Efficient Diastereoselective Syntheses of erythro- Or threo-a-Alkyl-β-hydroxy Sulfones by Reductions of α-Alkyl-β-keto Sulfones with TiCI4/BHg or LiEtsBH/CeCl3, Respectively

Article abstract of DOI:10.1021/jo972284k

A stereoselective synthesis of erythro- and threo-α-alkyl-β-hydroxy sulfones by reduction of the corresponding α-alkyl-β-keto sulfones has been developed. The pivotal role in this methodology is played by the chelating or nonchelating properties of the Lewis acid employed. The strong chelating TiCl₄ led to the erythro isomer in high diastereomeric excess in noncoordinating solvents (CH₂Cl₂) at -78 °C using BH₃/py as reducing agent, while the nonchelating CeCl₃ gave a high excess of the threo isomer in coordinating solvents (THF) at the same temperature using lithium triethylborohydride (LiEt₃BH) as reducing agent. Moreover, this methodology has been successfully utilized for the synthesis of α-allyl-β-hydroxy sulfones, which are useful synthetic intermediates to obtain 2,5-disubstituted tetrahydrofurans by electrophilic cyclization.

Full text of DOI:10.1021/jo972284k

3624
J . Org. Chem. 1998, 63, 3624-3630
Efficien t Dia ster eoselective Syn th eses of er yth r o- or
th r eo-r-Alk yl-â-h yd r oxy Su lfon es by Red u ction s of r-Alk yl-â-k eto
Su lfon es w ith TiCl4/BH3 or LiEt3BH/CeCl3, Resp ectively
Enrico Marcantoni* and Simone Cingolani
Dipartimento di Scienze Chimiche, via S. Agostino 1, I-62032 Camerino (MC), Italy
Giuseppe Bartoli,* Marcella Bosco, and Letizia Sambri
Dipartimento di Chimica Organica “A. Mangini”, v.le Risorgimento 4, I-40136 Bologna, Italy
Received December 17, 1997
A stereoselective synthesis of erythro- and threo-R-alkyl-â-hydroxy sulfones by reduction of the
corresponding R-alkyl-â-keto sulfones has been developed. The pivotal role in this methodology is
played by the chelating or nonchelating properties of the Lewis acid employed. The strong chelating
TiCl4 led to the erythro isomer in high diastereomeric excess in noncoordinating solvents (CH2Cl2)
at -78 °C using BH3/py as reducing agent, while the nonchelating CeCl3 gave a high excess of the
threo isomer in coordinating solvents (THF) at the same temperature using lithium triethylboro-
hydride (LiEt3BH) as reducing agent. Moreover, this methodology has been successfully utilized
for the synthesis of R-allyl-â-hydroxy sulfones, which are useful synthetic intermediates to obtain
2,5-disubstituted tetrahydrofurans by electrophilic cyclization.
In tr od u ction
synthesis of erythro- or threo-R-alkyl-â-hydroxy sulfones
is a challenging problem for synthetic organic chemists.
Addition of a metalated sulfone to an aldehyde or ketone
During the last 20 years, organic sulfur compounds
have become increasingly important in organic synthesis.
In this field, the benzenesulfonyl group is a versatile and
flexible functionality that enjoys increasing popularity
as a temporary control element and activating group in
organic synthesis.1-6 In particular, the ready availability
of â-hydroxy sulfones and their derivatives from conden-
sation on a sulfonyl carbanion with a carbonyl compound
makes them attractive as intermediates for the regiospe-
cific synthesis of trans olefins.7 The formation of mix-
tures of stereoisomers in such reactions appears quite
general, although for applications involving the J ulia’s
elimination, this is of no consequence. More recently, it
has found that â-hydroxy sulfones are also versatile
synthetic intermediates for the synthesis of 2,5-disub-
stituted tetrahydrofurans.8-10 These units are found in
many natural products, including polyether antibiotics11
and furanoterpenes.12 For this reason, the stereoselective
has been successfully employed for this purpose.13,14
A
promising alternative solution to this problem is the
stereoselective reduction of the corresponding R-alkyl-â-
keto sulfones. Selective reduction with L-Selectride15 or
sodium borohydride16 has been reported to give R-alkyl-
â-hydroxy sulfones of the threo configuration. Here, we
wish to report an extremely simple and effective alterna-
tive procedure for the highly stereoselective synthesis of
erythro- or threo- R-alkyl-â-hydroxy sulfones through the
reduction of the corresponding â-keto sulfones with
BH3‚py or lithium triethylborohydride (LiEt3BH) in the
presence of TiCl4 or dry CeCl3, respectively. Indeed, the
correct choice of hydrides, solvent, and Lewis acid has
been the switch for either chelation or nonchelation
control in these reactions17 in order to obtain high
diastereomeric excess.
Resu lts a n d Discu ssion s
(1) Recent overview: Trost, B. M. Bull. Chem. Soc. J pn. 1988, 61,
107.
(2) Magnus, P. D. Tetrahedron 1977, 33, 2019.
A series of R-alkyl-â-keto sulfones 1 was submitted to
reduction with BH3‚py complex in the presence of TiCl4
or with LiEt3BH in the presence of CeCl3 as the Lewis
acid (Scheme 1).
Red u ction in th e P r esen ce of Tita n iu m Tetr a -
ch lor id e. Recently, DiMare reported the system BH3‚
py as an efficient reducing agent in reduction of ketones
promoted by titanium tetrachloride.18 In fact, the amine
(3) Schank, K. Methoden der Organischen Chemie (Houben-Weyl),
4th ed.; Thieme: Stuttgart, 1985; Vol. E11, p 1129.
(4) Durst, T. In Comprehensive Organic Chemistry; Barton, D. H.
R., Ollis, W. D., Eds.; Pergamon Press: Oxford, 1979; Vol. 3, pp 171-
197.
(5) The Chemistry of Sulfones and Sulphoxides; Patai, S., Rappoport,
Z., Stirling, C. J . M., Eds.; Wiley: Chichester, 1988; pp 1-1210.
(6) Fuchs, P. L.; Breish, T. F. Chem. Rev. 1986, 86, 903.
(7) For an excellent review on sulfone-based olefination reactions
(J ulia olefination), see: Kocienski, P. Phosphorus Sulfur Relat. Elem.
1985, 24, 97-127. See also: J ulia, M.; Paris, J .-M. Tetrahedron Lett.
1973, 4833. Hird, N. W.; Lee, T. V.; Leigh, A. J .; Maxwell, J . R.;
Peakman, T. M. Tetrahedron Lett. 1989, 30, 4867.
(8) Williams, D. R.; Harigaya, Y.; Moore, J . L.; D’sa, A. J . Am. Chem.
Soc. 1984, 106, 2641.
(12) Kondo, K.; Matsumoto, M. Tetrahedron Lett. 1976, 17, 4364.
(13) Kocienski, P. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 6, p 987.
(14) Hart, D. J .; Wu, W. L. Tetrahedron Lett. 1996, 37, 5283.
(15) J ulia, M.; Launay, M.; Stacino, J .-P.; Verpeaux, J .-N. Tetrahe-
dron Lett. 1982, 23, 2465.
(16) Grossert, J . S.; Dharmaratue, H. R. W.; Cameron, T. S.; Vincent,
B. R. Can. J . Chem. 1988, 66, 2860.
(17) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.; Sambri,
L. Chem. Eur. J . 1997, 12, 1941.
(9) Noda, I.; Horita, K.; Oikawa, Y.; Yonemitsu, O. Tetrahedron Lett.
