Chiral resolution of alcohols by extractive separation of acetals

Article abstract of DOI:10.1007/s00706-013-1139-8

A new class of enantiomerically pure lactols is presented that react with rac-alkylarylcarbinols in high diastereoselectivity and can be used for the extractive racemate resolution of alkylarylcarbinols. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-013-1139-8

Monatsh Chem (2014) 145:1631–1641
DOI 10.1007/s00706-013-1139-8
ORIGINAL PAPER
Chiral resolution of alcohols by extractive separation of acetals
•
•
•
Keramatollah Mehraban Gu¨nter Gmeiner Ernst Urban
•
Peter Gartner Simon Eppacher Christian R. Noe
•
¨
Received: 13 February 2013 / Accepted: 17 December 2013 / Published online: 23 August 2014
Ó Springer-Verlag Wien 2014
Abstract A new class of enantiomerically pure lactols is
presented that react with rac-alkylarylcarbinols in high
diastereoselectivity and can be used for the extractive
racemate resolution of alkylarylcarbinols.
stereo and stereoelectronic effects [1]. We have been
interested in investigating these effects. To help explain
them, the ‘‘b, pl, H-rule’’ was proposed by us, defining the
arrangements of ligands at a chiral carbon [2]. Descriptors
‘‘A’’ and ‘‘B’’ were also introduced, and a nomenclature
was suggested where an ‘‘A’’ descriptor is obtained by
looking along the C-O bond and a clockwise arrangement
of the bulky, planar, and hydrogen substituent is observed
as the counterclockwise arrangement yields a ‘‘B’’
descriptor (Fig. 1).
Keywords Acetal formation ꢀ Enantiomer selectivity ꢀ
Extractive racemate resolution ꢀ
Resolution of racemic alkylarylcarbinols
The reaction of such compounds (e.g., lactol of Fig. 1)
under thermodynamic conditions with an excess of racemic
alkylarylcarbinol leads to a preferred BB structure in com-
parison to the BA compound [3]. In order to provide an
understanding of this preferred formation of the structure, we
will first discuss the stereoelectronic effects [4]. By analyz-
ing the steric effects we find a preferred antiperiplanar
arrangement of the C(3)-C(2) bond and the C*-b bond in the
BB, as in the BA structure. Thus, the anomeric effect
between the lone pair of the endocyclic oxygen and the r* of
the C(2)-O(2a) bond, and the exo anomeric effect between
the pro-S lone pair of O(2a) and the r* of the C(2)-O(1) bond
are operating in the BB as well as in the BA structure [1].
However, the stereoelectronic effect between the pro-R lone
pair of O(2a) and the r* of the C*-C(pl) bond in the BB form
should be preferred over the stereoelectronic effect in the BA
form between the pro-S lone pair of O(2a) and the r* of the
C*-C(pl) bond, since this leads to an unfavorable double
involvement of the pro S lone pair. In addition, in the BA
structure a 1,3-diaxial steric interaction between the O(1)-
C(2) and the C*-C(pl) bond is found, and a steric clash of the
bridgehead methyl group and the pl group can be expected.
In this paper, we present a two-fold use of this inter-
action. On the one hand, the introduction of a sterically
demanding group decreases the available space in this area,
Introduction
As it can be found in textbooks, a prochiral substrate reacts
with a pair of enantiomers to form a racemate with a ratio
of 1:1. In contrast, an enantiomerically pure compound
reacts with a racemate to form a mixture of diastereomers
with a ratio that is usually different from 1:1. In many cases
the ratio of diastereomers can be explained on the basis of
This publication is dedicated to Simon Eppacher, who died tragically
during the preparation of this manuscript.
K. Mehraban ꢀ E. Urban ꢀ S. Eppacher ꢀ C. R. Noe (&)
Department of Medicinal Chemistry, University of Vienna,
Althanstraße 14, A-1090 Vienna, Austria
e-mail: christian.noe@univie.ac.at
S. Eppacher
e-mail: simon.eppacher@me.com
¨
G. Gmeiner ꢀ P. Gartner
Institute of Applied Synthetic Chemistry, Technical University
of Vienna, Getreidemarkt 9, A-1060 Vienna, Austria
Present Address:
G. Gmeiner
Seibersdorf research GmbH, Seibersdorf, Austria
123

1632
K. Mehraban et al.
B
Scheme 1
B
3
H
O
2a
O
H
b
O
1
2
O
H
S
N
O
O
O
pl
C*
b
O
R
R
H
pl
R
R'
COOH
B
A
Fig. 1 Explanation for the preferred BB structure in comparison to
the BA structure. Sulfonamide dilactols and extractable sulfonamide
dilactols
causing an increase of the steric interaction between the pl
group and the bridgehead substituted methyl group to
significantly increase the observed enantiomer selectivity.
On the other hand, we will show the utility of this position
to introduce a functional group with the possibility to
facilitate the reaction protocol of these lactols as reagents
for a racemate resolution. In a preceding paper, we inves-
tigated the influence of a sterically demanding sulfonamide
group on the bridgehead methyl group. As expected, the
reduced available space leads to an increased steric inter-
action between the planar group and the substituted methyl
group, and therefore, the BA product is additionally dis-
favored. In comparison to their unsubstituted analogues [5,
6], these compounds exhibit higher diastereoselectivity in
acetal formation with alkylarylcarbinols due to steric and
stereoelectronic effects [1]. In this paper, we present sul-
fonamides with an acidic side chain. This substituent is still
sterically demanding and additionally extractable with a
base (Fig. 1).
preparation of the compounds, required hydrophilic-lipo-
philic solubility properties of the diastereomers, and easy
handling during extraction were also considered to be
important criteria. For this purpose, we took into consid-
eration the compounds 8-13 listed in Scheme 1, which
were accessible from sulfonamides 2-7. Sulfonamides 2-7
were prepared from dilactolsulfonyl chloride 1 with the
corresponding amines and triethylamine as the base [8]
(Scheme 1).
The free carboxylic acids 8-13 were then obtained from
the esters by hydrolysis with NaOH in EtOH [9]. Figure 2
and Table 1 show the investigated acetals 16-27 and their
corresponding diastereoisomers 16a-27a, which were
formed by the reaction of lactols 8-13 with alcohols 14 and
15. Table 2 summarizes the diastereoselectivities obtained
for these reactions in CH2Cl2.
High enantiomeric purity can be obtained if the diaste-
reoisomer is isolated in a crystalline form. In this case the
isolation is easy and usually occurs with high yield.
However, if the obtained diastereoisomer does not crys-
tallize, excess alcohol enriched with the unreacted
enantiomer has to be removed, preferably by flash chro-
To assess solvent influence, we tested the reaction of
selected lactols with 2,2-dimethyl-1-phenyl-1-propanol
(14) and 1-phenylethanol (15) in CCl4 in addition to
CH2Cl2, because a higher selectivity could be expected in
the less polar solvent (see Table 3).
matography [4, 7]. In order to develop
a more
straightforward modification of this process, we chose to
synthesize lactols with an acidic side chain, which can be
separated from the excess of carbinol by extraction of their
salt. The sequence of enantiomer selective acetal formation
of a racemic arylalkylcarbinol, followed by extractive
isolation of one diastereomer and acetal cleavage gives
direct access to the pure enantiomer of the arylalkylcarbi-
nol. This sequence is, to the best of our knowledge, a novel
approach in racemate resolution.
As a result of these experiments we decided to use the L-
proline substituted sulfonamide 9 and CCl4 as solvents for
further investigations (Scheme 2). Due to its low polarity
(dielectric constant), CCl4 exhibits a high diastereoselec-
tivity and leads easily to full conversion in the reaction.
As a catalyst we used triphenylphosphine hydrobromide
[10, 11], which was sufficiently soluble in CCl4. In the
extraction step, the tensidic character of the carboxy-substi-
tuted acetals hampered the phase separation. This problem
could be circumvented by using diluted solutions and ethanol
as a co-solvent. To avoid premature acetal cleavage, care was
taken that during the liberation of the carboxylic acids from
their salts the pH was set not too far below 3.
Results and discussion
A prerequisite for the applicability of this method of
extractive racemate resolution is high enantiomer selec-
tivity in acetal formation [4, 6]. At the same time, facile
The liberation of the alcohol from the acetal requires a
quantitative conversion, a racemization-free separation,
123

Chiral resolution of alcohols
1633
Fig. 2 Synthesized
sulfonamide substituted lactols
16-27
Table 1 Acetals synthesized with alcohols 14, 15, and dilactols 8-13
Scheme 2
BB-Form
NR1R2
BA-Form
NR1R2
b
b
16 N(Bn)CH2COOH
17 N(Bn)CH2COOH
18 L-Proline
t-Bu 16a N(Bn)CH2COOH
Me 17a N(Bn)CH2COOH
t-Bu 18a L-Proline
Me 19a L-Proline
t-Bu 20a D-Proline
Me 21a D-Proline
t-Bu 22a N(CH2COOH)2
Me 23a N(CH2COOH)2
t-Bu 24a NH(CH2)2COOH
Me 25a NH(CH2)2COOH
t-Bu
Me
t-Bu
Me
19 L-Proline
20 D-Proline
t-Bu
Me
21 D-Proline
22 N(CH2COOH)2
23 N(CH2COOH)2
24 NH(CH2)2COOH
25 NH(CH2)2COOH
t-Bu
Me
t-Bu
Me
26 N(Bn)(CH2)2COOH t-Bu 26a N(Bn)(CH2)2COOH t-Bu
27 N(Bn)(CH2)2COOH Me 27a N(Bn)(CH2)2COOH Me
and a non-destructive recycling of the starting material.
Since there is an inherent racemization potential in many
alkylarylcarbinols, conditions for acetal cleavage had to be
worked out carefully. In order to achieve this goal we used
a solvent mixture of MeCN/H2O = 4/1, 4-5 h reaction time,
and 0.4 equivalents of para-toluenesulfonic acid for the
acetal 18. In case of the acetal 19, 1-phenylethanol (15)
showed to be much more sensitive toward racemization
than 2,2-dimethyl-1-phenyl-1-propanol (14). We were,
however, able to obtain a racemization-free product within
10 min reaction time and using 1.2 equivalents of para-
toluenesulfonic acid under optimized reaction conditions.
