Synthesis of acyldodecaheterocycles derived from (1R)-(-)-myrtenal and evaluation as chiral auxiliaries

Article abstract of DOI:10.1016/j.tetasy.2012.10.013

New (1R)-(-)-myrtenal-derived macrocycles 5a and 5b were efficiently used as chiral auxiliaries in the diastereoselective nucleophilic addition of several nucleophiles (RMgX, RLi, LiAlH₄, and NaBH₄). We observed that the diastereosel

Full text of DOI:10.1016/j.tetasy.2012.10.013

Tetrahedron: Asymmetry 23 (2012) 1588–1595
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of acyldodecaheterocycles derived from (1R)-(–)-myrtenal
and evaluation as chiral auxiliaries
a
b
b
Ma. Elena Vargas-Díaz , Humberto L. Mendoza-Figueroa , M. Jonathan Fragoso-Vázquez ,
b
c
b,
⇑
Francisco Ayala-Mata , Pedro Joseph-Nathan , L. Gerardo Zepeda
Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. de Carpio y Plan de Ayala S/N, Col. Santo Tomás, Deleg.
Miguel Hidalgo, México, DF 11340, Mexico
a
b
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. de Carpio y Plan de Ayala S/N, Col. Santo Tomás,
Deleg. Miguel Hidalgo, México, DF 11340, Mexico
c
Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado 14-740, México, DF 07000, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 October 2012
Accepted 17 October 2012
New (1R)-(–)-myrtenal-derived macrocycles 5a and 5b were efficiently used as chiral auxiliaries in the
diastereoselective nucleophilic addition of several nucleophiles (RMgX, RLi, LiAlH
observed that the diastereoselectivity depended on the nucleophile, with the stereoselectivity order
being RMgX (>99:1 dr) > RLi (7:3 dr) > AlLiH P NaBH (6:4 dr). The absolute configuration of the result-
4 4
, and NaBH ). We
4
4
ing carbinols was established by X-ray diffraction of adducts 9a and 9b, and through chemical correlation
of carbinols 9b and 9c with diols of known absolute configuration.
Ó 2012 Elsevier Ltd. All rights reserved.
1
. Introduction
R
O
R
S
O
O
The formation of carbon–carbon bonds via nucleophilic addi-
O
O
tion of organometallic reagents onto substrates bearing a carbonyl
group has in recent years shown a significant progress to control
chirality. Such transformations are mainly performed by using chi-
1
2
R
S
1
O
ral coadjuvants (auxiliaries and/or chiral ligands), which are often
the key tools in the synthesis of a wide variety of chiral biologically
active molecules. At present, the search for new chiral auxiliaries is
still a central target of great importance in asymmetric synthesis.
Among these, particular emphasis on chiral auxiliaries possessing
EtO
S
OEt
O
R
S
2
C symmetry has been made since they usually promote higher
OTBS
2
–4
levels of stereochemical control.
O
O
We have already described5 the synthesis of several (1R)-(–)-
myrtenal-derived chiral auxiliaries bearing an acyl group, which
showed 8:2 to >99:1 diastereomeric ratios (dr) under nucleophilic
additions wherein a Cram-chelated transition state determined
a–f
3
4
Figure 1. (1R)-(–)-Myrtenal derived chiral auxiliaries (R = alkyl or aryl group).
RMgX > RLi > LiAlH
4
as the preferred order of diastereoselectivity.
that this stereoselectivity order is essentially due to steric effects,
5a,b
Among these chiral auxiliaries are acyloxathianes 1,
acyldiox-
and acyldioxadithiadodecahet-
5
f
rather than to chelation effects. In continuation of this work, we
were encouraged to prepare macrocycles 5a and 5b in order to
evaluate their chiral auxiliary capabilities in the context of (1R)-
5
c
5d,e
anes 2, acyl-S,O-thioacetals 3,
5
f
erocycles 4 (Fig. 1). The latter compounds showed high stereo-
selectivity (>99:1 dr) regardless of the chemical features of the
nucleophile used, representing a new diastereoselectivity order
not previously observed in structurally similar chiral auxiliaries
prepared from (1R)-(–)-myrtenal5a–e or pulegone. It was assumed
(
–)-myrtenal 6 derived chiral auxiliaries, particularly with regard
5f
to its structural analogue 4.
6
2
. Results and discussion
The reaction sequence to obtain the title compounds is shown
in Scheme 1. Treatment of (1R)-(–)-myrtenal 6 with thiolacetic
⇑
Corresponding author. Tel.: +52 55 5729 6300x62412; fax: +52 55 5396 3503.
E-mail address: lzepeda@woodward.encb.ipn.mx (L.G. Zepeda).
0
957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.10.013

M. E. Vargas-Díaz et al. / Tetrahedron: Asymmetry 23 (2012) 1588–1595
1589
SAc
SH
OH
AcSH, py
LiAlH , THF
4
O
91%, two steps
6
O
7
+
H C(OMe) , H
98%
2
2
15
1
8
S 13
S
11
22
S
S
RCOCH(OR')2, H+
2
1
3
8
41%
1
R' = Me or Et
O
5
O
O
OH OH
8
R
5
5
a R= Ph
b R= Me
Scheme 1. Preparation of macroheterocycles 5a,b.
thane in the presence of a catalytic amount of p-TsOH to give
diol 8 in 98% yield. Macrocyclization was achieved through a
transacetalization reaction of diol 8 with the corresponding
a-
ketoacetal to afford, after column chromatography, acyldioxadithi-
adodecacycles 5a,b in 41% yields. The low yield was due to side
reactions resulting from the hydrolysis of the thioacetal group to
afford hydroxythiol 7 and the concomitant formation of the
5
a,b
corresponding acyloxathiane 1.
The structural characterization of compounds 5a,b was carried
out by NMR measurements and single crystal X-ray diffraction
analysis. Projections of the X-ray structures of 5a,b are depicted
in Figure 2, which show that both compounds differ in the confor-
mation of the acyl group in the solid state, since in 5a, the carbonyl
group of the benzoyl moiety is almost coplanar with H-5, whereas
in compound 5b the carbonyl group of the acetyl moiety is copla-
nar with O4. It is worth noting that in both compounds, C-5 is a
pseudostereogenic center, so
a or b projection of this center repre-
sents the same structure for either compound. This structural fea-
ture confers compounds 5a and 5b similar properties to those of
chiral auxiliaries with C symmetry.
2
The results obtained after diastereoselective addition of several
organometallic reagents on the pro-stereogenic center of com-
pounds 5a,b to yield carbinols 9a–h and 10a–h are summarized
in Table 1. In contrast to the results observed for compound 4,5
in which all of the nucleophilic reagents showed very similar ste-
reoselectivities, the diastereoselectivity of the nucleophilic addi-
tions on to compounds 5a,b depends on the nature of the
nucleophile. For instance, Grignard reagents showed excellent
yields and diastereoselectivities (entries 1–6, 11 and 12), whereas
f
4 4
lithium alkylides and hydrides (LiAlH and NaBH ) showed signif-
icantly lower diastereoselectivities (entries 7–10). The above dia-
stereoselectivity is in close agreement with that shown by
5
a,b
5c
5d,e
acyloxathianes,
acyldioxanes, and acyl-S,O-thioacetals
in
which the stereoselectivity was explained by means of a Cram che-
7
lated transition state.