1986, 27, 1917.
(10) Brussani, G.; Ley, S. V.; Wright, J . L.; Williams, D. J . J . Chem.
Soc., Perkin Trans. 1 1986, 303.
(11) Bartlett, P. A. Tetrahedron 1980, 36, 46.
S0022-3263(97)02284-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/12/1998

Synthesis of erythro- or threo-R-Alkyl-â-hydroxy Sulfones
J . Org. Chem., Vol. 63, No. 11, 1998 3625
Sch em e 1
Sch em e 2
Ta ble 1. Ster eoselective Red u ction of â-Keto Su lfon es
(1) to â-Hyd r oxy Su lfon es w ith BH3/P y in th e P r esen ce of
TiCl4 in CH2Cl2 a t -78°C
starting
entry material
erythro/ yieldc
R1
R2
producta threob
(%)
1
2
3
4
5
6
7
8
9
1a a
1a b
1a c
1a d
1a e
1a f
1cb
1gb
1h b
1cb
1cb
Me
Me
Me
Me
Me
Me
Ph
Me
Et
Ph
c-C6H11
allyl
2a a
2a b
2a c
2a d
2a e
2a f
2cb
2gb
2h b
2cb
2cb
87/13
90/10
95/5
92/8
93/7
94/6
>99/1
94/6
85
90
94
90
87
86
88
88
83
76
54
CH2Ph
Et
4-MeOPh Et
4-NO2Ph Et
Ph
Ph
93/7
10
11
Et
Et
50/50d
70/30e
Ta ble 2. Ster eoselective Red u ction of â-Keto Su lfon es (1)
to â-Hyd r oxy Su lfon es w ith LiBEt3H in th e P r esen ce of
CeCl3 Dr y in THF a t -78 °C
a
By adding the BH3/py complex to the solution of the CH2Cl2
solution of 1/TiCl4 complex at -78 °C. bDetermined by 1H and 13C
time threo/ yieldc
c
starting
entry material
NMR spectroscopy. Calculated on the mixture of diastereomers
R1
R2
producta (h) erythrob (%)
isolated by column chromatography. dThe reaction was carried out
e
in THF. Temperature was held at -50 °C for 15 min.
1
2
3
4
5
6
7
8
9
1a a
1a a
1a b
1a c
1a d
1a e
1a f
1cb
1gb
1h b
Me
Me
Me
Me
Me
Me
Me
Ph
Me
Me
Et
Ph
c-C6H11
allyl
2a a
2a a
2a b
2a c
2a d
2a e
2a f
2cb
2gb
2h b
3.0 h >99/1
85
3.0 h
3.0 h
3.5 h
3.0 h
3.5 h
2.5 h
54/46d 89
97/3
96/4
81/19
98/2
95/5
88
90
79
88
89
83
81
82
boranes are among the strongest nonionic hydride donors,
which are valuable reducing agents because of their
solubility in many organic solvents. In reactions with
positively charged electrophiles, they are more reactive
hydride donors than trialkylsilanes and comparable with
NaBH3CN. As a consequence, amine boranes may re-
place this expensive and toxic reagent in many applica-
tions. We found that the reduction of 1 in dichlo-
romethane at low temperature (-78 °C) with BH3‚py (1.5
equiv) in the presence of TiCl4 (1.5 equiv) led to the
prevalent formation of erythro-â-hydroxy sulfones (erythro-
2) (Table 1). This result can be rationalized if the
formation of a chelate between the oxygen atoms to the
carbonyl function and to the sulfonyl group with metal
atom is assumed. The resulting six-membered cyclic
intermediate is then attacked by the incoming hydride,
preferentially from the less hindered opposite axial side
of the most populated conformation A (Scheme 2). We
also found interesting solvent effects. While the reactions
were successfully carried out in CH2Cl2, which ensured
good yields and high diastereoselectivity, on the contrary,
the reactions carried out in a coordinating solvent, such
as THF, led to the complete loss of diastereoselectivity
(Table 1, entry 10). Temperature is also an important
factor in these reductions: values higher than -78 °C
considerably lower both selectivity and yields (Table 1,
entry 11).
CH2Ph
Et
4.0 h >99/1
4.0 h >99/1
6.0 h >99/1
4-MeOPh Et
4-NO2Ph Et
10
a
By adding a 1 M solution of LiBEt3H in THF to the THF
solution of 1-CeCl3 complex at -78 °C. bDetermined by 1H and
13C NMR spectroscopy. Calculated on the mixture of diastereo-
c
mers isolated by column chromatography. dThe reaction was
carried out in CH2Cl2.
controlled mechanism, the minimum level of stereose-
lectivity should be observed when R1 and R2 are the small
methyl group; in fact, an erythro/ threo ratio of 87/13 is
obtained in this unfavorable case under our experimental
conditions. It is obvious that every increase in bulkiness
of both R1 and R2, shifting the conformational equilibrium
toward the more stable A conformation, increases the
erythro/ threo ratio (Table 1, entries 2-9).
Redu ction in th e P r esen ce of Dr y Cer iu m Tr ich lo-
r id e. The reduction of â-keto sulfones with a THF
solution of LiEt3BH in the presence of dry CeCl3 proceeds
smoothly at low temperature (-78 °C), giving the ex-
pected â-hydroxy sulfones in good yields, but with
reversed stereoselectivity with respect to the TiCl4/BH3‚
py system (Table 2). These findings strongly support an
open-chain mechanism, and the threo selectivity may
explained by Felkin-Anh’s model19 controlled reaction.
In fact, the sterically demanding alkyl chains favor the
C over the D conformation, and the hydride anion attacks
the â-carbonyl group from the side opposite to the bulky
sulfonyl group leading to the threo isomer (Scheme 3).
The fact that â-keto sulfones give essentially the threo-
â-hydroxy sulfones indicates that the â-chelate pathway,
The most relevant finding from data reported in Table
1 is that this reductive system always ensure a high
stereoselectivity level, independent of the size of the R1
and R2 substituents. In accordance with a chelation-
(18) Sarko, C. R.; Collibee, S. E.; Knorr, A. L.; DiMare, M. J . Org.
Chem. 1996, 61, 868.

3626 J . Org. Chem., Vol. 63, No. 11, 1998
Marcantoni et al.
Sch em e 3
approach at an angle of about 109° with respect to the
plane of the carbonyl group, the attack to the C confor-
mation should be preferred by steric effects. This means
that it is no longer necessary to make the somewhat
dubious assumption that the R2 group should be gauche
to the oxygen atom of the carbonyl group in the preferred
transition sate. Alternatively, it may be assumed that
the two conformations C and D are energetically similar
and that differentiation arises out of nonbonded interac-
tions between the incoming nucleophile with an R2 group
and between the two substituents R1 and R2, in the D
conformation (Scheme 3). When R2 is an R-branched
alkyl group such as a cyclohexyl framework, a low threo/
erythro ratio is observed, demonstrating that the steric
demand of this group is higher than that of the linear
alkyl chain on interaction with oxygen atom of the
carbonyl group.
