Enantioselective synthesis of 1-alkyl-substituted 1-phenyl-1,2-ethanediols using a myrtenal-derived chiral auxiliary

Article abstract of DOI:10.1016/j.tetasy.2003.07.017

The enantioselective synthesis of several 1-phenyl-1,2-ethanodiol derivatives using 2-benzoyl-1,3-oxathiane 1 as a chiral auxiliary is described. Nucleophilic additions of Grignard reagents, methyl lithium and LS-Selectride on benzoyloxathiane 1 proceeded in >95% diastereomeric ratio (dr) affording the corresponding tertiary carbinols, which were successively hydrolyzed and reduced to give the title derivatives in >95% enantiomeric excess (ee).

Full text of DOI:10.1016/j.tetasy.2003.07.017

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3225–3232
Enantioselective synthesis of 1-alkyl-substituted
1-phenyl-1,2-ethanediols using a myrtenal-derived chiral auxiliary
Mar´ıa Elena Vargas-D´ıaz,a Luis Chaco´n-Garc´ıa,a Pedro Vela´zquez,a Joaqu´ın Tamariz,a
Pedro Joseph-Nathanb and L. Gerardo Zepedaa,*
aDepartamento de Qu´ımica Orga´nica, Escuela Nacional de Ciencias Biolo´gicas, Instituto Polite´cnico Nacional,
Prol. de Carpio y Plan de Ayala, Me´xico, D.F., 11340 Mexico
bDepartamento de Qu´ımica, Centro de Investigacio´n y de Estudios Avanzados del Instituto Polite´cnico Nacional,
Apartado 14-740, Me´xico, D.F., 07000 Mexico
Received 1 July 2003; accepted 25 July 2003
Abstract—The enantioselective synthesis of several 1-phenyl-1,2-ethanodiol derivatives using 2-benzoyl-1,3-oxathiane 1 as a chiral
auxiliary is described. Nucleophilic additions of Grignard reagents, methyl lithium and LS-Selectride on benzoyloxathiane 1
proceeded in >95% diastereomeric ratio (dr) affording the corresponding tertiary carbinols, which were successively hydrolyzed
and reduced to give the title derivatives in >95% enantiomeric excess (ee).
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
which can be used as key precursors for the preparation
of both known and new bioactive compounds.
Substituted 1-phenyl-1,2-ethanediols having an alkyl
group at C-1 widely occur in biologically active
molecules such as antifungal,1,2 herbicidal,3 anticonvul-
sant,4 immunosupresor,5 muscarinic M3 receptor antag-
onist,6 hair growth stimulant,7 antitumoral8 and
antiperspirant compounds.9,10 Some of these biological
activities were described using racemic 1-phenyl-1,2-
ethanediol derivatives to prepare the active com-
pound,4,8–10 and therefore we were encouraged to
develop a practical methodology to achieve the enan-
tioselective synthesis of the former molecules. Thus,
taking advantage of the recently published synthesis of
a new (1R)-myrtenal-derived chiral auxiliary,11 herein is
presented an easy synthetic methodology, starting from
benzoyloxathiane 1, for the preparation of enantiomeri-
cally pure 1-alkyl-substituted 1-phenyl-1,2-ethanediols,
2. Results and discussion
In a previous paper we described the synthesis of
hydroxythiol 2 in both excellent yield and high enan-
tiomeric excess,11 a compound which was now used as
the starting material for the synthesis of the new ben-
zoyl-1,3-oxathiane 1 (Chart 1).12 Thus, hydroxythiol 2,
which is easely obtained in higher yield and enan-
tiomeric purity than the hydroxythiol derived from
(R)-(+)-pulegone,13 was treated with 1.2 equiv. of a,a-
diethoxyacetophenone in boiling toluene and in the
presence of catalytic amounts of p-TsOH, giving ben-
zoyloxathiane 1 in 58% yield. The substantial higher
yield obtained in this reaction, as compared to the
Chart 1.
* Corresponding author. Fax (52 55) 5396 3503; e-mail: lzepeda@woodward.encb.ipn.mx
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.07.017

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M. E. Vargas-D´ıaz et al. / Tetrahedron: Asymmetry 14 (2003) 3225–3232
preparation of the structural analogous 2-acetyl-1,3-
oxathiane,11 could be due to the slightly better stability
shown by a,a-diethoxyacetophenone, as compared to
a,a-dimethoxyacetone under the same acidic reaction
conditions. This can be accounted by the presence of
more by-products when the later acetal is used as the
acylating agent. The (R)-configuration of the new
stereogenic center, C-5, was assigned by means of
NMR NOE experiments, since upon irradiation of H-5,
the signals owing to H-3axial and H-7 showed 6 and
8% enhancement, respectively. Implicitly, this experi-
ment confirmed the (R)- and (S)-configuration at C-2
and C-7, respectively. Similarly to the preparation of
the structural analogue 2-acetyl-1,3-oxathiane,11 forma-
tion of benzoyloxathiane 1 was accompanied by traces
of the corresponding axial epimer.
ically at lower field for the (S) epimer. Notation
‘]99:1’ as diastereomeric ratio means that only the
major adduct was detected. It can be observed that the
highest stereoselectivity is obtained in the expected
order:13 Grignard reagents>RLi]aluminum hydrides.
However, the better stereoselectivity observed with
MeLi ($ as MeMgBr) with regard to n-BuLi is not yet
well understood. Efforts are underway to clarify this
behavior. As predictable in this type of heterocyclic
systems, major adducts (compounds 3) are formed in
agreement to the preferred nucleophilic attack through
the Re face of the carbonyl group, according to the
Cram chelated model.15
In Table 2 are summarized the chemical yields and
enantiomeric excess (ee%) obtained after hydrolysis of
adducts 3a–c, 3f,g and 3i, as well as the subsequent
reduction of the corresponding aldehydes. Best results
of adduct hydrolysis were achieved by using AgNO3,
NCS in MeCN:H2O for 5 min.13 Since the intermediate
aldehydes were unstable during chromatographic sepa-
ration, they were transformed, by means of NaBH4 or
LiAlH4, to the corresponding diols without further
purification. We observed that the milder reductions
with NaBH4 were more efficient than reductions using
LiAlH4, thus allowing also a better recovery of the
chiral auxiliary 2, probably due to the easier work-up
protocol followed in the former. Therefore, yields of
most diols shown in Table 2 were obtained from
NaBH4 reductions (except entry 7) and after purifica-
tion by column chromatography. It should be men-
tioned that hydrolysis of adduct 3g, and subsequent
LiAlH4 reduction of the corresponding aldehyde, fur-
nished a mixture of diol 5g and the styrene derivative
5k, which was formed by the conjugated 1,4-addition of
hydride. Since this mixture was difficult to separate by
column chromatography, it was converted into diol 5j
by means of catalytic hydrogenation. The non-enan-
Table 1 shows diastereoselectivity and chemical yields
obtained when benzoyloxathiane 1 was subjected to
nucleophilic additions with several organometallic and
reducing agents to afford mixtures of adducts 3 and 4.