Figure 3 shows a representative flow diagram of the whole
racemate resolution procedure (in this particular case
CH2Cl2 was used as a solvent in the acetal formation step).
To improve the efficiency of the resolution step, which
is limited by the enantiomer selectivity of the acetal for-
mation, the following procedures could be applied to
increase the enantiomeric purity of resolved alcohols
beyond this level:
Table 2 Diastereoselectivity in the acetal formation with dilactols 8-
13 and 2,2-dimethyl-1-phenyl-1-propanol (14) and 1-phenylethanol
(15) in CH2Cl2
NR2
b/Ph
t-Bu/Ph
Me/Ph
16/17
18/19
20/21
22/23
24/25
26/27
N(Bn)CH2COOH
L-Proline
10.0 : 1
7.8 : 1
14.0 : 1
7.7 : 1
5.6 : 1
9.0 : 1
4.0 : 1
3.5 : 1
3.5 : 1
4.4 : 1
2.9 : 1
3.1 : 1
D-Proline
N(CH2COOH)2
NHCH2CH2COOH
N(Bn)CH2CH2COOH
Table 3 Diastereoselectivity in the acetal formation with dilactols 8-
10 and 2,2-dimethyl-1-phenyl-1-propanol (14) and 1-phenylethanol
(15) in CCl4
NR2
b/Ph
t-Bu/Ph
Me/Ph
8
N(Bn)CH2COOH
L-Proline
11.0 : 1
13.0 : 1
13.7 : 1
–
(a) Replication of the procedure presented in Fig. 3.
(b) Diastereomeric enrichment of obtained crystalline
acetals by crystallization. Recrystallization of acetal
9
3.7 : 1
–
10
D-Proline
123

1634
K. Mehraban et al.
Fig. 3 Representative flow
diagram for the separation of the
rac-carbinol 14 with the
extractable dilactol 9
Table 4 Selective hydrolysis of acetal 18/18a at room temperature
Experimental
Time/h
Ratio of
acetals
Ratio of
alcohols
Conversion/%
All melting points were determined on a Kofler apparatus. 1H
and 13C NMR spectra were recorded on a Bruker 200 MHz
spectrometer at 200 MHz and 50 MHz, respectively. Optical
rotations were measured on a Perkin-Elmer 241 polarimeter.
For vacuum flash chromatography and column chromatogra-
phy, silica gel 0.04–0.06 mm (Merck) was used. TLCs were
carried out on silica gel 60 F254 precoated plates (Merck) and
were visualized with UV light or by spraying with ethanolic
solution of ammonium 12-molybdatophosphate.
BB:BA
7.5:1
B:A
0
–
0
5
1
10.5:1
15.0:1
Only BB
–
1:1.68
1:1.19
2.46:1
6.8:1
4.5
24
48
17
38
100
18 yielded 2,2-dimethyl-1-phenyl-1-propanol (14)
with an ee of 99 %.
General procedure for the preparation of dilactol esters
2-7
(c) Enrichment by selective hydrolysis. The fact that the
thermodynamically more labile BA acetal is hydro-
lyzed faster than its diastereoisomer BB can be used
to enrich the BB diastereomer. Table 4 shows the
selectivity of hydrolysis of acetal 18 at room
temperature.
To a 5 % solution of lactonsulfonyl chloride 1 in anhydrous
DMF we added the corresponding amine (as free amine or
hydrochloride) and cooled the mixture to 5 °C. To this
reaction mixture triethylamine was added, and it was stirred
at room temperature for about 0.5–2 h (TLC control). The
reaction mixture was added to cold 0.5 N HCl and extracted
with diethyl ether. The organic phase was extracted two
times with 0.5 N HCl, dried (Na2SO4), concentrated, and
purified by vacuum flash chromatography if necessary.
Conclusions
The results given above demonstrate a novel extractive
method for the resolution of racemic alkylarylcarbinols.
The method is based on enantiomer selective acetal for-
mation of alkylarylcarbinols with extractable lactols. The
applicability of this approach is demonstrated in principle.
It was shown that the efficiency of resolution can be
optimized by specific adaptations. Selectivities of up to
99 % ee were obtained for the alcohol 15.
[2S-[2a(20R*,30aS*,40S*,70R*,70aS*),3aa,4b,7b,7aa]]-
2,20-oxybis[N-[[(octahydro-8,8-dimethyl-
4,7-methanobenzofurane-7-yl)methyl]sulfonyl]-
N-(phenylmethyl)glycine isopropyl ester]
(2, C48H68N2O11S2)
Lactonsulfonyl chloride 1 (3 g, 5.25 mmol), 4.7 g
benzylglycine isopropyl ester (16 mmol), and 7.1 cm3
123

Chiral resolution of alcohols
1635
triethylamine (51.5 mmol) gave, after vacuum flash
chromatography, 3.62 g (76 %) 2. Colorless foam; m.p.:
68–70 °C; DC: Rf = 0.6 (PE/EE = 2:1); 1H NMR (CDCl3):
d = 7.40 (m, 5H, aromatic H), 5.59 (s, 1H, H-2), 5.00 (sep,
1H, CH(CH3)2), 4.65–4.30 (dd and d, NCH2CO and H-7a),
4.10–3.80 (dd, PhCH2), 3.70–2.90 (AB system, J = 13 Hz,
2H, CH2SO2), 2.40–1.00 (m, 20H) ppm; 13C NMR
(CDCl3): d = 169.0 (s, CO), 135.5 (s, C(Ph)-1), 128.7 (d,
C(Ph)-4), 128.6 (d, C(Ph)-3, C(Ph)-5), 128.0 (d, C(Ph)-2,
C(Ph)-6), 99.7 (d, C-2), 86.9 (d, C-7a), 69.06 (d,
OCH(CH3)2, 51.7 (t, NCH2CO), 51.0 (t, CH2SO2), 49.4
(s, C-7), 48.3 (s, C-8), 47.6 (t, PhCH2N), 47.6 (d, C-4), 46.1
(d, C-3a), 38.4 (t, C-3), 28.9 (t, C-5), 28.6 (t, C-6), 23.1,
22.6, 21.8, 20.4 (4 q, 4 CH3) ppm.
3H, H-b, H-c), 2.01 (m, 2H, H-3), 1.78 (m, 1H, H-4), 1.70
(m, 1H, H-6eq), 1.40 (m, 1H, H-5eq), 1.30 (m, 1H, H-6ax),
1.10 (m, 1H, H-5ax), 0.99, 0.87 (2 s, 6H, 2 CH3) ppm; 13
C
NMR (CDCl3): d = 172.5 (s, CO), 99.1 (d, C-2), 86.3 (d,
C-7a), 59.8 (d, C-a), 52.0 (q, OCH3), 49.9 (t, CH2SO2),
49.0 (s, C-7), 47.7 (t, C-d), 47.6 (s, C-8), 47.1 (d, C-4), 45.8
(d, C-3a), 37.9 (t, C-3), 30.6 (t, C-b), 28.9 (t, C-5), 28.5 (t,
C-6), 24.5 (t, C-c), 22.7, 20.0 (2 q, 2 CH3) ppm.
[2S-[2a(20R*,30aS*,40S*,70R*,70aS*),3aa,4b,7b,7aa]]-
2,20-oxybis[N-[[(octahydro-8,8-dimethyl-4,7-
methanobenzofurane-7-yl)methyl]sulfonyl]-
N-(2-methoxy-2-oxoethyl)glycine methyl ester]
(5, C36H56N2O15S2)
Lactonsulfonyl chloride 1 (2.83 g, 5.00 mmol), 1.69 g
iminodicarboxylic acid dimethyl ester (10.5 mmol), and 4.4
cm3 triethylamine (31.5 mmol) gave, after vacuum flash
chromatography, 2.2 g (52 %) 5. Colorless oil; b.p.:
decomp. at about 150 °C; [a]2D0 = -45.4° (c = 1.51/
[2S-[2a(20R*,30aS*,40S*,70R*,70aS*),3aa,4b,7b,7aa]]-
2,20-oxybis[1-[[(octahydro-8,8-dimethyl-4,7-
methanobenzofurane-7-yl)methyl]sulfonyl]-L-proline
methyl ester] (3, C 36H56N2O11S2)
1
CH2Cl2); DC: Rf = 0.65 (petrol ether/EtOAc = 3:7); H
Lactonsulfonyl chloride 1 (1.0 g, 1.75 mmol), 1.8 g L-
proline methyl ester hydrochloride (10.9 mmol), and 7.5
cm3 triethylamine (54.5 mmol) gave, after vacuum flash
chromatography, 1 g (71 %) 3. Colorless foam; m.p.:
81–83 °C; [a]2D0 = 126° (c = 0.79/CH2Cl2); DC: Rf = 0.45
(petrol ether/EtOAc = 1:1); 1H NMR (CDCl3): d = 5.43 (d,
1H, H-2), 4.51 (dd, J = 9 Hz, 3 Hz, 1H, H-a), 4.32 (d, J =
7.5 Hz, 1H, H-7a), 3.74 (s, 3H, OCH3), 3.57 (d, J = 13 Hz,
1H, CHSO2), 3.55 (m, 2H, H-d), 3.06 (d, J = 13 Hz, 1H,
CHSO2), 2.30 (m, 1H, H-b), 2.25 (m, 1H, H-3a), 2.03 (m,
2H, H-3), 1.80–2.00 (m, 3H, H-b, H-c), 1.72 (m, 1H,
H-6eq), 1.67 (m, 1H, H-4), 1.40 (m, 1H, H-5eq), 0.88 (m,
1H, H-5ax), 1.07 (m, 1H, H-6ax), 0.98, 0.83 (2 s, 6H, 2
CH3) ppm; 13C NMR (CDCl3): d = 173.1 (s, CO), 100 (d,
C-2), 87 (d, C-7a), 60.3 (d, C-a), 52.3 (q, OCH3), 50.3 (s,
C-7), 49.4 (s, C-8), 48.2 (t, CH2SO2), 47.7 (t, C-d), 47.5 (d,
C-4), 46.2 (d, C-3a), 38.4 (t, C-3), 30.9 (t, C-b), 28.9 (t,
C-5), 28.4 (t, C-6), 24.9 (t, C-c), 23.1, 20.4 (2 q, 2 CH3)
ppm.