The presence of CeCl3 is essential for the reaction, and
at -78 °C, the reduction with LiEt3BH alone is extremely
slow and the yields are low (30%) too. Reduction can be
carried out over a short time interval at 0 °C, but a
detriment of diastereoselectivity and of yields was ob-
served. When the reaction is carried out at 0 °C in the
presence of CeCl3, the same low yields and low diaste-
reoselectivity are observed.
even if feasible, does not participate in these cases to a
noticeable extent. To explain this, we have proposed that
the system LiEt3BH/CeCl3 reacts mainly under nonch-
elation control because of the weak donor ability of the
sulfonyl group.20 Then, we believe that the â-keto
sulfones would complex with TiCl4, but it is likely that
they will not complex with CeCl3, even though this is
apparently a good Lewis acid and its anhydrous form is
highly hydroscopic.21
The reduction of R-alkyl-â-keto sulfone 1a a was stud-
ied in different solvents such as dichloromethane and
THF. This latter solvent turned out to be a suitable
solvent for the reaction, since the use of coordinating
solvents ensures good yields and high diastereoselectiv-
ity. On the other hand, an appreciable diastereoselec-
tivity lowering was observed when substrate 1a a was
dissolved in CH2Cl2 (Table 2, entry 2). It may be expected
that the use of noncoordinating solvents favors chelation
phenomena, but the poor chelating ability of Ce(III) on
these â-keto sulfones causes only a decrease in diaste-
reoselectivity and not a complete inversion to erythro
products, as the powerful chelating TiCl4.
As previously outlined, the 1-CeCl3 complex can be
represented by an equilibrium between C and D confor-
mations (Scheme 3) and is completely shifted to the top,
if the steric demand of R2 is smaller than the sulfonyl
group. Obviously, bulky R1 moieties have the same
positive effect on the conformational equilibrium. How-
ever, in the present case, this effect is not evident, since
a high diastereoselectivity is even observed when both
R1 and R2 are the small methyl groups (Table 2, entry
1). Invoking the Bu¨rgi-Dunitz trajectory,22,23 that is,
Further, the parent compound of LiEt3BH, lithium
borohydride,24 does not work at -78 °C with or without
CeCl3. To eliminate complexity due to the disproportion
of the reducing species, those having complex hydride
anions of a less dissociative nature should have been the
choice. After examination of various types of metal
hydride complex, LiEt3BH was among the best. The data
clearly reveal that lithium triethylborohydride is an
exceptionally powerful hydride reducing agent,25 far more
powerful than lithium borohydride. Then the LiEt3BH
exhibits a remarkable selectivity, a property normally
considered to be characteristic of relatively mild reducing
agent, such as lithium borohydride.
Finally, since both LiEt3BH and CeCl3 are required for
efficient and selective reduction at -78 °C, the existence
of reducing species requiring examination: THF is a
polar solvent system, and the cerium hydride species
(CeHnCl3-n) may be one possibility for the reaction.
However, Fukazawa et al.26 have suggested that such
hydride species are unlikely to be the reducing agent in
the reduction reactions with LiAlH4 in the presence of
CeCl3; therefore, from our results, a similar behavior
seems to be plausible.
Ster eoselective Red u ction of r-Ch lor o-â-k eto Su l-
fon es. On extending our procedure to obtain both
erythro- and threo-R-alkyl-â-hydroxy sulfones by reduc-
tion of the corresponding â-keto sulfones, the stereose-
lectivity of the reduction on â-keto sulfones without
R-hydrogens was examined (Scheme 4). The preferential
choice of R-chloro-â-keto sulfone 4 as a model substrate
was made because the erythro- and threo-â-hydroxysul-
(22) (a) Bu¨rgi, H. B.; Dunitz, J . D.; Shefter, E. J . J . Am. Chem. Soc.
1973, 95, 5065. (b) Bu¨rgi, H. B.; Dunitz, J . D.; Lehn, J . M.; Wipff, G.
Tetrahedron 1974, 30, 1563.
(23) Bu¨rgi, H. B.; Lehn, J . M.; Wipff, G. J . Am. Chem. Soc. 1974,
96, 1956.
(19) (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrhedron Lett. 1968,
2199. (b) Anh, N. T.; Einsenstein, O. Nouv. J . Chim. 1977, 1, 61.
(20) Bordwell, F. G.; Van Der Puy, M.; Vanier, N. R. J . Org. Chem.
1976, 41, 1883.
(21) It has been recently reported (Evans, W. J .; Feldman, J . D.;
Ziller, J . W. J . Am. Chem. Soc. 1996, 118, 4581) that the material
obtained after drying of CeCl3‚7H2O (at 150 °C and 0.03 Torr for 12 h)
was [CeCl3‚(H2O)]n. We have not analyzed the CeCl3 prepared by the
present procedure; however, the material was highly efficient without
a large excess of reducing agent.
(24) Bartoli, G.; Bosco, M.; Marcantoni, E.; Sambri, L. Tetrahedron
Lett. 1996, 37, 7421.
(25) Brown, H. C.; Kim, S. C.; Krishnamurthy, S. J . Org. Chem.
1980, 45, 1.
(26) Fukuzawa, S.; Fujinami, T.; Yamanchi, S.; Sakai, S. J . Chem.
Soc., Perkin Trans. 1 1986, 1929.

Synthesis of erythro- or threo-R-Alkyl-â-hydroxy Sulfones
J . Org. Chem., Vol. 63, No. 11, 1998 3627
Sch em e 4a
Sch em e 5a
a
Key: (A) I2, NA2CO3, CH3CN, RT, 2.5 H.
Sch em e 6
a
Key: (a) TiCl4 in CH2Cl2 at -78 °C, then BH3/py, 87/13
erythro/ threo isomers; (b) CeCl3 in THF at -78 °C, then LiBEt3H,
4/96 erythro/ threo isomers.
fones 5,27 which are obtained by reduction, may be
converted upon treatment with base into cis- and trans-
epoxides.28,29 These compounds are known to be labile
compounds that are easily rearranged to R-substituted
aldehydes and ketones.30 Very interestingly, once more,
the reduction with BH3‚py in the presence of strong
chelating TiCl4 gave erythro-5 isomer as a major product,
and the reduction with LiBEt3H in the presence of CeCl3
afforded threo-5 predominantly. This last excellent threo
selectivity may again be explained by Felkin-Ahn’s
model, in which the hydride anion attacks the â-carbonyl
group at the opposite side of the bulky sulfonyl group
(Scheme 3). In addition, the reduction of ketone 4 shows
that the method does not involve the base-catalyzed
cleavage of R-chloro-â-keto sulfones;31,32 in fact, the
hydroxy sulfones 5 were found not to be contaminated
with benzyl alcohol, from which purification is difficult.
Syn th esis of 2,5-Disu bstitu ted Tetr a h yd r ofu r a n
Un its. R-Allyl-â-hydroxy sulfones are key intermediates
in the synthesis of 2,5-disubstituted tetrahydrofurans
with high regioselectivity, since they can undergo easy
electrophilic cyclization.33 For this purpose, the reaction
mixtures obtained from reduction of 1a e with TiCl4/
BH3‚py (Table 1, entry 5) and CeCl3/LiEt3BH (Table 2,
entry 6), respectively, were separated. These compounds,
submitted to iodocyclization,34 gave the 2,5-disubstituted
tetrahydrofurans in high yields, and any formation of six-
membered cyclic product was not observed (Scheme 5).
To elucidate the stereochemical problem of these two
reactions, the four possible isomeric products generated
group in the ring appeared at lower field owing to the
deshield effects of both sulfonyl and iodomethyl groups
cis to that proton.35 These findings suggest that the
introduction of a sulfonyl group facilitates the separation
and the identification of the products. Since a sulfonyl
group and iodine would be converted into other functional
groups, the present strategy may be widely applicable
to organic synthesis, and we are currently expanding the
synthetic utility of this methodology.
