Enantioselective Ring Opening of meso-Epoxides with Silicon Tetrachloride Catalyzed by Pyridine N-Oxides Fused with the Bicyclo[3.3.1]nonane Framework

Article abstract of DOI:10.1002/ejoc.201500762

The synthesis of new chiral Lewis basic organocatalysts that contain pyridine N-oxide moieties fused with the bicyclo[3.3.1]nonane framework is reported. The obtained pyridine N-oxides were employed as catalysts in the enantioselective ring opening of meso-epoxides with silicon tetrachloride. Derivative 1b endowed with two 2,4-diaryl-substituted pyridine N-oxide moieties proved to be a particularly effective catalyst for desymmetrization of norbornene oxide 16i to furnish Wagner-Meerwein rearrangement product 20i in unprecedented 96 % ee. Difunctional congener 3, which is striped of the 4-aryl substituents, exhibited moderate to high levels of asymmetric induction (47-88 % ee) with alicyclic epoxide substrates. Chiral Lewis basic catalysts with pyridine N-oxide moieties fused with a bicyclo[3.3.1]nonane framework were used in the enantioselective ring opening of meso-epoxides. 2,4-Diaryl-substituted N-oxide exhibited excellent asymmetric induction with norbornene oxide (96 % ee), whereas less-substituted congener was most effective with alicyclic epoxide substrates (47-88 % ee).

Full text of DOI:10.1002/ejoc.201500762

FULL PAPER
DOI: 10.1002/ejoc.201500762
Enantioselective Ring Opening of meso-Epoxides with Silicon Tetrachloride
Catalyzed by Pyridine N-Oxides Fused with the Bicyclo[3.3.1]nonane
Framework
[a]
[a]
ˇ
ˇ
Algirdas Neniskis and Sigitas Stoncius*
Keywords: Synthetic methods / Asymmetric catalysis / Lewis bases / Epoxides / Amine oxides / Silanes
The synthesis of new chiral Lewis basic organocatalysts that
contain pyridine N-oxide moieties fused with the bicyclo-
[3.3.1]nonane framework is reported. The obtained pyridine
N-oxides were employed as catalysts in the enantioselective
lyst for desymmetrization of norbornene oxide 16i to furnish
Wagner–Meerwein rearrangement product 20i in unprece-
dented 96% ee. Difunctional congener 3, which is striped of
the 4-aryl substituents, exhibited moderate to high levels of
ring opening of meso-epoxides with silicon tetrachloride. De- asymmetric induction (47–88% ee) with alicyclic epoxide
rivative 1b endowed with two 2,4-diaryl-substituted pyridine
N-oxide moieties proved to be a particularly effective cata-
substrates.
N,NЈ-dioxide L3,[8] helical chiral N-oxide L4,[9] bipyridine
N-monooxide L5 (PINDOX),[10] as well as dipyridylmeth-
ane,[11] bis(tetrahydroisoquinoline)[12] and bipyridine[13]
N,NЈ-dioxides promote enantioselective chlorohydrin for-
mation.
Introduction
Hypervalent silicon species play important roles as rea-
gents and intermediates in contemporary organic chemis-
try.[1] In particular, the use of neutral chiral Lewis bases in
conjunction with electrophilic halosilanes has emerged as a
mechanistic alternative for the development of synthetically
useful catalytic asymmetric transformations. Activation of
electrophilic silanes by coordination with Lewis bases leads
to both enhanced nucleophilicity of the peripheral groups
as well as enhanced electrophilicity at the silicon atom. Ow-
ing to the augmented reactivity of such transient penta- or
hexa-coordinate silicates, significant progress has been
made in the development of asymmetric reactions that rely
on the efficient transfer of chirality from the Lewis basic
catalyst into the product.[2,3]
The combined use of chlorosilanes and chiral Lewis basic
catalysts allows chloride ions to be employed as nucleo-
philes for asymmetric bond-forming processes, such as de-
symmetrization of meso-epoxides.[4] Denmark[5] reported on
the first enantioselective ring opening of meso-epoxides
with silicon tetrachloride, which was catalyzed by chiral
phosphoramide L1 (Figure 1). Mechanistically, the reaction
is thought to proceed by coordination of one or more Lewis
bases to SiCl4, which generates a cationic silicon species
that activates an epoxide towards chloride addition.[6] Sub-
sequent reports revealed that pyridine-type N-oxides, such
as planar chiral N-oxide L2,[7] axially chiral bisisoquinoline
Figure 1. Selected Lewis basic pyridine-type N-oxide and phos-
phine oxide organocatalysts.
[a] Department of Organic Chemistry, Vilnius University,
Naugarduko 24, 03225 Vilnius, Lithuania
E-mail: sigitas.stoncius@chf.vu.lt
Chiral phosphine oxides, such as axially chiral L6 (BI-
NAPO),[14] its heteroaromatic congeners,[15] or allene-de-
rived bisphosphine oxide L7,[16] have been also shown to
http://www.chf.vu.lt/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500762.
Eur. J. Org. Chem. 2015, 6359–6369
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6359

A. Nenisˇkis, S. Stoncˇius
FULL PAPER
catalyze enantioselective ring-opening of meso-epoxides the effect of such “connectivity” between the two functional
with SiCl4. Nevertheless, the Lewis basic catalysts devel- units in the molecule, we also set out to prepare bis(N-ox-
oped so far proved to be rather fastidious with respect to ide) 3 that is striped of the 4,10-aryl substituents (ArЈ = H),
the epoxide substrate. As a rule, the ability to impart high as well as corresponding monofunctional congeners 2a and
levels of enantioselection is limited to the derivatives of cis- 2b for a comparison with their difunctional counterparts.
stilbene oxide (87–97% ee with catalysts L1–L4, L6, and
For the synthesis of catalyst candidates, readily available
L7), whereas in the case of the less sterically demanding (+)-(1S,5S)-bicyclo[3.3.1]nonane-2,6-dione (4;[19] Scheme 1)
aliphatic substrates and, in particular, with cyclic epoxides, was used as a source of chirality. The latter in our previous
the enantioselectivity drops to moderate levels. Pinene-de- work has been successfully used as a key building-block for
rived N-monooxide PINDOX[10] (L5; Figure 1), which is the synthesis of related enantiomerically pure structures,[20]
most effective with saturated cyclic substrates that contain self-assembling supramolecular tectons,[21] and ligands for
more than seven carbon atoms and norbornene oxide (87– asymmetric catalysis.[22] The initial synthetic strategy to
90% ee) but inefficient with cis-stilbene oxide (16% ee), is access pyridine derivatives involved the use of exocyclic en-
a notable exception.
ones, such as 3,7-dibenzylidenebicyclo[3.3.1]nonane-2,6-di-
Desymmetrization of meso-epoxides is an attractive strat- one (5),[23] as Michael acceptors. However, the Kröhnke an-
egy for asymmetric synthesis as two contiguous stereogenic nulation reaction[24] of 5 with the corresponding Kröhnke
centers can be unveiled through a single transformation.[17] salt derived from 2Ј,4Ј,6Ј-trimethoxyacetophenone (6a)
Therefore further development, which enhances the catalyst failed to produce desired bis(pyridine) derivative 8a.
efficiency and broadens the scope of such reactions is desir-
able. Herein we present the synthesis of new Lewis bases
that feature a pyridine N-oxide fragment attached to a chi-
ral bicyclo[3.3.1]nonane backbone, and their application in
enantioselective ring opening of meso-epoxides with silicon
tetrachloride.