NMR (CDCl3): d = 5.47 (s, 1H, H-2), 4.38 (d, J = 6 Hz, 1H,
H-7a), 4.30 (d, J = 17 Hz, 2H, N(CH)2), 4.21 (d, J = 17 Hz,
2H, N(CH)2), 3.67 (d, J = 14 Hz, 1H, CHSO2), 3.07 (d, J =
14 Hz, 1H, CHSO2), 3.80 (s, 6H, OCH3), 2.36 (m, 1H,
H-3a), 2.04 (m, 2H, H-3), 1.82 (m, 1H, H-4), 1.72 (m, 1H,
H-6eq), 1.43 (m, 1H, H-5eq), 1.27 (m, 1H, H-6ax), 1.02 (m,
1H, H-5ax), 1.02, 0.88 (2 s, 6H, 2 CH3) ppm; 13C NMR
(CDCl3): d = 169.3 (s, CO), 99.3 (d, C-2), 86.4 (d, C-7a),
51.9 (q, OCH3), 51.9 (t, N-CH2), 49.0 (s, C-7), 48.0 (s, C-8),
47.9 (t, CH2SO2), 47.1 (d, C-4), 45.7 (d, C-3a), 37.9 (t, C-3),
28.5 (t, C-5), 27.9 (t, C-6), 22.6, 20.0 (2 q, 2 CH3) ppm.
[2S-[2a(20R*,30aS*,40S*,70R*,70aS*),3aa,4b,7b,7aa]]-
2,20-oxybis-[N-[[(octahydro-8,8-dimethyl-4,7-
methanobenzofuran-7-yl)methyl]sulfonyl]-b-alanine
methyl ester] (6, C32H52N2O11S2)
Lactonsulfonyl chloride 1 (1.0 g, 1.85 mmol), 0.57 g
b-alanine methyl ester hydrochloride (4.1 mmol), and 1.70
cm3 triethylamine (12.3 mmol) gave, after vacuum flash
chromatography, 1.19 g (91 %) 6. Colorless oil; [a]D20
=
[2S-[2a(20R*,30aS*,40S*,70R*,70aS*),3aa,4b,7b,7aa]]-
2,20-oxybis[1-[[(octahydro-8,8-dimethyl-4,7-
-78° (c = 1.64/CH2Cl2); DC: Rf = 0.65 (petrol ether/
1
EtOAc = 3:7); H NMR (CDCl3): d = 5.43 (s, 1H, H-2),
methanobenzofurane-7-yl)methyl]sulfonyl]-D-proline
methyl ester] (4, C36H56N2O11S2)
5.05 (t, J = 6 Hz, 1H, NH), 4.37 (d, J = 7 Hz, 1H, H-7a),
3.71 (s, 3H, OCH3), 3.51 (d, J = 13 Hz, 1H, CHSO2), 3.42
(dt, 2H, NCH2), 2.93 (d, J = 13 Hz, 1H, CHSO2), 2.65 (t,
J = 6 Hz, 2H, CH2CO), 2.37 (m, 1H, H-3a), 2.04 (m, 2H,
H-3), 1.80 (m, 1H, H-4), 1.72 (m, 1H, H-6eq), 1.48 (m,
1H, H-5eq), 1.10 (m, 1H, H-6ax), 0.89 (m, 1H, H-5ax),
1.00, 0.85 (2 s, 6H, 2 CH3) ppm; 13C NMR (CDCl3): d =
172.0 (s, CO), 99.7 (d, C-2), 86.5 (d, C-7a), 51.5 (t,
OCH3), 50.6 (t, CH2SO2), 49.0 (s, C-7), 47.9 (s, C-8), 47.0
(d, C-4), 45.9 (d, C-3a), 38.5 (t, C-3), 38.5 (t, NCH2), 34.4
(t, CH2CO), 28.4 (t, C-5), 28.2 (t, C-6), 22.6, 20.0 (2 q, 2
CH3) ppm.
Lactonsulfonyl chloride 1 (1.0 g, 1.75 mmol), 670 mg D-
proline methyl ester hydrochloride (4.1 mmol), and 2.8 cm3
triethylamine (20.5 mmol) gave, after vacuum flash
chromatography, 1.36 g (97 %) 4. Colorless foam; m.p.:
131–134 °C; [a]D20 = -37° (c = 1.34/CH2Cl2); DC: Rf =
1
0.40 (petrol ether/EtOAc = 1:1); H NMR (CDCl3): d =
5.41 (d, 1H, H-2), 4.50 (dd, 1H, H-a), 4.38 (d, J = 7.5 Hz,
1H, H-7a), 3.78 (s, 3H, OCH3), 3.59 (d, J = 14 Hz, 1H,
CHSO2), 3.57 (m, 2H, H-d), 2.96 (d, J = 14 Hz, 1H,
CHSO2), 2.35 (m, 1H, H-b), 2.29 (m, 1H, H-3a), 2.06 (m,
123

1636
K. Mehraban et al.
[2S-[2a(20R*,30aS*,40S*,70R*,70aS*),3aa,4b,7b,7aa]]-
2,20-oxybis-[N-[[(octahydro-8,8-dimethyl-4,7-
methanobenzofuran-7-yl)methyl]sulfonyl]-
CH2CO), 50.7 (t, CH2Ph), 49.3 (s, C-7), 48.5 (s, C-8), 47.4
(d, C-4), 46.0 (t, CH2SO2), 46.0 (d, C-3a), 38.2 (t, C-3), 28.9
(t, C-5), 27.3 (t, C-6), 23.0, 19.9 (2 q, 2 CH3) ppm.
N-(phenylmethyl)-b-alanine methyl ester]
(7, C46H64N2O11S2)
[2S-[2a(20R*,30aS*,40S*,70R*,70aS*),3aa,4b,7b,7aa]]-
2,20-oxybis[1-[[(octahydro-8,8-dimethyl-4,7-
Lactonsulfonyl chloride 1 (1.0 g, 1.75 mmol), 0.8 g N-
(phenylmethyl)-b-alanine methyl ester hydrochloride (4.1
mmol), and 2.8 cm3 triethylamine (20.5 mmol) gave, after
vacuum flash chromatography, 0.47 g (30 %) 7. Colorless
oil; [a]2D0 = -59° (c = 1.25/CH2Cl2); DC: Rf = 0.70 (petrol
methanobenzofurane-7-yl)methyl]sulfonyl]-L-proline]
(9, C35H54N2O11S2)
Ester 3 (1 g, 1.32 mmol) and 264 mg NaOH (6.6 mmol) gave
960 mg (quantitative) 9. Colorless crystals; m.p.: 121–125
°C; [a]2D0 = 115° (c = 1.04/CH2Cl2); 1H NMR (CDCl3): d =
9.10 (bs, 1H, COOH), 5.38 (s, 1H, H-2), 4.57 (dd, J = 8 Hz,
4.5 Hz, 1H, H-a), 4.40 (d, J = 7 Hz, 1H, H-7a), 3.60 (d, J = 13
Hz, 1H, CHSO2), 3.50 (m, 2H, H-d), 3.03 (d, J = 13 Hz, 1H,
CHSO2), 2.31 (m, 1H, H-3a), 2.21 (m, 1H, H-b), 1.80-2.04
(m, 2H, H-b, H-c), 1.99 (m, 2H, H-3), 1.78 (m, 1H, H-6eq),
1.69 (m, 1H, H-4), 1.45 (m, 1H, H-5eq), 0.90 (m, 1H, H-5ax),
1
ether/EtOAc = 1:1); H NMR (CDCl3): d = 7.38 (m, 5H,
aromatic Hs), 5.45 (s, 1H, H-2), 4.47 (d, J = 16 Hz, 1H,
NCHPh), 4.38 (d, J = 16 Hz, 1H, NCHPh), 4.35 (d, J = 7
Hz, 1H, H-7a), 3.60 (s, 3H, OCH3), 3.52 (t, J = 7 Hz, 2H,
NCH2), 3.36 (d, J = 13 Hz, 1H, CHSO2), 2.77 (d, J = 13
Hz, 1H, CHSO2), 2.50 (t, J = 7 Hz, 2H, CH2CO), 2.33 (m,
1H, H-3a), 2.01 (m, 2H, H-3), 1.80 (m, 1H, H-4), 1.68 (m,
1H, H-6eq), 1.42 (m, 1H, H-5eq), 1.24 (m, 1H, H-6ax),
1.04 (m, 1H, H-6ax), 0.98, 0.83 (2 s, 6H, 2 CH3) ppm; 13
C
NMR (CDCl3): d = 176.2 (s, CO), 99.8 (d, C-2), 86.6 (d,
C-7a), 59.9 (d, C-a), 49.8 (t, CH2SO2), 49.1 (s, C-7), 49.1 (s,
C-8), 47.8 (t, C-d), 47.1 (d, C-4), 45.8 (d, C-3a), 38.0 (t, C-3),
30.4 (t, C-b), 28.4 (t, C-5), 28.3 (t, C-6), 26.6 (t, C-c), 22.6,
19.9 (2 q, 2 CH3) ppm.
1.10 (m, 1H, H-5ax), 0.90, 0.80 (2 s, 6H, 2 CH3) ppm; 13
C
NMR (CDCl3): d = 171.8 (s, CO), 136.5 (s, C(Ph)-1), 128.7
(d, C(Ph)-2, C(Ph)-6), 128.6 (d, C(Ph)-3, C(Ph)-5), 128.0
(d, C(Ph)-4), 100.0 (d, C-2), 87.0 (d, C-7a), 52.3 (q,
OCH3), 51.6 (t, CH2Ph), 50.2 (t, CH2SO2), 49.4 (s, C-7),
48.3 (s, C-8), 47.6 (d, C-4), 46.2 (d, C-3a), 43.7 (t, NCH2),
38.4 (t, C-3), 34.1 (t, CH2CO), 28.9 (t, C-5), 28.3 (t, C-6),
23.1, 20.4 (2 q, 2 CH3) ppm.