Chemical yields range from good to excellent. However,
when EtMgBr, i-PrMgBr and i-BuMgBr were used,
significant presence of reduction products was
observed.14 It should be emphasized that the hydride
provided by the above Grignard reagents yield the same
adduct as that formed by addition of LAH, DIBAL
and LS-Selectride (Table 1, entries 10, 11 and 12).
Similarly, addition of MeLi and MeMgBr afforded the
same compound (Table 1, entries 1 and 9) revealing
that the attack to the carbonyl group by both reagents
is taking place on the same molecular face. The yields
reported in entries 8, 10 and 11, are described for
mixtures of the corresponding epimers.
Diastereoselectivity was measured by means of 1H
NMR by integrating H-5 in the crude reaction mixture,
since the chemical shifts of this proton appear systemat-
Table 1. Addition reactions to benzoyloxathiane 1
Entry
Reagent
R
Comp. (%)a
Ratio 3:4c
1
2
3
4
5
6
7
8
MeMgBr
EtMgBr
Me
Et
i-Pr
PhCH2
i-Bu
CH2ꢀCH
PhCꢁC
n-Bu
Me
3a (>99)
3b (85)
3c (60)
3d (80)
3e (71)
3f (90)
3g (97)
3h (78)b
3a (>99)
3i (92)b
3i (70)b
3i (82)
]99:1
]99:1
]99:1
]99:1
]99:1
]99:1
]99:1
84:16
i-PrMgBr
PhCH2MgCl
i-BuMgBr
CH2ꢀCHMgBr
PhCꢁCMgBr
n-BuLi
MeLi
LAH
DIBAL
LS-Selectride
9
]99:1
82:18
89:11
10
11
12
H
H
H
]99:1
a Calculated after purification by column chromatography.
b Calculated as mixture of 3 and 4.
c Determined by 1H NMR integration of H-5 on the crude reaction mixture.

M. E. Vargas-D´ıaz et al. / Tetrahedron: Asymmetry 14 (2003) 3225–3232
Table 2. Hydrolysis of adducts 3
3227
Entry
R
Yield (%)a
[h]b
Ee (%)c
1
2
3
4
Me
Et
i-Pr
CH2ꢀCH
PhCꢁC
PhCH2CH2
PhCHꢀCH
H
5a (92)
5b (75)
5c (80)
5f (89)
5g (90)d
5j (90)
5k (35)
5i (73)
+5.7
−7.2
>98
>98
>98
>98
>98
>98
–
−19.0
−43.4
+11.0
+10.6
5
6e
7f
8
h
–
+38.6
>98
Reaction conditions: (i) AgNO3, CH3CN, rt, 1–5 min; (ii) NaBH4, THF. Yield of recovered hydroxythiol: 60–80%.
a After column chromatography.
b See Section 3 for solvent used.
c See Section 3 for ee% of described diols.
d Obtained when NaBH4 was used as reducing agent.
e Obtained by catalytic hydrogenation (Pd/C) of diol 5g.
f Formed by conjugated addition of LiAlH4 to diol 5g.
h Not measured.
tioselective syntheses of diols 5g16 and 5j17 were previ-
ously described, but complete spectroscopic data and
specific rotations were not reported. Taking into
account the high diastereoselectivity obtained in the
addition of PhCꢁCMgBr to benzoyloxathiane 1 (entry
7, Table 1), and assuming no racemization occurs dur-
ing the subsequent transformations, we are confident
that the present optical data for 5g and 5j are for the
pure enantiomer (see below). On the other hand, diol
5a was obtained in essentially the same chemical yield
and enantiomeric purity as its enantiomer, which was
previously prepared through the addition of C6H5MgBr
to 2-acetyloxathiane,11 followed by hydrolysis and
reduction of the corresponding intermediates.
capillary melting point apparatus and are uncorrected.
Infrared spectra were recorded on a Perkin–Elmer
1
Spectrum 2000 spectrophotometer. H and 13C NMR
spectra were obtained on a Varian Mercury spectrome-
ter at 300 and 75.4 MHz, respectively, using CDCl3 as
solvent and TMS as internal standard. The low resolu-
tion mass spectra (LRMS) were recorded on HP 5971A
or Varian Saturn 2000 GC/Selective Mass Detectors,
either using EI (70 eV) or CI, as it is specified. High-
resolution FABMS data were collected on a JMS-SX
102 mass spectrometer. Thin-layer chromatograms were
done on precoated TLC sheets of silica gel 60 F254 (E.
Merck). Flash chromatography was carried out using
Merck silica gel (230–400 mesh). THF used in the
nucleophilic additions was distilled from Na immedi-
ately prior to use, and all other reagents were used
without further purification. Optical rotations were
measured at 589 nm using a 1 dm cell on a JASCO
DIP-370 polarimeter.
As can be appreciated in Tables 1 and 2, the enan-
tiomeric excess obtained for each diol was consistent
with the diastereomeric ratio observed at the corre-
sponding adduct stage, and therefore, essentially no
racemization is taking place during the hydrolysis and
reduction conditions. Thus, the (S)-absolute configura-
tion of all prepared diols is in agreement with the above
mentioned Cram chelated model operating at the nucle-
ophilic addition on benzoyloxathiane 1. In conclusion,
present results describe a really accessible methodology
toward the previously non trivial enantioselective syn-
thesis of optically active terminal 1,2-diols bearing a
tertiary carbinol as the stereogenic center.