Results and Discussion
We set out to prepare a set of potential Lewis basic or-
ganocatalysts of general structure 1 that contains two 2,4-
diaryl-substituted pyridine N-oxide moieties fused with a
bicyclo[3.3.1]nonane framework (Figure 2).
Figure 2. New pyridine-derived organocatalysts.
The presence of electron-rich 2,4,6-trimethoxyphenyl
Scheme 1. Reagents and conditions: (a) 4, PhCHO, piperidine
substituent next to the N-oxide group, as in 1a–1c and 3,
(cat.), PhH, reflux (59%); (b) ArЈCHO, KOH, MeOH, room temp.
was found to have a beneficial effect on enantioselectivity
(80–97%); (c) (i) 4, 1,2-ethanedithiol, BF3·Et2O, PhH, room temp.
(82–91%), (ii) Ra/Ni, EtOH, reflux, (iii) Jones reagent, acetone,
in the case of METHOX[18] (L8; Figure 1), a particularly
effective catalyst for allylation of aldehydes with allyltri- room temp. (70–71%); (d) 7, NaH, DMF, 0 °C, then NH4OAc,
AcOH, 120 °C (31–65%); (e) m-CPBA, K2CO3, CH2Cl2, room
temp. (1a–1c: 43–51%; 2a and 2b: 78–86%) or m-CPBA, CH2Cl2,
room temp. (1d: 78%).
chlorosilane. In addition, as a result of the concave molec-
ular geometry of 1a–1d, the ArЈ group on the one side of
the molecule is arranged in the proximity of the catalytic
N-oxide site on the other side of the molecule, and vice
Other classical methodologies, such as TiCl4-mediated
versa (see Supporting Information, Figure S1). We envis- Mukaiyama–Michael reaction of trimethylsilyl (TMS) enol
aged that ArЈ groups could have impact on the asymmetric ether of 6a with 5 or Michael addition of lithium enolate
induction by influencing the arrangement of the substrate of 6a to bis(enone) 5 and subsequent cyclization (AcOH,
and the silane reagent in the reactive complex. To evaluate NH4OAc), were equally unproductive. An alternative strat-
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Enantioselective Ring Opening of meso-Epoxides
egy employed Michael acceptors 7a–7d, which in turn were
attained in high yields by condensation of acetophenones
6a and 6c with corresponding aromatic aldehydes. The best
results were obtained when Michael reaction of diketone
4 and enones 7a–7d was performed in dimethylformamide
(DMF) with sodium hydride as a base. The crude bis(1,5-
diketone) intermediates were obtained as mixtures of dia-
stereomers and without further purification were used in
subsequent cyclization reactions to furnish corresponding
bis(pyridines) 8a–8d in 31–48% yield.
The same protocol was applied for the synthesis of
monofunctional congeners 10a and 10b from bicyclo[3.3.1]-
nonan-2-one (9; Scheme 1). The latter was obtained from
2,6-dione 4 in a three-step procedure,[25] which includes
monothioketalization and subsequent Raney Ni reduction,
followed by Jones oxidation of the resulting alcohol
(Scheme 1). Thus, Michael addition of ketone 9 to chalc-
ones 7a and 7b, followed by cyclization with ammonium
acetate in acetic acid furnished desired pyridines 10a and
10b in 65 and 47% yield, respectively.
Although oxidation of 8d with m-chloroperoxybenzoic
acid (m-CPBA) under standard conditions in CH2Cl2 pro-
ceeded uneventfully to give corresponding bis(N-oxide) 1d
in 78% yield, the synthesis of electron rich 2,4,6-trimeth-
oxyphenyl-substituted congeners 1a–1c and 2a–2b unexpec-
tedly proved to be a formidable synthetic challenge. Oxid-
ation of 8a–8c, 10a and 10b with m-CPBA as well as with
Scheme 2. Reagents and conditions: (a) TiCl4, Cl(CH2)2COCl, 1,2-
DCE; (b) TEA, CH2Cl2 (18–43%); (c) (i) DMF, POCl3, 0 °C
(98%), (ii) H2C=CHMgBr, THF, 0 °C (80%); (d) IBX, THF/
DMSO, room temp. (67%); (e) Me2NH2Cl, iPrOH, Δ (91%); (f) 4,
TEA, 180 °C, then NH2OH·HCl, EtOH, Δ (30%); (g) m-CPBA,
K2CO3, CH2Cl2, room temp. (38%).
a number of other oxidants produced intractable mixtures ible yields (18–43%). The major drawback of this approach
apparently as a result of oxidation of the 2,4,6-trimethoxy- was instability of 13a under Friedel–Crafts reaction condi-
phenyl groups to generate phenolic by-products,[26,27] which tions; β-chloroketone was prone to elimination to yield en-
undergo further oxidation to quinones if exposed to air. one 11, which then underwent facile TiCl4-mediated
Recent experimental and DFT studies suggest that hydrox- Michael reaction with electron-rich 12 to give correspond-
ylation of electron-rich aromatic compounds with peroxy- ing 1,3-bis(2,4,6-trimethoxyphenyl)propan-1-one as a major
acids proceeds through electrophilic aromatic substitution by-product. Finally, we settled for a three-step synthesis of
reaction, which is promoted by the presence of a Brønsted 11, which involved Vilsmeier–Haack formylation of 12, fol-
acid.[28] With this in mind, we have tested a number of basic lowed by Grignard reaction of the resulting aldehyde with
additives and were pleased to find that the addition of solid vinylmagnesium bromide to produce allylic alcohol 14. The
potassium carbonate substantially suppressed the hydroxyl- final oxidation step of 14 required some optimization, be-
ation side reaction. Oxidation of 8a–8c and 10a–10b with cause a number of standard oxidants led either to decom-
m-CPBA in the presence of K2CO3 gave rise to desired position (PDC, PCC, DMP) or low conversions (MnO2,
bis(N-oxides) 1a (51%), 1b (43%), 1c (49%) and monofunc- TPAP/NMO) and formation of substantial amounts of cin-
tional congeners 2a (86%), 2b (78%).
namic aldehyde by-product through the competing oxidat-
The synthesis of pyridine derivative 3 commenced with ive [3,3]-sigmatropic rearrangement. Although oxidation
preparation of enone 11 (Scheme 2), the synthesis of which with 2-iodoxybenzoic acid (IBX) under standard conditions
merits a brief comment.
in dimethyl sulfoxide (DMSO) was low yielding (23%), the
Initial attempts to obtain 11 from acetophenone 6a undesired side reactions were largely suppressed in THF, in
(Scheme 1) through a Mannich reaction (Me2NH2Cl, which IBX is poorly soluble. Oxidation of 14 with IBX at
CH2O, iPrOH) met little success because of the proclivity room temperature in THF and DMSO (5 equiv.) furnished
of the electron-rich aromatic ring towards electrophilic sub- enone 11 in 67% yield.