The facial diastereoselectivity was evidenced by X-ray diffrac-
Figure 2. X-Ray structures of macroheterocycles 5a (top) and 5b (bottom).
tion of carbinols 9a,b and chemical correlation of carbinols 9b,c
8
with diols of known absolute configuration. Thus, the X-ray struc-
ture of adducts 9a and 9b showed an (S)-absolute configuration at
the new stereogenic center (Fig. 3), revealing that the nucleophilic
attack took place from the re-face of the carbonyl group. In turn,
the absolute configuration of the new stereogenic center of
acid and successive reduction of the corresponding Michael adduct
4
with LiAlH afforded hydroxythiol 7 in 91% overall yield. Com-
pound 7, in a benzene solution, was reacted with dimethoxyme-

1
590
M. E. Vargas-Díaz et al. / Tetrahedron: Asymmetry 23 (2012) 1588–1595
Table 1
Diastereoselective nucleophilic additions to macroheterocycles 5a,b
15
18
S 13
S
11
22
S
S
S
S
21
Nu-
3
8
+
1
THF, rt
O
5
O
O
R
O
R
O
O
R1
OH
R1
R
O
OH
5
5
a R= Ph
b R=Me
9
10
R1
Major adduct
Yield (%)
⁄
9:10 (dr)
Entry
R
Nucleophile
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH
CH
MeMgBr
EtMgBr
BnMgBr
PhC„CMgBr
CH„CMgBr
Me
Et
Bn
PhC„C–
CH„C–
CH @CH–
2
Me
Et
H
H
9a
9b
9c
9d
9e
9f
9a
9b
9g
9g
98
98
98
92
90
90
55
60
99
99
95
95
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
7:3
2
CH @CHMgBr
MeLi
EtLi
7:3
LiAlH
4
>7:3
>6:4
1:>99
9:1
1
1
1
0
1
2
NaBH
4
⁄
⁄
3
3
PhMgBr
BnMgBr
Ph
Bn
10a
9h
⁄
Diastereomeric ratio obtained by 1H NMR integration of H-5 signals in the crude reaction mixture. Major adduct 10a in entry 11 corresponds to minor adduct obtained in
⁄⁄
1 3
entry 1 (R = Ph; R = CH ).
carbinol 10a should be (R) (entry 11) since in this case the acyl
group (CH CO–) and the incoming nucleophile (PhMgBr) are oppo-
resulting Cram chelated model7 by coordinating the C@O group
of the acyl moiety and O4 or O6, respectively, with the nucleophilic
reagent, as shown in Figure 4. In model 5a.1, which shows a similar
conformation to compound 5b in the solid state (Fig. 2), a strong
steric interaction between the nucleophile and the geminal methyl
groups of the pinane system can be observed. In contrast, model
5a.2 yields a more stable chelated complex since the coordinating
nucleophile lacks significant steric interactions. Such a transition
state will allow a free nucleophile approach onto the re-face of
the C@O group, which is in close agreement with the absolute con-
figuration shown at the carbinol stereogenic center of the addition
products.
3
site to those shown in entry 1. As mentioned above, the stereofacial
preference of the nucleophilic addition onto 5a was also confirmed
by chemical correlation with diols 11a and 11b of known absolute
8
configuration. Oxidative hydrolysis of carbinols 9b and 9c, fol-
lowed by reduction of the intermediate
NaBH , afforded the corresponding tertiary carbinols 11a and
1b with excellent enantiomeric excesses (Scheme 2), while enan-
a-hydroxyaldehydes with
4
1
tiopure chiral auxiliary diol 8 was recovered.
Furthermore, Table 1 shows that the addition of MeLi and EtLi
(
(
entries 7 and 8) onto compound 5a afforded the same products
carbinols 9a and 9b, respectively), when this compound was trea-
ted with MeMgBr and EtMgBr (entries 1 and 2). Treatment of 5a
with hydrides (LiAlH and NaBH , entries 9 and 10) also gave car-
3
. Conclusion
4
4
binol 9g. Accordingly, it was possible to propose that all nucleo-
philic additions take place preferably on the same face of the
carbonyl group.
Compounds 5a,b provide a new structural feature in the series
of chiral auxiliaries prepared from (1R)-(–)-myrtenal 6. Although
the observed diastereoselectivities of lithium alkylides and hy-
drides were lower when compared to those obtained with acyl-
macroheterocycle 4, the addition of Grignard reagents is still
highly diastereoselective, affording the antipode of diols obtained
According to the observed nucleophilic order RMgX > RLi > -
4 4
LiAlH P NaBH , it is feasible to propose that the preferred product
7
is generated through a rigid Cram chelated model in which the
diastereoselectivity depends on the coordinating capability of the
metal belonging to the nucleophilic reagent; this is in agreement
with the same mechanism as observed for previously described
5
f
with 4 after completion of the present protocol. In addition, the
hydrolysis of the resulting carbinols can be achieved under milder
conditions as compared to those employed when acylmacrohete-
5
a–e
structural analogues.
In this context, despite conformations of
5
f
rocyle 4 was used. A mechanism for the nucleophilic addition
onto compounds 5a,b has been proposed, in which transition state
the acyl group and the macrocycle differing in compounds 5a
and 5b in the solid state, it can be inferred that the coordinating
site of the nucleophilic reagent must be the same in both com-
pounds, since the X-ray structures of carbinols 9a and 9b and the
chemical correlation of 9b and 9c strongly support the idea that
the addition of the nucleophile takes place from the re-face. Fur-
thermore, the inverse protocol followed for the nucleophilic addi-
tion on both compounds afforded epimeric products at the carbinol
center (entries 1, 11, 3 and 12). This implies that the resulting che-
lated complex formed between the C@O groups of the acetyl and
benzoyl moieties with the nucleophilic reagent must be similar
in the corresponding transition state. Under this premise, transi-
tion states 5a.1 and 5a.2 were proposed taking into account the
5
a.2, where chelation takes place between the carbonyl group oxy-
gen atom and O6, satisfactorily explains the observed re-facial
stereoselectivity.
4. Experimental
4.1. General
Melting points were determined on an Electrothermal capillary
melting point apparatus and are uncorrected. Optical rotations
were measured at 589 nm using a 1 dm cell on a JASCO DIP-370

M. E. Vargas-Díaz et al. / Tetrahedron: Asymmetry 23 (2012) 1588–1595
1591
15
S
S
H
H
H 8
2
X
1
6
H
4
O
O
Mg
H
O
R
5
a.1
15
S
S
H
H
8
H
2
1
6
H
O
X
4
O
Mg
R
H
O
5
a.2
Figure 4. Non-preferred 5a.1 (top) and preferred 5a.2 (bottom) transition states for
the diastereoselective nucleophilic addition on acylmacrocycles 5a,b.
(
HRFABMS) were recorded on a VG 7070 high-resolution mass
spectrometer at the UCR Mass Spectrometry Facility, University
of California, Riverside, CA. High resolution electronic impact mass
spectra (HREIMS) were determined using a JEOL GCmate spec-
trometer. Thin layer chromatograms were performed on precoated
TLC sheets of silica gel 60 F254 (E. Merck). Flash chromatography
was carried out using silica gel (Merck 230–400 mesh). The THF
used in the nucleophilic additions was distilled from Na immedi-
ately prior to use, and all other reagents were used without further
purification.
4
.2. Preparation of macroheterocycles 5a,b
Figure 3. X-Ray structures of carbinols 9a (top) and 9b (bottom).
4
1
.2.1. (1S,2R,8R,9S,13S,17S)-4,6-Dioxa-14,16-dithia-5-benzoyl-
0,10,20,20-tetramethylpentacyclo-[17.1.1.1 .0 .0 ]-
9
,11 2,17 8,13
polarimeter. Infrared spectra were recorded on a Perkin-Elmer
docosane 5a
1
13
Spectrum 2000 spectrophotometer. H and C NMR spectra were
obtained on a Varian Mercury spectrometer at 300 and 75.4 MHz,
respectively, or 500 and 125 MHz on a Varian System as specified,
A well-stirred solution of 500 mg (1.3 mmol) of diol 8, 406 mg
(1.95 mmol) of 2,2-diethoxyacetophenone, and 50 mg of p-TsOH
in 8 mL of benzene was stirred at 60 °C for 3 h. The reaction mix-
using CDCl
3
as the solvent and TMS as the internal standard.
ture was poured into a cold saturated solution of NaHCO , ex-
3
The high-resolution fast atomic bombardment mass spectra
tracted with DCM, washed with a saturated solution of NaHCO3
1
5
18
S 13
S
1
1
OH
S
S
a) CH CN/H O(9:1)
3
2
2
1
22
3
8
DCM, p-TsOH
OH
Ph
+
1
O
5
O
R1
b) NaBH , EtOH
4
OH OH
HO
R1
Ph
1
11a R = Et
1b R = Bn
8
1
1
1
9
9
b R = Et
1
c R = Bn
Scheme 2. Hydrolysis of adducts 9b and 9c.