Syn th esis of r-Alk yl-â-k eto Su lfon es. There are
various methods to prepare R-alkyl-â-keto sulfones. The
alkylation reaction of unsubstituted â-keto sulfones36 was
found to be somewhat sluggish, and the reaction proceeds
smoothly with short alkyl chains (R2 ) Me, Et) or with
highly reactive derivatives, such as benzyl bromide,
under phase-transfer conditions, especially using an
ultrasonic bath to assist with the stirring.37 Therefore,
it is more convenient to prepare these compounds from
the reaction of R-sulfonyl anions 11 followed by quench-
ing of the reaction mixture with the appropriate ester
12 (Scheme 6). However, this procedure,38 used on the
metalation of 10 with a slight excess of LDA (1.2 equiv),
needed a stoichiometric ratio of 2.2:1 between 10 and the
ester because 1 equiv of 10 was engaged in the irrevers-
ible abstraction of the very acidic proton of the R-alkyl-
â-keto sulfone 1. Certainly, this fast enolization process
1
[6a e to 9a e] were isolated and characterized by H and
13C NMR. In the products (8a e and 9a e), the methyl
group must be cis to the sulfonyl group because its proton
signal appeared at lower field (1.53 and 1.61 ppm).
Moreover, in the trans 2,5-disubstituted tetrahydrofurans
(6a e and 9a e), one of the proton signals of the methylene
(27) To avoid ambiguity when indicating the hydroxy sulfones 5 we
will follow the relative position of hydroxy group and R-ethyl group.
(28) Bohlmann, F.; Haffer, G. Chem. Ber. 1969, 102, 4017.
(29) Grossert, J . S.; Dharmaratne, H. R. W.; Cameron, T. S.; Vincent,
B. R. Can. J . Chem. 1988, 66, 2860.
(30) Reinach-Hirtzbach, F.; Durst, T. Tetrahedron Lett. 1976, 3677.
(31) Scholz, D. Chem. Ber. 1981, 114, 909.
(32) Grossert, J . S.; Dubey, P. K.; Elwood, T. Can. J . Chem. 1985,
63, 1263.
(33) Harding, K. E.; Toner, T. H. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 4, pp 363-415.
(34) Ireland, R. E.; Habich, D.; Norbeck, D. W. J . Am. Chem. Soc.
1985, 107, 3271.
(35) Ueno, Y.; Khare, R. K.; Okawara, M. J . Chem. Soc., Perkin
Trans. 1 1983, 2637.
(36) O’Sullivan, W. I.; Tavares, D. F.; Hauser, C. R. J . Am. Chem.
Soc. 1961, 83, 3453.
(37) Ezquerra, J .; Alvarez-Builla, J . J . Chem. Soc., Chem. Commun.
1984, 54.
(38) Trost, B. M.; Lynch, J .; Renaut, P.; Steinman, D. H. J . Am.
Chem. Soc. 1986, 108, 284.

3628 J . Org. Chem., Vol. 63, No. 11, 1998
Marcantoni et al.
Ta ble 3. Syn th esis of â-Keto Su lfon es (1) fr om Rea ction
of Alk yl Su lfon es (10), An ion s, a n d Ester s (12) in THF a t
-78 °C
× 0.25 mm, with 0.25 µm film thickness of 5% phenylmeth-
ylsilicone gum. The temperature program used the initial
temperature of 65 °C for 3 min and then ramped at 15 °C min-1
to 280 °C. Column chromatography was carried out using
230-400 mesh silica. Diastereomeric purity was determined
by NMR analysis. In all compounds listed in Tables 1 and 2,
we have noted an upfield shift of the carbinol carbons in the
erythro isomer compared with those in the threo isomer. Alkyl
sulfones 1042 and 1-phenyl-2-chloro-2-(phenylsulfonyl)butan-
1-one (4)29 were prepared according to the published proce-
dures.
Gen er a l P r oced u r e for P r ep a r in g r-Alk yl-â-k eto Su l-
fon es (1). A solution of lithium 2,2,6,6-tetramethylpiperidide
(2.3 equiv) was prepared in THF (35 mL) from 2,2,6,6-
tetramethylpiperidine (2.28 mL) and a 1.6 M solution (8.32
mL) of n-butyllithium in hexane under nitrogen at -30 °C.
After 30 min, to this reagent solution was added with stirring,
under nitrogen at -30 °C, a solution of the alkyl sulfone 10
(5.89 mmol) in THF (2.5 mL). Stirring was continued for 1 h,
and then the mixture was cooled to -78 °C and a solution of
the ester 12 (14.7 mmol) in THF (2.5 mL) was added. Two
hours later, the reaction was allowed to reach room temper-
ature and then quenched with diluted HCl (10%) and extracted
with diethyl ether. The combined organic extracts were
washed with saturated aqueous NaCl, dried, and evaporated
to give the crude product, which was purified by flash column
chromatography on silica gel to afford the pure product.
Spectra and analytical data of new R-alkyl-â-keto sulfones
prepared are as follows.
alkyl
entry sulfone
yielda
(%)
R2
ester
R1
product
1
2
3
4
5
6
7
8
9
1a a
1a b
1a c
1a d
1a e
1a f
1cb
1gb
1h b
Me
Et
Ph
12a
12a
12a
Me
Me
Me
Me
Me
Me
Ph
1a a
1a b
1a c
1a d
1a e
1a f
1cb
1gb
1h b
88
87
88
77b
79
90
90
85
89
c-C6H11 12a
allyl
CH2Ph
Et
Et
Et
12a
12a
12c
12g
12h
4-MeOPh
4-NO2Ph
a
Calculated on the product purified by column chromatography.
bBy adding dried cerium trichloride.
prevents ketone 1 from undergoing a further nucleophilic
addition of 11, but serious difficulties arise in the
separation of 1 and 10. We modified this methodology
by simply metalating 10 with 2.5 equiv of a strong
nonnucleophilic base, such as lithium tetramethylpip-
eridide (LiTMP). Its presence does not interfere with
ester and 10 can be remetalated by the excess of LiTMP,
so that R-alkyl-â-keto sulfones 1 are obtained in high
yields on the basis of 10. This procedure has been proven
to be very efficient in preparing a large variety of R-alkyl-
â-keto sulfones (Table 3), demonstrating once more the
potential of our synthesis of easily enolizable com-
pounds.24 It completely fails when R2 is a branched alkyl
substituent, where the enolization of the ester 12 becomes
an important side reaction, and this drawback can be
efficiently avoided by adding dry cerium trichloride39-41
to the R-sulfonyl anion (Table 3, entry 4).
3-(P h en ylsu lfon yl)p en ta n -2-on e (1a b): IR (neat) 1712,
1
1320, 1118 cm-1; H NMR δ 0.84 (t, 3H, J ) 7.33 Hz), 1.85-
1.92 (m, 2H), 2.37 (s, 3H), 3.97 (dd, 1H, J ) 4.9, 7.6 Hz), 7.49-
7.68 (m, 3H), 7.70-7.78 (m, 2H); EI-MS m/z 226 (M+), 184,
169 (100), 141, 77, 51, 43. Anal. Calcd for C11H14O3S: C, 58.38;
H,6.23; S, 14.17. Found: C, 58.39; H, 6.20; S, 14.12.