[2S-[2a(20R*,30aS*,40S*,70R*,70aS*),3aa,4b,7b,7aa]]-
2,20-oxybis[1-[[(octahydro-8,8-dimethyl-4,7-
methanobenzofurane-7-yl)methyl]sulfonyl]-D-proline]
(10, C34H52N2O11S2)
General procedure for the preparation of dilactol acids
Ester 4 (500 mg, 0.66 mmol) and 132 mg NaOH (3.3
mmol) gave 480 mg (quantitative) 10. Colorless crystals;
8-13
1
m.p.: 124–128 °C; [a]2D0 = -22.1° (c = 0.56/CH2Cl2); H
A 5 % solution of esters 2-7 in ethanol was treated with
sodium hydroxide under reflux for one hour (TLC control).
The solution was concentrated to dryness, and the residue
was dissolved in water and extracted with diethyl ether.
The aqueous phase was treated with conc. HCl to pH 1 and
extracted with diethyl ether. The organic phase was dried
with Na2SO4 and concentrated to give acids 8-13.
NMR (CDCl3): d = 9.10 (bs, 1H, COOH), 5.38 (s, 1H,
H-2), 4.65 (dd, J = 8 Hz, 4.5 Hz, 1H, H-a), 4.40 (d, J = 7
Hz, 1H, H-7a), 4.05 (d, J = 13 Hz, 1H, CHSO2), 3.69 (m,
1H, H-d), 3.51 (m, 1H, H-d), 3.00 (d, J = 13 Hz, 1H,
CHSO2), 2.35 (m, 1H, H-b), 2.30 (m, 1H, H-3a), 2.35 (m,
1H, H-b), 2.00 (m, 2H, H-3), 1.78 (m, 1H, H-4), 1.70 (m,
1H, H-6eq), 1.43 (m, 1H, H-5eq), 1.30 (m, 1H, H-6ax),
1.10 (m, 1H, H-5ax), 0.96, 0.85 (2 s, 6H, 2 CH3) ppm; 13
C
[2S-[2a(20R*,30aS*,40S*,70R*,70aS*),3aa,4b,7b,7aa]]-
2,20-oxybis[N-[[(octahydro-8,8-dimethyl-4,7-
NMR (CDCl3): d = 179.5 (s, CO), 98.0 (d, C-2), 86.0 (d,
C-7a), 59.7 (d, C-a), 51.1 (t, CH2SO2), 49.0 (s, C-7), 47.6
(s, C-8), 47.0 (d, C-4), 47.0 (t, C-d), 45.7 (d, C-3a), 37.8 (t,
C-3), 30.8 (t, C-b), 28.7 (t, C-5), 27.2 (t, C-6), 24.5 (t, C-c),
22.7, 19.7 (2 q, 2 CH3) ppm.
methanobenzofurane-7-yl)methyl]sulfonyl]-
N-(phenylmethyl)glycine] (8, C42H56N2O11S2)
Ester 2 (2 g, 2.2 mmol) and 440 mg NaOH (11 mmol) gave
1.71 g (94 %) 8. Colorless crystals; m.p.: 113–117 °C; [a]D20
1
= -67° (c = 1.05/CH2Cl2); DC: Rf = 0.55 (E); H NMR
[2S-[2a(20R*,30aS*,40S*,70R*,70aS*),3aa,4b,7b,7aa]]-
2,20-oxybis[N-(carboxymethyl)-N-[[(octahydro-8,8-
dimethyl-4,7-methanobenzofuran-7-yl)methyl]-
(CDCl3): d = 7.37 (m, 5H, aromatic Hs), 5.45 (s, 1H, H-2),
4.65–4.30 (AB-system, 2H, NCH2CO), 4.30–4.18 (dd,
PhCH2), 4.48 (d, J = 8 Hz, 1H, H-7a), 4.28 (d, J = 9 Hz,
1H, CHCO), 3.60–3.00 (AB system, J = 13 Hz, 2H,
CH2SO2), 2.40–1.00 (m, 8H), 0.92, 0.84 (2 s, 6H, 2 CH3)
ppm; 13C NMR (CDCl3): d = 176.7 (s, CO), 135.2 (s, C(Ph)-
1), 128.8 (d, C(Ph)-2, C(Ph)-6), 128.4 (d, C(Ph)-3, C(Ph)-
5), 128.2 (d, C(Ph)-4), 98.6 (d, C-2), 86.4 (d, C-7a), 52.0 (t,
sulfonyl]glycine] (11, C32H46N2O15S2)
Ester 5 (1.75 g, 2.1 mmol) and 430 mg NaOH (10.7 mmol)
gave 1.6 g (98 %) 11. Colorless crystals; m.p.: 122–125 °C;
1
[a]2D0 = -65° (c = 0.93/acetone); H NMR (CDCl3): d =
5.25 (bs, 1H, H-2), 4.40–4.15 (bs, 5H, 2 NCH2, H-7a), 3.70
(d, 1H, CHSO2), 3.05 (d, 1H, CHSO2), 2.30–1.00 (m, 8H,
123

Chiral resolution of alcohols
1637
aliphatic Hs), 0.90, 0.75 (2 s, 6H, 2 CH3) ppm; 13C NMR
(CDCl3): d = 170.7 (s, CO), 99.7 (d, C-2), 86.5 (d, C-7a),
65.0 (t, NCH2), 50.7 (t, CH2SO2), 48.9 (s, C-7), 48.4 (s,
C-8), 47.8 (d, C-4), 45.5 (d, C-3a), 38.9 (t, C-3), 28.2 (t,
C-5), 27.8 (t, C-6), 22.6, 19.7 (2 q, 2 CH3) ppm.
NaHCO3. The aqueous phase was treated with 2 N HCl to
pH 3 and extracted with diethyl ether. The organic layer
was dried (Na2SO4) and evaporated. The characterization
of the diastereoisomers was carried out from this residue.
[2S-[2a(R*),3aa,4b,7b,7aa]]-N-[[[2-(2,2-Dimethyl-1-
phenylpropoxy)octahydro-8,8-dimethyl-4,7-
[2S-[2a(20R*,30aS*,40S*,70R*,70aS*),3aa,4b,7b,7aa]]-
2,20-oxybis-[N-[[(octahydro-8,8-dimethyl-4,7-
methanobenzofuran-7-yl)methyl]sulfonyl]-
methanobenzofuran-7-yl]methyl]sulfonyl]-N-
(phenylmethyl)glycine (16) and [2S-[2a(S*),-
b-alanine] (12, C30H48N2O11S2)
3aa,4b,7b,7aa]]-N-[[[2-(2,2-dimethyl-1-phenylpro-
poxy)octahydro-8,8-dimethyl-4,7-methanobenzofuran-7-yl]-
methyl]sulfonyl]-N-(phenylmethyl)glycine (16a)
Dilactol 8 (200 mg, 0.24 mmol) and 316 mg 2,2-dimethyl-
1-phenylpropanol (14, 1.9 mmol) gave 230 mg (84 %) 16/
16a (10:1) as colorless foam from which the diastereomers
were characterized.
Ester 6 (650 mg, 0.92 mmol) and 110 mg NaOH (2.76
mmol) gave 610 mg (98 %) 12. Colorless foam; m.p.:
113–120 °C; [a]D20 = -87° (c = 0.98/CH2Cl2); H NMR
1
(CDCl3): d = 9.65 (bs, 1H, COOH), 5.91 (dd, 1H, NH), 5.34
(s, 1H, H-2), 4.40 (d, J = 7 Hz, 1H, H-7a), 3.52 (d, J = 13 Hz,
1H, CHSO2), 3.38 (m, 2H, NCH2), 2.98 (d, J = 13 Hz, 1H,
CHSO2), 2.65 (m, 2H, CH2CO), 2.39 (m, 1H, H-3a), 2.07
(m, 2H, H-3), 1.80 (m, 1H, H-4), 1.71 (m, 1H, H-6eq), 1.55
(m, 1H, H-5eq), 1.25 (m, 1H, H-6ax), 1.10 (m, 1H, H-5ax),
1.12, 0.87 (2 s, 6H, 2 CH3) ppm; 13C NMR (CDCl3): d =
175.9 (s, CO), 99.4 (d, C-2), 87.2 (d, C-7a), 51.3 (t,
CH2SO2), 49.5 (s, C-7), 48.5 (s, C-8), 47.4 (d, C-4), 46.3 (d,
C-3a), 38.7 (t, C-3), 38.1 (t, NCH2), 34.6 (t, CH2CO), 29.4
(t, C-5), 28.9 (t, C-6), 22.9, 20.4 (2 q, 2 CH3) ppm.
1
16: H NMR (CDCl3): d = 7.37 (m, 10H, aromatic Hs),
4.92 (d, J = 4 Hz, 1H, H-2), 4.57 (d, J = 7 Hz, 1H, H-7a),
4.29 (s, 1H, H-C*), 4.28 (d, J = 9 Hz, 1H, CHCO), 4.20 (d,
J = 9 Hz, 1H, CHO), 3.58 (d, J = 13 Hz, 1H, CHSO2), 2.98
(d, J = 13 Hz, 1H, CHSO2), 2.34 (m, 1H, H-3a), 2.02 (m,
2H, H-3), 1.76 (m, 1H, H-4), 1.80 (m, 1H, H-6eq), 1.47 (m,
1H, H-5eq), 1.10 (m, 1H, H-6ax), 0.89 (m, 1H, H-5ax), 0.87
(s, 9H), 0.90, 0.78 (2 s, 6H, 2 CH3) ppm; 13C NMR (CDCl3):
d = 173.6 (s, CO), 139.5 (s, C(Ph)-1), 135.5 (s, C(Bn)-1),
128.8 (d, C(Ph)-2, C(Ph)-6, C(Bn)-2, C(Bn)-6)), 128.4 (d,
C(Bn)-3, C(Bn)-5), 128.1 (d, C(Bn)-4), 127.3 (d, C(Ph)-3,
C(Ph)-5), 127.0 (d, C(Ph)-4), 101.2 (d, C-2), 86.8 (d, C-7a),
83.6 (d, C*), 52.2 (t, CH2CO), 51.1 (t, CH2Ph), 49.4 (t,
CH2SO2), 48.4 (s, C-7), 47.6 (s, C-8), 46.6 (d, C-4), 46.3 (d,
C-3a), 38.4 (t, C-3), 35.0 (s, C(CH3)3), 28.9 (t, C-5), 28.7 (t,
C-6), 26.3 (q, C(CH3)3), 23.1, 20.5 (2 q, 2 CH3) ppm.