stitution reactions.[29] Diisopropylammonium trifluoroacet-
The Michael addition (NaH, DMF) and cyclization
ate mediated α-methylenation[30] of acetophenone 6a with (AcOH, NH4OAc) sequence developed earlier for the syn-
paraformaldehyde did produce enone 11, but suffered from thesis of pyridine derivatives 8a–8c, 10a and 10b (Scheme 1)
low (≈ 60%) conversions. An alternative strategy involved was found to be less effective in the case of enone 11, but
TiCl4-mediated Friedel–Crafts acylation of 1,3,5-trimeth- produces corresponding bis(pyridine) 15 in 13% yield. Ac-
oxybenzene 12 with 3-chloropropionyl chloride to furnish ceptable yields of the latter were obtained by heating diket-
corresponding β-chloroketone 13a, which was immediately one 4 in the pressure vial with TEA and ammonium salt
used in the subsequent elimination step [triethylamine 13b,[31] derived from enone 11, and subsequent cyclization
(TEA), CH2Cl2] to afford 11 in moderate and unreproduc- with hydroxylamine hydrochloride in ethanol (Scheme 2).
Eur. J. Org. Chem. 2015, 6359–6369
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A. Nenisˇkis, S. Stoncˇius
FULL PAPER
In the end game, oxidation of 15 with m-CPBA in the pres- Table 1. Desymmetrization of meso-epoxides with SiCl4, catalyzed
by pyridine N-oxides 1a–1d, 2a, 2b and 3.[a]
ence of K2CO3 gave rise to desired bis(N-oxide) 3 (38%).
With pyridine N-oxides 1a–1d, 2a, 2b and 3 in hand, the
efficiency of these Lewis basic catalysts in the asymmetric
reactions of chlorosilanes was evaluated. Allylation of benz-
aldehyde with allyltrichlorosilane, which has become a stan-
dard testing ground for new chiral Lewis basic organocata-
lysts, was initially examined (Scheme 3).
Entry
Cat.
R
Time Yield[b] ee[c]
[h]
[%]
[%]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
2a
2b
1a
1a
1a
1a
1a
1a
1a
3
–(CH2)4– (16a)
–(CH2)4– (16a)
–(CH2)4– (16a)
–(CH2)4– (16a)
–(CH2)4– (16a)
–(CH2)4– (16a)
–(CH2)3– (16b)
–(CH2)5– (16c)
–C2H4CH=CHC2H4– (16d)
–(CH2)6– (16e)
C6H5 (16f)
4-F-C6H4 (16g)
4-Me-C6H4 (16h)
–(CH2)4– (16a)
–(CH2)3– (16b)
–(CH2)5– (16c)
–C2H4CH=CHC2H4– (16d)
–(CH2)6– (16e)
C6H5 (16f)
24
24
24
24
24
24
24
24
48
96
48
48
48
24
24
24
48
96
48
72
85
81
73
79
75
86
80
84
64
93
93
91
77
85
85
81
59
89
32
18
27
3
Scheme 3. Allylation reaction of benzaldehyde with allyltrichloro-
silane.
15
11
15
38
45
49
43
41
45
47
88
77
70
60
32
Rather disappointingly bis(N-oxides) 1a–1d, 3, and
monofunctional congeners 2a and 2b exhibited low catalytic
activity even at room temperature. Reaction of benzalde-
hyde with allyltrichlorosilane (1.5 equiv.) in the presence of
(iPr)2NEt (3 equiv.) and 10 mol-% of the respective catalyst
in acetonitrile (or dichloromethane) for 48 h proceeded with
9
10[d]
11[e]
12[e]
incomplete conversions to give corresponding homoallylic 13[e]
14
15
alcohol in 24–68% yields and unimpressive enantio-
selectivities (14–37% ee).
3
3
3
3
16
Next, we examined the new catalysts as Lewis basic acti-
17
18[d]
19[e]
vators in the desymmetrization reaction of meso-epoxides
with silicon tetrachloride (Table 1), by using cyclohexene
oxide (16a) as a test substrate.
3
[a] The reactions were carried out at 0.25 mmol scale with SiCl4
(1.5 equiv.), (iPr)2NEt (3 equiv.) and catalyst (10 mol-%) at –78 °C
in dichloromethane, unless stated otherwise; PNB = 4-nitrobenz-
oyl. [b] Isolated yield of 4-nitrobenzoate 18, unless stated otherwise.
[c] Determined by chiral HPLC; chlorohydrins 17a and 17f were
(S,S)-configured, as established by comparison of their optical ro-
tation with the literature data. The absolute configuration of the
remaining chlorohydrins is assumed to be (S,S) in analogy with
17a, and 17f, but has not been unequivocally established. [d] The
reaction was carried out at –40 °C. [e] Isolated as chlorohydrin 17.
The opening of epoxide 16a with SiCl4 was carried out
in CH2Cl2 at –78 °C in the presence of (iPr)2NEt (3 equiv.)
and catalyst (10 mol-%). To facilitate both the isolation of
rather volatile chlorohydrin and subsequent analysis by chi-
ral HPLC, crude 17a was converted into corresponding 4-
nitrobenzoate 18a. Desymmetrization of 16a catalyzed by
bis(N-oxide) 1a furnished 18a in high yield and non-negligi-
ble enantioselectivity (Table 1, Entry 1), whereas catalysts
1b–1c exhibited somewhat diminished asymmetric induc-
tion (Table 1, Entries 2 and 3). Compound 1a notably out- enantioselectivity (49% ee; Table 1, Entry 10) comparable
performed 2,4,6-trimethylphenyl congener 1d (Table 1, En- to that attained with epoxides 16c–16d at –78 °C. In the
try 4), which suggests a beneficial effect of electron-rich case of stilbene oxides 16f–16h, variation in the substituents
2,4,6-trimethoxyphenyl substituents on enantioselectivity. on the aromatic rings had little effect on asymmetric induc-
Ring opening of 16a catalyzed by monofunctional N-oxides tion, and corresponding chlorohydrins 17f–17h were ob-
2a and 2b proceeded in good yields, but modest stereoselec- tained in high yields, but moderate enantioselectivity
tivity (Table 1, Entries 5 and 6).
(Table 1, Entries 11–13).