1-(4-Met h oxyp h en yl)-2-(p h en ylsu lfon yl)b u t a n -1-on e
1
(1gb): mp 104-105 °C; IR (Nujol) 1678, 1339, 1017 cm-1; H
NMR δ 0.89 (t, 3H, J ) 7.32 Hz), 2.05-2.20 (m, 2H), 3.73 (s,
3H), 4.89 (dd, 1H, J ) 4.20, 10.44 Hz), 6.83-6.92 (m, 2H),
7.18-7.23 (d, 2H, J ) 8.71 Hz), 7.51-7.67 (m, 3H), 7.86-7.95
(m, 2H); EI-MS m/z 318 (M+), 176, 163, 141, 135 (100), 109,
77, 51. Anal. Calcd for C17H18O4S: C, 64.13; H, 5.70; S, 10.07.
Found: C, 64.11; H, 5.62; S, 10.06.
Con clu sion
In conclusion, we have shown that a general highly
efficient multistep methodology can be set up to obtain
both erythro- and threo-â-hydroxy sulfones, key interme-
diates for the synthesis of 2,5-disubstituted tetrahydro-
furans. The success of this methodology has been the
correct choice of chelating or nonchelating metallic
complexes. In the former case (TiCl4/BH3‚py), the erythro
isomer largely prevails, while in the latter one (CeCl3/
LiEt3BH) the threo isomer is obtained. Hence, it has
been clearly demonstrated that cerium trichloride cannot
give chelation when a six-membered transition state is
involved. To summarize, we have developed a new and
convenient methodology that reaches the goal of a high-
yield and high-purity synthesis of R-alkyl-â-hydroxy
sulfones from easily available and cheap starting materi-
als. Finally, we are currently expanding the synthetic
utility of this reducing methodology, and our efforts will
be reported in the future.
1-(4-Nitr oph en yl)-2-(ph en ylsu lfon yl)bu tan -1-on e (1h b):
1
mp 112-115 °C; IR (Nujol) 1680, 1550, 1332, 1086 cm-1; H
NMR δ 0.89 (t, 3H, J ) 7.40 Hz), 2.03-2.17 (m, 2H), 4.99 (dd,
1H, J ) 4.07, 10.50 Hz), 7.51-7.66 (m, 2H), 7.70-7.78 (m, 3H),
8.14-8.19 (m, 2H), 8.31-8.37 (m, 2H); EI-MS m/z 333 (M+),
305, 269, 150 (100), 141, 104, 77, 51. Anal. Calcd for C16H15
-
NO3S: C, 57.65; H,5.01; S, 10.64. Found: C, 57.62; H, 4.96; S,
10.63.
P r ep a r a tion of 1-Cycloh exyl-1-(p h en ylsu lfon yl)p r o-
p a n -2-on e (1a d ). The alkyl sulfone 10d (1 mmol) was
dissolved in Et2O at room temperature and cooled to -78 °C.
To the cooled solution was added n-BuLi (1.2 mmol) to give a
bright yellow solution. The anion was stirred at the same
temperature for 0.5 h before cannulation to cerium(III) chloride
dried according to Imamoto’s procedure.39 The suspension was
stirred for 0.5 h, and the reaction was quenched with ester
12a (2 mmol). The reaction mixture was slowly warmed to
room temperature to ensure complete reaction as assayed by
TLC. The reaction was then quenched with diluted HCl (10%).
The organic layer was separated, and the aqueous layer was
extracted with ether. The combined organic layers were
washed with aqueous saturated sodium bicarbonate solution
and saturated brine solution and dried over anhydrous sodium
sulfate. The extracts were then concentrated under reduced
pressure, and the residue was chromatographed on silica gel
column (eluent: hexane-ethyl acetate 9:1) to give the corre-
sponding R-alkyl-â-keto sulfone (yield 77%) as an oil: IR (neat)
Exp er im en ta l Section
Gen er a l Com m en ts. 1H and 13C NMR data were collected
on a 200 MHz NMR spectrometer with TMS as internal
reference in CDCl3. All mass spectra were determined on a
HP5890 Series II capillary GC operating in split mode with
helium carrier gas and fitted with a mass selective detector
(MSD). The column used was a HP5 capillary column 30 m
1
1710, 1330, 1075 cm-1; H NMR δ 1.15-1.25 (m, 4H), 1.61-
(39) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J . Am. Chem. Soc. 1989, 111, 4392.
(40) Anderson, M. B.; Fuchs, P. L. Synth. Commun. 1987, 17, 621.
(41) Imamoto, T. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, pp 231-250.
1.72 (m, 6H), 2.20 (s, 3H), 3.98 (d, 1H, J ) 6.91 Hz), 7.52-
7.67 (m, 3H), 7.82-7.86 (m, 2H); EI-MS m/z 280 (M+), 238,
199 (100), 141, 79, 51, 43. Anal. Calcd for C15H20O3S: C,
64.25; H, 7.19; S, 11.43. Found: C, 64.24; H, 7.12; S, 11.40.

Synthesis of erythro- or threo-R-Alkyl-â-hydroxy Sulfones
J . Org. Chem., Vol. 63, No. 11, 1998 3629
Gen er a l TiCl4-BH3.p y Red u ction P r oced u r e. To a cold
(-78 °C) solution of keto sulfone 1 (1.0 mmol) in 10 mL of dry
CH2Cl2 was added TiCl4 (1.3 mmol, solution 1 M in CH2Cl2)
to give immediately a bright yellow solution, which was stirred
for 10 min at this temperature. The complex BH3‚py (1.3
mmol) in 5 mL of CH2Cl2 was then added. After 15 min, 25
mL of 1 N HCl was added, and the reaction was warmed to
room temperature. The organic layer was separated, the
aqueous layer was washed with CH2Cl2, and the combined
organics were concentrated in vacuo. The resulting residue
was partitioned between Et2O and H2O. The etheral layer was
washed with water and brine, dried over anhydrous Na2SO4,
and concentrated in vacuo. Flash column chromatography
gave erythro-R-alkyl-â-hydroxy sulfones 243 contaminated only
by a minor amount of the threo-diastereoisomer. Diastereo-
meric purity, determined by NMR analysis, and yields are
reported in Table 1. Elemental analyses of products were
performed on diastereomeric mixtures.
169 (100), 148, 141, 91, 77, 51. Anal. Calcd for C16H18O3S:
C, 66.18; H, 6.24; S, 11.64. Found: C, 66.14; H, 6.17; S, 11.01.
(R*,S*)-1-(4-Meth oxyp h en yl)-2-(p h en ylsu lfon yl)bu ta n -
1-ol (er yth r o-2gb): IR (neat) 3490, 1318, 1100 cm-1; 1H NMR
δ 0.66 (t, 3H, J ) 7.57 Hz), 1.86-1.94 (m, 2H), 3.04 (t, 1H, J
) 3.58 Hz), 3.42 (bs, 1H, OH), 3.78 (s, 3H), 5.35 (d, 1H, J )
5.90 Hz), 6.81-6.86 (m, 2H), 7.14-7.27 (m, 2H), 7.57-7.71 (m,
3H), 7.92-8.00 (m, 2H); EI-MS m/z 320 (M+), 302, 178, 163,
141, 137 (100), 109, 77, 51. Anal. Calcd for C17H20O4S: C,
63.72; H, 6.29; S, 10.00. Found: C, 63.70; H, 6.21; S, 9.98.
