Synthesis of a new (1R)-(-)-myrtenal-derived dioxadithiadodecacycle and its use as an efficient chiral auxiliary

Article abstract of DOI:10.1021/ol062319f

(Chemical Equation Presented) The new macrocycle 9 (>70% yield from hydroxythiol 10) was treated with several nucleophilic reagents (RMgX, RLi, and LiAlH₄) affording carbinols 12a-j (80-96% yield, >99:1 dr). Oxidative hydrolysis of 12a,c,e, followed by LiAlH₄ reduction of the resulting mixture, gave 16a,c,e in >95% ee,16c being a key precursor for the preparation of fungicide 17. The absolute configuration of 9 and 12j (Nu = H) was established by single-crystal X-ray diffraction analyses and chemical correlation.

Full text of DOI:10.1021/ol062319f

ORGANIC
LETTERS
2007
Vol. 9, No. 1
13-16
Synthesis of a New
(1R)-( )-Myrtenal-Derived
−
Dioxadithiadodecacycle and Its Use as
an Efficient Chiral Auxiliary
M. Elena Vargas-D´ıaz,† Pedro Joseph-Nathan,‡ Joaqu´ın Tamariz,† and
L. Gerardo Zepeda*,†
Departamento de Qu´ımica Orga´nica, Escuela Nacional de Ciencias Biolo´gicas,
Instituto Polite´cnico Nacional, Prol. de Carpio y Plan de Ayala, Me´xico, D.F.,
11340 Mexico, and Departamento de Qu´ımica, Centro de InVestigacio´n y de Estudios
AVanzados del Instituto Polite´cnico Nacional, Apartado 14-740, Me´xico, D.F.,
07000 Mexico
lzepeda@woodward.encb.ipn.mx
Received September 20, 2006
ABSTRACT
The new macrocycle 9 (>70% yield from hydroxythiol 10) was treated with several nucleophilic reagents (RMgX, RLi, and LiAlH4) affording
carbinols 12a j (80 96% yield, >99:1 dr). Oxidative hydrolysis of 12a,c,e, followed by LiAlH4 reduction of the resulting mixture, gave 16a,c,e
−
−
in >95% ee,16c being a key precursor for the preparation of fungicide 17. The absolute configuration of 9 and 12j (Nu
by single-crystal X-ray diffraction analyses and chemical correlation.
) H) was established
After the pioneering work of Eliel concerning the use of
chiral 2-acyl-1,3-oxathianes 1-4 as chiral auxiliaries,1
structural analogues 5-82-5 were developed by other re-
search groups. From them, compounds 3, 4, and 6-8 are
synthesized from natural products (Figure 1). The main
application of these compounds in asymmetric synthesis has
been focused on the diastereoselective addition of several
nucleophilic reagents to the prostereogenic CdO group,
wherein RMgX ∼ K and L-selectride > RLi > DIBAL ∼
LAH is the most common diastereoselectivity trend.1-5
After the synthesis of macrocycle 8a was described,6 we
decided to explore the chiral auxiliary proficiency of this
new structural arrangement. Thus, preparation of bissulfoxide
† Escuela Nacional de Ciencias Biolo´gicas-IPN.
‡ Centro de Investigacio´n y de Estudios Avanzados del IPN.
(1) (a) Eliel, E. L.; Koskimies, J. K.; Lohri, B. J. Am. Chem. Soc. 1978,
100, 1614. (b) Eliel, E. L.; Frazee, W. J. J. Org. Chem. 1979, 44, 3598. (c)
Eliel, E. L.; Lynch, J. E. Tetrahedron Lett. 1981, 22, 2855. (d) Eliel, E. L.;
Soai, K. Tetrahedron Lett. 1981, 22, 2859. (e) Eliel, E. L.; Morris-Natschke,
S. J. Am. Chem. Soc. 1984, 106, 2937.
(2) Solladie´-Cavallo, A.; Balaz, M.; Salisova, M.; Suteu, C.; Nafie, L.
A.; Cao, X.; Freedman, T. B. Tetrahedron: Asymmetry 2001, 12, 2605.
(3) Chaco´n-Garc´ıa, L.; Lagunas-Rivera, S.; Pe´rez-Estrada, S.; Vargas-
D´ıaz, M. E.; Joseph-Nathan, P.; Tamariz, J.; Zepeda, L. G. Tetrahedron
Lett. 2004, 45, 2141.
(4) Mart´ınez-Ramos, F.; Vargas-D´ıaz, M. E.; Chaco´n-Garc´ıa, L.; Tamariz,
J.; Joseph-Nathan, P.; Zepeda, L. G. Tetrahedron: Asymmetry 2001, 12,
3095.
(5) Vargas-D´ıaz, M. E.; Chaco´n-Garc´ıa, L.; Vela´zquez, P.; Tamariz, J.;
Joseph-Nathan, P.; Zepeda, L. G. Tetrahedron: Asymmetry 2003, 14, 3225.
(6) (a) Vargas-D´ıaz, M. E. M. Sc. dissertation, Escuela Nacional de
Ciencias Biolo´gicas-IPN, Mexico City, 2002. (b) Solladie´-Cavallo, A.; Balaz,
M.; Salisova, M. Eur. J. Org. Chem. 2003, 337.
10.1021/ol062319f CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/09/2006

