Chiral building blocks from R-(-)-carvone: N-bromosuccinimidemediated addition-sceletal rearrangement of (-)-cis-carveol

Article abstract of DOI:10.1016/j.mencom.2010.03.004

Synthetically valuable bicyclic blocks 5, 7 and 9 were prepared by the oxidative cleavage of the double bond of 4 with the RuCl₃-NaIO₄ system and O₃.

Full text of DOI:10.1016/j.mencom.2010.03.004

Mendeleev
Communications
Mendeleev Commun., 2010, 20, 77–79
Chiral building blocks from R-(–)-carvone: N-bromosuccinimide-
mediated addition–sceletal rearrangement of (–)-cis-carveol
Ruslan F. Valeev, Nataliya K. Selezneva, Zoya A. Starikova,
Evgenii Yu. Pankrat’ev and Mansur S. Miftakhov*
Institute of Organic Chemistry, Ufa Scientific Centre of the Russian Academy of Sciences, 450054 Ufa,
Russian Federation. Fax: +7 347 235 6066; e-mail: bioreg@anrb.ru
DOI: 10.1016/j.mencom.2010.03.004
Synthetically valuable bicyclic blocks 5, 7 and 9 were prepared by the oxidative cleavage of the double bond of 4 with the RuCl3–
NaIO system and O .
4
3
Over the last few years, available and inexpensive R-(–)-carvone
has been intensively used as a chiral starting material in
1
1
O
the total synthesis of complex structures. At the same time,
CrO3·DMP
RuCl3 cat., NaIO4
30 s, 89%
–)-carveol 2 has been less widely used in the total synthesis.2
3
O
(
6
5%
O
O
To transform (–)-carveol into new synthetically useful func-
tionalized chiral blocks, we have planned to obtain and study
the reactions of intramolecular (–)-carveol haloetherification
products. According to published data, (–)-cis-carveol is produced
O
O
I
4
5
Scheme 2
3
by the reduction of (–)-carvone with LiAlH in diethyl ether or
4
4
Red-Al in THF at –78 °C and Luche reagent (NaBH –CeCl )
4
3
According to the spectral data, enol 7 is an isomeric pure
compound, but the configuration of its double bond is not
specified. The structure of a more preferable and less hindered
E-isomer is shown below. During the ozonolysis of 4 (MeOH,
78 °C), enol 7 did not react with ozone. By this reason, the
ozonolysis of 7 was carried out in a solution of MeOH at –40 °C.
As a result, a mixture of furanones 8 and 9 was produced in a
ratio of 1:1 ( H NMR). The mixture was placed in an acidic
water medium to transform into compound 9 (Scheme 3).
The inclination of α-ketoaldehyde 6 for the enolization is not
quite clear. The possible reasons are steric hindrance and electro-
in MeOH.5 The latter procedure, which afforded 2 in 90%
yield, is more convenient and practical. Oxacyclization reac-
tions promoted by electrophilic agents are possible due to the
favourable spatial orientation of the hydroxyl and isopropenyl
groups in (–)-cis-carveol. For example, a quick synthesis of
–7
–
(
+)-pinol from 2 by the oxymercuration–demercuration is known,3
and the intramolecular bromoetherification of mentadienol by
1
treatment with NBS was also described. At first, we tested I as
†
2
an electrophilic agent for the cyclization of 2. The reaction of 2
with I in MeCN was explored to initiate the intramolecular
2
formation of the ether, resulting, as expected, in bicyclic iodine
derivative 3 (Scheme 1). Compound 3 was considered as a more
convenient partially protected synthetic equivalent of 2 for
the following differentiation of functional groups to oxidative
cleavage of a double bond because 3 can be smoothly frag-
static repulsion of all-cis oxo functions and CH I substituent in
compound 6. In this case, enolization in α-ketoaldehyde fragment
decreases somewhat the strain in the highly strained substituted
2
†
(
2R,3aR,6aS)-2-Acetyl-6a-methyltetrahydrofuro[3,4-b]furan-4(2H)-one
2
0
5
: white crystalline solid, yield 89%, mp 98–99 °C; [a] +11.8 (c 0.63,
8
D
mented into 2 by treating with Zn in EtOH.