16a (only signals different from 16 are given): 1H NMR
(CDCl3): d = 5.21 (d, J = 4.5 Hz, 1H, H-2), 4.02 (d, J = 7
Hz, 1H, H-7a), 4.04 (s, J = 7 Hz, 1H, H-C*), 3.35 (d, J = 12
Hz, 1H, CHSO2), 2.82 (d, J = 12 Hz, 1H, CHSO2), 0.90,
0.82 (2 s, 6H, 2 CH3) ppm; 13C NMR (CDCl3): d = 173.8
(s, CO), 140.5 (s, C(Ph)-1), 135.3 (s, C(Bn)-1), 128.6 (d,
C(Ph)-2, C(Ph)-6, C(Bn)-2, C(Bn)-6)), 128.4 (d, C(Bn)-3,
C(Bn)-5), 128.1 (d, C(Bn)-4), 127.6 (d, C(Ph)-3, C(Ph)-5),
126.9 (d, C(Ph)-4), 106.8 (d, C-2), 88.5 (d, C-7a), 87.0 (d,
C*), 51.1 (t, CH2CO), 50.8 (t, CH2Ph), 49.0 (t, CH2SO2),
48.2 (s, C-7), 47.6 (t, C-46.3 (d, C-4), 46.0 (d, C-3a), 38.6
(t, C-3), 35.0 (s, C(CH3)3), 28.6 (t, C-5), 27.6 (t, C-6), 26.0
(q, C(CH3)3), 23.0, 20.2 (2 q, 2 CH3) ppm.
[2S-[2a(20R*,30aS*,40S*,70R*,70aS*),3aa,4b,7b,7aa]]-
2,20-oxybis-[N-[[(octahydro-8,8-dimethyl-4,7-
methanobenzofuran-7-yl)methyl]sulfonyl]-
N-(phenylmethyl)-b-alanine] (13, C44H60N2O11S2)
Ester 7 (300 mg, 0.34 mmol) and 68 mg NaOH (1.69 mmol)
gave 290 mg (quantitative) 13. Colorless foam; m.p.: 93–98
°C; 1H NMR (CDCl3): d = 7.36 (m, 5H, aromatic Hs), 7.20
(bs, 1H, COOH), 5.47 (s, 1H, H-2), 4.45 (s, 2H, NCH2Ph),
4.38 (d, J = 7 Hz, 1H, H-7a), 3.50 (dd, 2H, NCH2), 3.50 (d,
J = 13 Hz, 1H, CHSO2), 2.85 (d, J = 13 Hz, 1H, CHSO2),
2.58 (dd, 2H, CH2CO), 2.38 (m, 1H, H-3a), 2.01 (m, 2H,
H-3), 1.81 (m, 1H, H-4), 1.71 (m, 1H, H-6eq), 1.45 (m, 1H,
H-5eq), 1.26 (m, 1H, H-6ax), 1.10 (m, 1H, H-5ax), 0.92,
0.82 (2 s, 6H, 2 CH3) ppm; 13C NMR (CDCl3): d = 177.0 (s,
CO), 136.3 (s, C(Ph)-1), 128.7 (d, C(Ph)-2, C(Ph)-6), 128.4
(d, C(Ph)-3, C(Ph)-5), 128.0 (d, C(Ph)-4), 99.4 (d, C-2), 87
(d, C-7a), 51.7 (t, CH2SO2), 50.6 (t, CH2Ph), 49.4 (s, C-7),
48.3 (s, C-8), 47.4 (d, C-4), 46.2 (d, C-3a), 43.1 (t, NCH2),
38.3 (t, C-3), 33.6 (t, CH2CO), 28.9 (t, C-5), 28.1 (t, C-6),
23.1, 20.3 (2 q, 2 CH3) ppm.
Representative preparation of diasteromeric sulfamides
with a carboxyl function
[2R-[2a(S*),3aa,4b,7b,7aa]]-N-[[[Octahydro-8,8-
dimethyl-2-(1-phenylethoxy)-4,7-methanobenzofuran-
7-yl]methyl]sulfonyl]-N-(phenylmethyl)glycine (17)
and [2R-[2a(R*),3aa,4b,7b,7aa]]-N-[[[octahydro-
8,8-dimethyl-2-(1-phenylethoxy)-4,7-methanobenzofuran-
7-yl]methyl]sulfonyl]-N-(phenylmethyl)glycine (17a)
Dilactol 8 (200 mg, 0.24 mmol) and 235 mg 1-phenyleth-
anol (15, 1.9 mmol) gave 260 mg (100 %) 17/17a (4:1) as
A 5 % solution of dilactol 8-13 in anhydrous CH2Cl2 and 4
equiv. of carbinol 14 or 15 was treated with 10 mg of
triphenylphosphin hydrobromide (THB), stirred for 12 h,
quenched with NEt3, and evaporated. The residue was
distributed between PE/E (8/2) and an aqueous solution of
123

1638
K. Mehraban et al.
colorless foam from which the diastereomers were
characterized.
18a (only signals different from 18 are given): 1H NMR
(CDCl3): d = 5.21 (d, J = 5 Hz, 1H, H-2), 4.07 (d, J = 6.5
Hz, 1H, H-7a), 4.05 (s, 1H, H-C*), 3.27 (d, J = 14 Hz, 1H,
CHSO2), 2.95 (d, J = 14.5 Hz, 1H, CHSO2), 0.87, 0.81 (2 s,
6H, 2 CH3) ppm; 13C NMR (CDCl3): d = 106.5 (d, C-2),
87.9 (d, C-7a), 87.4 (d, C*) ppm.
1
17: H NMR (CDCl3): d = 7.37 (m, 10H, aromatic Hs),
5.01 (d, J = 4 Hz, 1H, H-2), 4.78 (q, J = 6.5 Hz, 1H, H-C*),
4.58 (d, J = 7 Hz, 1H, H-7a), 4.28 (d, J = 9 Hz, 1H,
CHCO), 4.20 (d, J = 9 Hz, 1H, CHO), 3.64 (d, J = 14 Hz,
1H, CHSO2), 3.05 (d, J = 13 Hz, 1H, CHSO2), 2.34 (m, 1H,
H-3a), 2.02 (m, 2H, H-3), 1.76 (m, 1H, H-4), 1.80 (m, 1H,
H-6eq), 1.47 (m, 1H, H-5eq), 1.43 (d, J = 6 Hz, 3H, C*-
CH3), 1.10 (m, 1H, H-6ax), 0.89 (m, 1H, H-5ax), 0.93, 0.82
(2 s, 6H, 2 CH3) ppm; 13C NMR (CDCl3): d = 173.6 (s,
CO), 139.5 (s, C(Ph)-1), 135.5 (s, C(Bn)-1), 128.8 (d,
C(Ph)-2, C(Ph)-6, C(Bn)-2, C(Bn)-6)), 128.4 (d, C(Bn)-3,
C(Bn)-5), 128.1 (d, C(Bn)-4), 127.3 (d, C(Ph)-3, C(Ph)-5),
127.0 (d, C(Ph)-4), 101.9 (d, C-2), 86.7 (d, C-7a), 72.8 (d,
C*), 52.1 (t, CH2CO), 51.2 (t, CH2Ph), 49.4 (t, CH2SO2),
48.4 (s, C-7), 47.6 (s, C-8), 46.6 (d, C-4), 46.3 (d, C-3a),
38.4 (t, C-3), 28.9 (t, C-5), 28.7 (t, C-6), 26.3 (q, C(CH3)3),
23.2 (q, C*-CH3), 23.1, 20.5 (2 q, 2 CH3) ppm.
[2R-[2a(S*),3aa,4b,7b,7aa]]-1-[[[Octahydro-8,8-
dimethyl-2-(1-phenylethoxy)-4,7-methanobenzofuran-7-
yl]methyl]sulfonyl]-L-proline (19) and
[2R-[2a(R*),3aa,4b,7b,7aa]]-N-[[[octahydro-8,8-dime-
thyl-2-(1-phenylethoxy)-4,7-methanobenzofuran-7-
yl]methyl]sulfonyl]-L-proline (19a)
Dilactol 9 (100 mg, 0.14 mmol) and 184 mg 1-phenyleth-
anol (15, 1.1 mmol) gave 100 mg (77 %) 19/19a (3.5:1) as
colorless foam from which the diastereomers were
characterized.
1
19: H NMR (CDCl3): d = 7.37 (m, 5H, aromatic Hs),
4.98 (d, J = 4.5 Hz, 1H, H-2), 4.74 (q, J = 6.5 Hz, 1H,
H-C*), 4.55 (dd, 1H, H-a), 4.47 (q, J = 7 Hz, 1H, H-7a),
3.58 (t, 2H, H-d), 3.46 (d, J = 13.5 Hz, 1H, CHSO2), 3.05
(d, J = 13.5 Hz, 1H, CHSO2), 2.52–1.04 (m, 12H, H-3,
H-3a, H-4, H-5, H-6, H-b, H-d), 1.43 (d, J = 6 Hz, 3H, C*-
CH3), 0.90, 0.80 (2 s, 6H, 2 CH3) ppm; 13C NMR (CDCl3):
d = 176.2 (s, CO), 139.5 (s, C(Ph)-1), 128.7 (d, C(Ph)-2,
C(Ph)-6), 127.2 (d, C(Ph)-3, C(Ph)-5), 126.8 (d, C(Ph)-4),
102.1 (d, C-2), 86.7 (d, C-7a), 73.1 (d, C*), 60.3 (d, C-a),
49.6 (t, CH2SO2), 49.3 (s, C-7), 48.1 (t, C-d), 48.1 (s, C-8),
47.4 (d, C-4), 46.2 (d, C-3a), 38.4 (t, C-3), 30.7 (t, C-b),
28.8 (t, C-5), 28.1 (t, C-6), 25.0 (t, C-c), 23.2 (q, C*-CH3),
23.0, 20.3 (2 q, 2 CH3) ppm.
