 89%): H NMR
f
) 0.24 (Et O/hexane 60/40); mp 76-
2
1
δ 4.02-3.71 (m, 4H), 3.70 (s, 3H), 3.08 (m, 1H), 2.17 (m, 2H);
1
3
C NMR δ 174.0, 70.0, 68.0, 51.7, 43.5, 29.4.
(
()-3-F or m yltetr a h yd r ofu r a n , 7. A 1 M solution of
3
3
, 2H), 1.59-1.10 (m, 4H), 1.24 (t, CH ), 0.78 (t, 3H).
DIBAL in toluene (2.82 mL, 2.82 mmol) was added to a
solution of 3-carbomethoxytetrahydrofuran (0.367 g, 2.82
1-(Eth ylsu lfon yl)-1-p h en yl-2-[(tr im eth ylsilyl)oxy]p en -
ta n e, 3a ′. Obtained as a mixture (cf. Table 1). Deprotection
occurred upon chromatography: 1H NMR δ 3a I′ (m in or ) 7.6
(m, 2H), 7.38 (m, 3H), 4.78 (td, J ) 3.5, 7, 7, 1H), 3.96 (d, J )
mmol) in a mixture of Et O/pentane (1/9, 10 mL) at -78 °C.
2
After the mixture was stirred for 1 h, a saturated solution of
diethyl tartrate (6 mL) was added carefully. The stirring was
maintained for 1 h, and the resulting two-phase solution was
3.5, 1H), 2.73 (AB of an ABX , 2H), 1.6-1.15 (m, 4H), 1.22 (t,
3
3H), 0.88 (t, 3H), 0.15 (s, 9H); 3a II′ (m a jor ) 7.30 (m, 5H), 4.5
(td, J ) 2.5, 2.5, 9, 1H), 4.25 (d, J ) 9, 1H), 2.6 (AB of an
diluted with Et
phase was extracted with Et
2
O (30 mL). After separation, the aqueous
O (30 mL), and the combined
2
3
ABX , 2H), 1.6-1.1 (m, 7H), 0.7 (t, 3H), 0.0 (s, 9H).
1
-(Eth ylsu lfon yl)-3,4-(isop r op ylid en ed ioxy)-1-p h en yl-
b u t a n -2-ol, 5a . 5a I (1S,2R,3R): white powder; R ) 0.35
) +2 (c ) 1.02 ,
); IR 3550; H NMR δ 7.60 (m, 2H), 7.40 (m, 3H), 4.70
(
(
12) Riley, F. L.; Rothstein, E. J . Chem. Soc. 1964, 3860.
13) Achmatowicz, B.; Baranowska, E.; Daniewski, A. R.; Pankowski,
f
(Et
CH
2
O/hexane 80/20); mp 108-111 °C; [R]
D
1
J .; Wicha, J . Tetrahedron Lett. 1985, 26, 5597.
2 2
Cl
14) Bordwell, F. G.; Pitt, B. M. J . Am. Chem. Soc. 1955, 77, 572.
(
ddd, J ) 1.5, 3, 9, 1H), 4.47 (d, J ) 1.5, 1H), 4.00 (AB part of
ABX, J AB ) 9, J AX ≈ 5, J BX ≈ 6, ∆ν ) 25, 2H), 3.52 (ddd, J )
R. W.; Crowley, H.; Simko, B. J . Med. Chem. 1983, 26, 1561.
9
1
, 6, 5, 1H), 3.26 (d, J ) 3, OH), 2.80 (AB part of ABX
3
, 2H),
(
16) J ackson, D. Y. Synth. Commun. 1988, 18, 337.
.49 (s, 3H), 1.27 (t, 3H), 1.25 (s, 3H); 13C NMR δ 131.2, 130.6,
(17) Ito, Y.; Kobayashi, Y.; Kawabata, T.; Takase, M.; Terashima,
S. Tetrahedron 1989, 45, 5767.
129.3, 129.1, 128.9, 129.2, 109.8, 74.8, 69.7, 67.6, 67.1, 46.3,

2
694 J . Org. Chem., Vol. 61, No. 8, 1996
7.2, 25.4, 6.1. Anal. Calcd for C15 S: C, 57.30; H, 7.05.
) 0.26 (Et O/hexane 80/
Solladi e´ -Cavallo et al.