3.2. (1S,2R,5R,7S,9R)-5-Benzoyl-10,10-dimethyl-4-oxa-
6-thiatricyclo[7.1.1.02,7]undecane 1
A well stirred solution of 3 g (16.1 mmol) of hydroxy-
thiol 2,11 4 g (19.2 mmol) of a,a-diethoxyacetophenone
and 300 mg of p-TsOH in 200 mL of toluene was
refluxed at room temperature for 45 min. The reaction
mixture was poured into a cold saturated solution of
NaHCO3, extracted with ethyl ether, washed with a
saturated solution of NaHCO3 (2×50 mL), dried over
anhydrous Na2SO4 and evaporated to dryness. The oily
residue was flash chromatographed using a mixture of
hexane:EtOAc (99:1) as the eluent, obtaining 2.2 g
(45%) of benzoyloxathiane 1 as a white solid, mp
3. Experimental
3.1. General
Melting points were determined on an electrothermal

3228
M. E. Vargas-D´ıaz et al. / Tetrahedron: Asymmetry 14 (2003) 3225–3232
67–69°C. [h]2D5=−68.4 (c 0.19, CHCl3). 1H NMR: l
8.11 (bd, 2H, J=7.4 Hz, H-o), 7.58 (bt, 1H, J=7.4
Hz, H-p), 7.46 (bt, 2H, J=7.4 Hz, H-m), 6.22 (s, 1H,
H-5), 4.23 (dd, 1H, J=11.0, 2.8 Hz, H-3e), 3.99 (dt,
1H, J=11.0, 8.8 Hz, H-7), 3.80 (t, 1H, J=11.0 Hz,
H-3a), 2.63 (m, 2H, H-2, H-11e), 2.40 (dddd, 1H,
J=13.0, 8.8, 5.0, 2.2 Hz, H-8e), 2.15 (bq, 1H J=5.0
Hz, H-9), 1.82 (t, 1H, J=6.0 Hz, H-1), 1.79 (ddd,
1H, J=13.0, 11.0, 1.4 Hz, H-8a), 1.29 (s, 3H, H-13),
1.22 (s, 3H, H-12), 1.06 (d, 1H, J=10.0 Hz, H-11a).
13C NMR: l 192.1 (C-1%), 133.8 (C-i ), 133.7 (C-p),
129.5 (C-o), 128.4 (C-m), 86.9 (C-5), 76.4 (C-3), 51.2
(C-2), 45.7 (C-9), 43.4 (C-1), 42.6 (C-7), 39.5 (C-11),
39.0 (C-10), 33.4 (C-8), 29.5 (C-13), 24.6 (C-12). IR
(KBr): 2917, 1735, 1692, 1449, 1072, 756 cm−1. EIMS
m/z (rel. int.): 302 (M+, <1), 197 (100), 35 (2), 77 (2).
HRFABMS m/z 303.1405 (calcd for C18H22O2S+H,
303.1419).
reaction outcome was purified through a Chroma-
totron system using a mixture of hexane:EtOAc (19:1)
as the eluent to give 88 mg (>99%) of 3a as a color-
less oil. [h]2D5=−62.4 (c 0.21, CHCl3). 1H NMR: l
7.50 (dd, 2H, J=8.1, 1.2 Hz, H-o), 7.36 (t, 1H, J=
7.0 Hz, H-p), 7.29 (t, 2H, J=8.1 Hz, H-m), 5.11 (s,
1H, H-5), 4.09 (dd, 1H, J=11.1, 2.9 Hz, H-3e), 3.68
(t, 1H, J=11.1 Hz, H-3a), 3.62 (t, 1H, J=10.0, 8.2
Hz, H-7), 2.95 (s, 1H, OH), 2.58 (m, 1H, H-11e),
2.40 (ddd, J=11.1, 10.5, 2.9 Hz, H-2), 2.29 (m, 1H,
H-8e), 2.10 (q, 1H, J=5.2 Hz, H-9), 1.81 (t, 1H,
J=5.9 Hz, H-1), 1.66 (s, 3H, H-2%), 1.62 (m, 1H,
H-8a), 1.24 (s, 3H, H-13), 1.10 (s, 3H, H-12), 0.97 (d,
1H, J=9.6 Hz, H-11a). 13C NMR: l 143.0 (C-i ),
127.9 (C-p), 127.3 (C-m), 125.2 (C-o), 93.3 (C-5), 76.4
(C-1%), 75.7 (C-3), 51.3 (C-2), 45.5 (C-9), 43.3 (C-1),
40.8 (C-7), 39.3 (C-11), 39.0 (C-10), 33.5 (C-8), 29.6
(C-13), 27.2 (C-2%), 24.5 (C-12). IR (neat): 3501, 2914,
1447, 1057, 758, 736, 699 cm−1. EIMS m/z (rel. int.):
318 (M+, <1), 197 (M−121, 100), 135 (32), 121 (39),
107 (68), 93 (72), 79 (81), 43 (85). HRFABMS m/z
319.1749 (calcd for C19H26O2S+H, 319.1732).
3.2.1. General procedure for the addition of Grignard
reagents to benzoyloxathiane 1. To a solution of ben-
zoyloxathiane 1 (1 equiv.) in anhd. THF was added
the Grignard reagent (1.5–2 equiv.) at −78°C under a
nitrogen atmosphere. After stirring for 2 h at the
same temperature, the reaction mixture was allowed
to warm up to room temperature and further stirred
for 1 h. The reaction mixture was quenched with 10
mL of a saturated solution of ammonium chloride,
the THF was eliminated by evaporation and the
remaining emulsion was extracted with ethyl ether.
The organic layer was washed with a saturated solu-
tion of ammonium chloride, dried over anhd. Na2SO4
and concentrated to dryness, giving the corresponding
pure diastereoisomer 3 (or admixed with 4) as a col-
orless oil.