1
592
M. E. Vargas-Díaz et al. / Tetrahedron: Asymmetry 23 (2012) 1588–1595
(
2 ꢀ 50 mL), dried over anhydrous Na
2
SO4, and concentrated to
4.3.1. (1S,2R,8R,9S,13S,17S)-4,6-Dioxa-14,16-dithia-5-[(S)-1-
phenyleth-1-yl-1-ol]-10,10,20,20-tetramethylpentacyclo-[17.1.
1.1 .0 .0 ]-docosane 9a
dryness. The residue was flash chromatographed using a mixture
of hexane/EtOAc (9:1) as the eluent, affording 260 mg (41%) of
9
,11 2,17 8,13
2
5
dodecaheterocycle 5a as a white solid, mp 166–167 °C, ½
a
ꢁ
¼
To a solution of 300 mg (0.6 mmol) of macroheterocycle 5a in
5 mL of anhydrous THF was added 0.3 mL (0.9 mmol) of MeMgBr
(3.0 M) under a nitrogen atmosphere. After the usual work-up,
303 mg (98%) of carbinol 9a was obtained as a white solid mp
D
ꢂ1
1
þ294:5 (c 0.49, CHCl
3
). IR (cm
)
m
max: 2909, 1467, 1057, 689.
H
NMR (500 MHz, CDCl
3
): d 8.15 (dd, 2H, J = 8.4, 1.3 Hz, H-o), 7.55
tt, 1H, J = 7.5, 1.3 Hz, H-p), 7.43 (bt, 2H, J = 8.4 Hz, H-m), 5.25 (s,
(
2
D
5
ꢂ1
1
3
H, H-5), 4.01 (dd, 1H, J = 9.9, 3.8 Hz, H-3a), 3.90 (dd, 1H, J = 9.9,
.3 Hz, H-3b), 3.86 (d, 1H, J = 14.2 Hz, H-15a), 3.85 (dd, 1H,
167–168 °C, ½
aꢁ
¼ þ163 (c 0.20, CHCl
3
). IR (cm
)
m
max: 3733,
1
2915, 1448, 1385, 1050, 1027, 757. H NMR (300 MHz, CDCl
3
): d
J = 9.4, 3.3 Hz, H-17), 3.82 (d, 1H, J = 14.2 Hz, H-15b), 3.75–3.67
m, 3H, H-7a, H-7b, H-13), 2.60–2.52 (m, 2H, H-12eq, H-18eq),
7.49 (dd, 2H, J = 8.5, 1.5 Hz, H-o), 7.33 (t, 2H, J = 8.5 Hz, H-m),
7.26 (t, 1H, J = 8.5 Hz, H-p), 4.35 (s, 1H, H-5), 3.87–3.60 (m, 6H,
H-3a, H-3b, H-7a, H-15a, H-15b, H-17), 3.46 (m, 1H, H-13), 3.13
(dd, 1H, J = 8.8, 4.3 Hz, H-7b), 2.75 (bs, 1H, OH), 2.63–2.33 (m,
4H, H-12eq, H-18eq, H-21eq, H-22eq), 2.26 (m, 1H, H-8), 2.08–
1.82 (m, 7H, H-1, H-2, H-9, H-11, H-12ax, H-18ax, H-19), 1.57 (s,
3H, Me-28), 1.19 (s, 3H, Me-26), 1.16 (d, 1H, J = 9.9 Hz, H-22ax),
1.15 (s, 3H, Me-24), 1.07 (s, 3H, Me-25), 0.97 (d, 1H, J = 9.9 Hz, H-
(
2.47 (m, 1H, H-21eq), 2.41 (m, 1H, H-22eq), 2.28 (m, 1H, H-8),
2.13–1.90 (m, 7H, H-2, H-1, H-12ax, H18ax, H-19, H-9, H-11),
1.20 (s, 3H, Me-26), 1.15 (d, 1H, J = 9.7 Hz, H-22ax), 1.10 (s, 3H,
Me-24), 1.05 (d, 1H, J = 9.7 Hz, H-21ax), 1.04 (s, 3H, Me-25), 0.87
1
3
(
(
7
(
s, 3H, Me-23). C NMR (125 MHz, CDCl
C-i), 133.4 (C-p), 129.6 (C-m), 128.2 (C-o), 102.3 (C-5), 70.9 (C-
), 70.8 (C-3), 49.7 (C-2), 48.9 (C-8), 46.9 (C-1), 45.4 (C-9), 42.4
C-19), 41.9 (C-11), 38.8 (C-20), 38.5 (C-10), 37.5 (2C, C-18 and
C-12), 35.7 (C-21), 34.6 (C-15), 34.1 (C-13), 33.7 (C-17), 33.4 (C-
2), 27.8 (C-24), 27.7 (C-26), 24.9 (C-23), 24.4 (C-25). HREIMS
Calcd for C29 (M+1): 501.2497. Found: 501.2501.
3
): d 194.0 (CO), 134.1
1
3
3
21ax), 0.84 (s, 3H, Me-23). C NMR (75.4 MHz, CDCl ): d 144.2
(Ci), 127.8 (C-m), 126.9 (C-p), 125.8 (C-o), 106.8 (C-5), 76.1 (C-
27), 75.9 (C-7), 69.9 (C-3), 50.3 (C-2), 49.5 (C-8), 46.6 (C-1), 45.1
(C-9), 42.2 (C-19), 41.5 (C-11), 38.3 (C-10), 37.9 (C-20), 37.6 (C-
18), 37.1 (C-12), 35.8 (C-21), 35.5 (C-13), 35.3 (C-15), 34.0 (C-17),
2
40 2 3
H S O
3
2.4 (C-22), 28.0 (C-26), 27.2 (C-24), 25.2 (C-25), 25.0 (C-28),
4
1
.2.2. (1S,2R,8R,9S,13S,17S)-4,6-Dioxa-14,16-dithia-5-acetyl-
23.6 (C-23). HREIMS Calcd for C30
Found: 517.2794.
44 2 3
H S O : (M+1): 517.2810.
0,10,20,20-tetramethypentacyclo-[17.4.1.1.19 .0 .0 ]-
,11
2,17 8,13
docosane 5b
A well-stirred solution of 500 mg (1.3 mmol) of diol 8, 230 mg
4.3.2. (1S,2R,8R,9S,13S,17S)-4,6-Dioxa-14,16-dithia-5-[(S)-1-phe-
(
1.95 mmol) of pyruvic aldehyde dimethyl acetal, and 50 mg of
p-TsOH in 8 mL of benzene was refluxed for 3 h. The reaction mix-
ture was poured into a cold saturated solution of NaHCO , ex-
tracted with DCM, washed with a saturated solution of NaHCO
SO , and concentrated to
nylpro-1-yl-1-ol]-10,10,20,20-tetramethylpentacyclo-[17.1.1.