We next surveyed ring opening of a set of epoxides 16b–
In contrast to the behavior of 2,4-diaryl-substituted pyr-
16h with bis(N-oxide) 1a as catalyst (Table 1). Among the idine N-oxides 1a–1c, bis(N-oxide) 3 exhibited a rather dif-
cyclic substrates, a slight increase of asymmetric induction ferent stereoselectivity profile. Thus, although the ring
was observed with increasing size of the cycloalkene oxide opening of cyclohexene oxide (16a) proceeded with moder-
ring. Thus, although desymmetrization of cyclopentene ate, but higher, enantioselectivity relative to 1a (Table 1, En-
oxide (16b) proceeded with low selectivity (15% ee; Table 1, try 14, relative to Table 1, Entry 1), desymmetrization of
Entry 7), cycloheptene epoxide (16c) and 1,5-cycloocta- cyclopentene oxide (16b) furnished chlorohydrin 17b in
diene-derived monooxide 16d afforded chlorohydrins in 38 88% ee (Table 1, Entry 15, relative to Table 1, Entry 7). Any
and 45% ee, respectively (Table 1, Entries 8 and 9, relative increase in ring size resulted in slight erosion of selectivity,
to Table 1, Entry 1). Cyclooctene oxide (16e), which proved and 16c and 16d furnished chlorohydrins in 77 and 70% ee,
to be a challenging substrate with other Lewis basic cata- respectively (Table 1, Entries 16 and 17). Nevertheless, to
lysts,[5,14] exhibited much lower reactivity and yielded only the best of our knowledge, the enantioselectivities attained
trace amounts of chlorohydrin 17e at –78 °C after 48 h. with bis(N-oxide) 3 are the highest reported to date for the
Even at elevated temperatures (–40 °C), ring opening of 16e Lewis base catalyzed desymmetrization of cyclic substrates
required prolonged reaction time, but proceeded with 16b–16d with SiCl4. The reason for the precipitous drop of
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Enantioselective Ring Opening of meso-Epoxides
selectivity in the case of cyclohexene oxide (16a), however, oxide moieties with 4-aryl substituents, is a prerequisite for
is rather difficult to rationalize.[32] Ring opening of cyclo- high asymmetric induction. It could be envisioned that the
octene oxide (16e) at –40 °C again required prolonged reac- 4-aryl and 2,4,6-trimethoxyphenyl groups adjacent to the
tion time to yield corresponding chlorohydrin in 60% ee coordinating N-oxide center (vide supra) apparently creates
(Table 1, Entry 18), whereas desymmetrization of stilbene a chiral environment that is particularly effective in con-
oxide (16f) proceeded with rather modest enantioselectivity trolling the enantioselectivity of the rearrangement of 16i
(Table 1, Entry 19).
to 20i.
The tricyclic norbornene oxide (16i) represents a sub-
stantially different type of epoxide substrate. It has been
demonstrated that desymmetrization of the latter with SiCl4
catalyzed by PINDOX[10] or phosphine oxides L6 and
L7[14b,16,33] (Figure 1) proceeds by a Wagner–Meerwein re-
arrangement to furnish syn,exo-chloroalcohol 20i as a
major product, rather than vicinal chlorohydrin 17i
(Scheme 4).
Table 2. Desymmetrization of norbornene oxide 16i with SiCl4, cat-
alyzed by pyridine N-oxides 1a–1d, 2a, 2b and 3.[a]
Entry
Catalyst
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
1a
1b
1c
1d
2a
2b
3
1b
2b
1b
32
50
28
16
32
36
91
96
90
0
2
2
12 (35[d]
)
26 (46[d]
96 (77[d]
)
)
)
8[e]
9[f]
10[g]
50 (7[d]
34 (25[d]
30
)
)
3 (34[d]
92
[a] The reactions were carried out at 0.25 mmol scale with SiCl4
(1.5 equiv.), (iPr)2NEt (3 equiv.) and catalyst (10 mol-%) at –78 °C
for 24 h in dichloromethane, unless stated otherwise. [b] Isolated
yield of p-nitrobenzoate 21i. [c] Determined by chiral HPLC; the
absolute configuration of 21i and 23i was determined to be
(1S,2S,4S,7R) and (1R,3R,6S), respectively. [d] Yield and enantio-
meric excess of nortricyclanol 4-nitrobenzoate 23i. [e] The reaction
was carried out at 1.0 mmol scale. [f] The reaction was carried out
with 20 mol-% catalyst loading. [g] The reaction was carried out
with 5 mol-% catalyst loading.
Scheme 4. Ring opening of norbornene oxide 16i with SiCl4.
When the ring opening of 16i catalyzed by 1b was per-
The tendency of 16i to undergo Wagner–Meerwein re- formed on a 1 mmol scale, we were able to isolate a small
arrangements to yield a mixture of products is well docu- amount of nortricyclanol 4-nitrobenzoate 23i in 77% ee
mented.[34] Similarly to the pyridinium chloride promoted (Table 2, Entry 8). The (+)-(1S,2S,4S,7R) and (+)-
ring opening,[34b,34c] in our hands reaction of norbornene (1R,3R,6S) absolute configuration of 20i and 22i
oxide (16i) with SiCl4 catalyzed by DMF and subsequent (Scheme 5), respectively, was inferred from chemical corre-
derivatization furnished 4-nitrobenzoates 18i and 21i of vic- lation and by comparison of their optical rotation with the
inal (17i) and rearranged (20i) chlorohydrins, respectively, available literature data (for further details see the Support-
as well as nortricyclanol derivative 23i. In contrast to ing Information). The disparity in enantiomeric purity of
DMF-mediated reaction, ring opening of 16i catalyzed by the two products suggests that the high level of asymmetric
pyridine N-oxides 1a–1d, 2a, 2b and 3 produced only trace induction attained in transformation of 16i to 20i does not
amounts of vicinal derivative 17i. The amounts of syn,exo- necessarily reflect the actual stereoselectivity of the
chloroalcohol 20i and nortricyclanol 22i significantly de- Wagner–Meerwein rearrangement (AǞB) step (Scheme 5).
pended on the structure of the catalyst, e.g. ring opening Initially, norbornene oxide is activated by coordination with
catalyzed by bis(N-oxide) 1b produced 20i as a major prod- chiral silicon species to form an intermediate hypervalent
uct, whereas 3 favored formation of 22i.[35]
silicate, such as pentacoordinate complex A depicted in
Gratifyingly, the bis(N-oxides) 1a–1c were found to be Scheme 5. Subsequent enantioselective Wagner–Meerwein
particularly stereoselective catalysts for desymmetrization rearrangement generates transient chiral non-classical nor-
of 16i (Table 2). Bis(N-oxide) 1b was the most efficient li- bornyl cation[37] B, a common precursor to both 20i and
gand for this transformation and furnished 21i in 50% yield 22i, still bound with chlorosilane through the oxygen atom.
and unprecedented 96% ee (Table 2, Entry 2).[36] In stark Apparently the chiral Lewis base still coordinated to Si
contrast to the behavior of 1a–1c, 2,4,6-trimethyl congener atom exerts significant influence on the fate of the two dia-
1d (Table 2, Entry 4) and monofunctional N-oxides 2a and stereomeric complexes B·SiCl3·L* and (ent)-B·SiCl3·L* and
2b (Table 2, Entries 5 and 6) provided racemic product 21i, leads to chemodivergent parallel kinetic resolution[38] of
whereas difunctional congener 3, which is striped of the 4- transient cationic species.
aryl substituents, exhibited a low level of asymmetric induc-
Thus, the major diastereomeric complex B·SiCl3·L* pref-
tion (Table 2, Entry 7). Such striking difference in selectivity erentially undergoes nucleophilic addition of a chloride
suggests that a combination of electron-rich 2,4,6-trimeth- anion, which most likely is delivered intramolecularly from
oxyphenyl substituents next to N-oxide group and two N- the chlorosilane coordinated to oxygen, to yield (+)-
Eur. J. Org. Chem. 2015, 6359–6369
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6363

A. Nenisˇkis, S. Stoncˇius
FULL PAPER
cyclo[3.3.1]nonane backbone. These compounds were em-
ployed as catalysts in the enantioselective ring opening of
meso-epoxides with silicon tetrachloride. Difunctional de-
rivative 1b endowed with two 2,4-diaryl-substituted pyr-
idine N-oxide moieties proved to be particularly effective
catalyst for desymmetrization of norbornene oxide 16i,
which furnished Wagner–Meerwein rearrangement product
20i in unprecedented 96% ee. The overall stereoselectivity
seems to be governed by both enantioselective Wagner–
Meerwein rearrangement and subsequent chemodivergent
parallel kinetic resolution of the resulting transient cationic
species. The bis(N-oxide) congener 3, which is striped of
the 4-aryl substituents, exhibited moderate to high levels of
asymmetric induction (47–88% ee) with alicyclic epoxide
substrates. Most notably, high levels of asymmetric induc-
tion were attained in the opening of epoxides derived from
cyclopentene (16b, 88% ee), cycloheptene (16c, 77% ee),
and 1,5-cyclooctadiene (16d, 70% ee), which proved to be
challenging substrates for other Lewis basic catalysts
(Յ 57% ee).