3.4. (1S,2R,5R,7S,9R)-5-[(1%S)-1%-Hydroxy-1%-phenyl-1%-
propyl)]-10,10-dimethyl-4-oxa-6-thiatricyclo[7.1.1.02,7]-
undecane 3b
A solution of 169 mg (0.56 mmol) of 1 in 5 mL of
anhydrous THF was treated with 112 mg (0.84 mmol)
of ethylmagnesium bromide in ethyl ether. After
work-up 158 mg (85%) of pure 3b were obtained as a
single diastereoisomer (colorless oil). [h]2D5=−72.8 (c
0.36, CHCl3). 1H NMR: l 7.45–7.22 (m, 5H, Ar),
5.14 (s, 1H, H-5), 4.09 (dd, 1H, J=10.5, 2.3 Hz,
H-3e), 3.7 (t, 1H, J=10.5 Hz, H-3a), 3.65 (dt, 1H,
J=10.5, 9.0 Hz, H-7), 2.77 (bs, 1H, OH), 2.55 (m,
1H, H-11e), 2.40 (bt, 1H, J=10.5, H-2), 2.22 (m, 2H,
H-2%a, H-8e), 2.08 (q, 1H, J=5.2 Hz, H-9), 1.91 (m,
1H, H-2%b), 1.80 (t, 1H, J=5.9 Hz, H-1), 1.61 (t, 1H,
J=12.0 Hz, H-8a), 1.24 (s, 3H, H-13), 1.01 (s, 3H,
H-12), 0.96 (d, 1H, J=9.4 Hz, H-11a), 0.70 (t, 3H,
J=7.0 Hz, H-3%). 13C NMR: l 141.2 (C-i ), 127.9
(C-p), 127.1 (C-m), 125.9 (C-o), 93.0 (C-5), 78.4 (C-
1%), 76.4 (C-3), 51.3 (C-2), 45.5 (C-1), 43.2 (C-9), 40.8
(C-7), 39.3 (C-11), 38.9 (C-10), 33.5 (C-8), 31.8 (C-2%),
29.5 (C-13), 24.6 (C-12), 7.6 (C-3%). IR (neat): 3359,
2933, 1448, 1059, 736, 699 cm−1. CIMS m/z (rel. int.):
333 (MH+, 11), 315 (100), 197 (9), 147 (27), 135 (46),
57 (25). HRFABMS m/z 333.1891 (calcd for
C20H28O2S+H, 333.1888).
3.3. (1S,2R,5R,7S,9R)-5-[(1%S)-1%-Hydroxy-1%-phenyl-1%-
ethyl)]-10,10-dimethyl-4-oxa-6-thiatricyclo[7.1.1.02,7]-
undecane 3a
This compound was obtained by the following two
procedures:
Method a: According to the above general procedure,
to a well-stirred cooled (−78°C) solution of 158 mg
(0.52 mmol) of 1 in 5 ml of anhd. THF under a
nitrogen atmosphere, 187 mg (1.56 mmol) of methyl-
magnesium bromide in ethyl ether were added drop-
wise. After work-up, 166 mg (>99%) of pure 3a were
obtained as a single diastereoisomer (colorless oil).
Method b: A well-stirred cooled (−78°C) solution of
84 mg (0.28 mmol) of benzoyloxathiane 1 in 3 mL of
anhydrous THF was treated with 0.42 mmol of MeLi
in cyclohexane and stirred under a nitrogen atmo-
sphere for 2 h. The mixture was quenched with 1 mL
of a saturated soln. of ammonium chloride and
allowed to warm up to room temperature. The THF
was evaporated and the residue extracted with 50 mL
of ethyl ether. The organic layer was washed with 5%
aq. HCl (3×30 mL) and brine (1×30 mL), dried over
anhd. Na2SO4 and evaporated to dryness. The crude
3.5. (1S,2R,5R,7S,9R)-5-[(1%S)-1%-Hydroxy-2%-methyl-1%-
phenyl-1%-propyl)]-10,10-dimethyl-4-oxa-6-thiatricyclo-
[7.1.1.02,7]undecane 3c
A solution of 109 mg (0.36 mmol) of 1 in 4 mL of
anhydrous THF was treated with 80 mg (0.54 mmol)
of iso-propylmagnesium bromide in ethyl ether. After
work-up 74 mg (60%) of pure 3c were obtained as a
single diastereoisomer (colorless oil). [h]2D5=−68.1 (c
0.26, CHCl3). 1H NMR: l 7.43 (d, 2H, J=8.4 Hz,
H-o), 7.38–7.23 (m, 1H, H-p, 2H, H-m), 5.43 (s, 1H,

M. E. Vargas-D´ıaz et al. / Tetrahedron: Asymmetry 14 (2003) 3225–3232
3229
H-5), 4.17 (dd, 1H, J=10.7, 3.2 Hz, H-3e), 3.73 (dt,
1H, J=10.0, 8.8, H-7), 3.69 (t, 1H, J=11.1 Hz, H-3a),
2.83 (s, 1H, OH), 2.59 (m, 1H, H-11e), 2.31 (m, 3H,
H-2, H-2%, H-8e), 2.10 (q, 1H, J=5.0 Hz, H-9), 1.80 (t,
1H, J=6.0 Hz, H-1), 1.60 (m, 1H, H-8a), 1.3 (s, 3H,
H-13), 1.10 (s, 3H, H-12), 0.90 (d, 1H, J=9.4 Hz,
H-11a), 0.85 (d, 3H, J=6.9 Hz, H-3%). 13C NMR: l
140.2 (C-i ), 127.3 (C-m), 127.0 (C-p), 126.43 (C-o),
91.0 (C-5), 80.0 (C-1%), 76.4 (C-7), 51.3 (C-2%), 45.5
(C-1), 43.2 (C-9), 41.3 (C-7), 39.3 (C-11), 39.0 (C-10),
35.2 (C-2), 33.4 (C-8), 29.6 (C-13), 24.6 (C-12), 17.8
(C-3%a), 17.0 (C-3%b). IR (neat): 3563, 2912, 1448, 734
cm−1. CIMS m/z (rel. int.): 347 (MH+, 68), 329 (M+−18,
72), 161 (91), 135 (100), 107 (8). HRFABMS m/z
347.2041 (calcd for C21H30O2S+H, 347.2045).
(C-p), 127.0 (C-m), 125.7 (C-o), 94.8 (C-5), 78.6 (C-1%),
76.4 (C-3), 51.4 (C-2), 47.4 (C-2%), 45.5 (C-9), 43.2
(C-1), 40.7 (C-7), 39.4 (C-11), 38.9 (C-10), 33.5 (C-8),
29.6 (C-13), 24.5 (C-12), 24.5 (C-4%b), 24.1 (C-4%a), 24.0
(C-3%). IR (neat): 3564, 2950, 1448, 1057, 682 cm−1.