1
CHCl3). H NMR (300 MHz, CDCl ) d: 1.44 (s, 3H), 2.16 (s, 3H),
3
2
.47–2.52 (m, 1H), 2.63–2.70 (m, 1H), 2.89–2.92 (m, 1H), 4.19 (d, 1H,
1
3
O
HO
J 9 Hz), 4.44–4.48 (m, 1H), 4.54 (d, 1H, J 9 Hz). C NMR (75 MHz,
NaBH4–CeCl3
MeOH
I2, MeCN
73%
O
CDCl ) d: 20.2, 25.5, 31.6, 49.2, 75.3, 83.1, 87.9, 177.5, 208.1. IR (KBr,
n/cm ): 1759, 1720. MS (APCI), m/z (%): 185 [M + H] (100), 202
3
1
6
–
+
(
93.5), 217 (58.1). Found (%): C, 58.54; H, 6.59. Calc. for C H O (%):
9 12 4
I
C, 58.70; H, 6.52.
1
2
3
(2S,5R)-5-Acetyl-2-iodomethyl-2-methyldihydrofuran-3-one 9: yellow
20
1
oil, yield 61%; [a] +105.5 (c 2.35, CH Cl ). H NMR (300 MHz, CDCl )
Scheme 1
D
2
2
3
d: 1.39 (s, 3H), 2.45 (s, 3H), 2.72–2.75 (m, 2H), 3.26 (d, 1H, J 9 Hz),
6
The (S)-configuration of the C chiral centre in 3 was assigned
by a set of chemical transformations illustrated in Scheme 2 to
give 5 from 3 via oxidation with CrO ·DMP and subsequent
RuO cleavage (Katsuki–Sharpless reaction). Note that cyclo-
hexenone 4 is synthetically attractive as self-protected and stable
-oxo derivative of (–)-cis-carveol. Then, the reaction of the
ozonolytic cleavage of a double bond in 4 was studied. The
ozonolysis was carried out in a solution of MeOH at –78 °C, the
3.35 (d, 1H, J 9 Hz), 4.60–4.65 (m, 1H). 13C NMR (75 MHz, CDCl ) d:
3
–
1
9.35, 20.86, 26.47, 37.49, 77.65, 82.39, 208.60. IR (KBr, n/cm ): 1761,
1716. Found (%): C, 33.85; H, 4.01; I, 44.61. Calc. for C H IO (%):
†
9
3
8
11
3
1
0
C, 34.06; H, 3.93; I, 44.99.
,6 ,7 )-6,7-Dibromo-3-bromomethyl-1,3-dimethyl-2-oxabicyclo[2.2.2]-
4
(3S S R
2
0
octane 11: white crystalline solid, yield 64%, mp 86–87 °C; [a] –26.1
4
D
1
(
3
c 5.0, CH Cl ). H NMR (300 MHz, CDCl ) d: 1.39 (s, 3H), 1.51 (s,
2
2
3
H), 2.16 (m, 1H), 2.29–2.32 (m, 2H), 2.81–2.90 (m, 2H), 3.22 (d, 1H,
13
J 10.5 Hz), 3.34 (d, 1H, J 10.5 Hz), 4.13–4.24 (m, 2H). C NMR (75 MHz,
residue was purified using column chromatography on SiO after
a standard work-up procedure. It was revealed that ketoaldehyde
initially observed (using TLC) transforms into enol 7.
2
2
[ H ]acetone) d: 25.3, 26.1, 34.8, 37.4, 38.0, 40.5, 48.6, 48.8, 76.4, 78.3.
6
–1
IR (KBr, n/cm ): 1458, 1449, 1379, 1088. Found (%): C, 30.91; H, 3.77;
6
Br, 61.01. Calc. for C H Br O (%): C, 30.69; H, 3.84; Br, 61.38.