1
2
H
22
O
5
8a III: isolated; R
f
) 0.22 (Et
2
O/hexane 70/30); H NMR δ
Found: C, 57.89; H, 6.90.
a II (1R,2S,3R): white powder; R
2
3
7.32 (m, 10H), 4.80 (dt, J ) 2.5, 2.5, 10, 1H), 4.47 (s, 2H), 4.05
(d, J ) 10, 1H), 3.20 (m + q, 3H), 3.07 (d, J ) 2.5, OH), 1.37
5
f
2
1
13
0); H NMR δ 7.60 (m, 2H), 7.40 (m, 3H), 4.65 (dt, J ) 3.5,
(t, 3H), 1.06 (d, J ) 6, 3H); C NMR δ 137.9, 130.1, 129.6,
.5, 5, 1H), 4.20 (q, J ) 5, 1H), 4.05 (d, J ) 3.5, 1H), 3.87 (AB
129.4, 129.2, 128.5, 127.9, 127.8, 74.7, 71.7, 70.8, 69.3, 49.6,
part of ABX, J AB ) 8.5, J AX ≈ 6, J BX ≈ 6, ∆ν ) 42, 2H), 2.82
12.5, 6.7.
1
(
(
1
AB part of ABX
3
, 2H), 2.80 (d, J ) 3.5, OH), 1.44 (s, 3H), 1.33
8a IV: isolated; R
f
) 0.16 (Et
2
O/hexane 70/30); H NMR δ
s, 3H), 1.21 (t, 3H); 13C NMR δ 130.9, 130.4, 129.5, 129.1,
7.28 (m, 10H), 4.45 (d, J ) 11, 1H + AB part of ABXY, 2H),
3.93 (d, J ) 11, 1H), 3.25 (m, 3H), 3.01 (q, 2H), 1.31 (t, 3H),
1.25 (d, J ) 6, 3H); 13C NMR δ 137.8, 130.9, 129.9, 129.1, 128.4,
127.9, 127.8, 74.5 , 73.4, 70.8, 70.6, 48.5, 15.5, 6.3.
10.1, 76.9, 70.4, 70.1, 65.8, 46.2, 26.6, 25.2, 5.6.
5
a III: white powder, 90/10 mixture of 5a III and 5a IV; R
f
1
)
2
0.17 (Et O/hexane 80/20); H NMR δ 7.41 (s, 5H), 4.67 (dt,
J ) 3.5, 3.5, 9, 1H), 4.05 (d, J ) 9, 1H), 3.90 (m, 3H), 3.20 (d,
J ) 3.5, OH), 3.14 (q, 2H), 1.40 (s, 3H), 1.36 (t, 3H), 1.26 (s,
(()-3-[2′-(Eth ylsu lfon yl)-2′-p h en yl-1′-eth a n ol]tetr a h y-
d r ofu r a n , 9a . Anal. Calcd for C14
20 4
H O S: C, 59.13; H, 7.08.
3
H).
Found: C, 59.41; H, 7.33. The diastereomers have not been
isolated in pure forms but as enriched mixtures of two isomers,
5
a IV: white powder, 88/12 mixture of 5a IV and 5a III; R
f
1
)
0.12 (Et
2
O/hexane 80/20); H NMR δ 7.30 (b s, 5H), 4.35
I + II and III + IV.
1
(
ddd, J ) 1.5, 6, 10, 1H), 4.25 (d, J ) 10, 1H), 3.53 (m, 3H),
9a I: R
f
) 0.13 (Et
2
O/hexane 90/10); H NMR δ 7.60 (m, 2H),
3
1
.17 (d, J ) 6, OH), 3.00 (q, 2H), 1.39 (s, 3H), 1.28 (t, 3H),
.15 (s, 3H).
3
7.35 (m, 3H), 4.71 (ddd, J ) 2, 2.5, 8, 1H), 4.06 (d, J ) 2, 1H),
3.78 (m, 4H), 3.41 (d, J ) 2.5, OH), 2.75 (q, 2H), 2.05 (quint,
J ) 8, 1H), 1.8 (m, 1H), 1.6 (qd, J ) 7, 7, 7, 10, 1H), 1.21 (t,
,4-(Isopr opyliden edioxy)-1-ph en yl-1-(ph en ylsu lfon yl)-
bu ta n -2-ol, 5b. 5bI (1S,2R,3R): white powder; R ) 0.31
Et O/hexane 50/50); mp 118-120 °C; [R] ) +54 (c ) 1.0,
CHCl ); IR 3540; H NMR δ 7.72 (m, 2H), 7.55 (m, 1H), 7.45
m, 4H), 7.35 (m, 3H), 4.56 (ddd, J ) 1.5, 2, 9, 1H), 4.43 (d, J
1.5, 1H), 3.96 (AB part of ABX, J AB ) 9, J AX ≈ 3.5, J BX ≈ 6,
f
3H).