CIMS m/z (rel. int.): 361 (MH+, 11), 343 (100), 209
(10), 175 (15), 135 (43), 107 (4). HRFABMS m/z
361.2201 (calcd for C22H32O2S+H, 361.2194).
3.8. (1S,2R,5R,7S,9R)-5-[(1%S)-1%-Hydroxy-1%-phenyl-2%-
propen-1%-yl)]-10,10-dimethyl-4-oxa-6-thiatricyclo-
[7.1.1.02,7]undecane 3f
Compound 1 (100 mg, 0.33 mmol) in anhydrous THF
(5 mL) was treated with vinylmagnesium bromide (65
mg, 0.49 mmol) in ethyl ether. After work-up pure 3f
was obtained as a single diastereoisomer (colorless oil:
3.6. (1S,2R,5R,7S,9R)-5-[(1%S)-1%-Hydroxy-1%,2%-di-
phenyl-1%-ethyl)]-10,10-dimethyl-4-oxa-6-thiatricyclo-
[7.1.1.02,7]undecane 3d
1
98 mg, 90%). [h]2D5=−68.1 (c 0.26, CHCl3). H NMR: l
7.46 (d, 2H, J=7.5 Hz, H-o), 7.39–7.22 (m, 3H, Ar),
6.35 (dd, 1H, J=17.6, J=10.5 Hz, H-2%), 5.43 (d, 1H,
J=17.6 Hz, H-3%b), 5.34 (s, 1H, H-5), 5.27 (d, 1H,
J=10.5 Hz, H-3%a), 4.07 (dd, 1H, J=10.6, 2.3 Hz,
H-3e), 3.68 (t, 1H, J=11.1 Hz, H-3a), 3.63 (dt, 1H,
J=9.3, 8.3 Hz, H-7), 3.05 (s, 1H, OH), 2.53 (m, 1H,
H-11e), 2.40 (bt, 1H, J=9.5 Hz, H-2), 2.25 (m, 1H,
H-8e), 2.07 (q, 1H, J=5.8 Hz, H-9), 1.80 (t, 1H, J=6.0
Hz, H-1), 1.65 (t, 1H, J=11.7 Hz, H-8a), 1.24 (s, 3H,
H-13),1.01 (s, 3H, H-12), 0.98 (d, 1H, J=9.4 Hz,
H-11a). 13C NMR: l 141.3 (C-i ), 141.2 (C-2%), 128.0
(C-m), 127.5 (C-p), 125.6 (C-o), 114.5 (C-3%), 92.0 (C-
5), 77.8 (C-1%), 76.5 (C-3), 51.2 (C-2), 45.5 (C-1), 43.2
(C-9), 40.8 (C-7), 39.3 (C-11), 38.9 (C-10), 33.4 (C-8),
29.5 (C-13), 24.5 (C-12). IR (neat): 3501, 2914, 1447,
1057, 736, 699 cm−1. EIMS m/z (rel. int.): 330 (M+, 1),
197 (100), 135 (28), 107 (42), 93 (32), 79 (22).
HRFABMS m/z 331.1729 (calcd for C20H26O2S+H,
331.1732).
A solution of 120 mg (0.40 mmol) of 1 in 4 mL of
anhydrous THF was treated with 90 mg (0.60 mmol) of
benzylmagnesium chloride in ethyl ether. After work-
up, 126 mg (80%) of pure 3d were obtained as a single
diastereoisomer (colorless oil). [h]2D4=−86.6 (c 0.26,
1
CHCl3). H NMR: l 7.37–6.81 (m, 10H, Ar), 5.24 (s,
1H, H-5), 4.18 (dd, 1H, J=10.9, J=3.1 Hz, H-3e), 3.72
(t, 1H, J=10.9 Hz, H-3a), 3.63 (dt, 1H, J=10.5, 8.8,
H-7), 3.35 and 3.26 (AB, 2H, J=13.5 Hz, CH2Ph), 2.53
(m, 1H, H-11e), 2.83 (bs, 1H, OH), 2.58 (m, 1H,
H-11e), 2.42 (bt, 1H, J=10.5 Hz, H-2), 2.25 (m, 1H,
H-8e), 2.20 (bq, 1H, J=5.4 Hz, H-9), 1.81 (t, 1H,
J=5.8 Hz, H-1), 1.63 (m, 1H, H-8a), 1.23 (s, 3H,
H-13), 1.16 (s, 3H, H-12), 0.99 (d, 1H, J=9.5 Hz,
H-11a). 13C NMR: l 141.6 (C-i%), 136.3 (C-i ), 130.7
(C-m%), 127.7 (C-m), 127.6 (C-o%), 127.3 (C-p%), 126.3
(C-p), 126.0 (C-o), 91.8 (C-5), 78.3 (C-1%), 76.4 (C-3),
51.3 (C-2), 45.5 (C-1), 45.5 (CH2Ph), 43.3 (C-9), 40.9
(C-7), 39.4 (C-11), 39.0 (C-10), 33.5 (C-8), 29.6 (C-13),
24.5 (C-12). IR (neat): 3448, 2920, 1449, 1050, 757, 693,
cm−1. EIMS m/z (rel. int.): 394 (M+, <1), 197 (92), 135
(19), 107 (46), 105 (100), 77 (94), 41 (35).