1
0
15
3
©
2010 Mendeleev Communications. All rights reserved.
– 77 –

Mendeleev Commun., 2010, 20, 77–79
O
O
I
I
O
O
C(8)
O(1)
C(6)
i, ii
4
C(1)
CHO
OH
C(10)
O
OHC
C(9)
C(5)
6
7
Br(3)
Br(2)
C(7)
O
C(2)
OMe
MeO
I
I
C(4)
O
O
Br(1)
iii
C(3)
+
O
O
Figure 1 Molecular structure of 11.
8
9
H3O+
2
11
Scheme 3 Reagents and conditions: i, O , MeOH, –78 °C, Me S; ii, SiO ,
3
2
2
NBS
EtOAc; iii, O , MeOH, –40 °C, Me S, 2 N HCl.
3
2
II
THF system, and it is a driving force of the transformation 6 ® 7.
An unexpected result was obtained during the study of the
reaction of 2 with NBS. The experiment showed that this reac-
tion led smoothly to an individual compound, the spectral charac-
teristics of which corresponded to the structure of bicyclic tri-
O
O
Br+ Br
Br
O
I
I
Br
Br–
Br
Br
1
0
A
B
II
†
bromide 11. Similarly, 3 was transformed into trihalo derivative
1
2 similar to 11 by treating with NBS in MeCN (Scheme 4).
H
Br
Br
Br
O
O
O
3
2
O
NBS
O 1
Br
2
3
4
Br
Br
Br
MeCN, 6 h
6
5
C
D
E
6
4%
Br
Br
Br
7
8
Scheme 5
1
0
11
which further coordinates Br+ to give bromonium cation A,
undergoing further transformation as detailed in Scheme 5.
Here two alternative transformation ways are possible. The
simplest way is concerted bromonium ion opening and migra-
tion of the antiperiplanar CO bond in A to form carbocation B
attacked stereoselectively with Br (path I). In this case, the
direction of Br attack is characterized by the fact that a carbo-
nium centre in A is stabilized by a neighbouring O atom and in
its three-centred oxonium fragment an antiperiplanar Br approach
is advantageous. The following mechanism (path II) is a classic
migration of C–C and C–H bonds. In cation A the migration of
the bridge bond leads to oxonium cation C, which transforms
into D by 1,2-migration of the methyl group. The 1,2-migration
of hydride in the latter leads to more stable oxonium cation E,
which finally collapses to the symmetric structure of 11 via the
migration of a Br-containing carbon atom and the addition of
NBS
O
I
MeCN, 4 h
6
8%
Br
Br
1
2
Scheme 4
–
–
Finally, the structure of 11 was confirmed by the X-ray data
Figure 1). This work presents a new skeleton rearrangement
of cis-carveol, which accompanied the bromination of the latter
by NBS. Wolinsky et al. described the Favorsky type rearrange-
ment and Grob type fragmentation of carvone tribromides. The
synthesis of dibromide similar to 11 via bromine-assisted epoxide
ring expansion of (+)-cis-limenone oxide was also described by
Davies et al.12 The mechanism of the rearrangement 2 ® 11 can
be gleaned from the smooth formation of iodo ether 3 in the
‡
(
–
11
reaction of 2 with I . It looks as if the reaction of 2 with NBS
also started by the generation of analogous bromo ether 10,
–
2
Br to B. Then, to estimate the migration properties of the
bonds in variants I and II, model epoxide 14 was synthesized
1
3
(
Scheme 6).