Scheme 5. Plausible mechanism for the formation of 20i and 22i.
(1S,2S,4S,7R)-20i with enhanced enantiomeric purity
(Scheme 5). The minor diastereomer (ent)-B·SiCl3·L* is de-
pleted somewhat faster through a competing pathway that
involves proton abstraction to furnish nortricyclanol (–)-
22i. As a consequence, such kinetic preference results in di-
minished enantiopurity of the eventually isolated (+)-
(1R,3R,6S)-enantiomer of 23i (Table 2, Entry 8). Neverthe-
less, a moderate combined yield (57%) of nitrobenzoates
21i and 23i suggests that the overall mechanism is far more
complex than that depicted in Scheme 5. No products other
than 21i and 23i could be isolated and, as a consequence,
the other pathways[39] by which epoxide 16i is consumed
remain unclear. The bis(N-oxide) 3, which favors the forma-
tion of (+)-23i (Table 2, Entry 7) in 46% ee, apparently ex-
hibits markedly different kinetic preference; nevertheless, as
a result of rather non-stereoselective Wagner–Meerwein re-
arrangement, the enantiomeric purity of both 21i and 23i
was unremarkable. It could be argued that the two pyridine
N-oxide moieties in the difunctional bis(N-oxides) 1a–1c act
as two independent catalytically active sites so that the ef-
fective catalyst loading is 20 mol-% and the low levels of
asymmetric induction exhibited by monofunctional conge-
ners 2a and 2b is a result of lower catalyst loading (Table 2,
Entries 2 and 6). Low efficiency of 2b was corroborated by
a control experiment with 20 mol-% catalyst loading, which
produced 21i in virtually the same yield and selectivity
(Table 2, Entry 9 relative to Entry 6). Enantiopurity of nor-
tricyclanol 22i was also unremarkable and similar to that
attained with difunctional congener 3 (Table 2, Entry 7). By
contrast, desymmetrization of 16i in the presence of 5 mol-
% of catalyst 1b afforded 21i in 30% yield and still respect-
able 92% enantiomeric purity (Table 2, Entry 9 relative to
Entries 2 and 8).
Experimental Section
General: 1H and 13C NMR spectra were recorded in CDCl3 or [D6]-
DMSO at 400 MHz for 1H and 100 MHz for 13C, unless stated
otherwise. Chemical shifts are reported in ppm relative to solvent
resonance signal as an internal standard (1H NMR δ = 7.26 ppm
and 13C NMR δ = 77.0 ppm for CHCl3, and 1H NMR δ =
2.50 ppm and 13C NMR δ = 39.52 ppm for DMSO). IR spectra
were recorded as KBr pellets. Optical rotations were measured at
589 nm and 20 °C, and concentrations are given in units of g/
100 cm3. Melting points were recorded with a Gallenkamp melting
apparatus. High-resolution mass spectra (HRMS) were recorded
on a quadrupole, time-of-flight mass spectrometer with electro-
spray ionization (ESI) (micrOTOF-Q II, Bruker Daltonik GmbH).
The enantiomeric excesses were determined by using HPLC system,
equipped with diode array detector and CHIRALPAK IA-3, IB-
3 and IC-3 analytical (250ϫ 4.6 mm) columns. The chiral HPLC
methods were calibrated with the corresponding racemic mixtures.
All solvents and reagents for the reactions were of reagent grade
and were dried and distilled under argon before use as follows:
dichloromethane from phosphorus pentoxide, 1,2-dichloroethane
(DCE), DMF, TEA and diisopropylethylamine (DIPEA) from cal-
cium hydride, tetrahydrofuran from sodium. Thin-layer chromatog-
raphy was carried out on Kieselgel 60 F254 (Merck) sheets coated
with silica gel, and Kieselgel 60 silica gel (0.040–0.063 mm, Merck)
was used for column chromatography. Petroleum ether refers to the
fraction boiling in the range 40–60 °C.
Enantiomerically pure (1S,5S)-bicyclo[3.3.1]nonane-2,6-dione (4)
[19]
and (1S,5S)-bicyclo[3.3.1]nonan-2-one (9)[25] were prepared by
following the reported procedures. Chalcones 7a–7d (except 7c) are
known compounds and were obtained through a modified litera-
ture procedure[40] in 80–97% yields.
General Procedure for the Synthesis of Chalcones 7a–7d: KOH
(5.6 g, 0.1 mol) in MeOH (30 mL) was added to a solution of aceto-
phenone 6a or 6d (10 mmol) and corresponding aldehyde
(11 mmol) in MeOH (30 mL), and the reaction mixture was stirred
at r.t. for 20 h. If a solid precipitate formed (7b), H2O (200 mL)
Conclusions
We have developed a set of chiral Lewis basic catalysts
with pyridine N-oxide moieties attached to the chiral bi- was added to the mixture and the resulting precipitate was filtered,
6364 Eur. J. Org. Chem. 2015, 6359–6369
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Enantioselective Ring Opening of meso-Epoxides
washed with H2O and dried. The obtained solid was purified by
recrystallization from MeOH/H2O. If a solid precipitate was not
formed (7a, 7c, and 7d), the reaction mixture was neutralized with
10% HCl and extracted with EtOAc (3ϫ 25 mL). The combined
organic fraction was washed with brine, dried (Na2SO4), evapo-
rated and the obtained residue was purified by column chromatog-
raphy on silica gel (petroleum ether/EtOAc).
(CH2), 55.32 (CH3), 55.35 (CH3), 55.81 (CH3), 91.1 (CH), 112.4
(C), 113.3 (CH), 125.4 (CH), 126.0 (C), 130.3 (CH), 131.9 (C),
148.8 (C), 151.3 (C), 158.9 (C), 159.0 (C), 159.3 (C), 161.0 (C) ppm.
IR (KBr): ν = 2933, 2835, 1609, 1586, 1513, 1249, 1224, 1204,
˜
1153, 1126 cm–1. HRMS (ESI): calcd. for C47H47N2O8 [M + H]+
767.3332; found 767.3360.