1
(
2
D
9a II: R
f
) 0.13 (Et
2
O/hexane 90/10); H NMR δ 7.60 (m,
1
3
2H), 7.35 (m, 3H), 4.71 (ddd, J ) 2.5, 3, 8, 1H), 3.87 (d, J )
(
)
∆
1
1
2.5, 1H), 3.70 (m, 4H), 3.44 (d, J ) 3, OH), 2.75 (q, 2H), 2.1
(quint, J ) 8, 1H), 1.8 (m, 2H), 1.25 (t, 3H).
1
ν ) 31, 2H), 3.54 (ddd, J ) 3.5, 6, 9, 1H), 3.42 (d, J ) 2, OH),
9a III: R
f
) 0.11 (Et
2
O/hexane 90/10); H NMR δ 7.39 (m,
1
3
.26 (s, 3H), 1.21 (s, 3H); C NMR δ 137.8, 133.9, 131.6, 129.0,
5H), 4.76 (dt, J ) 3, 3, 9, 1H), 4.13 (d, J ) 9, 1H), 3.54 (m,
28.7, 128.6, 128.4, 109.7, 75.1, 71.1, 70.2, 66.9, 27.0, 25.3.
5H), 2.82 (m, 2H) 2.20-1.52 (m, 3H), 1.27 (t, 3H).
1
Anal. Calcd for C19
2.78; H, 6.18.
bII not isolated, the ratio was determined on H2 signals
before isolation of 5bI.
-(t er t -Bu t ylsu lfon yl)-3,4-(isop r op ylid e n e d ioxy)-1-
H
22
O
5
S: C, 62.96; H, 6.11. Found: C,
9a IV: R
f
) 0.11 (Et
2
O/hexane 90/10); H NMR δ 7.39 (m,
6
5H), 4.70 (dt, J ) 3, 3, 9, 1H), 4.07 (d, J ) 9, 1H), 3.54 (m,
5
5H), 2.85 (q, 2H) 2.20-1.52 (m, 3H), 1.20 (t, 3H).
(4S,5R,6R)-6-(Eth ylsu lfon yl)-5-h ydr oxy-6-ph en yl-4-h ex-
1
a n olid e, 11. A 1 M solution of AlMe
0.51 mmol) was added dropwise to a solution of ethanethiol
(0.02 mL, 0.27 mmol) in CH Cl (1 mL) at rt. After being
stirred for 30 min, this mixture was added to a solution of
lactoepoxide 1013 (50 mg, 0.24 mmol) in CH
Cl . The reaction
was quenched after 2 h with a saturated Na SO solution (1
mL). The stirring was maintained for 1 h. The mixture was
then diluted in CH Cl , dried over MgSO , filtered, and
concentrated. The resulting oil (20 mg, 0.075 mmol) was taken
up in MeOH (1 mL) and cooled to 0 °C. A buffered (KH PO
pH ) 5) solution of Oxone (50 mg, 0.16 mmol) in H O (1 mL)
was then added. The reaction was stirred for 1 h, quenched
with water, and extracted with Et
O (2 × 20 mL). The
combined organic layers were washed with brine (30 mL),
dried over MgSO , and concentrated. Pure 11 (11 mg, 15%)
was recovered after flash chromatography: R ) 0.11 (Et O/
20/80); H NMR δ 7.52-7.38 (m, 5H), 4.65 (ddd, J )
3
in hexane (0.51 mL,
p h en ylbu ta n -2-ol, 5c. 5cI was isolated pure from the
mixture 5cI/5cIII obtained using tBu-P4 as base, 5cII and
5
2
2
cIV were obtained as mixtures.
cI (1S,2R,3R): white powder; R
0); mp 86-88 °C; [R] ) +2 (c ) 0.33, CHCl
5
f
) 0.29 (Et
2
O/hexane 50/
); IR 3550; H
2
2
1
5
D
3
2
4
NMR δ 7.62 (b s, 2H), 7.40 (m, 3H), 4.74 (ddd, J ) 1.5, 2, 9.5,
1
J
H), 4.65 (d, J ) 1.5, 1H), 4.97 (AB part of ABX, J AB ) 8.5,
AX ≈ 4.5, J BX ≈ 6, ∆ν ) 24, 2H), 3.39 (ddd, J ) 4, 5.5, 9.5,
H), 3.23 (d, J ) 2, OH), 1.62 (s, 3H), 1.47 (s, 3H), 1.26
2
2
4
1
2
4
,
1
3
(
7
C
s, 9H); C NMR δ 131.6, 129.9, 129.0, 128.7, 128.4, 109.6,
4.5, 71.3, 67.61, 64.3, 62.9, 27.0, 25.3, 24.0. Anal. Calcd for
S: C, 59.53; H, 7.65. Found: C, 59.71 ; H, 7.64.