(R *,S *)-1-(4-Nit r op h e n yl)-2-(p h e n ylsu lfon yl)b u t a n -
1-ol (er yth r o-2h b): IR (neat) 3495, 1545, 1302, 1107 cm-1
;
1H NMR δ 0.68 (t, 3H, J ) 7.50 Hz), 1.79-1.93 (m, 2H), 3.06-
3.12 (m, 1H), 3.40 (bs, 1H, OH), 5.54 (d, 1H, J ) 5.85 Hz),
7.43-7.49 (m, 2H), 7.55-7.75 (m, 3H), 7.97-8.02 (m, 2H),
8.15-8.20 (m, 2H); EI-MS m/z 335 (M+), 317, 193, 178, 152
(100), 141, 77, 51. Anal. Calcd for C16H17NO5S: C, 57.30; H,
5.11; N, 4.17; S, 9.56. Found: C, 57.29; H, 5.07; N, 4.12; S,
9.54.
(R*,S*)-3-(P h en ylsu lfon yl)bu ta n -2-ol (er yth r o-2a a ):IR
(neat) 3480, 1305, 1148 cm-1; 1H NMR δ 1.19 (d, 3H, J ) 6.55
Hz), 1.32 (d, 3H, J ) 7.17 Hz), 2.94-3.13 (m, 2H), 4.39-4.47
(m, 1H), 7.54-7.69 (m, 3H), 7.87-7.94 (m, 2H); EI-MS m/z
170, 141, 105, 77, 73 (100), 55, 44. Anal. Calcd for
(R*,R*)-1-P h en yl-2-ch lor o-2-(p h en ylsu lfon yl)b u t a n -
1-ol (er yth r o-5): IR (neat) 3495, 1303, 1148, 731 cm-1 1H
;
NMR δ 1.09 (t, 3H, J ) 7.37 Hz), 2.26-2.30 (m, 1H), 2.60-
2.68 (m, 1H), 4.21 (bs, 1H, OH), 5.11 (s, 1H), 7.31-7.38 (m,
3H), 7.46-7.72 (m, 5H), 7.94-8.06 (m, 2H); 13C NMR δ 8.77,
26.20, 73.52, 91.93, 128.15, 128.50, 129.11, 129.40, 133.96,
134.10, 138.96, 139.75; EI-MS m/z 326 (M+ + 2), 324 (M+),
220, 218, 203, 147, 141, 107 (100), 105, 91, 77, 51. Anal. Calcd
for C16H17ClO3S: C, 59.16; H, 5.27; S, 9.87. Found: C, 59.14;
H, 5.22; S, 9.84.
Gen er a l CeCl3-LiEt3BH Red u ction P r oced u r e. Finely
ground CeCl3‚7H2O (3.2 mmol) was dried by heating at 140
°C/01 Torr for 2 h. Dry THF (10 mL) was then added at 0 °C,
and the milky suspension was stirred overnight under nitrogen
at room temperature. At this temperature, a solution of 1 (1
mmol) in 5 mL of THF was added and left to stir for 1 h. Then
it was cooled to -78 °C, and LiEt3BH (2 mmol, solution 1 M
in THF) was added by syringe. The reaction mixture was then
left to stir until TLC indicated that no starting material
remained (Table 2). The reaction was quenched with 0.5 N
HCl and extracted with Et2O. The ethereal extracts were
combined and washed with water and brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. Flash column
chromatography gave threo-R-alkyl-â-hydroxy sulfones 2 con-
taminated only by a minor amount of the erythro-diastereomer.
Diastereomeric purity, determined by NMR analysis, and
yields are reported in Table 2. Elemental analyses of products
were performed on diastereomeric mixtures.
C
10H14O3S: C, 56.05; H, 6.58; S, 14.96. Found: C, 56.01; H,
6.50; S, 14.95.
(R*,S*)-3-(P h en ylsu lfon yl)p en ta n -2-ol (er yth r o-2a b): IR
(neat) 3496, 1300, 1100 cm-1; 1H NMR δ 0.95 (t, 3H, J ) 7.63
Hz), 1.25 (d, 3H, J ) 6.10 Hz), 1.86-1.91 (m, 2H), 2.80-2.84
(m, 1H), 3.21 (bs, 1H, OH), 4.31-4.38 (m, 1H), 7.54-7.66 (m,
3H), 7.86-7.90 (m, 2H); EI-MS m/z 213, 184, 169, 143, 141,
87, 77, 51, 45 (100). Anal. Calcd for C11H16O3S: C, 57.87; H,
7.06; S, 14.04. Found: C, 57.85; H, 7.01; S, 14.02.
(R*,S*)-1-P h en yl-1-(ph en ylsu lfon yl)pr opan -2-ol (er yth r o-
2a c): IR (neat) 3499, 1300, 1105 cm-1; 1H NMR δ 1.77 (d, 3H,
J ) 6.10 Hz), 3.12 (bs, 1H, OH), 3.95 (d, 1H, J ) 4.74 Hz),
4.96-4.99 (m, 1H), 7.21-7.50 (m, 7H), 7.53-7.61 (m, 3H); EI-
MS m/z 232, 141, 135 (100), 91, 77, 55, 43. Anal. Calcd for
C
15H16O3S: C, 65.19; H, 5.83; S, 11.60. Found: C, 65.18; H,
5.79; S, 11.57.
(R*,S*)-1-Cycloh exyl-1-(p h en ylsu lfon yl)p r op a n -2-ol
(er yth r o-2a d ): IR (neat) 3487, 1325, 1109 cm-1 1H NMR δ
;
1.16-1.34 (m, 4H), 1.37 (d, 3H, J ) 6.64 Hz), 1.43-1.87 (m,
8H), 2.95 (t, 1H, J ) 4.15 Hz), 4.19-4.23 (m, 1H), 7.59-7.67
(m, 3H), 7.88-7.93 (m, 2H); 13C NMR δ 20.75, 25.83, 26.92,
27.03, 31.68, 36.52, 65.97, 128.05, 129.00, 129.26, 133.67,
139.85; EI-MS m/z 238, 141, 123, 81 (100), 77, 65, 51, 44. Anal.
Calcd for C15H22O3S: C, 63.79; H, 7.85; S, 11.35. Found: C,
63.77; H, 7.79; S, 11.33.
(R*,R*)-3-(P h en ylsu lfon yl)bu ta n -2-ol (th r eo-2a a ): IR
(neat) 3492, 1307, 1130 cm-1; 1H NMR δ 1.13 (d, 3H, J ) 7.17
Hz), 1.23 (d, 3H, J ) 6.37 Hz), 3.10-3.18 (m, 1H), 4.16-4.20
(m, 1H), 5.45 (bs, 1H, OH), 7.52-7.67 (m, 3H), 7.84-7.90 (m,
2H); EI-MS m/z 170, 141, 105, 77, 73 (100), 55, 43. Anal.
Calcd for C10H14O3S: C, 56.05; H, 6.58; S, 14.96. Found: C,
56.01; H, 6.56; S, 14.93.
(R*,S*)-3-(P h en ylsu lfon yl)h ex-6-en -2-ol (er yth r o-2a e):
IR (neat) 3490, 1640, 1309, 1117 cm-1; 1H NMR δ 1.28 (d, 3H,
J ) 6.63 Hz), 2.18 (bs, 1H, OH), 2.60-2.64 (m, 2H), 3.00-
3.07 (m, 1H), 4.39 (dq, 1H, J ) 1.60, 6.65 Hz), 4.92-5.05 (m,
2H), 5.54-5.74 (m, 1H), 7.27-7.78 (m, 3H), 7.87-7.92 (m, 2H);
13C NMR δ 20.76, 27.76, 65.49, 69.42, 125.81, 129.11, 129.86,
135.27, 139.53, 148.02; EI-MS m/z 239, 143, 141, 97, 83, 77,
51, 43 (100), 41. Anal. Calcd for C12H16O3S: C, 59.97; H, 6.71;
S, 13.34. Found: C, 59.95, H, 6.68; S, 13.30.