17a (only signals different from 17 are given): 1H NMR
(CDCl3): d = 5.39 (d, J = 3.5 Hz, 1H, H-2), 4.75 (q, J = 6.5
Hz, 1H, H-C*), 4.17 (d, J = 6.5, 1H, H-7a), 3.58 (d, J =
13.5 Hz, 1H, CHSO2), 3.00 (d, J = 13.5 Hz, 1H, CHSO2),
0.95, 0.85 (2 s, 6H, 2 CH3) ppm; 13C NMR (CDCl3): d
=102.7 (d, C-2), 86.9 (d, C-7a), 73.0 (d, C*) ppm.
[2S-[2a(R*),3aa,4b,7b,7aa]]-1-[[[2-(2,2-Dimethyl-1-
phenylpropoxy)octahydro-8,8-dimethyl-4,
7-methanobenzofuran-7-yl]methyl]sulfonyl]-L-proline
(18) and [2S-[2a(S*),3aa,4b,7b,7aa]]-1-[[[2-
(2,2-dimethyl-1-phenylpropoxy)octahydro-8,8-
dimethyl-4,7-methanobenzofuran-7-yl]methyl]-
sulfonyl]-L-proline (18a)
19a (only signals different from 19 are given): 1H NMR
(CDCl3): d = 5.38 (d, J = 4 Hz, 1H, H-2), 4.52 (q, J = 7.5
Hz, 1H, H-C*), 4.35 (d, J = 7.5 Hz, 1H, H-7a), 3.02 (d, J =
Dilactol 9 (147 mg, 0.2 mmol) and 264 mg 2,2-dimethyl-1-
phenylpropanol (14, 1.61 mmol) gave 200 mg (96 %) 18/
18a (9:1) as colorless foam from which the diastereomers
were characterized. Crystals of pure 18 were obtained by
crystallization with acetonitrile (136 mg, 68 %).
18: Colorless crystals; m.p.: 127–130 °C; [a]2D0 = -157°
13.5 Hz, 1H, CHSO2), 0.87, 0.81 (2 s, 6H, 2 CH3) ppm; 13
C
NMR (CDCl3): d = 102.8 (d, C-2), 86.8 (d, C-7a), 73.1 (d,
C*) ppm.
[2S-[2a(R*),3aa,4b,7b,7aa]]-1-[[[2-(2,2-Dimethyl-1-
phenylpropoxy)octahydro-8,8-dimethyl-4,7-
1
(c = 1.04/CH2Cl2); H NMR (CDCl3): d = 7.37 (m, 5H,
methanobenzofuran-7-yl]methyl]sulfonyl]-D-proline
(20) and [2S-[2a(S*),3aa,4b,7b,7aa]]-1-[[[2-(2,2-
dimethyl-1-phenylpropoxy)octahydro-8,8-dimethyl-4,7-
methanobenzofuran-7-yl]methyl]sulfonyl]-D-proline (20a)
Dilactol 10 (80 mg, 0.11 mmol) and 144 mg 2,2-dimethyl-
1-phenylpropanol (14, 0.88 mmol) gave 100 mg (87 %) 20/
20a (14:1) as colorless foam from which the diastereomers
were characterized.
aromatic Hs), 4.88 (d, J = 4.5 Hz, 1H, H-2), 4.55 (dd, 1H,
H-a), 4.49 (d, J = 7Hz, 1H, H-7a), 4.28 (s, 1H, H-C*), 3.58
(t, 2H, H-d), 3.46 (d, J = 13.5 Hz, 1H, CHSO2), 3.04 (d, J =
13.5 Hz, 1H, CHSO2), 2.52–1.04 (m, 12H, H-3, H-3a, H-4,
H-5, H-6, H-b, H-d), 0.87 (s, 9H, C(CH3)3), 0.87, 0.80 (2 s,
6H, 2 CH3) ppm; 13C NMR (CDCl3): d = 176.2 (s, CO),
139.5 (s, C(Ph)-1), 128.7 (d, C(Ph)-2, C(Ph)-6), 127.2 (d,
C(Ph)-3, C(Ph)-5), 126.8 (d, C(Ph)-4), 101.3 (d, C-2), 86.5
(d, C-7a), 83.6 (d, C*), 60.3 (d, C-a), 49.6 (t, CH2SO2),
49.3 (s, C-7), 48.1 (t, C-d), 48.1 (s, C-8), 47.4 (d, C-4), 46.2
(d, C-3a), 38.4 (t, C-3), 34.9(s, C(CH3)3), 30.7 (t, C-b),
28.8 (t, C-5), 28.1 (t, C-6), 26.1 (q, C(CH3)3), 25.0 (t, C-c),
23.0, 20.3 (2 q, 2 CH3) ppm.
1
20: H NMR (CDCl3): d = 7.37 (m, 5H, aromatic Hs),
4.84 (d, J = 4.5 Hz, 1H, H-2), 4.55 (dd, 1H, H-a), 4.49 (d,
J = 6.5 Hz, 1H, H-7a), 4.30 (s, 1H, H-C*), 3.58 (t, 2H,
H-d), 3.52 (d, J = 13.5 Hz, 1H, CHSO2), 2.91 (d, J = 13.5
Hz, 1H, CHSO2), 2.52–1.04 (m, 12H, H-3, H-3a, H-4, H-5,
H-6, H-b, H-d), 0.87 (s, 9H, C(CH3)3), 0.87, 0.80 (2 s, 6H,
123

Chiral resolution of alcohols
1639
2 CH3) ppm; 13C NMR (CDCl3): d = 176.2 (s, CO), 139.5
(s, C(Ph)-1), 128.7 (d, C(Ph)-2, C(Ph)-6), 127.2 (d, C(Ph)-
3, C(Ph)-5), 126.8 (d, C(Ph)-4), 101.2 (d, C-2), 86.5 (d,
C-7a), 83.5 (d, C*), 60.3 (d, C-a), 49.6 (t, CH2SO2), 49.3
(s, C-7), 48.1 (t, C-d), 48.1 (s, C-8), 47.4 (d, C-4), 46.2 (d,
C-3a), 38.4 (t, C-3), 34.9 (s, C(CH3)3), 30.7 (t, C-b), 28.8
(t, C-5), 28.1 (t, C-6), 26.1 (q, C(CH3)3), 25.0 (t, C-c), 23.0,
20.3 (2 q, 2 CH3) ppm.
20a (only signals different from 20 are given): 1H NMR
(CDCl3): d = 5.11 (d, J = 5 Hz, 1H, H-2), 4.16 (d, J = 6.5
Hz, 1H, H-7a), 4.05 (s, 1H, H-C*), 2.86 (d, J = 14 Hz, 1H,
CHSO2) ppm; 13C NMR (CDCl3): d = 107.1 (d, C-2), 87.6
(d, C-7a), 87.0 (d, C*) ppm.
(100 %) 22/22a (5.1:1) as colorless foam from which the
diastereomers were characterized.
1
22: H NMR (CDCl3): d = 7.37 (m, 5H, aromatic Hs),
5.00 (d, J = 4 Hz, 1H, H-2), 4.49 (q, J = 7.5 Hz, 1H,
H-C7a), 4.40–4.15 (bs, 4H, 2 NCH2), 4.30 (s, 1H, H-C*),
3.35 (d, J = 14.5 Hz, 1H, CHSO2), 2.88 (d, J = 13.5 Hz, 1H,
CHSO2), 2.30-1.00 (m, 8H, aliphatic Hs), 0.87 (s, 9H,
C(CH3)3), 0.89, 0.78 (2 s, 6H, 2 CH3) ppm; 13C NMR
(CDCl3): d = 170.7 (s, CO), 139.5 (s, C(Ph)-1), 128.7 (d,
C(Ph)-2, C(Ph)-6), 127.2 (d, C(Ph)-3, C(Ph)-5), 126.8 (d,
C(Ph)-4), 100.8 (d, C-2), 86.8 (d, C-7a), 83.4 (d, C*), 65.0
(t, NCH2), 50.7 (t, CH2SO2), 48.9 (s, C-7), 48.4 (s, C-8),
47.8 (d, C-4), 45.5 (d, C-3a), 38.9 (t, C-3), 28.2 (t, C-5),
27.8 (t, C-6), 26.1 (q, C(CH3)3), 22.6, 19.7 (2 q, 2 CH3)
ppm.
22a (only signals different from 22 are given): 1H NMR
(CDCl3): d = 5.24 (d, J = 4.5 Hz, 1H, H-2), 4.04 (s, 1H,
H-C*), 3.32 (d, J = 14 Hz, 1H, CHSO2), 2.82 (d, J = 14.5
Hz, 1H, CHSO2), 0.85, 0.78 (2 s, 6H, 2 CH3) ppm; 13C
NMR (CDCl3): d = 107.4 (d, C-2), 88.2 (d, C-7a), 86.8 (d,
C*) ppm.
[2R-[2a(S*),3aa,4b,7b,7aa]]-1-[[[Octahydro-8,8-
dimethyl-2-(1-phenylethoxy)-4,7-methanobenzofuran-
7-yl]methyl]sulfonyl]-D-proline (21) and [2R-
[2a(R*),3aa,4b,7b,7aa]]-N-[[[octahydro-8,8-dimethyl-
2-(1-phenylethoxy)-4,7-methanobenzofuran-7-yl]methyl]-
sulfonyl]-D-proline (21a)
Dilactol 10 (80 mg, 0.11 mmol) and 107 mg 1-phenyleth-
anol (15, 0.88 mmol) gave 100 mg (95 %) 21/21a (3.2:1)
as colorless foam from which the diastereomers were
characterized.