2
17
H
26
O
5
2
1
5
cII: R
f
) 0.26 (Et O/hexane 50/50); H NMR δ 7.38 (b s,
2
5
H), 4.70 (d, J ) 10, 1H), 4.52 (dt, J ) 1.5, 1.5, 10, 1H), 4.42
4
(
3
1
t, J ) 1.5, OH), 3.95 (t, J ) 6.5, 1H), 3.74 (t, J ) 6.5, 1H),
f
2
1
.55 (tt, J ) 1.5, 1.5, 6.5, 6.5, 1H), 1.46 (s, 3H), 1.25 (s, 9H),
2 2
CH Cl
.15 (s, 3H).
1.5, 2.5, 10, 1H), 4.50 (d, J ) 10, 1H), 4.13 (t, J ) 1.5, 1H),
4.07 (tdd, J ) 1.5, 1.5, 4, 8, 1H), 2.98-2.65 (m, 4H) 2.44-1.13
1
5
cIII: R
f
) 0.19 (Et
2
O/hexane 50/50); H NMR δ 7.47 (m,
2
1
H), 7.37 (m, 3H), 4.52 (dd, J ) 5, 6.5, 1H), 4.48 (d, J ) 6.5,
(m, 2H), 1.30 (t, 3H). Anal. Calcd for C14
H, 6.08. Found: C, 56.09; H, 6.28.
18 5
H O S: C, 56.36;
H), 4.00 (m, 3H), 1.45 (s, 3H), 1.25 (s, 9H), 1.20 (s, 3H).
1
5
cIV: R
f
) 0.12 (Et
2
O/hexane 50/50); H NMR δ 7.58 (b s,
The author has deposited atomic coordinates for the struc-
ture of 5a I with the Cambridge Crystallographic Data Centre.
The coordinates can be obtained, on request, from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ, UK.
2
1
2
H), 7.39 (m, 3H), 4.74 (dt, J ) 4, 6, 6, 1H), 4.25 (d, J ) 4,
H), 4.08 (q, J ) 6, 1H), 3.97 (t, J ) 6, 1H), 3.72 (t, J ) 6, 1H),
.88 (d, J ) 6, OH), 1.39 (s, 3H), 1.26 (s, 3H), 1.20 (s, 9H).
3
-(Ben zyloxy)-1-(eth ylsu lfon yl)-1-p h en ylbu ta n -2-ol, 8a .
a I-(1R,2S,3S): isolated as a 97/3 mixture of I and II from
) 0.33 (Et O/hexane
); IR 3550; H NMR δ 7.52
8
the tBuP4 experiment; colorless oil; R
0/30); [R] ) +37 (c ) 1.74, CHCl
f
2
1
7
D
3
Ack n ow led gm en t. We would like to thank CIBA-
GEIGY (Basel) for financial support as well as Dr. M.
Lang and Dr. G. Bold from CIBA-GEIGY for their
interest and for constructive discussions.
(
)
)
m, 2H), 7.32 (m, 8H), 4.62 (ddd, J ) 2, 3, 8.5, 1H), 4.57 (d, J
2, 1H), 4.50 (d, J ) 11, 1H), 4.07 (d, J ) 11, 1H), 3.32 (d, J
3, OH), 3.12 (dq, J ) 6, 6, 6, 8.5, 1H), 2.78 (q, 2H), 1.30 (d,
1
3
J ) 6, 3H), 1.22 (t, 3H); C NMR δ 138.3, 131.4, 130.0, 129.1,
1
5
28.8, 128.5, 127.85, 127.8, 74.9, 72.2, 70.5, 68.0, 46.3, 16.0,
.9. Anal. Calcd for C19
H
24
O
4
S: C, 65.39; H, 6.94. Found:
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra (11 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
C, 65.31; H, 6.95.
a II: not isolated; R
1
8
f
) 0.33 (Et
2
O/hexane 70/30); H NMR
δ 7.6 (m, 2H), 7.45 (m, 3H), ∼4.6 (2H, overlaped with 8a I),
4
1
.47 (d, J ) 11, 1H), 4.13 (d, J ) 3.5, 1H), 3.62 (quint, J ) 6,
H), ∼2.9 (m, 3H, overlaped with 8a I), 1.35-1.15 (6H, over-
laped with 8a I).
J O9518967