Figure 1. Acyloxathiane derivatives used in asymmetric synthesis (1-5) and pinane-based chiral auxiliaries 6-9.
8b was the first derivative recently described,7 which was
successfully used as an efficient chiral acyl donor (Figure
1). In connection with that work, we now report the efficient
synthesis of benzoyl derivative 9 and its assessment as a
chiral auxiliary by performing nucleophilic addition of
Grignard reagents, lithium alkylides, and LiAlH4. The results
revealed that all nucleophilic additions were highly diaste-
reoselective (>99:1 dr) irrespective of the kind of nucleophile
used, representing a new diastereoselectivity order not
previously shown by chiral auxiliaries 1-7.
Thus, treatment of 104 with 0.5 equiv of 2,2-diethoxyac-
etophenone catalyzed with Et2O‚BF3 (Scheme 1) gave 11a,
Figure 2. X-ray structure (a) and MMFF major conformer (b) of
macrocycle 9.
Scheme 1
Initial evidence for the stereochemical route followed from
the X-ray structure of 12j (Figure 3), which shows the R
configuration for the new chiral center, denoting that the
diastereofacial attack of the hydride proceeded through the
si face of the carbonyl group. Interestingly, the addition of
EtMgBr and i-PrMgBr led predominantly to the same
carbinol 12j obtained by addition of LiAlH4, confirming the
approach of the reagents from the same face of the carbonyl
group. The addition of EtLi also gave carbinol 12j in a
smaller ratio. In these three cases, the availability of protons
which reacted with CH2(OMe)2 and p-TsOH to give 9 (91%).
X-ray analysis of 9 provided the structure shown in Figure
2, which evidenced that the thioacetalic carbon atom is a
pseudostereogenic center, generating only one diastereoiso-
mer. Conversely, chiral auxiliaries 1-7 lack a pseudoste-
reogenic center.
All carbinols 12a-j (Table 1) were obtained from 9 in a
highly diastereoselective manner irrespective of the reagent
used. This is the first report in which nucleophilic additions
performed on a carbonylic prostereogenic center at the R
position of O,O-, S,O-, or S,S-acetals, by employing either
of the above nucleophiles, proceed in >99:1 diastereomeric
ratios (dr) in a chiral auxiliary based protocol.
Figure 3. X-ray structure (a) and MMFF major conformer (b) of
macrocycle 12j.
(7) Vargas-D´ıaz, M. E.; Lagunas-Rivera, S.; Joseph-Nathan, P.; Tamariz,
J.; Zepeda, L. G. Tetrahedron Lett. 2005, 46, 3297.
14
Org. Lett., Vol. 9, No. 1, 2007