3.9. (1S,2R,5R,7S,9R)-5-[(1%S)-1%-Hydroxy-1%,3%-
diphenyl-2%-propyn-1%-yl)]-10,10-dimethyl-4-oxa-6-thiatri-
cyclo[7.1.1.02,7]undecane 3g
3.7. (1S,2R,5R,7S,9R)-5-[(1%S)-1%-Hydroxy-3%-methyl-1%-
phenyl-1%-butyl)]-10,10-dimethyl-4-oxa-6-thiatricyclo-
[7.1.1.02,7]undecane 3e
A solution of compound 1 (100 mg, 0.33 mmol) in
anhydrous THF (5 mL) was treated with phenylethynil-
magnesium bromide (102 mg, 0.49 mmol) in ethyl
ether. After work-up pure 3g was obtained as a single
diastereoisomer, mp 62–65°C (97%). [h]2D5=−27.1 (c
0.14, CHCl3). 1H NMR: l 7.75 (dd, 2H, J=7.8, 1.5 Hz,
H-o%), 7.53–7.23 (m, 8H, Ar), 5.29 (s, 1H, H-5), 4.15
(dd, 1H, J=10.9, J=3.1 Hz, H-3eq), 3.70 (t, 1H,
J=10.9 Hz, H-3ax), 3.66 (dt, 1H, J=10.5, 8.8 Hz,
H-7), 3.58 (bs, 1H, OH), 2.53 (m, 1H, H-11e), 2.41 (bt,
1H, J=10.5 Hz, H-2), 2.26 (m, 1H, H-8e), 2.10 (q, 1H,
J=5.4 Hz, H-9), 1.81 (t, 1H, J=5.8 Hz, H-1), 1.65 (m,
1H, H-8a), 1.24 (s, 3H, H-13), 1.10 (s, 3H, H-12), 0.99
(d, 1H, J=9.5 Hz, H-11a). 13C NMR: l 139.8 (C-i ),
131.9 (C-o%), 128.5 and 128.3 (C-p, C-p%), 128.2 and
128.0 (C-m, C-m%), 126.0 (C-o%), 122.4 (C-i%), 92.8 (C-5),
90.4 (C-2%), 85.1 (C-3%), 76.6 (C-1%), 74.5 (C-3), 51.1
(C-2), 45.5 (C-1), 43.3 (C-9), 40.9 (C-7), 39.3 (C-11),
39.0 (C-10), 33.4 (C-8), 29.7 (C-13), 24.5 (C-12). IR
A solution of 150 mg (0.50 mmol) of 1 in 5 ml of
anhydrous THF was treated with 80 mg (0.75 mmol) of
iso-butylmagnesium bromide in ethyl ether. After
work-up 128 mg (71%) of pure 3e were obtained as a
single diastereoisomer (colorless oil). [h]2D0=−68.8 (c
1
0.5, EtOH). H NMR: l 7.46 (d, 1H, J=7.5 Hz, H-o),
7.37 (t, 2H, J=7.5 Hz, H-p), 7.28 (t, 2H, J=7.5 Hz,
H-m), 5.08 (s, 1H, H-5), 4.10 (dd, 1H, J=10.6, 3.7 Hz,
H-3e), 3.68 (t, 1H, J=10.6 Hz, H-3a), 3.60 (dt, 1H,
J=10.0, 8.7 Hz, H-7), 2.77 (s, 1H, OH), 2.55 (m, 1H,
H-11e), 2.39 (bt, 1H, J=10.6 Hz, H-2), 2.22 (m, 1H,
H-8e), 2.10 (m, 2H, H-9, H-2%), 1.94 (m, 2H, H-1, H-2%),
1.58 (m, 1H, H-8a), 1.47 (m, 1H, H-3%), 1.23 (s, 3H,
H-13), 1.10 (s, 3H, H-12), 0.96 (d, 1H, J=10.0 Hz,
H-11a), 0.92 (d, 1H, J=7.5 Hz, H-4%a), 0.63 (d, 1H,
J=6.2 Hz, H-4%b). 13C NMR: l 141.9 (C-i ), 127.9

3230
M. E. Vargas-D´ıaz et al. / Tetrahedron: Asymmetry 14 (2003) 3225–3232
(neat): 3448, 2920, 2200, 1449, 1050, 757, 693, cm−1.
EIMS m/z (rel. int.): 404 (M+, 2), 197 (100), 129 (24),
107 (25), 93 (39), 79 (43). HRFABMS m/z 405.1890
(calcd for C26H28O2S+H, 405.1888).
brine (2×5 mL), dried over anhd. Na2SO4 and evapo-
rated to dryness. The residue was flash chro-
matographed using a mixture of hexane:EtOAc (99:1)
as the eluent, giving 70 mg (70%) of 3i as a colorless
oil.
3.10. (1S,2R,5R,7S,9R)-5-[(1%S)-1%-Hydroxy-1%-phenyl-
1%-pentyl)]-10,10-dimethyl-4-oxa-6-thiatricyclo[7.1.1.02,7]-
undecane 3h
Method c: To a cold (−78°C) solution containing 110
mg (0.36 mmol) of 1 in 5 mL of dry toluene were
added dropwise 0.54 mmol of LS-Selectride in THF
and the mixture was stirred under a nitrogen atmo-
sphere for 4 h. The reaction mixture was allowed to
warm up to room temperature and stirred overnight,
cooled at −78°C and quenched with a saturated solu-
tion of aq. NH4Cl. After reaching room temperature,
the organic layer was dried over Na2SO4 and evapo-
rated to dryness. The residue was treated with 5 mL
of cold hexane and the formed white precipitate was
filtered. The solvent was evaporated to dryness and
the residue was flash chromatographed using a mix-
ture of hexane–EtOAc (99:1) to give 82 mg (82%) of
3i as a colorless oil. Only adduct 3i was fully charac-
terized. [h]2D5=−45.9 (c 0.22, CHCl3). 1H NMR: l
7.36 (m, 5H, H-Ar), 5.16 (d, 1H, J=3.5 Hz, H-5),
5.05 (d, 1H, J=3.5 Hz, H-1%), 4.06 (dd, 1H, J=11.1,
2.9 Hz, H-3e), 3.68 (t, 1H, J=11.1 Hz, H-3a), 3.62
(dt, 1H, J=8.8, 10.5 Hz, H-7), 2.84 (bs, 1H, OH),
2.60 (ddd, 1H, J=9.4, 5.9, 1.8 Hz, H-11e), 2.44 (ddd,
1H, J=11.1, 10.5, 2.7 Hz, H-2), 2.27 (m, 1H, H-8e),
2.07 (q, 1H, J=5.5 Hz, H-9), 1.80 (t, 1H, J=6.0 Hz,
H-1), 1.69 (m, 1H, H-8a), 1.24 (s, 3H, H-13), 1.10 (s,
3H, H-12), 0.99 (d, 1H, J=9.4 Hz, H-11a). 13C
NMR: l 137.9 (Ci ), 127.2 (C-m), 127.0 (C-p), 125.3
(C-o), 89.7 (C-1%), 75.4 (C-3), 74.3 (C-5), 50.4 (C-2),
44.6 (C-1), 42.7 (C-9), 39.7 (C-7), 38.4 (C-11), 38.0
(C-10), 32.5 (C-8), 28.7 (C-13), 23.4 (C-12). IR (neat):
3446, 2910, 1452, 1054, 698, 649 cm−1. EIMS m/z
(rel. int.): 304 (M+, <1), 197 (100), 115 (20), 107 (44),
79 (65). HRFABMS m/z 305.1546 (calcd for
C18H24O2S+H, 305.1575).