(6R,12R)-4,10-Bis(4-fluorophenyl)-2,8-bis(2,4,6-trimethoxyphenyl)-
5,6,11,12-tetrahydro-6,12-methanocycloocta[1,2-b:5,6-bЈ]dipyridine
(8c): Purified by column chromatography (petroleum ether/EtOAc/
TEA, 50:50:3) to afford 8c as an off-white solid (710 mg, 48%),
(E)-3-(4-Fluorophenyl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one
(7c): Purified by column chromatography (petroleum ether/EtOAc,
75:25) to afford 7c as yellow solid (2.85 g, 90%), m.p. 114–116 °C.
1H NMR (300 MHz, CDCl3): δ = 3.77 (s, 6 H), 3.86 (s, 3 H), 6.16
(s, 2 H), 6.88 (dd, J = 16.1, 0.5 Hz, 1 H), 7.0–7.11 (m, 2 H), 7.33
(d, J = 16.1 Hz, 1 H), 7.47–7.55 (m, 2 H) ppm. 13C NMR (75 MHz,
1
m.p. Ͼ 250 °C. [α]D = +38 (c 1.0, MeOH). H NMR (CDCl3): δ =
2.36 (s, 2 H), 3.08 (d, J = 17.0 Hz, 2 H), 3.23 (dd, J = 17.0, 5.7 Hz,
2 H), 3.59 (s, 12 H), 3.66 (br. s, 2 H), 3.82 (s, 6 H), 6.16 (s, 4 H),
CDCl3): δ = 55.4 (CH3), 55.9 (CH3), 90.7 (CH), 111.7 (C), 115.9 6.96 (s, 2 H), 7.04 (t, J = 8.7 Hz, 4 H), 7.31–7.38 (m, 4 H) ppm.
(d, J = 21.8 Hz, CH), 128.7 (d, J = 2.2 Hz, CH), 130.2 (d, J =
13C NMR (CDCl3): δ = 28.1 (CH2), 36.1 (CH), 36.3 (CH2), 55.4
8.5 Hz, CH), 131.2 (d, J = 3.3 Hz, C), 142.6 (CH), 158.8 (C), 162.4 (CH3), 55.8 (CH3), 91.2 (CH), 112.2 (C), 114.9 (d, J = 21.3 Hz,
(C), 163.8 (d, J = 251.2 Hz, C), 194.0 (CO) ppm. IR (KBr): ν =
CH), 125.4 (CH), 125.9 (C), 130.7 (d, J = 8.0 Hz, CH), 135.4 (d, J
= 3.3 Hz, C), 148.2 (C), 151.5 (C), 158.8 (C), 159.4 (C), 161.2 (C),
˜
2996, 2947, 2844, 1647, 1608, 1588, 1229, 1156, 1131 cm–1. HRMS
(ESI): calcd. for C18H17FNaO4 [M + Na]+ 339.1003; found
339.1005.
162.3 (d, J = 247.0 Hz, C) ppm. IR (KBr): ν = 2935, 2837, 1735,
˜
1712, 1608, 1586, 1508, 1223, 1204, 1156, 1125 cm–1. HRMS (ESI):
calcd. for C45H41F2N2O6 [M + H]+ 743.2927; found 743.2943.
General Procedure for the Synthesis of Pyridine Derivatives 8a–8d,
10a, and 10b: NaH (320 mg, 60% dispersion in mineral oil, 8 mmol)
was added to a solution of corresponding chalcone 7 (4.2 mmol)
in DMF (4 mL) at 0 °C. A solution of ketone 4 (304 mg, 2 mmol)
(6R,12R)-4,10-Diphenyl-2,8-bis(2,4,6-trimethylphenyl)-5,6,11,12-
tetrahydro-6,12-methanocycloocta[1,2-b:5,6-bЈ]dipyridine (8d): Puri-
fied by column chromatography (petroleum ether/EtOAc, 8:2) to
or 9 (553 mg, 4 mmol) in DMF (4 mL) was then added dropwise afford 8d as a colorless solid (560 mg, 46%), m.p. Ͼ 250 °C. [α]D
1
to the resulting suspension over 15 min. The reaction mixture was
stirred at 0 °C for 2.5 h, then quenched with 10% HCl and ex-
tracted with EtOAc (3ϫ 20 mL). The combined organic phase was
washed with H2O, saturated NaHCO3 solution and brine, dried
(Na2SO4), and the solvents evaporated. The obtained brown resi-
due was dissolved in glacial AcOH (10 mL) and NH4OAc (1.5 g,
= –30 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.92 (br.
s, 12 H), 2.27 (s, 6 H), 2.46 (s, 2 H), 3.06 (d, J = 16.9 Hz, 2 H),
3.19 (dd, J = 16.9, 5.0 Hz, 2 H), 3.64 (br. s, 2 H), 6.86 (br. s, 6 H),
7.14–7.20 (m, 4 H), 7.31–7.40 (m, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 20.1 (CH3), 21.0 (CH3), 28.7 (CH2), 36.2 (CH), 36.8
(CH2), 123.0 (CH), 125.9 (C), 127.7 (CH), 128.1 (CH), 128.2 (CH),
20 mmol) was added. The reaction mixture was heated at 120 °C 128.4 (CH), 135.6 (C), 137.1 (C), 137.6 (C), 139.0 (C), 150.3 (C),
under an air atmosphere for 12 h, then cooled to r.t. and evapo-
rated under reduced pressure. The residue was quenched with satu-
157.3 (C), 159.6 (C) ppm. IR (KBr): ν = 2920, 1613, 1586, 1539,
˜
1494, 1450, 1440, 1374, 771, 703 cm–1. HRMS (ESI): calcd. for
rated NaHCO3 solution and extracted with CH2Cl2 (3ϫ 20 mL), C45H43N2 [M + H]+ 611.3421; found 611.3430.
organic phase was washed with saturated NaHCO3 solution and
(6R,10S)-4-Phenyl-2-(2,4,6-trimethoxyphenyl)-5,6,7,8,9,10-hexa-
hydro-6,10-methanocycloocta[b]pyridine (10a): Purified by column
chromatography (petroleum ether/EtOAc/TEA, 80:20:3) to afford
brine, dried (Na2SO4) and the solvents evaporated. The obtained
residue was purified by column chromatography on silica gel to
afford pyridine derivatives 8a–8d, 10a, and 10b as off-white solids.
10a as an off-white solid (1.08 g, 65%), m.p. 156–158 °C. [α]D
=
(6R,12R)-4,10-Diphenyl-2,8-bis(2,4,6-trimethoxyphenyl)-5,6,11,12- +24 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.18–1.33
tetrahydro-6,12-methanocycloocta[1,2-b:5,6-bЈ]dipyridine (8a): Puri-
fied by column chromatography (petroleum ether/EtOAc/TEA,
(m, 1 H), 1.35–1.46 (m, 1 H), 1.58–1.79 (m, 3 H), 1.85–2.05 (m, 3
H), 2.17–2.27 (m, 1 H), 2.50 (d, J = 18.0 Hz, 1 H), 3.0 (dd, J =
18.0, 7.2 Hz, 1 H), 3.30 (br. s, 1 H), 3.71 (s, 6 H), 3.83 (s, 3 H),
50:50:3) to afford 8a as an off-white solid (590 mg, 42 %), m.p.