(R*,S*)-4-P h en yl-3-(ph en ylsu lfon yl)bu tan -2-ol (er yth r o-
2a f): IR (neat) 3500, 1315, 1103 cm-1; 1H NMR δ 1.24 (d, 3H,
J ) 6.68 Hz), 3.15 (d, 2H, J ) 5.92 Hz), 3.30 (bs, 1H, OH),
3.34-3.41 (m, 1H), 4.31-4.36 (m, 1H), 7.00-7.05 (m, 2H),
7.14-7.20 (m, 3H), 7.48-7.64 (m, 3H), 7.83-7.88 (m, 2H); EI-
MS m/z 199, 168, 148, 141, 131, 105, 91 (100), 77, 51, 43. Anal.
Calcd for C16H18O3S: C, 66.18; H, 6.24; S, 11.04. Found: C,
66.16; H, 6.17; S, 11.02.
(R*,R*)-3-(P h en ylsu lfon yl)p en ta n -2-ol (th r eo-2a b): IR
(neat) 3496, 1300, 1100 cm-1; 1H NMR δ 0.95 (t, 3H, J ) 7.03
Hz), 1.33 (d, 3H, J ) 6.40 Hz), 1.60-1.76 (m, 2H), 2.96-3.02
(m, 1H), 3.52 (bs, 1H, OH), 4.29-4.35 (m, 1H), 7.54-7.67 (m,
3H), 7.88-7.92 (m, 2H); EI-MS m/z 228 (M+), 213, 184, 169,
141, 87, 77, 51, 45 (100). Anal. Calcd for C11H16O3S: C, 57.87;
H, 7.06; S, 14.04. Found: C, 57.84; H, 7.00; S, 14.00.
(R*,R*)-1-P h en yl-1-(p h en ylsu lfon yl)p r op a n -2-ol (th r eo-
1
2a c): IR (neat) 3500, 1580, 1320, 1109 cm-1; H NMR δ 1.05
(d, 3H, J ) 6.10 Hz), 3.26 (bs, 1H, OH), 4.95-5.02 (m, 1H),
7.19-7.27 (m, 4H), 7.34-7.39 (m, 3H), 7.45-7.55 (m, 3H); EI-
MS m/z 276 (M+), 232, 141, 135 (100), 91, 77, 43. Anal. Calcd
for C15H16O3S: C, 65.19, H, 5.83; S, 11.60. Found: C, 65.18;
H, 5.82; S, 11.52.
(R*,S*)-1-P h en yl-2-(ph en ylsu lfon yl)bu tan -1-ol (er yth r o-
2cb): IR (neat) 3469, 1307, 1109 cm-1; 1H NMR δ 0.63 (t, 3H,
J ) 7.60 Hz), 1.86-1.95 (m, 2H), 3.05-3.10 (m, 1H), 3.45 (bs,
1H, OH), 5.39 (d, 1H, J ) 5.07 Hz), 7.21-7.33 (m, 5H), 7.59-
7.73 (m, 3H), 7.97-8.01 (m, 2H); EI-MS m/z 290 (M+), 184,
(R*,R*)-1-Cycloh exyl-1-(p h en ylsu lfon yl)p r op a n -2-ol
(th r eo-2a d ): IR (neat) 3490, 1321, 1115 cm-1 1H NMR δ
;
1.13-1.28 (m, 4H), 1.36 (d, 3H, J ) 6.47 Hz), 1.40-1.76 (m,
8H), 2.99 (dd, 1H, J ) 2.16, 6.65 Hz), 4.31-4.34 (m, 1H), 7.54-
7.66 (m, 3H), 7.90-7.95 (m, 2H); 13C NMR δ 23.00, 25.93,
26.74, 27.06, 28.86, 31.66, 38.05, 65.46, 75.46, 128.23, 129.14,
133.60, 140.63; EI-MS m/z 282 (M+), 238, 141, 123, 81 (100),
(42) Crandall, J . K.; Pradat, C. J . Org. Chem. 1985, 50, 1327.
(43) Descriptors R*,S* indicate that diastereomeric compounds are
obtained as racemates. We prefer this terminology to avoid the
ambiguities that could arise from the use of erythro,threo.

3630 J . Org. Chem., Vol. 63, No. 11, 1998
Marcantoni et al.
77, 55, 51, 44. Anal. Calcd for C15H22O3S: C, 63.79; H, 7.85;
S, 11.35. Found: C, 63.77; H, 7.88; S, 11.29.
P r ep a r a t ion of 1-Met h yl-2-(p h en ylsu lfon yl)-5-(iod o-
m eth yl)tetr a h yd r ofu r a n s (6a e a n d 7a e). To a stirred
solution of erythro-2a e (1 mmol) in 11 mL of dry acetonitrile
were added anhydrous sodium carbonate (10 mmol) and iodine
(5.02 mmol). The mixture was stirred in the dark for 2 h at
room temperature, diluted with 35 mL of ether, and then
treated with 17 mL of 10% aqueous Na2SO3. The organic layer
was separated, washed with 20 mL of saturated aqueous NaCl,
dried (Na2SO4), and evaporated to give a mixture (yield 94%)
of two diastereomers 6a e and 7a e (5.5:4.5 ratio by NMR),
which were separated by column chromatography.
(R*,R*)-3-(P h en ylsu lfon yl)h ex-6-en -2-ol (th r eo-2a e): IR
1
(neat) 3501, 1638, 1315, 1109 cm-1; H NMR δ 1.33 (d, 3H, J
) 6.54 Hz), 2.41-2.49 (m, 2H), 3.15-3.37 (m, 1H), 3.40 (bs,
1H, OH), 4.24-4.34 (m, 1H), 4.97-5.05 (m, 2H), 5.58-5.75 (m,
1H), 7.54-7.70 (m, 3H), 7.88-7.91 (m, 2H); 13C NMR δ 21.09,
30.79, 66.62, 70.31, 118.65, 129.18, 129.77, 134.19, 134.48,
138.89; EI-MS m/z 240 (M+), 143, 141, 97, 83, 77, 51, 43 (100).
Anal. Calcd for C12H16O3S: C, 59.97; H, 6.71; S, 13.34.
Found: C, 59.93; H, 6.68; S, 13.30.
(R*, S*, S*)-6a e: IR (neat) 1310, 1140 cm-1; 1H NMR δ 1.23
(d, 3H, J ) 6.10 Hz), 2.19-2.23 (m, 1H), 2.30-2.41 (m, 1H),
3.25 (d, 2H, J ) 5.10 Hz), 3.39-3.42 (m, 1H), 4.39-4.45 (m,
2H), 7.56-7.70 (m, 3H), 7.85-7.92 (m, 2H); 13C NMR δ 7.65,
17.90; 34.85, 65.78, 76.30, 77.90, 128.15, 129.43, 133.97,
139.76; EI-MS m/z 354 (M+), 239, 224, 143, 125, 97 (100%),
83, 79, 77. Anal. Calcd for C11H15IO3S: C, 37.29; H, 4.26; S,
9.05. Found: C, 37.26; H, 4.20; S, 9.05.
(R*,R*)-4-P h en yl-3-(p h en ylsu lfon yl)bu ta n -2-ol (th r eo-
2a f): IR (neat) 3498, 1313, 1108 cm-1; 1H NMR δ 1.34 (d, 3H,
J ) 6.40 Hz), 2.90-2.98 (m, 1H), 3.06-3.13 (m, 1H), 3.47-
3.51 (m, 1H), 4.25-4.30 (m, 2H), 7.01-7.04 (m, 2H), 7.14-
7.17 (m, 3H), 7.48-7.61 (m, 3H), 7.81-7.84 (m, 2H); EI-MS
m/z 290 (M+), 199, 168, 148, 141, 131, 105, 91 (100), 77, 51,
43. Anal. Calcd for C16H18O3S: C, 66.18, H, 6.24; S, 11.04.
Found: C, 66.17; H, 6.18; S, 10.99.