Following method b to obtain carbinol 3a, 54 mg
(0.18 mmol) of benzoyloxathiane 1 in 2 mL of anhy-
drous THF were treated with 17 mg (0.26 mmol) of
BuLi in cyclohexane and stirred under a nitrogen
atmosphere for 2 h. After the usual work-up, the
crude reaction was purified through a radial chro-
matography (Chromatotron apparatus) using a mix-
ture of hexane:EtOAc (19:1) as the eluent to give 28
mg (78%) of a mixture of 3h and 4h as a colorless
oil. NMR data of major adduct 3h: 1H NMR: l
7.50–7.26 (m, 5H, Ar), 5.13 (s, 1H, H-5), 4.11 (dd,
1H, J=11.0, 3.0 Hz, H-3e), 3.68 (t, 1H, J=11.0 Hz,
H-3a), 3.62 (dt, 1H, J=10.2, 9.0 Hz, H-7), 2.66 (s,
1H, OH), 2.55 (m, 1H, H-11e), 2.36 (bt, 1H, J=11.0
Hz, H-2), 2.23 (m, 1H, H-8e), 2.13–2.02 (m, 3H, H-9,
H-2a%, 2b%), 1.94–172 (m, 3H, H-1, H-3a%, 3b%), 1.61
(m, 1H, H-8a), 1.40–1.12 (m, 2H, H-4a%, 4b%), 1.24 (s,
3H, H-13), 1.11 (s, 3H, H-12), 0.96 (d, 1H, J=9.6
Hz, H-11a), 0.84 (t, 3H, J=7.2 Hz, H-5%). 13C NMR:
l 142.0 (C-i ), 128.1 (C-m), 127.34 (C-p), 125.9 (C-o),
93.5 (C-5), 78.4 (C-1%), 76.7 (C-3), 51.5 (C-2), 45.8
(C-9), 43.5 (C-1), 41.1 (C-7), 39.6 (C-11), 39.2 (C-10),
39.1 (C-2%), 33.7 (C-8), 29.8 (C-13), 24.7 (C-12), 25.6
(C-3%), 23.3 (C-4%), 14.3 (C-5%).
3.11. (1S,2R,5R,7S,9R)-5-[(1%S)-1%-Hydroxymethyl-
phenyl)]-10,10-dimethyl-4-oxa-6-thiatricyclo[7.1.1.02,7]-
undecane 3i
This compound was prepared following the three pro-
cedures described in a previous paper.11
3.12. General procedure for the hydrolysis of carbinols
3a–i and successive reduction of the corresponding alde-
hydes to obtain 1-phenyl-1,2-ethanodiols 5
Method a: A solution of 100 mg (0.33 mmol) of 1 in
5 mL of dry ethyl ether was added to a stirred and
cooled (−78°C) suspension of 31 mg (0.82 mmol) of
LiAlH4. The mixture was further stirred for 4 h and
50 mL of ethyl ether were added. The reaction was
quenched by the slow successive addition of 0.1 mL
of EtOH and 0.2 g of cold water. The formed white
precipitated was filtered and the organic layer was
washed with brine (2×25 mL), dried over Na2SO4 and
evaporated to dryness, yielding a mixture of 3i and 4i
in a 41:9 ratio (92 mg, 92%).
Method a: Following the procedure described by Eliel
et al.,13 1 equiv. of carbinol 3 in 5 mL of CH3CN
were treated with 2 equiv. of NCS and AgNO3 in 35
ml of CH3CN–H2O (4:1) at 0–4°C during 1–5 min.
The work-up was carried out by successively adding
solutions of NaCl, Na2SO3 and Na2CO3 (1 ml, each),
the white precipitated was filtered, and the filtrated
was extracted with a mixture of hexane:methylene
chloride (1:1). The organic layer was dried with anhd.
Na2SO4, filtered and concentrated to dryness, giving a
Method b: A cold (−78°C) solution of 124 mg (0.41
mmol) of 1 in 2 mL of toluene was treated dropwise
with 88 mg (0.62 mmol) of DIBAL in THF and
stirred under a nitrogen atmosphere for 2 h. The
reaction mixture was quenched with 0.5 mL of a sat-
urated solution of aq. NH4Cl at −78°C and allowed
to warm up to room temperature. Were added 15 mL
of ethyl ether, the organic layer was washed with
1
crude yellowish oil, whose H NMR spectrum showed
the presence of aldehydes 4 and the expected sultine.
This mixture was treated with LiAlH4 without further
purification in anhd. ethyl ether at room temperature
during 3 h. After the usual work-up and purification
through column chromatography, was recovered
hydroxythiol 2 (60–80%) and the corresponding diol.

M. E. Vargas-D´ıaz et al. / Tetrahedron: Asymmetry 14 (2003) 3225–3232
3231
Method b: After having carried out the hydrolysis as
described above, the residue was treated with NaBH4
in a mixture of acetonitrile:water (1:1). The resulting
mixture was stirred at room temperature for 3 h, 10
ml of hot water were added, stirring continued for 20
min and the mixture was extracted with ethyl ether.
The organic layer was dried with anhd. Na2SO4, con-
centrated to dryness and the yellow oily residue was
H-1a), 3.75 (dd, 1H, J=11.2, 8.0 Hz, H-1b), 3.18 (bs,
1H, OH), 2.23 (bdd, 1H, J=8.0, 6.1 Hz, OH). 13C
NMR: l 140.9 (C-1%), 132.1 (C-2¦, C-6¦), 129.1–128.6
(C-2%, C-3%, C-5%, C-6%, C-3¦, C-5¦), 126.1 (C-4%), 122.2
(C-1%%), 89.4 (C-3), 86.9 (C-4), 74.5 (C-2), 72.4 (C-1).