[2R-[2a(S*),3aa,4b,7b,7aa]]-N-(Carboxymethyl)-N-
[[[octahydro-8,8-dimethyl-2-(1-phenylethoxy)-4,7-metha-
nobenzofuran-7-yl]methyl]sulfonyl]glycine (23) and [2R-
[2a(R*),3aa,4b,7b,7aa]]-N-(carboxymethyl)-N-[[[octa-
hydro-8,8-dimethyl-2-(1-phenylethoxy)-4,7-methanoben-
zofuran-7-yl]methyl]sulfonyl]glycine (23a)
1
21: H NMR (CDCl3): d = 7.37 (m, 5H, aromatic Hs),
4.93 (d, J = 4.5 Hz, 1H, H-2), 4.78 (q, J = 6.5 Hz, 1H,
H-C*), 4.55 (dd, 1H, H-a), 4.38 (d, J = 7.5 Hz, 1H, H-7a),
3.58 (t, 2H, H-d), 3.46 (d, J = 13.5 Hz, 1H, CHSO2), 2.93
(d, J = 13.5 Hz, 1H, CHSO2), 2.52–1.04 (m, 12H, H-3,
H-3a, H-4, H-5, H-6, H-b, H-d), 1.43 (d, J = 6 Hz, 3H, C*-
CH3), 0.87, 0.80 (2 s, 6H, 2 CH3) ppm; 13C NMR (CDCl3):
d = 176.2 (s, CO), 139.5 (s, C(Ph)-1), 128.7 (d, C(Ph)-2,
C(Ph)-6), 127.2 (d, C(Ph)-3, C(Ph)-5), 126.8 (d, C(Ph)-4),
101.2 (d, C-2), 86.5 (d, C-7a), 72.5 (d, C*), 60.3 (d, C-a),
49.6 (t, CH2SO2), 49.3 (s, C-7), 48.1 (t, C-d), 48.1 (s, C-8),
47.4 (d, C-4), 46.2 (d, C-3a), 38.4 (t, C-3), 30.7 (t, C-b),
28.8 (t, C-5), 28.1 (t, C-6), 25.0 (t, C-c), 23.2 (q, C*-CH3),
23.0, 20.3 (2 q, 2 CH3) ppm.
21a (only signals different from 21 are given): 1H NMR
(CDCl3): d = 5.11 (d, J = 5 Hz, 1H, H-2), 4.16 (d, J = 6.5
Hz, 1H, H-7a), 4.05 (s, 1H, H-C*), 2.86 (d, J = 14 Hz, 1H,
CHSO2) ppm; 13C NMR (CDCl3): d = 102.1 (d, C-2), 86.7
(d, C-7a), 72.5 (d, C*) ppm.
Dilactol 11 (100 mg, 0.119 mmol) and 157 mg 1-phenyl-
ethanol (15, 0.88 mmol) gave 110 mg (93 %) 23/23a
(4.4:1) as colorless foam from which the diastereomers
were characterized.
1
23: H NMR (CDCl3): d = 7.37 (m, 5H, aromatic Hs),
5.06 (d, J = 4 Hz, 1H, H-2), 4.77 (q, J = 6.5 Hz, 1H, H-C*),
4.49 (q, J = 7.5 Hz, 1H, H-C7a), 4.40–4.15 (bs, 4H, 2
NCH2), 3.47 (d, J = 13.5 Hz, 1H, CHSO2), 2.97 (d, J = 13.5
Hz, 1H, CHSO2), 2.30–1.00 (m, 8H, aliphatic Hs), 1.40 (d,
J = 6 Hz, 3H, C*-CH3), 0.90, 0.80 (2 s, 6H, 2 CH3) ppm;
13C NMR (CDCl3): d = 170.7 (s, CO), 139.5 (s, C(Ph)-1),
128.7 (d, C(Ph)-2, C(Ph)-6), 127.2 (d, C(Ph)-3, C(Ph)-5),
126.8 (d, C(Ph)-4), 101.7 (d, C-2), 86.9 (d, C-7a), 72.9 (d,
C*), 65.0 (t, NCH2), 50.7 (t, CH2SO2), 48.9 (s, C-7), 48.4
(s, C-8), 47.8 (d, C-4), 45.5 (d, C-3a), 38.9 (t, C-3), 28.2 (t,
C-5), 27.8 (t, C-6), 23.1 (q, C*CH3), 22.6, 19.7 (2 q, 2 CH3)
ppm.
23a (only signals different from 23 are given): 1H NMR
(CDCl3): d = 5.40 (d, J = 4 Hz, 1H, H-2), 4.74 (q, J = 6.5
Hz, 1H, H-C*), 3.47 (d, J = 13.5 Hz, 1H, CHSO2), 2.97 (d,
J = 13.5 Hz, 1H, CHSO2), 0.96, 0.88 (2 s, 6H, 2 CH3) ppm;
13C NMR (CDCl3): d = 102.9 (d, C-2), 88.2 (d, C-7a), 73.5
(d, C*) ppm.
[2S-[2a(R*),3aa,4b,7b,7aa]]-N-(Carboxymethyl)-N-[[[2-
(2,2-dimethyl-1-phenylpropoxy)octahydro-8,8-dimethyl-
4,7-methanobenzofuran-7-yl]methyl]sulfonyl]glycine
(22) and [2S-[2a(S*),3aa,4b,7b,7aa]]-N-(carboxymethyl)-
N-[[[2-(2,2-dimethyl-1-phenylpropoxy)octahydro-8,8-
dimethyl-4,7-methanobenzofuran-7-yl]methyl]-
sulfonyl]glycine (22a)
Dilactol 11 (100 mg, 0.119 mmol) and 157 mg 2,2-
dimethyl-1-phenylpropanol (14, 0.88 mmol) gave 130 mg
[2S-[2a(R*),3aa,4b,7b,7aa]]-N-[[[2-(2,2-Dimethyl-1-
phenylpropoxy)octahydro-8,8-dimethyl-4,7-
123

1640
K. Mehraban et al.
methanobenzofuran-7-yl]methyl]sulfonyl]-b-alanine (24)
and [2S-[2a(S*),3aa,4b,7b,7aa]]-N-[[[2-(2,2-dimethyl-1-
phenylpropoxy)octahydro-8,8-dimethyl-4,7-
methanobenzofuran-7-yl]methyl]sulfonyl]-
b-alanine (24a)
C-2), 86.2 (d, C-7a), 72.6 (d, C*), 51.3 (t, CH2SO2), 49.5 (s,
C-7), 48.5 (s, C-8), 47.4 (d, C-4), 46.3 (d, C-3a), 38.7 (t, C-3),
38.1 (t, NCH2), 34.6 (t, CH2CO), 29.4 (t, C-5), 28.9 (t,
C-6),24.5 (q, C*-CH3), 22.9, 20.4 (2 q, 2 CH3) ppm.
25a (only signals different from 25 are given): 1H NMR
(CDCl3): d = 5.37 (d, J = 4.5 Hz, 1H, H-2), 4.74 (q, J = 6.5
Hz, 1H, H-C*), 4.34 (d, J = 8 Hz, 1H, H-7a), 3.48 (d, J = 14
Hz, 1H, CHSO2), 2.90 (d, J = 13.5 Hz, 1H, CHSO2), 0.89,
0.84 (2 s, 6H, 2 CH3) ppm; 13C NMR (CDCl3): d = 102.8
(d, C-2), 86.8 (d, C-7a), 72.9 (d, C*) ppm.
Dilactol 12 (80 mg, 0.118 mmol) and 155 mg 2,2-dimethyl-
1-phenylpropanol (14, 0.95 mmol) gave 90 mg (77 %) 24/
24a (5.6:1) as colorless foam from which the diastereomers
were characterized.
1
24: H NMR (CDCl3): d = 9.65 (bs, 1H, COOH), 7.37
(m, 5H, aromatic Hs), 5.91 (dd, 1H, NH), 4.87 (d, J = 4.5
Hz, 1H, H-2), 4.48 (d, J = 7.5 Hz, 1H, H-7a), 4.29 (s, 1H,
H-C*), 3.55 (d, J = 14.5 Hz, 1H, CHSO2), 3.38 (m, 2H,
NCH2), 2.92 (d, J = 13 Hz, 1H, CHSO2), 2.65 (m, 2H,
CH2CO), 2.39 (m, 1H, H-3a), 2.07 (m, 2H, H-3), 1.80 (m,
1H, H-4), 1.71 (m, 1H, H-6eq), 1.55 (m, 1H, H-5eq), 1.25
(m, 1H, H-6ax), 1.10 (m, 1H, H-5ax), 0.87 (s, 9H,
C(CH3)3), 0.89, 0.78 (2 s, 6H, 2 CH3) ppm; 13C NMR
(CDCl3): d = 175.9 (s, CO), 139.5 (s, C(Ph)-1), 128.7 (d,
C(Ph)-2, C(Ph)-6), 127.2 (d, C(Ph)-3, C(Ph)-5), 126.8 (d,
C(Ph)-4), 101.2 (d, C-2), 86.5 (d, C-7a), 83.4 (d, C*), 51.3
(t, CH2SO2), 49.5 (s, C-7), 48.5 (s, C-8), 47.4 (d, C-4), 46.3
(d, C-3a), 38.7 (t, C-3), 38.1 (t, NCH2), 34.6 (t, CH2CO),
29.4 (t, C-5), 28.9 (t, C-6), 26.2 (q, C(CH3)3), 22.9, 20.4 (2
q, 2 CH3) ppm.
24a (only signals different from 24 are given): 1H NMR
(CDCl3): d = 5.18 (d, J = 4.5 Hz, 1H, H-2), 4.01 (s, 1H,
H-C*), 3.32 (d, J = 14 Hz, 1H, CHSO2), 3.32 (d, J = 14.5
Hz, 1H, CHSO2), 0.90, 0.82 (2 s, 6H, 2 CH3) ppm; 13C
NMR (CDCl3): d = 103.7 (d, C-2), 88.0 (d, C-7a), 86.8 (d,
C*) ppm.