(R*,R*)-1-P h en yl-2-(p h en ylsu lfon yl)bu ta n -1-ol (th r eo-
2cb): IR (neat) 3489, 1307, 1118 cm-1; 1H NMR δ 0.52 (t, 3H,
J ) 8.00 Hz), 1.29-1.38 (m, 1H), 1.57-1.67 (m, 1H), 3.24-
3.30 (m, 1H), 4.37 (bs, 1H, OH), 5.03 (d, 1H, J ) 5.80 Hz),
7.32-7.35 (m, 5H), 7.55-7.71 (m, 3H), 7.91-7.95 (m, 2H); EI-
MS m/z 290 (M+), 184, 169 (100), 148, 141, 91, 77, 51. Anal.
Calcd for C16H18O3S: C, 66.18; H, 6.24; S, 11.04. Found: C,
66.15; H, 6.17; S, 11.01.
(R*,R*)-1-(4-Meth oxyp h en yl)-2-(p h en ylsu lfon yl)bu ta n -
1-ol (th r eo-2gb): IR (neat) 3500, 1309, 1107 cm-1; 1H NMR δ
0.53 (t, 3H, J ) 7.40 Hz), 1.81-1.87 (m, 2H), 3.21-3.26 (m,
2H), 3.73 (s, 3H), 4.98 (d, 1H, J ) 5.85 Hz), 6.81-6.85 (m,
2H), 7.19-7.27 (m, 2H), 7.51-7.67 (m, 3H), 7.86-7.95 (m, 2H);
EI-MS m/z 320 (M+), 302, 178, 163, 141, 137 (100), 109, 77,
51. Anal. Calcd for C17H20O4S: C, 63.72; H, 6.29; S, 10.00.
Found: C, 63.09; H, 6.27; S, 9.97.
(R*, S*, R*)-7a e: IR (neat) 1310, 1140 cm-1; 1H NMR δ 1.22
(d, 3H, J ) 6.18 Hz), 1.89-2.01 (m, 1H), 2.52-2.62 (m, 1H),
3.22 (d, 2H, J ) 5.09 Hz), 3.32-3.36 (m, 1H), 4.39-4.45 (m,
2H), 7.55-7.73 (m, 3H), 7.88-7.93 (m, 2H); 13C NMR δ 9.87,
16.95, 33.65, 65.44, 76.20, 76.95, 128.10, 129.43, 133.76,
138.30; EI-MS m/z 354 (M+), 239, 224, 143, 125, 97 (100%),
83, 79, 77. Anal. Calcd for C11H15IO3S: C,37.29; H,4.26; S,9.05.
Found: C, 37.26; H, 4.20; S, 9.05.
Similar treatment of threo-(2a e) with iodine and sodium
carbonate in acetonitrile gave a mixture (yield 93%) of two
tetrahydrofurans 8a e and 9a e (8.3:1.7 ratio by NMR) which
were separated by column chromatography.
(R*,R*,R*)-8a e: IR (neat) 1308, 1109 cm-1; 1H NMR δ 1.53
(d, 3H, J ) 6.68 Hz), 1.91-2.08 (m, 2H), 3.15-3.21 (m, 2H),
3.72-3.82 (m, 1H), 3.95-4.00 (m, 1H), 4.48-4.58 (m, 1H),
7.52-7.76 (m, 3H), 7.86-7.90 (m, 2H); 13C NMR δ 10.69, 16.99,
33.74, 65.67, 75.72, 76.40, 128.05, 129.43, 133.95, 138.45; EI-
MS m/z 354 (M+), 239, 224, 143, 125, 97 (100), 79, 77. Anal.
Calcd for C11H15IO3S: C, 37.29; H, 4.26; S, 9.05. Found: C,
37.26; H, 4.01; S, 8.99.
(R *,R *)-1-(4-Nit r op h e n yl)-2-(p h e n ylsu lfon yl)b u t a n -
1
1-ol (th r eo-2h b): IR (neat) 3494, 1502, 1309, 1105 cm-1; H
NMR δ 0.58 (t, 3H, J ) 7.43 Hz), 1.74-1.78 (m, 2H), 3.13-
3.20 (m, 2H), 5.17 (d, 1H, J ) 5.96 Hz), 7.02-7.08 (m, 2H),
7.44-7.50 (m, 2H), 7.56-7.78 (m, 3H), 7.98-8.04 (m, 2H); EI-
MS m/z 335 (M+), 317, 193, 178, 152 (100), 141, 77, 51. Anal.
Calcd for C16H17NO5S: C, 57.30; H, 5.11; N, 4.17; S, 9.56.
Found: C, 57.30; H, 5.07; N, 4.10; S, 9.52.
(R*,R*,S*)-9a e: IR (neat) 1308, 1109 cm-1; 1H NMR δ 1.61
(d, 3H, J ) 6.63 Hz), 2.17-2.27 (m, 2H), 3.19-3.35 (m, 2H),
3.72-3.84 (m, 1H), 3.95-4.00 (m, 1H), 4.39-4.45 (m, 1H),
7.52-7.76 (m, 3H), 7.86-7.90 (m, 2H); 13C NMR δ 7.12, 17.85,
34.89, 65.79, 76.62, 77.87, 128.14, 129.43, 133.90, 139.78; EI-
MS m/z 354 (M+), 239, 224, 143, 141, 125, 97 (100), 79, 77.
Anal. Calcd for C11H15IO3S: C, 37.29; H, 4.26; S, 9.05.
Found: C, 37.26; H, 4.01; S, 8.99.
(R*,S*)-1-P h en yl-2-ch lor o-2-(p h en ylsu lfon yl)b u t a n -
1-ol (th r eo-5): IR (neat) 3495, 1305, 1140, 736 cm-1; 1H NMR
δ 0.72 (t, 3H, J ) 7.37 Hz), 1.88-2.06 (m, 2H), 4.26 (bs, 1H,
OH), 5.54 (s, 1H), 7.26-7.34 (m, 3H), 7.39-7.44 (m, 2H), 7.58-
7.76 (m, 3H), 8.02-8.07 (m, 2H); 13C NMR δ 9.10, 29.23, 74.65,
92.82, 128.09, 128.45, 129.45, 129.72, 133.89, 134.01, 138.43,
139.60; EI-MS m/z 326 (M+ + 2), 324 (M+), 220, 218, 203, 147,
Ack n ow led gm en t. Financial support from the Uni-
versity of Camerino and from the MURST of Italy is
gratefully acknowledged. We also would like to thank
Dr. Beatrice Accorroni for sharing preliminary results.
143, 141, 107 (100), 105, 91, 79, 77. Anal. Calcd for C16H17
-
ClO3S: C, 59.16; H, 5.27; S, 9.87. Found: C, 59.14; H, 5.20;
S, 9.84.
J O972284K