1
Ͼ 250 °C. [α]D = +28 (c 1.0, MeOH). H NMR (CDCl3): δ = 2.36 6.20 (s, 2 H), 6.99 (s, 1 H), 7.31–7.47 (m, 5 H) ppm. 13C NMR
(s, 2 H), 3.10 (d, J = 17.1 Hz, 2 H), 3.28 (dd, J = 5.7, 17.2 Hz, 2
(CDCl3): δ = 18.4 (CH2), 27.5 (CH), 31.2 (CH2), 32.4 (CH2), 33.2
H), 3.57 (s, 12 H), 3.65 (br. s, 2 H), 3.81 (s, 6 H), 6.15 (s, 4 H), 7.01
(CH2), 33.9 (CH2), 37.5 (CH), 55.4 (CH3), 56.1 (CH3), 91.3 (CH),
(s, 2 H), 7.28–7.41 (m, 10 H) ppm. 13C NMR (CDCl3): δ = 28.2 112.9 (C), 124.8 (CH), 127.3 (CH), 128.1 (CH), 128.5 (C), 128.7
(CH2), 36.1 (CH), 36.4 (CH2), 55.3 (CH3), 55.8 (CH3), 91.1 (CH), (CH), 140.2 (C), 147.8 (C), 150.8 (C), 159.0 (C) 159.8 (C), 161.0
112.3 (C), 125.4 (CH), 125.9 (C), 127.4 (CH), 127.9 (CH), 129.0
(CH), 139.5 (C), 149.1 (C), 151.3 (C), 158.8 (C), 159.3 (C), 161.0
(C) ppm. IR (KBr): ν = 2926, 2848, 1610, 1586, 1452, 1435, 1411,
˜
1224, 1204, 1155, 1126 cm–1. HRMS (ESI): calcd. for C27H30NO3
(C) ppm. IR (KBr): ν = 2934, 1712, 1609, 1586, 1224, 1204, 1154, [M + H]+ 416.2218; found 416.2220.
˜
1126 cm–1. HRMS (ESI): calcd. for C45H43N2O6 [M + H]+
(6R,10S)-4-(4-Methoxyphenyl)-2-(2,4,6-trimethoxyphenyl)-
5,6,7,8,9,10-hexahydro-6,10-methanocycloocta[b]pyridine (10b):
(6R,12R)-4,10-Bis(4-methoxyphenyl)-2,8-bis(2,4,6-trimethoxyphen- Purified by column chromatography (petroleum ether/EtOAc/TEA,
707.3116; found 707.3121.
yl)-5,6,11,12-tetrahydro-6,12-methanocycloocta[1,2-b:5,6-bЈ]dipyrid-
ine (8b): Purified by column chromatography (petroleum ether/
EtOAc/TEA, 40:60:3) to afford 8b as an off-white solid (470 mg,
31%), m.p. Ͼ 250 °C. [α]D = –56 (c 1.0, CHCl3). 1H NMR (CDCl3):
80:20:3) to afford 10b as an off-white solid (830 mg, 47%), m.p.
154–156 °C. [α]D = +36 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 1.17–1.32 (m, 1 H), 1.35–1.45 (m, 1 H), 1.59–1.77 (m,
3 H), 1.83–2.06 (m, 3 H), 2.23 (br. s, 1 H), 2.52 (d, J = 18.0 Hz, 1
δ = 2.36 (s, 2 H), 3.13 (d, J = 17.0 Hz, 2 H), 3.27 (dd, J = 17.0, H), 3.02 (dd, J = 18.0, 7.2 Hz, 1 H), 3.29 (br. s, 1 H), 3.71 (s, 6 H),
5.6 Hz, 2 H), 3.57 (s, 12 H), 3.64 (br. s, 2 H), 3.81 (s, 12 H), 6.15
3.83 (s, 3 H), 3.85 (s, 3 H), 6.20 (s, 2 H), 6.92–6.99 (m, 3 H), 7.29–
(s, 4 H), 6.88 (d, J = 8.6 Hz, 4 H), 6.98 (s, 2 H), 7.32 (d, J = 8.6 Hz,
7.36 (m, 2 H) ppm. 13C NMR (CDCl3): δ = 18.4 (CH2), 27.5 (CH),
4 H) ppm. 13C NMR (CDCl3): δ = 28.2 (CH2), 36.2 (CH), 36.5 31.3 (CH2), 32.4 (CH2), 33.3 (CH2), 33.9 (CH2), 37.6 (CH), 55.3
Eur. J. Org. Chem. 2015, 6359–6369
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6365

A. Nenisˇkis, S. Stoncˇius
= 247.6 Hz, C) ppm. IR (KBr): ν = 2938, 1711, 1604, 1587, 1226,
FULL PAPER
(CH3), 55.4 (CH3), 56.1 (CH3), 91.3 (CH), 113.0 (C), 113.6 (CH),
˜
124.9 (CH), 128.7 (C), 130.0 (CH), 132.5 (C), 147.4 (C), 150.8 (C), 1205, 1158, 1127 cm–1. HRMS (ESI): calcd. for C45H41F2N2O8 [M
158.9 (C), 159.0 (C) 159.8 (C), 161.0 (C) ppm. IR (KBr): ν = 2930, + H]+ 775.2825; found 775.2835.
˜
2850, 2836, 1712, 1608, 1583, 1512, 1454, 1247, 1224, 1205, 1156,
(6R,12R)-4,10-Diphenyl-2,8-bis(2,4,6-trimethylphenyl)-5,6,11,12-
1126 cm–1. HRMS (ESI): calcd. for C28H32NO3 [M + H]+
446.2326; found 446.2327.
tetrahydro-6,12-methanocycloocta[1,2-b:5,6-bЈ]dipyridine 1,7-Diox-
ide (1d): Purified by column chromatography (EtOAc/MeOH, 95:5)
to afford 1d as an off-white solid (250 mg, 78%), m.p. Ͼ 250 °C.
General Procedure for the Synthesis of Pyridine N-Oxides 1a–1d,
2a, 2b, and 3: K2CO3 (691 mg, 5 mmol) was added to a stirred
1
[α]D = +212 (c 1.0, CHCl3). H NMR (CDCl3): δ = 1.81 (s, 6 H),
solution of 8a–8c, 15 (0.5 mmol) or 10a, 10b (1 mmol) in CH2Cl2 2.10 (s, 6 H), 2.29 (s, 6 H), 2.31 (s, 2 H), 3.13 (dd, J = 17.8, 5.6 Hz,
(12 mL) at r.t. and to the resulting suspension m-CPBA (500 mg, 2 H), 3.30 (d, J = 17.8 Hz, 2 H), 4.26 (br. s, 2 H), 6.89 (s, 2 H),
70%, 2 mmol) was added portionwise over 4 h. The reaction mix-
6.91 (s, 2 H), 6.95 (s, 2 H), 7.14–7.21 (m, 4 H), 7.31–7.42 (m, 6
ture was then stirred at r.t. for 24 h, diluted with H2O (25 mL) and H) ppm. 13C NMR (CDCl3): δ = 19.3 (CH3), 20.0 (CH3), 21.1
extracted with EtOAc (2ϫ 20 mL). In the case of 8d, the oxidation
was carried out as described above, but without the addition of
K2CO3, and CH2Cl2 was used for extraction. The combined or-
ganic fraction was washed with saturated NaHCO3 solution and
brine, dried (Na2SO4) and the solvents evaporated. The obtained
residues were purified by column chromatography to afford pyr-
idine N-oxides 1a–1d, 2a, 2b, and 3 as off-white solids.