‡
Crystallographic data for 11. Crystals of 11, C H Br O, M = 390.95,
10
15
3
However, the use of Et SiOTf in CH Cl at –78 °C to initiate
3
2
2
are rhombic, space group P2 2 2 , at 100 K: a = 8.905(2), b = 11.483(2)
and c = 12.345(3) Å, V = 1262.5(4) Å , Z = 4, d = 2.057 g cm , crystal
size 0.55×0.25×0.15 mm. Intensities of 6489 reflections were measured
with a Bruker APEX2 CCD diffractometer [l(MoKα) = 0.71073 Å, w-scans,
1
1 1
the decomposition of 14 led to a mixture of products. On the
contrary, using BF ·Et O resulted in a single product, which was
isolated and characterized as acetate 15 (Scheme 7). The observed
3
–3
calc
3
2
NOE between Me (d 1.36 ppm) and H (d 5.10 ppm), CH I and
2
qmax = 56°] and 3010 independent reflections (Rint = 0.0570) were used
2
in a further refinement. Reflection intensities were integrated using the
SAINT software and the SADABS semi-empirical method. The structure
was solved by a direct method and refined by the full-matrix least-squares
H (d 5.10 ppm) confirms their cis orientation.
O
O
against F2 in an anisotropic (for non-hydrogen atoms) approximation.
OLA–
HO
hkl
Lewis
acid
For 11 the refinement converged to wR = 0.0875 and GOF = 0.998 for all
i, ii
iii
2
O
O
1
independent reflections [R = 0.0439 was calculated against F for 2292
(LA)
1
hkl
observed reflections with I > 2s(I)]. All calculations were performed using
the SHELXTL software.
I
I
CCDC 707529 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2010.
13
14
F
Scheme 6 Reagents and conditions: i, 30% H O , MeOH, 0.3 N K CO ;
ii, NaBH4–CeCl3, MeOH, 5–10 °C; iii, I2, NaHCO3, MeCN.
2
2
2
3
–
78 –

Mendeleev Commun., 2010, 20, 77–79
–1
The former reaction is endothermic by 14.3 kcal mol , whereas
the latter one is 4.9 kcal mol exothermic. These results indicate
F
–1
O
I
OAc
the preferable formation of classic cation C rather than B. How-
ever, the further transformation of C (C ® D) requires an activa-
i, BF3·Et2O, CH2Cl2, 0 °C
ii, Ac2O, Py, Δ
O
O
–
1
tion energy of 43.6 kcal mol , whereas approaching of the
I
–
counterion Br to B and their barrierless annihilation lead to
the stable molecular product of the reaction. Thus, our theoretical
results ultimately predict that the overall expenditure of energy
prohibits the classical way of the cation transformation, and the
novel alkoxy migration mechanism is the most likely isomeri-
zation reaction for intermediate A.
1
4
15
Scheme 7
To obtain a deeper insight into the chemical nature of cation A,
we performed ab initio MO calculations of the structural and
electronic properties of key intermediates, including A, products
of its unimolecular transformation B and C, transition states of
both pathways, TSAB and TSAC as well as stationary points
of the further isomerization of C, D and TSCD. All computations
were performed on the RI-MP2/L1 level of theory using the
Priroda software package. The structures were fully optimized,
and the RI-MP2/L2 refinement of total energy was used along
with RI-MP2/L1 harmonic frequency calculations to obtain the
standard enthalpy H0 and free energy G of the states of
interest. The geometry of the equilibrium structure of inter-
mediate A is shown in Figure 2. The definitive features of its
structure was found to be the almost formed C(2)–O bond (1.583 Å,
bond order of 0.70) as well as the substantially weakened C(1)–O
bond (1.532 Å, bond order of 0.73); i.e., intermediate A represents
the oxirane-type structure. The driving force of the formation of
an oxirane ring is, obviously, the prominent affinity of the oxygen
lone pairs to the cationic centre of the intermediate. Thus, the
structure of A by itself presupposes the isomerisation pathway
via further weakening of the C(1)–O bond, which finally leads to
intermediate B. Another possibility is a classical transformation
of A via the shift of C(7) atom to the cationic C(2) atom and charge
migration to the C(1) atom, resulting in intermediate C. The activa-
Online Supplementary Materials
Analytical and spectral data for compounds 2–4, 7, 12–15 can be
found in the online version at doi:10.1016/j.mencom.2010.03.004.
14
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Figure 2 Equilibrium structure of intermediate A.
Received: 15th October 2009; Com. 09/3404
–
79 –