[2S-[2a(R*),3aa,4b,7b,7aa]]-N-[[[2-(2,2-Dimethyl-1-
phenylpropoxy)octahydro-8,8-dimethyl-4,7-
methanobenzofuran-7-yl]methyl]sulfonyl]-N-
(phenylmethyl)-b-alanine (26) and [2S-[2a(S*),-
3aa,4b,7b,7aa]]-N-[[[2-(2,2-dimethyl-1-phenyl-
propoxy)octahydro-8,8-dimethyl-4,7-methanobenzofuran-
7-yl]methyl]sulfonyl]-N-(phenylmethyl)-b-alanine (26a)
Dilactol 13 (40 mg, 0.047 mmol) and 61 mg 2,2-dimethyl-
1-phenylpropanol (14, 0.373 mmol) gave 30 mg (53 %) 26/
26a (7.3:1) as colorless foam from which the diastereomers
were characterized.
26: 1H NMR (CDCl3):): d = 7.36 (m, 10H, aromatic Hs),
7.20 (bs, 1H, COOH), 4.91 (d, J = 4.5 Hz, 1H, H-2), 4.57
(d, J = 8 Hz, 1H, H-7a), 4.45 (s, 2H, NCH2Ph), 4.37 (s, 1H,
H-C*), 3.50 (dd, 2H, NCH2), 3.39 (d, J = 13.5 Hz, 1H,
CHSO2), 2.79 (d, J = 13.5 Hz, 1H, CHSO2), 2.58 (dd, 2H,
CH2CO), 2.38 (m, 1H, H-3a), 2.01 (m, 2H, H-3), 1.81 (m,
1H, H-4), 1.71 (m, 1H, H-6eq), 1.45 (m, 1H, H-5eq), 1.26
(m, 1H, H-6ax), 1.10 (m, 1H, H-5ax), 0.87 (s, 9H,
C(CH3)3), 0.85, 0.79 (2 s, 6H, 2 CH3) ppm; 13C NMR
(CDCl3): d = 177.0 (s, CO), 136.3 (s, C(Ph)-1), 135.5 (s,
C(Bn)-1), 128.7 (d, C(Ph)-2, C(Ph)-6, C(Bn)-2, C(Bn)-6)),
128.4(d, C(Bn)-3, C(Bn)-5, C(Ph)-3, C(Ph)-5), 128.1 (d,
C(Bn)-4), 128.0 (d, C(Ph)-4), 101.4 (d, C-2), 86.6 (d,
C-7a), 83.7 (d, C*), 51.7 (t, CH2SO2), 50.6 (t, CH2Ph), 49.4
(s, C-7), 48.3 (s, C-8), 47.4 (d, C-4), 46.2 (d, C-3a), 43.1 (t,
NCH2), 38.3 (t, C-3), 33.6 (t, CH2CO), 28.9 (t, C-5), 28.1
(t, C-6), 26.2 (q, C(CH3)3), 23.1, 20.3 (2 q, 2 CH3) ppm.
26a (only signals different from 26 are given): 1H NMR
(CDCl3): d = 5.20 (d, J = 4 Hz, 1H, H-2), 4.14 (q, J = 7 Hz,
1H, H-7a), 4.02 (s, 1H, H-C*), 3.17 (d, J = 14 Hz, 1H,
CHSO2), 2.70 (d, J = 13.5 Hz, 1H, CHSO2) ppm; 13C NMR
(CDCl3): d = 107.0 (d, C-2), 88.3 (d, C-7a), 86.6 (d, C*)
ppm.
[2R-[2a(S*),3aa,4b,7b,7aa]]-N-[[[Octahydro-8,8-
dimethyl-2-(1-phenylethoxy)-4,7-methanobenzofuran-7-
yl]methyl]sulfonyl]-b-alanine (25) and [2R-
[2a(R*),3aa,4b,7b,7aa]]-N-[[[octahydro-8,8-dimethyl-2-
(1-phenylethoxy)-4,7-methanobenzofuran-7-yl]methyl]-
sulfonyl]-b-alanine (25a)
Dilactol 12 (80 mg, 0.118 mmol) and 116 mg 1-phenyl-
ethanol (15, 0.95 mmol) gave 90 mg (84 %) 25/25a (2.9:1)
as colorless foam from which the diastereomers were
characterized.
25: 1H NMR (CDCl3): d = 9.65 (bs, 1H, COOH), 7.37 (m,
5H, aromatic Hs), 5.91 (dd, 1H, NH), 4.98 (d, J = 5 Hz, 1H,
H-2), 4.78 (q, J = 6.5 Hz, 1H, H-C*), 4.50 (d, J = 7.5 Hz, 1H,
H-7a), 3.58 (d, J = 13.5 Hz, 1H, CHSO2), 3.38 (m, 2H,
NCH2), 2.95 (d, J = 13.5 Hz, 1H, CHSO2), 2.50 (m, 2H,
CH2CO), 2.39 (m, 1H, H-3a), 2.07 (m, 2H, H-3), 1.80 (m, 1H,
H-4), 1.71 (m, 1H, H-6eq), 1.55 (m, 1H, H-5eq), 1.40 (d, J = 6
Hz, 3H, C*-CH3), 1.25 (m, 1H, H-6ax), 1.10 (m, 1H, H-5ax),
0.90, 0.82 (2 s, 6H, 2 CH3) ppm; 13C NMR (CDCl3): d =
175.9 (s, CO), 139.5 (s, C(Ph)-1), 128.7 (d, C(Ph)-2, C(Ph)-
6), 127.2 (d, C(Ph)-3, C(Ph)-5), 126.8 (d, C(Ph)-4), 101.8 (d,
[2R-[2a(S*),3aa,4b,7b,7aa]]-N-[[[Octahydro-8,8-
dimethyl-2-(1-phenylethoxy)-4,7-methanobenzofuran-7-
yl]methyl]sulfonyl]-N-(phenylmethyl)-b-alanine (27) and
[2R-[2a(R*),3aa,4b,7b,7aa]]-N-[[[octahydro-8,8-dime-
thyl-2-(1-phenylethoxy)-4,7-methanobenzofuran-7-
yl]methyl]sulfonyl]-N-(phenylmethyl)-b-alanine (27a)
Dilactol 13 (40 mg, 0.047 mmol) and 45.6 mg 1-phenyl-
ethanol (15, 0.373 mmol) gave 35 mg (69 %) 27/27a
123

Chiral resolution of alcohols
1641
Acknowledgments The work was supported to a large degree by
the Christian Doppler Forschungsgesellschaft. Significant parts of the
work were performed within the Christian Doppler Laboratorium fu¨r
Chirale Verbindungen: Chemische Synthese, first at the Institut fu¨r
(3.3:1) as colorless foam from which the diastereomers
were characterized.
1
27: H NMR (CDCl3): d = 7.36 (m, 10H, aromatic Hs),
7.20 (bs, 1H, COOH), 4.96 (d, J = 5 Hz, 1H, H-2), 4.88 (q,
J = 6.5 Hz, 1H, H-C*), 4.49 (d, J = 8 Hz, 1H, H-7a), 4.45
(s, 2H, NCH2Ph), 3.50 (dd, 2H, NCH2), 3.39 (d, J = 14 Hz,
1H, CHSO2), 2.78 (d, J = 14 Hz, 1H, CHSO2), 2.58 (dd,
2H, CH2CO), 2.38 (m, 1H, H-3a), 2.01 (m, 2H, H-3), 1.81
(m, 1H, H-4), 1.71 (m, 1H, H-6eq), 1.45 (m, 1H, H-5eq),
1.26 (m, 1H, H-6ax), 1.10 (m, 1H, H-5ax), 0.87 (s, 9H,
C(CH3)3), 0.92, 0.82 (2 s, 6H, 2 CH3) ppm.
¨
Organische Chemie der Technischen Universitat Wien, later at the
Institut fu¨r Pharmazeutische Chemie der Universitat Frankfurt and the
Department of Medicinal Chemistry, University of Vienna. The
authors also thank Produkem Molekulares Design GmbH, Vienna, for
supply of starting material.
¨
References
27a (only signals different from 27 are given): 1H NMR
(CDCl3): d = 5.35 (d, J = 4 Hz, 1H, H-2), 4.88 (q, J = 6.5
Hz, 1H, H-C*), 3.35 (d, J = 14 Hz, 1H, CHSO2), 2.78 (d,
J = 13.5 Hz, 1H, CHSO2) ppm.
1. Deslongchamps P (1984) Stereoelectronic effects in Organic
Chemistry. Pergamon Press, Oxford, New York, Beijing, Frank-
furt, Sao Paulo, Sydney, Tokyo, Toronto, p 375
2. Noe CR, Knollmueller M, Goestl G, Oberhauser B, Voellenkle H
(1987) Angew Chem 99:467
3. Noe CR, Knollmueller M, Miculka C, Dungler K, Wagner E,
Ettmayer P (1994) Chem Ber 127:887
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5. Noe CR (1982) Chem Ber 115:1576
Representative cleavage of an acetal
The diastereomeric mixture (1 g, 1.93 mmol) of acetals 18/
18a (7.2:1) in CH3CN/H2O = 4:1 was treated with 150 mg
(0.77 mmol, 0.4 equiv.) of para-toluenesulfonic acid under
reflux for 5 h. Then NaHCO3 was added, the mixture was
concentrated, aqueous saturated NaHCO3 solution was
added, and it was extracted with diethyl ether. The organic
solution was dried (Na2SO4) and evaporated to obtain 300
mg (95 %) 14 ((S):(R) = 6.9:1).
6. Noe CR (1982) Chem Ber 115:1591
7. Gmeiner G (1992) PhD Thesis ‘‘Untersuchungen zur Enant-
¨
iomerselekitvitat bei Acetalbildungsreaktionen’’. Vienna University
of Technology, Vienna, p 168
8. Weinreb SM, Demko DM, Lessen TA, Demers JP (1986) Tet-
rahedron Lett 27:2099
9. Saigo K, Kihara N, Hashimoto Y, Lin RJ, Fujimura H, Suzuki Y,
Hasegawa H (1990) J Am Chem Soc 112:1144
10. Bolitt V, Mioskowski C, Shin DS, Falck JR (1988) Tetrahedron
Lett 29:4583
The aqueous solution was acidified with 2 N HCl and
extracted with CH2Cl2. To the organic phase a small
amount of toluene was added, and it was dried (Na2SO4)
and evaporated to recover 640 mg (91 %) of dilactol 9.
11. Bestmann HJ, Mott L, Lienert J (1967) Justus Liebigs Ann Chem
709:105
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