9
,11 2,17 8,13
1
.0 .0 ]-docosane 9b
3
To a solution of 300 mg (0.6 mmol) of macroheterocycle 5a in
3
5 mL of anhydrous THF was added 0.3 mL (0.9 mmol) of EtMgBr
(3.0 M) under a nitrogen atmosphere. After the usual work-up,
311 mg (98%) of carbinol 9b was obtained as a white solid mp
(
2 ꢀ 50 mL), dried over anhydrous Na
2
4
dryness. The residue was flash chromatographed using a mixture
of hexane/EtOAc (19:1) as the eluent, affording 228 mg (41%) of
2
D
5
ꢂ1
162–163 °C, ½
aꢁ
¼ þ242 (c 0.10, CHCl
3
). IR (cm
)
m
max: 3563,
2
D
5
1
dodecaheterocycle 5b as a white solid, mp 103–105 °C, ½
aꢁ
¼
2908, 1449, 1385, 1061, 756. H NMR (500 MHz, CDCl
3
): d 7.43
ꢂ1
þ324:9 (c 0.40, CHCl
3
). IR (cm
)
m
max: 3425, 2910, 1469, 1061.5,
(d, 2H, J = 7.8 Hz, H-o), 7.34 (t, 2H, J = 7.8 Hz, H-m), 7.23 (t, 1H,
J = 7.8 Hz, H-p), 4.41 (s, 1H, H-5), 3.86–3.75 (m, 4H, H-3a, H-7a,
H-15a, H-15b), 3.62–3.56 (m, 2H, H-3b, H-13), 3.44–3.40 (m, 2H,
H-7b, H-17), 2.62 (bs, 1H, OH), 2.57 (m, 2H, H-12eq, H-18eq),
2.42–2.38 (m, 2H, H-21eq, H-22eq), 2.30 (bq, 1H, J = 4.9 Hz, H-8),
2.04–1.87 (m, 8H, H-2, H-1, H-11, H-12ax, H-18ax, H19, H-28a,b),
1.73 (t, 1H, J = 5.8 Hz, H-9), 1.19 (s, 3H, Me-26), 1.16 (d, 1H,
J = 9.8 Hz, H-22ax), 1.13 (s, 3H, Me-24), 1.02 (s, 3H, Me-25), 0.91
(d, 1H, J = 9.8 Hz, H-21ax), 0.90 (s, 3H, Me-23), 0.70 (t, 1H,
1
6
68.5. H NMR (500 MHz, CDCl
m, 5H, H-3a, H-3b, H-15a, H-15b, H-17), 3.65 (t, 1H, J = 9.0 Hz,
H-7a), 3.64 (m, 1H, H-13), 3.51 (dd, 1H, J = 9.0, 4.2 Hz, H-7b),
3
): d 4.39 (s, 1H, H-5), 3.93–3.79
(
2
2
2
1
1
.63–2.46 (m, 3H, H-12eq, H-18eq, H-22eq), 2.41 (m, 1H, H-21eq),
.29 (m, 1H, H-8), 2.19 (s, 3H, Me-28), 2.16–1.87 (m, 7H, H-1, H-
, H-11, H-12ax, H-18ax, H-19, H-9), 1.23 (s, 3H, Me-26), 1.24 (d,
H, J = 9.8 Hz, H-22ax), 1.20 (s, 3H, Me-24), 1.07 (s, 3H, Me-25),
.05 (d, 1H, J = 9.8 Hz, H-21ax), 0.97 (s, 3H, Me-23). 13C NMR
1
3
(
125 MHz, CDCl
3
): d 204.6 (CO), 104.1 (C-5), 72.2 (C-7), 71.3 (C-
3
J = 7.8 Hz, H-29). C NMR (125 MHz, CDCl ): d 142.2 (C-i), 127.7
3
), 49.8 (C-2), 48.8 (C-8), 47.2 (C-1), 44.7 (C-9), 42.4 (C-11), 41.8
(C-m), 126.5 (C-p), 126.1 (C-o), 106.1 (C-5), 79.1 (C-27), 75.2 (C-
7), 69.6 (C-3), 50.5 (C-2), 49.9 (C-8), 46.4 (C-1), 45.3 (C-9), 42.1
(C-19), 41.6 (C-11), 38.3 (C-20), 38.1 (C-10), 37.6 (C-18), 37.2 (C-
12), 35.9 (C-13), 35.6 (C-21), 35.5 (C-15), 34.4 (C-17), 32.8 (C-22),
28.8 (C-28), 27.9 (C-24), 27.3 (C-26), 24.9 (C-25), 23.7 (C-23), 7.0
(
C-19), 38.9 (C-10), 38.4 (C-20), 37.6 (C-12), 37.4 (C-18), 36.0 (C-
2
2
1), 34.7 (C-15), 33.9 (C-13), 33.2 (C-17), 32.4 (C-22), 28.2 (C-26),
7.4 (C-24), 25.4 (C-25), 25.1 (C-28), 24.1 (C-23). HRFABMS Calcd
for C29
40 2 3
H S O +Na: 461.2160. Found: 461.2160.
(
C-29). HREIMS Calcd for C31
46 2 3
H S O (M+1): 531.2961. Found:
4
.3. General procedure for the addition of Grignard reagents to
531.2956.
dodecaheterocycle
4
.3.3. (1S,2R,8R,9S,13S,17S)-4,6-Dioxa-14,16-dithia-5[(S)-1,2-
To a solution of 200 mg of dodecaheterocycle 5a or 5b in anhy-
drous THF was added the Grignard reagent (1.5–4.0 equiv) at
ꢂ78 °C under a nitrogen atmosphere. After stirring for 2 h at the
same temperature, the reaction mixture was allowed to warm to
room temperature and stirred for a further 2 h. The reaction mix-
diphenyleth-1-yl-1-ol]-10,10,20,20-tetramethylpentacyclo-[17.
1.1.1 .0 .0 ]-docosane 9c
To a solution of 300 mg (0.6 mmol) of macroheterocycle 5a in
5 mL of anhydrous THF was added 0.2 mL (0.9 mmol) of
9
,11 2,17 8,13
2
PhCH MgBr (3.0 M) under a nitrogen atmosphere. After the usual
4
ture was quenched with 100 mL of a saturated solution of NH Cl,
after which the THF was eliminated by evaporation and the
remaining emulsion was extracted with ethyl ether. The organic
work-up, 347 mg (98%) of carbinol 9c was obtained as a white solid
2
5
ꢂ1
mp 124–125 °C, ½
a
ꢁ
¼ þ196 (c 0.20, CHCl
3
). IR (cm
)
m
max: 3560,
D
1
2911, 1440, 1380, 1164, 710, H NMR (300 MHz, CDCl
3
): d 7.36 (dd,
0
0
layer was washed with a saturated solution of NH
4
Cl, dried over
2H, J = 8.2, 2.2 Hz, H-o), 7.28–7.19 (m, 3H, H-o , H-p ), 7.12–7.07 (m,
0
anhydrous Na SO , and evaporated to dryness, giving the corre-
2
4
3H, H-p,m), 6.95–6.92 (m, 2H, H-m ), 4.6 (s, 1H, H-5), 3.95 (dd, 1H,
sponding pure diastereoisomer 9a–f or 10a–f as a colorless oil or
J = 9.1, 6.0 Hz, H-3a), 3.87–3.75 (m, 3H, H-7a, H-15a, H-15b), 3.62–
a white solid, as specified.
3.53 (m, 3H, H-3b, H-7b, H-17), 3.44 (m, 1H, H-13), 3.25 (d, 1H,

M. E. Vargas-Díaz et al. / Tetrahedron: Asymmetry 23 (2012) 1588–1595
1593
J = 13.8 Hz, H-28a), 3.17(d, 1H, J = 13.8 Hz, H-28b), 2.84 (bs, 1H,
OH), 2.58–2.29 (m, 5H, H-8, H-12eq, H-18eq, H-21eq, H-22eq),
28.2 (C-26), 27.3 (C-24), 25.2 (C-25), 23.8 (C-23). HRFABMS Calcd
for C31 +Na: 549.2484. Found: 549.2575.
42 2 3
H S O
2
.06–1.88 (m, 6H, H-2, H-9, H-11, H-12ax, H-18ax, H-19), 1.69
td, 1H, J = 6.0, 1.3 Hz, H-9), 1.23 (s, 3H, Me-26), 1.16 (d, 1H,
J = 9.9 Hz, H-22ax), 1.08 (s, 3H, Me-24), 0.98 (s, 3H, Me-25), 0.95
(
4.3.6. (1S,2R,8R,9S,13S,17S)-4,6-Dioxa-14,16-dithia-5-[(S)-1-
phenyl-2-propyn-1-yl-1-ol]-10,10,20,20-tetramethylpentacy-
1
3
9,11 2,17 8,13
(
(
(
(
s, 3H, Me-23), 0.92 (d, 1H, J = 9.9 Hz, H-21ax).