Table 1. Diastereoselective Nucleophilic Additions to Dodecacycle 9
yield
(%)a
entry
nucleophile
MeMgBr
EtMgBr
BnMgCl
i-PrMgBr
CH2dCHMgBr
CH2dC(Me)CH2MgBr
CH3CCMgBr
PhCCMgBr
MeLi
Nu
product
dr 12/13b
1
2
3
4
5
6
7
8
9
Me
12a
12b/12j
12c
12d/12j
12e
12f
12g
12h
12a
12b/12j
12i
95
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
Et/Hd
Bn
30/70c
98
i-Pr/H
20/80c
98
CH2dCH
CH2dC(Me)CH2
CH3CC
PhCC
98
95
98
95
65/35c
98
95
Me
Et/Hd
n-Bu
H
10
11
12
EtLi
n-BuLi
LiAlH4
12j
a All reactions were carried out in THF at -78 °C. b Diastereoisomeric ratio (dr) as measured by 1H NMR. c In >94% yield of the mixture. d The fact that
EtMgBr favors reduction while EtLi favors addition is under consideration in our laboratory.
at the â position of the alkyl chain allows the hydride transfer
into the carbonyl group, thus affording adduct 12j as a
byproduct. Furthermore, addition of both MeMgBr and MeLi
also gave carbinol 12a, whereas ethylide transfer from
EtMgBr and EtLi yielded carbinol 12b. These results strongly
support a common diastereofacial selectivity by Grignard
reagents, RLi and LiAlH4, all of them preferring the si face
of the prostereogenic center.
In search of a reasonable mechanistic proposal to explain
the highly preferred si diastereofacial approach of the
nucleophiles, we performed the nucleophilic addition on
noncyclic benzoylthioacetal 11b, prepared (95%) by protect-
ing the hydroxyl groups of 11a with TBSCl in the presence
of Et3N and DMAP in CH2Cl2 (Scheme 1). The addition of
MeMgBr to 11b, under the same reaction conditions as those
used for 9, gave an equimolecular mixture of the two possible
adducts 14a and 14b in almost quantitative yield (Scheme
2a). This result shows the requirement of a cyclic structure
like 9 to achieve the highly diastereoselective nucleophilic
additions. Complementarily, the corresponding anion of
macroheterocycle 8a was reacted with benzaldehyde in THF
to afford a 35:65 mixture of carbinols 12j and 13j (Scheme
2b). Here, the requirement of a prostereogenic center forming
part of the molecule was evidenced. Furthermore, this result
supports the sole presence of diastereoisomer 12j after
LiAlH4 addition to 9 or when it is obtained as a byproduct
(Table 1, entries 2, 4, and 10) because the 1H NMR signals
of H-15 for both diastereoisomers 12j and 13j are easily
distinguishable (12j, δ H-15 4.44 ppm; 13j, δ H-15 5.01
ppm) and can be integrated accurately.
An additional question is whether a chelated transition state
(TS) could participate in the mechanistic model. First, it is
well-known that a Cram chelated8 TS is the most accepted
model for the observed diastereoselectivity when chiral
auxiliaries 1-7 are used.1-5 However, in these systems, an
oxygen atom is present at the R position of the prostereogenic
carbonyl group (they are S,O-acetals), being in principle that
both parts are the ideal mutual complement to form the rigid
Cram chelated TS by coordination with the metal. This
situation explains the above-mentioned diastereoselective
order of nucleophiles used, which match the coordinating
ability of the metal present in each nucleophilic reagent.
Conversely, it is worth noting that 9 does not possess any
oxygen atom R to the prostereogenic center (it is an S,S-
acetal), and therefore a Cram chelated-type TS, similar to
that formed with chiral auxiliaries 1-7, would not be
significant. Although a chelated TS such as that depicted in
Scheme 2
Org. Lett., Vol. 9, No. 1, 2007
15

