A.C. Sánchez-Chávez et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Table 1
Diastereoselectivity for nucleophilic addition to 3.
Entry
Reagent
Nu-
Major adduct
a/b (dr)a
Abs. conf. at C27 major isomer
1
2
3
4
LiAlH4
NaBH4
MeLi
H-
9a
9a
10a
10b
90:10
88:12
84:16
39:61
S
S
S
R
H-
Me-
Me-
MeMgBr
a
Diastereomeric ratios were calculated by integration of the 1H NMR signals for the H5 position in the crude reaction mixture.
the bis-sulfoxide anion of 9a was attempted with different bases.
For example, NaHDMS failed to form the bis-sulfoxide anion,
whereas NaH, n-BuLi, sec-BuLi, tert-BuLi and MeLi formed the
anion but the adduct easily dehydrated. In contrast, methylmagne-
sium bromide was able to form the bis-sulfoxide anion and reacted
with the aldehydes without further dehydration of the adducts.
Following this procedure, the bis-sulfoxide anion of 9a was reacted
with various aromatic aldehydes and butyraldehyde, producing
adducts 12–17 (Scheme 4).
Reactions conducted at -78 °C afforded slightly higher diastere-
oselectivity but lower yields compared to those at 0 °C (Table 2). Of
the four possible stereoisomers, two adducts with cis and two with
trans relative configuration at C5 and C15 carbinol groups, only
those with relative trans configuration were observed (Fig. 3 and
S23). At the new stereogenic center C28, the major adduct has an
R configuration and the minor adduct an S configuration. In
adducts 12a, 13a, 14a and 17a, the relative trans configuration
and absolute R configuration at C28 were established by single
crystal X-ray diffraction (Fig. S26, S29, S32 and S45, respectively).
ROESY NMR experiments served the same purpose for 15a and
16a (Fig. S35 for 15a and S41 for 16a). The S configuration at C28
of adduct 15b was assigned based on the correlation between
H28 and H13 and between H29 and H17 observed in the ROESY
experiment (Fig. S38). For the minor adducts, the relative trans
configuration at the C5 and C15 carbinol groups was determined
by ROESY NMR experiments recorded on 15b (Fig. S38). Hence,
the resulting correlations of H15 with H13, H17, and H7 provided
evidence of the intra-annular position of H15. The reason that the
cis isomers were not formed is probably due to an unfavorable
abstraction of the proton which would lead to these stereoisomers.
Considering the diastereomeric ratios shown in Table 2 (dr = 75:25
to 90:10), the electrophilic addition seems to not be influenced by
the C6H4-para-substituents of the aldehyde.
Scheme 3. Acid hydrolysis of adduct 10a-b (by the addition of MeLi) and reduction
of the resulting aldehydes. Reagents and conditions: a) HCl (40% v/v), MeCN, 60 °C,
10 h; b) NaBH4, MeOH, 0 °C, 2 h.
result of the almost equal chelation of magnesium to either oxygen
of the acetal group [29,30]. The inversion of diastereoselectivity is
probably caused by chelation of the magnesium atom to the sul-
foxide groups, forming a six-membered ring, which would induce
the geminal methyl groups of the pinane system to adopt such a
conformation to allow stronger chelation to the carbonyl function-
ality along with one oxygen (O6) of an acetal group during the
nucleophilic addition (Fig. 2B). This suggests that such addition
took place via the Si-face, which would likely be the less hindered
one.
Then, the diastereoselectivity of the reaction of the bis-sulfox-
ide anion of 3 with aldehydes was evaluated. Due to the ease of
preparation, adduct 9a was used in this reaction. Formation of
To rationalize the formation of both adducts, a model of a chair-
like reactive conformation is proposed (Fig. 4), maintaining a close
structural analogy with the X-ray perspective view of the chiral
center C28 of adduct 12a (Fig. 3). In the hypothetical model which
would explain the observed diastereoselectivity, the metal coordi-
nates the oxygen of one sulfoxide group, and the incoming alde-
hyde approaches the anion from the Si-face in such a way that
the most voluminous Ar or alkyl groups occupy the least hindered
pseudo-axial position (Fig. 4A). In contrast, when the aldehyde
approaches via the Re-face in the same model, the Ar or alkyl
Scheme 4. Electrophilic addition to 9a (the derivative of 3).
Table 2
Electrophilic addition of various aldehydes to 9a (the directed derivative of 3).
Entry
Electrophile
Major adduct
Yield (%)
dr (R:S) of C28a
0 °C
Abs. conf. at C28 major isomer
0 °C
-78 °C
-78 °C
1
2
3
4
5
6
4-Nitrobenzaldehyde
4-Formylbenzonitrile
4-Fluorobenzaldehyde
Butyraldehyde
p-Anisaldehyde
Benzaldehyde
12a
13a
14a
15a
16a
17a
>99
>99
92
72
70
45
50
58
56
64
30
68 : 32
72 : 28
75 : 25
74 : 26
74 : 26
84 : 16
76 : 24
75 : 25
80 : 20
78 : 22
79 : 21
90 : 10
R
R
R
R
R
R
34
a
Diastereomeric ratio established by integration of the 1H NMR signals for the H5 position in the crude reaction mixture.
Please cite this article as: A. C. Sánchez-Chávez, M. Elena Vargas-Díaz, J. and C. Ontiveros-Rodríguez et al., Synthesis and stereoselective evaluation of a
(1R)-(–)-myrtenal-derived pseudo C2-symmetric dodecaheterocycle as a potential heterofunctional chiral auxiliary, Tetrahedron Letters, https://doi.org/