CIMS m/z (rel. int.): 239 (M++H, 1), 221 (100), 207
(12), 193 (13), 143 (12).
flash chromatographed using
ane:ethyl acetate (8:1) as eluent, giving hydroxythiol 2
(65–85%) and the corresponding diol.
a mixture of hex-
3.18. (S)-trans-2,4-Diphenylbut-3-ene-1,2-diol 5k
The crude reaction mixture obtained from the hydrol-
ysis of adduct 3g was treated with LiAlH4 as
described in method a. From this mixture was charac-
terized diol 5k, which was formed from 3g by 1,4-
conjugated addition of hydride. Colorless oil (35%,
estimated by 1H NMR from crude reaction). 1H
NMR: l 7.22–7.53 (m, 5H, Ar), 6.72 (d, 1H, J=16.0
Hz, H-3), 6.46 (d, 1H, J=16.0 Hz, H-4), 3.87 (d, 2H,
J=6.2 Hz, H-1a, H-1b), 2.95 (bs, 1H, OH), 1.86 (bt,
1H, J=6.2 Hz, OH).
3.13. (S)-(+)-2-Phenylpropane-1,2-diol 5a
The crude reaction mixture obtained from the hydrol-
ysis of adduct 3a was treated with LiAlH4 as
described in method a. After column chromatography
were obtained hydroxythiol 2 (76%) and diol 5a
(92%). [h]2D3=+5.7 (c 0.45, EtOH), lit.18 for the (R)
enantiomer [h]2D3=−5.8 (c 0.17, EtOH). The remaining
spectral data are in agreement with those published.18
3.19. (S)-(+)-2,4-Diphenylbutane-1,2-diol 5j
3.14. (S)-(−)-2-Phenylbutane-1,2-diol 5b
The mixture of diols 5g and 5k, obtained above, was
hydrogenated over Pd/C (5%) in EtOAc (30 psi) at
room temperature for 72 h. The catalyst was elimi-
nated by filtration, and the filtrate was evaporated to
dryness to give diol 5j as a colorless oil (90%). [h]2D3=
+10.6 (c 0.15, EtOH). 1H NMR: l 7.02–7.49 (m,
10H, Ar), 3.86 (d, 1H, J=11.0 Hz, H-1a), 3.72 (d,
1H, J=11.0 Hz, H-1b), 2.66 (m, 1H, H-4a), 2.34 (m,
1H, H-4b), 2.11–2.39 (m, 2H, H-3a, H-3b). 13C
NMR: l 143.3 (C-1¦), 142.4 (C-1%), 128.8 (C-3%), 128.6
(C-2%), 128.5 (C-6%), 127.5 (C-7%), 126.0 (C-8%), 125.8
(C-4%), 77.5 (C-2), 71.1 (C-1), 40.6 (C-3), 29.7 (C-4).
EIMS m/z (rel. int.): 224 (M+−18, <1), 211 (100), 120
(10), 105 (20), 91 (62).
The crude reaction mixture obtained from the hydrol-
ysis of adduct 3b was treated with NaBH4 as
described in method b. After column chromatography
were obtained hydroxythiol 2 (57%) and diol 5b
(75%). [h]2D5=−7.2 (c 0.6, EtOH), lit.19 for the (R)
enantiomer [h]2D0=+7.3 (c 0.7, EtOH). The remaining
spectral data are in agreement with those published.19
3.15. (S)-(−)-3-Methyl-2-phenylbutane-1,2-diol 5c
The crude reaction mixture obtained from the hydrol-
ysis of adduct 3c was treated with NaBH4 as
described in method b. After column chromatography
were obtained hydroxythiol 2 (62%) and diol 5c (42
mg, 80%). [h]2D0=−19.5 (c 0.21, EtOH), lit.20 for the
(R) enantiomer [h]D25=+16.0 (c 1.6, EtOH). The
remaining spectral data are in agreement with those
published.20
3.20. (S)-(+)-1-Phenylethane-1,2-diol 5i
The crude reaction mixture obtained from the hydrol-
ysis of adduct 3i was treated with NaBH4 as
described in method b. After column chromatography
were obtained hydroxythiol 2 (78%) and diol 5i
(73%). [h]2D3=+38.6 (c 0.18, EtOH), lit.21 for the (R)
3.16. (S)-(−)-2-Phenylbut-3-ene-1,2-diol 5f
1
enantiomer [h]2D3=−38.4 (c 1.12, EtOH). H NMR: l
The crude reaction mixture obtained from the hydrol-
ysis of adduct 3f was treated with NaBH4 as
described in method b. After column chromatography
were obtained hydroxythiol 2 (74%) and diol 5f
(89%). [h]2D0=−43.4 (c 0.20, EtOH), lit.19 [h]2D0=−39.9
(c 1.0, EtOH). The remaining spectral data are in
agreement with those published.19
7.28–7.38 (m, 5H, Ar), 4.83 (dd, 1H, J=8.0, 3.6 Hz,
H-2), 3.76 (dd, 2H, J=11.3, 3.6 Hz, H-1b), 3.67 (dd,
2H, J=11.3, 8.0 Hz, H-1b), 2.62 (bs, 1H, OH), 1.64
(bs, 1H, OH).
Acknowledgements
3.17. (S)-(+)-2,4-Diphenylbut-3-yne-1,2-diol 5g
The authors wish to thank QFB Fernando Labarrios
for MS measurements. L.G.Z. acknowledges CGPI/
IPN (grant 20020683) and CONACyT (35013E).
L.C.-G. and M.E.V.-D. thank CONACyT (grants
92069 and 125225, respectively) and CGPI/IPN (PIFI)
postgraduate fellowships. P.V.-P. thanks Institutional
Fellowship (CGPI/IPN).
The crude reaction mixture obtained from the hydrol-
ysis of adduct 3g was treated with NaBH4 as
described in method b. After column chromatography
were obtained hydroxythiol 2 (80%) and diol 5g
1
(90%). [h]2D0=+11.0 (c 0.15, EtOH). H NMR: l 7.26–
7.73 (m, 10H, Ar), 3.86 (dd, 1H, J=11.2, 6.1 Hz,

3232
M. E. Vargas-D´ıaz et al. / Tetrahedron: Asymmetry 14 (2003) 3225–3232
10. Swaile, D. F. US Patent 6126928 A 20001003, 2000;
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