C
NMR
clo-[17.1.1.1 .0 .0 ]-docosane 9f
0
0
75.4 MHz, CDCl
3
): d 142.3 (C-i), 136.6 (C-i ), 130.7 (C-m ), 127.5
To a solution of 300 mg (0.6 mmol) of macroheterocycle 5a in
5 mL of anhydrous THF was added 1.8 mL (0.9 mmol) of
0
0
C-o ,p), 126.6 (C-o), 126.3 (C-p ), 126.0 (C-m), 104.7 (C-5), 78.9
C-27), 74.1 (C-7), 69.6 (C-3), 50.5 (C-2), 50.0 (C-8), 46.4 (C-1),
2
CH @CHMgBr (0.5 M) under a nitrogen atmosphere. After the usual
4
(
3
2
6
5.5 (C-9), 43.5 (C-28), 42.0 (C-19), 41.7 (C-11), 38.3 (C-10), 38.2
C-20), 37.5 (C-18), 37.3 (C-12), 35.9 (C-21), 35.5 (C-13, C-15),
4.5 (C-17), 33.2 (C-22), 27.9 (C-24), 27.5 (C-26), 24.8 (C-25),
work-up, 284 mg (90%) of 9f was obtained as a white solid, mp
2
5
ꢂ1
151–152 °C. ½
a
ꢁ
¼ þ236 (c 0.50, CHCl
3
). IR (cm
)
m
max: 3434,
): d
D
1
2909, 1449, 1366, 1127, 1053, 754. H NMR (500 MHz, CDCl
3
3.9 (C-23). HRFABMS Calcd for C36
15.2953.
H S
48 2
O
3
+Na: 615.2942. Found:
7.49 (dd, 2H, J = 7.9, 1.3 Hz, H-o), 7.31 (t, 2H, J = 7.9 Hz, H-m),
7.23 (bt, 1H, J = 7.9 Hz, H-p), 6.52 (dd, 1H, J = 17.3, 10.8 Hz, H-28),
5
.46 (dd, 1H, J = 17.3, 1.6 Hz, H-29a), 5.25 (dd, 1H, J = 10.8,
4
.3.4. (1S,2R,8R,9S,13S,17S)-4,6-Dioxa-14,16-dithia-5-[(S)-1,2-
1.6 Hz, H-29b), 4.46 (s, 1H, H-5), 3.83 (dd, 1H, J = 10.1, 4.7 Hz, H-
3a), 3.82 (d, 1H, J = 14.1 Hz, H-15a), 3.78 (d, 1H, J = 14.1 Hz, H-
15b), 3.71 (dd, 1H, J = 10.1, 2.5 Hz, H-3b), 3.68 (t, 1H, J = 8.7, H-
7a), 3.60 (m, 1H, H-17), 3.50 (m, 1H, H-13), 3.11 (dd, 1H, J = 8.7,
3.9 Hz, H-7b), 2.84 (bs, 1H, OH), 2.57 (m, 1H, H-12eq), 2.52–2.40
(m, 2H, H-18eq, H-21eq), 2.36 (m, 1H, H-22eq), 2.26 (m, 1H, H-8),
2.08–1.87 (m, 6H, H-2, H-1, H-11, H-12ax, H-18ax, H-19), 1.79
(td, 1H, J = 6.1, 2.2 Hz, H-9), 1.16 (d, 1H, J = 9.8 Hz, H-22ax), 1.15
(s, 6H, Me-26, Me-24), 0.96 (d, 1H, J = 9.8 Hz, H-21ax), 0.95 (s,
diphenyl-2-propyn-1-yl-1-ol]-10,10,20,20-tetramethylpenta-
cyclo-[17.1.1.1 .0 .0 ]-docosane 9d
9
,11 2,17 8,13
To a solution of 300 mg (0.6 mmol) of macroheterocycle 5a in
5
mL of anhydrous THF was added 0.9 mL (0.9 mmol) of
PhC CMgBr (1.0 M) under a nitrogen atmosphere. After the usual
work-up, 324 mg (90%) of carbinol 9d was obtained as a white so-
N
2
D
5
ꢂ1
lid mp 90–91 °C. ½
a
ꢁ
¼ þ247 (c 0.23, CHCl
3
). IR (cm
917, 1450, 1366, 1131, 1065, 757. H NMR (300 MHz, CDCl
.72 (dd, 2H, J = 8.8, 2.2 Hz, H-o), 7.48 (dd, 2H, J = 7.1, 2.2 Hz, H-
)
m
max: 3558,
1
2
7
3
): d
1
3
3
3H, Me-25), 0.84 (s, 3H, Me-23). C NMR (125 MHz, CDCl ): d
0
0
0
o ), 7.40–7.29 (m, 6H, H-p,p , m,m ), 4.46 (s, 1H, H-5), 3.92 (dd,
H, J = 10.0, 3.1 Hz, H-3a), 3.90 (d, 1H, J = 13.9 Hz, H-15a), 3.80
d, 1H, J = 13.9 Hz, H-15b), 3.79–3.66 (m, 3H, H-3b, H-7a, H-17),
.56 (m, 1H, H-13), 3.40 (bs, 1H, OH), 3.31 (dd, 1H, J = 8.8, 3.7 Hz,
H-7b), 2.60–2.42 (m, 4H, H-12eq, H-18eq, H-21eq, H-22eq), 2.36
m, 1H, H-8), 2.06–1.91 (m, 6H, H-2, H-1, H-11, H-12ax, H-18ax,
H-19), 1.78 (td, 1H, = 6.1, 2.2 Hz, H-9), 1.23 (d, 1H, J = 9.8 Hz, H-
142.6 (C-i), 140.1 (C-28), 127.9 (C-m), 127.1 (C-p), 126.9 (C-o),
115.1 (C-29), 106.5 (C-5), 78.2 (C-27), 76.7 (C-7), 69.6 (C-3), 50.5
(C-2), 49.2 (C-8), 46.5 (C-1), 45.1 (C-9), 42.2 (C-19), 41.5 (C-11),
38.4 (C-20), 37.9 (C-10), 37.7 (C-18), 37.2 (C-12), 35.7 (C-21),
35.4 (C-15), 35.3 (C-13), 34.3 (C-17), 32.2 (C-22), 27.9 (C-26),
27.2 (C-24), 25.4 (C-25), 23.7 (C-23). HREIMS Calcd for
1
(
3
(
31 44 2 3
C H S O (M+1): 529.2805. Found: 529.2796.