Figure 4a is not fully discarded, its participation would also
be questioned because it requires a large conformational
change to attain the coordinated arrangement 15.
EtOH)), having the R absolute configuration (Scheme 3).
Scheme 3
Also, diol 16e was obtained from 12e in 80% yield ([R]24
)
+35.5 (c ) 0.2, EtOH); lit.11 [R]24 ) +41.2 (c ) 1.2,
EtOH)). From these representative chemical correlations, and
from the X-ray structure of 12j, it is assumed that all
remaining carbinols possess the same absolute configuration.
Of particular interest is the preparation of diol 16c, a key
precursor12 for the synthesis of fungicide 17 (Scheme 3). This
goal was achieved by applying the same oxidative hydroly-
sis-reduction protocol to carbinol 12c, which allowed access
to the precursor 16c in 78% yield ([R]25 ) +59.5 (c ) 0.25,
EtOH)), this being the first time that diol 16c was prepared
in its optically pure form. The synthesis of 17 was completed
as shown in Scheme 3.12
In conclusion, the synthesis of 9 was achieved in two steps
and 70% overall yield from 10. The highly diastereoselective
nucleophilic additions performed on 9 with several kinds of
nucleophiles overcome the limitation of chiral auxiliaries
1-7 when they are reacted with less chelating and less
diastereoselective nucleophiles, such as lithium alkylides and
LiAlH4. The highly diastereofacial discrimination shown by
9 seems important in asymmetric synthesis to prepare chiral
targets in high optical purity, as proven for the highly
diastereoselective synthesis of carbinol 16c, a precursor of
fungicide 17.
Figure 4. (a) Hypothetic chelated TS illustrating how the bridging
gem-dimethyl moiety would block the nucleophilic addition through
the re face. (b) Perspective of the X-ray diagram of 9 showing the
preferred attack by nucleophiles, in which methylene C28 (C-12
in Figure 1) clearly blocks the re face of the carbonyl group.
According to the above arguments, a mechanistic model
that comprises steric effects as the main driving force to
explain the observed diastereoselectivity would be expected.
Analysis of the X-ray structure of 9, viewed in another
perspective in Figure 4b, shows the close proximity of CH2-
18 (C-28 in the X-ray structure) and the prostereogenic
carbonyl group, precluding the nucleophilic attack from the
re face (Figure 4b). It is worth noticing that there is
practically no conformational change of the macrocyclic ring
on going from 9 to 12j (Figures 2 and 3). A very similar
minimum energy conformation for both compounds was
found by calculation (MMFF94, Spartan 04)9 (Figures 2 and
3), suggesting that a significant conformational change of
the macrocyclic ring is not taking place at the TS, and
therefore the CH2-18 group could always preclude addition
of the nucleophile from the re face.
Acknowledgment. This work was supported by CONA-
CyT (grant 44157Q) and CGPI-IPN (grants 20030702 and
20040199). MEVD thanks CONACyT (125225) and CGPI/
IPN (PIFI) for postgraduate fellowships.
The stereofacial preference of the nucleophilic addition
to 9 was also confirmed by chemical correlation. Thus,
oxidative hydrolysis of 12a, followed by LiAlH4 reduction
of the resulting mixture, gave diol 16a in 71% yield ([R]24
) -5.7 (c ) 0.5, EtOH); lit.10 [R]24 ) -5.8 (c ) 0.17,
Supporting Information Available: All experimental
procedures and spectroscopic data for new compounds and
crystallographic data for compounds 9 (CCDC 627539) and
12j (CCDC 627540). This material is available free of charge
via the Internet at http://pubs.acs.org.
(8) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748.
(9) MMFF94 calculations were performed using the Spartan 04, v. 1.0.1
software package for Windows (Wavefunction Inc., Irvine, CA, 2004).
(10) Fujisawa, T.; Watai, T.; Sugiyama, T.; Ukaji, Y. Chem. Lett. 1989,
2045-2048 and references cited therein.
OL062319F
(11) Colombo, L.; Di Giacomo, M.; Brusotti, G.; Milano, E. Tetrahedron
Lett. 1995, 36, 2863.
(12) Kraatz, U. Ger. Patent DE 3703082 AI 19880811, 1988.
16
Org. Lett., Vol. 9, No. 1, 2007