2
2
2ax), 1.19 (s, 3H, Me-26), 1.12 (s, 3H, Me-24), 1.10 (s, 3H, Me-
1
3
5), 0.97 (d, 1H, J = 9.8 Hz, H-21ax), 0.83 (s, 3H, Me-23). C NMR
4.3.7. (1S,2R,8R,9S,13S,17S)-4,6-Dioxa-14,16-dithia-5-[(R)-1-
0
(
(
(
75.4 MHz, CDCl
3
): d 140.2 (C-i), 132.0 (C-o ), 128.5 (C-p), 128.4
phenyleth-1-yl-ol]-10,10,20,20-tetramethylpentacyclo-
0
0
0
9,11 2,17 8,13
C-m,m ), 128.2 (C-p ), 126.9 (C-o), 122.9 (C-i ), 106.5 (C-5), 89.9
C-28), 86.1 (C-29), 76.9 (C-27), 75.2 (C-7), 69.7 (C-3), 50.5 (C-2),
[17.1.1.1 .0 .0 ]-docosane 10a
To a solution of 300 mg (0.68 mmol) of macroheterocycle 5b in
5 mL of anhydrous THF was added 0.9 mL (0.9 mmol) of PhMgBr
(1.0 M) under a nitrogen atmosphere. After the usual work-up,
311 mg (98%) of carbinol 10a was obtained as a white solid
4
9.4 (C-8), 46.7 (C-1), 45.2 (C-9), 42.3 (C-19), 41.5 (C-11), 38.5
(
C-20), 37.9 (C-10), 37.7 (C-18), 37.1 (C-12), 35.9 (C-21), 35.2 (C-
1
2
6
5), 35.1 (C-13), 34.5 (C-17), 32.0 (C-22), 28.1 (C-26), 27.2 (C-24),
5.1 (C-25), 23.7 (C-23). HRFABMS Calcd for C37
25.2786. Found: 625.2761.
2
D
5
ꢂ1
H
46
2
S O
3
+Na:
mp = 103–105 °C, ½
3432, 2909, 1452, 1387, 1165, 754. H NMR (300 MHz, CDCl
.51 (d, 2H, J = 7.8 Hz, H-o), 7.32 (t, 1H, J = 7.8 Hz, H-m), 7.23 (t,
a
ꢁ
¼ þ333 (c 0.33, CHCl
3 max
). IR (cm ) m :
1
3
): d
7
4
.3.5. (1S,2R,8R,9S,13S,17S)-4,6-Dioxa-14,16-dithia-5-[(S)-1-
1H, J = 7.8 Hz, H-p), 4.37 (s, 1H, H-5), 3.91–3.61 (m, 5H, H-3a, H-
7a, H-15a, H-15b, H-17), 3.56 (dd, 1H, J = 10.1, 2.5 Hz, H-3b), 3.43
(m, 1H, H-13), 3.14 (dd, 1H, J = 8.9, 4.6 Hz, H-7b), 2.73 (bs, 1H,
OH), 2.64–2.41 (m, 3H, H-12eq, H-18eq, H-21eq), 2.34 (m, 1H, H-
8), 2.20–2.17 (m, 1H, H-22eq), 2.10–1.88 (m, 6H, H-2, H-1, H-11,
H-12ax, H-18ax, H-19), 1.72 (m, 1H, H-9), 1.53 (s, 3H, Me-28),
1.24 (s, 3H, Me-26), 1.13 (s, 3H, Me-24), 1.12 (d, 1H, J = 9.8 Hz, H-
phenyl-2-propyn-1-yl-1-ol]-10,10,20,20-tetramethylpentacyclo-
9
,11 2,17 8,13
[
17.1.1.1 .0 .0 ]-docosane 9e
To a solution of 300 mg (0.6 mmol) of macroheterocycle 5a in
5
mL of anhydrous THF was added 1.8 mL (0.9 mmol) of
HC CMgBr (0.5 M) under a nitrogen atmosphere. After the usual
work-up, 309 mg (98%) of carbinol 9e was obtained as a white solid
N
2
D
5
ꢂ1
mp 135–136 °C, ½
306, 2910, 1450, 1386, 1163, 1063, 755. H NMR (300 MHz,
CDCl ): d 7.67 (dd, 2H, J = 8.2, 1.6 Hz, H-o), 7.44–7.22 (m, 3H, H-
m,p), 4.41 (s, 1H, H-5), 3.92–3.65 (m, 5H, H-3a, H-7a, H-3b, H-
5a, H-15b), 3.59 (m, 1H, H-17), 3.44 (m, 1H, H-13), 3.37 (bs, 1H,
OH), 3.27 (dd, 1H, J = 8.8, 3.9 Hz, H-7b), 2.68–2.24 (m, 2H, H-
aꢁ
¼ þ180:3 (c 0.35, CHCl
3
). IR (cm
)
m
max
:
22ax), 1.05 (s, 3H, Me-25), 0.99 (d, 1H, J = 9.8 Hz, H-21ax), 0.86
1
13
3
3
(s, 3H, Me-23). C NMR (75.4 MHz, CDCl ): 144.6 (C-i), 127.8
3
(C-m), 126.8 (C-p), 125.7 (C-o), 106.8 (C-5), 76.2 (C-7), 75.0 (C-
27), 70.4 (C-3), 50.0 (C-2), 49.5 (C-8), 46.9 (C-9), 44.8 (C-1), 42.2
(C-11), 41.5 (C-19), 38.6 (C-20), 38.0 (C-10), 37.4 (C-12), 37.3
(C-18), 36.0 (C-21), 35.3 (C-13), 35.11 (C-15), 33.5 (C-17), 32.5
(C-22), 28.2 (C-26), 27.2 (C-24), 25.0 (C-25), 24.9 (C-28), 23.6 (C-
1
12eq, H-29), 2.52–2.40 (m, 2H, H-18eq, H-21eq), 2.39–2.26 (m,
2H, H-8, H-22eq), 2.10–1.88 (m, 6H, H-2, H-1, H-11, H-12ax, H-
18ax, H-19), 1.82 (m, 1H, H-9), 1.20 (d, 1H, J = 9.9 Hz, H-22ax),
1.20 (s, 3H, Me-26), 1.14 (s, 3H, Me-24), 1.08 (s, 3H, Me-25), 0.96
23). HREIMS Calcd for
517.2794.
30 44 2 3
C H S O (M+1): 517.2810. Found:
1
3
(
(
(
2
(
d, 1H, J = 9.9 Hz, H-21ax), 0.79 (s, 3H, Me-23).
75.4 MHz, CDCl ): d 139.8 (C-i), 128.3 (C-p), 128.1 (C-m), 126.8
C-o), 106.4 (C-5), 84.6 (C-28), 76.7 (C-27), 74.9 (C-7), 74.6 (C-
9), 69.8 (C-3), 50.6 (C-2), 49.6 (C-8), 46.5 (C-1), 45.3 (C-9), 42.4
C-19), 41.6 (C-11), 38.8 (C-20), 38.1 (C-10), 37.9 (C-18), 37.1 (C-
2), 35.9 (C-21), 35.7 (C-13), 35.5 (C-15), 35.1 (C-17), 32.0 (C-22),
C
NMR
4.3.8. (1S,2R,8R,9S,13S,17S)-4,6-Dioxa-14,16-dithia-5[(R)-1-
3
phenylprop-2-yl-2-ol]-10,10,20,20-tetramethylpentacyclo-[17.
9
,11 2,17 8,13
1.1.1 .0 .0 ]-docosane 9h
To a solution of 300 mg (0.68 mmol) of macroheterocycle 5b in
5 mL of anhydrous THF was added 2.7 mL (1.36 mmol) of
PhCH MgBr (3.0 M) under a nitrogen atmosphere. After the usual
2
1

1
594
M. E. Vargas-Díaz et al. / Tetrahedron: Asymmetry 23 (2012) 1588–1595
work-up, 254 mg (70%) of carbinol 9h was obtained as colorless oil,
4
quenched with 100 mL of a saturated solution of NH Cl. The THF
was eliminated by evaporation and the remaining emulsion was
extracted with ethyl ether. The organic layer was washed with a
25
ꢂ1
½
a
ꢁ
¼ þ269:7 (c 0.28, CHCl
3
). IR (cm
)
m
3
max: 3530, 2900, 1453,
): d 7.35–7.20 (m, 5H,
D
1
1
385, 1170, 765. H NMR (300 MHz, CDCl
H-Ar), 4.08 (s, 1H, H-5), 3.95 (dd, J = 10.1, 3.95 Hz, 1H, H-3a),
.92–3.55 (m, 6H, H-7a, H-3b, H-7b, H-15a, H-15b, H-17), 3.55
m, 1H, H-13), 2.84 (d, J = 13.5 Hz, 1H, H-28a), 2.79 (d,
J = 13.5 Hz, 1H, H-28b), 2.62–2.49 (m, 3H, H-8, H-18eq, H-22eq),
4 2 4
saturated solution of NH Cl, dried over anhydrous Na SO , and
concentrated to dryness, giving the corresponding diasteoisomer
9a or 9b as a colorless oil or a white solid, as specified.
3
(
2
1
1
2
.41 (m, 1H, H-12eq), 2.31 (m, 1H, H-21eq), 2.25–1.85 (m, 6H, H-
, H-2, H-11, 12ax, H-18ax, H-19), 1.70 (bt, 1H, J = 6.2 Hz, H-9),
.25 (s, 3H, H-26), 1.21 (s, 3H, H-24), 1.20 (d, 1H, J = 9.9 Hz, H-
2ax), 1.13 (s, 3H, Me-25), 1.10 (s, 3H, H-23), 1.03 (d, 1H,
4
.4.1. (1S,2R,8R,9S,13S,17S)-4,6-Dioxa-14,16-dithia-5-[1-pheny-
9,11
leth-1-yl-ol]-10,10,20,20-tetramethylpentacyclo-[17.1.1.1
2,17 8,13
.0
.0 ]-docosane 9a
To a solution of 300 mg (0.6 mmol) of macroheterocycle 5a in
mL of anhydrous THF was added 0.3 mL (0.9 mmol) of MeLi
13
J = 9.9 Hz, H-21ax), 0.97 (s, 3H, Me-29).
C NMR (75.4 MHz,
3
): d 137.3 (C-i), 130.7 (C-m), 127.9 (C-o), 126.2 (C-p), 105.9
5
CDCl
C-5), 75.6 (C-27), 74.4 (C-7), 67.2 (C-3), 50.4 (C-2), 49.8 (C-8),
7.3 (C-1), 45.2 (C-9), 43.9 (C-28), 42.3 (C-11), 41.7 (C-19), 38.6
(
9
3.0 M) under a nitrogen atmosphere. After the usual work-up,
2 mg (30%) of a mixture of carbinols 9a:10a (7:3) was obtained
as a colorless oil.
(
4
(
(
C-20), 38.2 (C-10), 37.6 (C-12,18), 37.4 (C-21), 36.1 (C-13), 35.1
C-15), 33.6 (C-17), 32.8 (C-22), 28.2 (C-26), 27.4 (C-24), 25.5 (C-
4
.4.2. (1S,2R,8R,9S,13S,17S)-4,6-Dioxa-14,16-dithia-5-[1-phenyl-
2
3), 23.9 (C-29), 22.2 (C-25). HREIMS Calcd for C31
46 3 2
H O S
9,11
pro-1-yl-ol]-10,10,20,20-tetramethylpentacyclo-[17.1.1.1
(
M+1): 531.2967. Found: 531.2972.
2
,17 8,13
.0
.0 ]-docosane 9b
To a solution of 300 mg (0.6 mmol) of macroheterocycle 5a in
4
.3.9. (1S,2R,8R,9S,13S,17S)-4,6-Dioxa-14,16-dithia-5-[(S)-phenyl-
5
0
mL of anhydrous THF was added 1.8 mL (0.9 mmol) of EtLi
.5 M under a nitrogen atmosphere, giving 63 mg (20%) of a mix-
9,11 2,17
methanol]-10,10,20,20-tetramethylpentacyclo-[17.1.1.1 .0
8
,13
.0
]-docosane 9g
Method 1. A solution of 300 mg (0.60 mmol) of dodecahetero-
cycle 5a in 5 mL of dry THF, cooled to ꢂ78 °C, was added to a
well-stirred suspension of 90.8 mg (2.4 mmol) of LiAlH . The mix-
ture of carbinols 9b:10b (7:3) as a colorless oil.
4
.5. General procedure for the hydrolysis of carbinols 9b and 9c
4
and successive reduction of the corresponding aldehydes to
obtain 1,2-propanodiols 11a and 11b
ture was stirred for a further 4 h after which 50 mL of ethyl ether
was added. The reaction was quenched by the slow addition small
of pieces of ice and 1 mL of cold water. The organic layer was
Carbinols 9b or 9c (1 equiv) were treated with a 10% solution of
washed with brine (2 ꢀ 25 mL), dried over Na
2 4
SO , and evaporated
3 2
p-TsOH in 5 mL of CH CN:H O:DCM (8:1:1) at 50 °C for 3 h. The
to dryness, giving 295 mg (86%) of a 73:27 mixture of 9g and 10g
work-up was carried out by adding 1 mL of water. The white pre-
cipitate was filtered, and the filtrate was extracted with a mixture
of hexane/DCM (1:1). The organic layer was dried over anhydrous
Na
lowish oil, whose H NMR spectrum showed the presence of alde-
hydes. This mixture was stirred with NaBH in ethanol at room
temperature for 2 h, after which 10 mL of hot water was added,
and stirring was continued for 20 min after which the mixture
was extracted with ethyl ether. The organic layer was dried over
1
as a colorless oil. H NMR data for 9g (300 MHz, CDCl
3
): d 7.45–
7
1
1
.29 (m, 5H, H-Ar), 4.67 (d, 1H, J = 5.7 Hz, H-5), 4.61 (d, J = 5.7 Hz,
H, H-27), 3.94–3.41 (m, 7H, H-3a, H-3b, H-7a, H-7b, H-15a, H-
5b, H-17), 2.90–2.86 (m, 1H, H-13), 2.73 (s, 1H, OH), 2.73–2.44
2 4
SO , filtered, and concentrated to dryness, giving a crude yel-
1
(
m, 4H, H-12eq, H-18eq, 21eq, H-22eq), 2.29–2.1.99 (m, 7H, H-1,
H-2, H-9, H-11, H-12ax, H-18ax, H-19), 1.25 (s, 3H, Me-26), 1.19
d, 2H, J = 9.9 Hz, H-22ax), 1.13 (s, 3H, Me-24), 1.10 (s, 3H, Me-
5), 1.04 (d, 1H, J = 9.9 Hz, H-21ax), 1.02 (s, 3H, Me-23). HREIMS
4
(
2
1
m/z Calcd for C29
NMR data for 10g (300 MHz, CDCl
4
3
2
42
H O
S
3 2
(M+1): 503.2654. Found: 503.2662.
H
2 4
anhydrous Na SO , evaporated to dryness and the yellowish oil
3
): d 7.45–7.29 (m, 10H, H-Ar),
residue was flash chromatographed using a mixture of hexane/
ethyl acetate (9:1) as the eluent, giving diol 8 and the correspond-
ing diols 11a or 11b.
.38 (d, 1H, J = 6.5 Hz, H-5), 4.28 (d, J = 6.5 Hz, 1H, H-27), 3.94–
.41 (m, 7H, H-3a, H-3b, H-7a, H-7b H-15a, H-15b, H-17), 2.90–
.86 (m, 1H, H-13), 2.73 (s, 1H, OH), 2.73–2.44 (m, 4H, H-12eq,
H-18eq, 21eq, H-22eq), 2.29–2.1.99 (m, 7H, H-1, H-2, H-9, H-11,
H-12ax, H-18ax, H-19), 1.25 (s, 3H, Me-26), 1.19 (d, 1H,
J = 9.9 Hz, H-22ax), 1.13 (s, 3H, Me-24), 1.10 (s, 3H, Me-25), 1.04
4
.5.1. (S)-2-Phenyl-3-butene-1,2-diol 11a
A 200 mg portion of the crude reaction mixture obtained after
4
hydrolysis of adduct 9b was treated with NaBH as described
above. Column chromatography gave 50 mg (80%) of diol 11a as
a
(
d, 1H, J = 9.9 Hz, H-21ax), 1.02 (s, 3H, Me-23). HREIMS m/z Calcd
for C29 (M+1): 503.2654. Found: 503.2662.
Method 2. A solution of 100 mg (0.20 mmol) of dodecahetero-
cycle 5a in 5 mL of ethanol was treated with NaBH (0.40 mmol).
H
42
O
S
3 2
22
D
8
colorless oil.
½
a
ꢁ
¼ þ6:7 (c 0.30, EtOH) >90% ee, Lit.
25
D
1
½
a
7
ꢁ
¼ þ7:3 (c 0.70, EtOH) >98% ee. H NMR (300 MHz, CDCl
3
): d
4
.42–7.35 (m, 3H, H-Ar), 7.28–7.25 (m, 2H, H-Ar), 3.82 (d, 1H,
The reaction mixture was stirred for 1 h, after which it was
quenched by the slow addition of small pieces of ice and 1 mL of
cold water. The organic layer was washed with brine (2 ꢀ 25
J = 11.2 Hz, H-1a), 3.69 (d, 1H, J = 11.2 Hz, H-1b), 2.59 (bs, 1H,
OH), 1.90–1.78 (m, 2H, H-3a,b), 1.25 (bs, 1H, OH), 0.77 (t, 3H,
J = 7.3 Hz, H-4).
2 4
mL), dried over Na SO , and evaporated to dryness, giving
1
08 mg (95%) of a 6:4 mixture of 9g and 10g as a colorless oil.
4
.5.2. (S)-2,3-Diphenylpropane-1,2-diol 11b
A 200 mg portion of the crude reaction mixture obtained after
4
.4. General procedure for the addition of lithium reagents to
4
hydrolysis of adduct 9c was treated with NaBH as described
dodecaheterocycle 5a
above. After purification by column chromatography 53 mg (70%)
2
1
of diol 11b was obtained as a colorless oil. ½
a
ꢁ
¼ þ56:7 (c 0.18,
1
D
8
25
D
To a solution of 200 mg (0.40 mmol) of dodecaheterocycle 5a in
anhydrous THF was added an organolithium reagent (1.5 equiv) at
ꢂ78 °C under a nitrogen atmosphere. After stirring for 2 h at the
same temperature, the reaction mixture was allowed to warm to
room temperature and stirred for 2 h. The reaction mixture was
EtOH) >90% ee, Lit.
NMR (300 MHz, CDCl
½
aꢁ
¼ þ59:5 (c 0.25, EtOH) >95% ee.
H
3
): d 7.38–6.98 (m, 10H, H-2Ar), 3.85 (d, 2H,
J = 12.4 Hz, H-1a), 3.77 (d, 2H, J = 12.4 Hz, H-1b), 3.18 (d, 2H,
J = 13.5 Hz, H-3a), 3.14 (d, 2H, J = 13.5 Hz, H-3b), 2.52 (bs, 1H,
OH), 1.25 (bs, 1H, OH).

M. E. Vargas-Díaz et al. / Tetrahedron: Asymmetry 23 (2012) 1588–1595
1595
Table 2
Single crystal X-ray data collection, processing, and refinement parameters
5
a
5b
9a
9b
Empirical formula
Formula weight
Crystal size (mm)
Wavelength (Å)
Crystal system
Space group
Cell a (Å)
C
29
H
40
O
3
S
2
C
24
H
38
O
3
S
2
C
31
H
46
O
3
S
2
30 44 3 2
C H O S
516.77
500.73
438.66
530.80
0.30 ꢀ 0.2 ꢀ 0.22
0.50 ꢀ 0.47 ꢀ 0.43
0.57 ꢀ 0.55 ꢀ 0.38
0.38 ꢀ 0.30 ꢀ 0.30
0.71073
0.71073
0.71073
1.54184
Monoclinic
P2
Monoclinic
P2
Monoclinic
P2
Monoclinic
P2
1
1
1
1
9.9640(7)
11.0740(9)
13.429(1)
110.665(2)
1386.4(2)
2
11.8571(2)
6.9562(1)
14.8009(3)
98.301(2)
1207.99(4)
2
10.2452(3)
11.3977(3)
12.9552(3)
105.216(3)
1459.77(7)
2
10.227(1)
11.209(2)
12.864(2)
105.81(2)
1418.9(3)
2
b (Å)
c (Å)
b (deg)
Volume (Å )
3
Z
q
l
3
Calc (mg/mm )
1.199
0.219
1.206
0.242
1.208
0.212
1.210
1.914
ꢂ1
(mm
)
F(000)
540
476
576
560
Theta range (deg)
Limiting indices
1.62–26.00
ꢂ12 6 h 6 11
ꢂ13 6 k 6 13
2.78–32.42
ꢂ17 6 h 6 17
ꢂ8 6 k 6 10
0 6 l 6 22
11178
6656
5368/268
1.044
2.73–32.55
ꢂ15 6 h<14
ꢂ16 6 k 6 16
0 6 l 6 19
14736
8618
6058/341
0.975
4.49–59.96
ꢂ11 6 h 6 11
0 6 k 6 12
0 6 l 6 14
2417
2231
2208/357
1.068
0
6 l 6 16
Reflections collected
Reflections unique
Data/parameters
Goodness-of-fit
Final R1 (%)
9278
5095
3196/315
0.884
3.9
3.5
3.9
2.7
wR2 (%)
9.0
7.4
9.9
7.4
Residual e (e.Å3)
ꢂ
0.256/ꢂ0.284
0.156/ꢂ0.217
0.269/ꢂ0.167
0.137/ꢂ0.121
⁄
⁄
⁄
⁄
CCDC deposition No.
,906776
,906777
,906778
,906779
4
.6. Single crystal X-ray structure determination
ico (Grants 105601 and 118493, respectively); and H.L.M.-F. and
F.A.-M. thank CONACYT-Mexico for fellowships. L.G.Z. and M.E.-
D. are fellows of the COFAA-IPN and EDI-IPN programs.
Data collection for 5a was carried out on a Bruker Smart 6000
CCD diffractometer using MoKa radiation (k = 0.7073 Å). A total
of 1321 frames were collected at a scan width of 0.3° and exposure
times of 10 s/frame. The data were processed with the SAINT soft-
ware package, provided by the diffractometer manufacturer, by
using a narrow-frame integration algorithm. Data for 5b and 9a
were collected on an Oxford XCalibur S diffractometer using
References
1.
2.
3.
Gnas, Y.; Glorius, F. Synthesis 2006, 1899.
Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
Bhowmick, K. C.; Joshi, N. N. Tetrahedron: Asymmetry 2006, 17, 1901.
4. (a) Pavlov; Valeri, A. Tetrahedron 2008, 64, 1147; (b) Okano, K. Tetrahedron 2011,
7, 2483.
6
MoK
Bruker-Nonius CAD4 diffractometer using CuK
.54184 Å). Specific information for each crystal studied is given
a
radiation (k = 0.7073 Å). Data for 9b were collected on a
5.
(a) Martinez-Ramos, F.; Vargas-Díaz, M. E.; Chacón-García, L.; Tamariz, J.;
Joseph-Nathan, P.; Zepeda, L. G. Tetrahedron: Asymmetry 2001, 12, 3095; (b)
Vargas-Díaz, M. E.; Chacón-Garcia, L.; Velázquez-Ponce, P.; Tamariz, J.; Joseph-
Nathan, P.; Zepeda, L. G. Tetrahedron: Asymmetry 2003, 14, 3225; (c) Becerra-
Martínez, E.; Velázquez-Ponce, P.; Sánchez-Aguilar, M. A.; Rodríguez-Hosteguín,
A.; Joseph-Nathan, P.; Tamariz, J.; Zepeda, L. G. Tetrahedron: Asymmetry 2007, 18,
2727; (d) Chacón-Garcia, L.; Lagunas-Rivera, S.; Pérez-Estrada, S.; Vargas-Díaz,
M. E.; Joseph-Nathan, P.; Tamariz, J.; Zepeda, L. G. Tetrahedron Lett. 2004, 45,
a
radiation (k =
1
in Table 2. The structures for 5a and 9b were solved by direct
methods using the SIR2002 program while the structures 5b and
9
a were solved using the SIR92 software. All structural refinements
2
were carried out by full-matrix least squares on F using the
SHELX97 program. The non-hydrogen atoms were treated aniso-
tropically, and the hydrogen atoms, included in the structure factor
calculation, were refined isotropically. Atomic coordinates, bond
lengths, bond angles, and anisotropic thermal parameters have
been deposited at the Cambridge Crystallographic Data Center.
2
141; (e) Pérez-Estrada, S.; Lagunas-Rivera, S.; Vargas-Díaz, M. E.; Velázquez-
Ponce, P.; Joseph-Nathan, P.; Zepeda, L. G. Tetrahedron: Asymmetry 2005, 16,
837; (f) Vargas Díaz, M. E.; Joseph Nathan, P.; Tamariz, J.; Zepeda, L. G. Org. Lett.
1
2007, 9, 13.
6
.
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(a) Lynch, J. E.; Eliel, E. L. J. Am. Chem. Soc. 1984, 106, 2943; (b) Frye, S. V.; Eliel, E.
L. J. Am. Chem. Soc. 1988, 110, 484; (c) Chen, X.; Hortelano, E. R.; Eliel, E. L.; Frye,
S. V. J. Am. Chem. Soc. 1990, 112, 6130.
(a) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748; For evidence for
Cram-chelated transition states, see: (b) Frye, S. V.; Eliel, E. L.; Cloux, R. J. Am.
Chem. Soc. 1987, 109, 1862; (c) Chen, X.; Hortelano, E. R.; Eliel, E. L. J. Am. Chem.
Soc. 1990, 112, 6130.
7
Acknowledgments
L.G.Z. acknowledges financial support from SIP/IPN (20100702
and 20110372); L.G.Z. and M.E.V.-D. acknowledge CONACYT-Mex-
8. (a) Colombo, L.; Di Giacomo, M.; Brusotti, G.; Milano, E. Tetrahedron Lett. 1995,
6, 2863; (b) Agami, C.; Couty, F.; Lequesne, Ch. Tetrahedron 1995, 51, 4043.
3