(CH3), 28.1 (CH2 and CH), 31.7 (CH2), 125.7 (CH), 128.1 (CH),
128.19 (CH), 128.23 (CH), 128.5 (2ϫCH), 130.4 (C), 131.1 (C),
136.2 (C), 136.5 (C), 137.7 (C), 138.4 (C), 138.7 (C), 146.9 (C),
149.5 (C) ppm. IR (KBr): ν = 2917, 1713, 1614, 1462, 1423, 1389,
˜
1273, 1256, 1178, 766, 702 cm–1. HRMS (ESI): calcd. for
C45H43N2O2 [M + H]+ 643.3319; found 643.3327.
(6R,10S)-4-Phenyl-2-(2,4,6-trimethoxyphenyl)-5,6,7,8,9,10-hexa-
(6R,12R)-4,10-Diphenyl-2,8-bis(2,4,6-trimethoxyphenyl)-5,6,11,12- hydro-6,10-methanocycloocta[b]pyridine 1-Oxide (2a): Purified by
tetrahydro-6,12-methanocycloocta[1,2-b:5,6-bЈ]dipyridine 1,7-Diox-
ide (1a): Purified by column chromatography (EtOAc/MeOH/TEA,
column chromatography (CHCl3/MeOH, 99:1) to afford 2a as an
off-white solid (370 mg, 86%), m.p. 156–158 °C. [α]D = +87 (c 1.0,
97:3:3) to afford 1a as an off-white solid (190 mg, 51%), m.p. Ͼ CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.09–1.31 (m, 1 H),
250 °C. [α]D = +202 (c 1.0, CHCl3). 1H NMR (CDCl3): δ = 2.20 1.41–1.73 (m, 4 H), 1.76–1.96 (m, 2 H), 2.08–2.28 (m, 2 H), 2.49
(s, 2 H), 3.16–3.29 (m, 4 H), 3.58 (s, 6 H), 3.70 (s, 6 H), 3.82 (s, 6
(d, J = 18.3 Hz, 1 H), 2.99 (dd, J = 18.3, 7.2 Hz, 1 H), 3.74 (s, 3
H), 4.25 (br. s, 2 H), 6.16 (s, 4 H), 7.06 (s, 2 H), 7.27–7.40 (m, 10 H), 3.75 (s, 3 H), 3.84 (s, 3 H), 4.0 (br. s, 1 H), 6.19 (s, 2 H), 7.0
H) ppm. 13C NMR (CDCl3): δ = 27.87 (CH2), 27.92 (CH), 31.7 (s, 1 H), 7.32–7.47 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ
(CH2), 55.4 (CH3), 55.8 (CH3), 55.9 (CH3), 90.8 (CH), 91.1 (CH), = 19.3 (CH2), 26.6 (CH), 27.5 (CH2), 29.1 (CH), 31.2 (CH2), 33.4
104.6 (C), 127.7 (CH), 127.9 (CH), 128.3 (CH), 129.0 (CH), 130.8
(CH2), 33.6 (CH2), 55.4 (CH3), 56.0 (2ϫCH3), 90.8 (CH), 91.0
(C), 138.0 (C), 138.3 (C), 141.9 (C), 149.3 (C), 158.9 (C), 159.2 (C), (CH), 105.0 (C), 126.9 (CH), 127.5 (CH), 128.2 (CH), 128.9 (CH),
162.2 (C) ppm. IR (KBr): ν = 2935, 1616, 1603, 1588, 1226, 1205, 132.9 (C), 136.7 (C), 139.0 (C), 141.5 (C), 150.6 (C), 159.08 (C),
˜
1156, 1127 cm–1. HRMS (ESI): calcd. for C45H43N2O8 [M + H]+
739.3022; found 739.3014.
159.12 (C), 162.0 (C) ppm. IR (KBr): ν = 2922, 2855, 1617, 1589,
˜
1455, 1417, 1392, 1286, 1227, 1204, 1154, 1126 cm–1. HRMS (ESI):
calcd. for C27H30NO4 [M + H]+ 432.2169; found 432.2169.
(6R,12R)-4,10-Bis(4-methoxyphenyl)-2,8-bis(2,4,6-trimethoxyphen-
yl)-5,6,11,12-tetrahydro-6,12-methanocycloocta[1,2-b:5,6-bЈ]dipyrid-
ine 1,7-Dioxide (1b): Purified by column chromatography (EtOAc/
(6R,10S)-4-(4-Methoxyphenyl)-2-(2,4,6-trimethoxyphenyl)-
5,6,7,8,9,10-hexahydro-6,10-methanocycloocta[b]pyridine 1-Oxide
MeOH/TEA, 95:5:3) to afford 1b as an off-white solid (170 mg, (2b): Purified by column chromatography (CHCl3/MeOH, 99:1) to
43 %), m.p. Ͼ 250 °C. [α]D = +165 (c 1.0, CHCl3). 1H NMR afford 2b as an off-white solid (360 mg, 78%), m.p. 174–175 °C.
(CDCl3): δ = 2.19 (s, 2 H), 3.19 (dd, J = 18.0, 5.5 Hz, 2 H), 3.27 [α]D = +95 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.10–
(d, J = 18.0 Hz, 2 H), 3.60 (s, 6 H), 3.70 (s, 6 H), 3.82 (s, 12 H),
1.30 (m, 1 H), 1.39–1.71 (m, 4 H), 1.76–1.97 (m, 2 H), 2.07–2.28
4.23 (br. s, 2 H), 6.16 (s, 4 H), 6.88 (d, J = 8.5 Hz, 4 H), 7.03 (s, 2 (m, 2 H), 2.51 (d, J = 18.2 Hz, 1 H), 3.0 (dd, J = 18.2, 7.1 Hz, 1
H), 7.28 (d, J = 8.5 Hz, 4 H) ppm. 13C NMR (CDCl3): δ = 27.96 H), 3.73 (s, 3 H), 3.74 (s, 3 H), 3.83 (s, 3 H), 3.84 (s, 3 H), 4.0 (br.
(CH2), 27.99 (CH2), 31.8 (CH), 55.32 (CH3), 55.39 (CH3), 55.88
s, 1 H), 6.19 (s, 2 H), 6.93–7.0 (m, 3 H), 7.28–7.35 (m, 2 H) ppm.
(CH3), 55.91 (CH3), 90.9 (CH), 91.1 (CH), 104.7 (C), 113.7 (CH), 13C NMR (75 MHz, CDCl3): δ = 19.3 (CH2), 26.7 (CH), 27.5
127.8 (CH), 130.2 (CH), 130.6 (C), 130.8 (C), 137.6 (C), 141.8 (C), (CH2), 29.1 (CH), 31.2 (CH2), 33.5 (CH2), 33.8 (CH2), 55.3 (CH3),
149.2 (C), 159.0 (C), 159.2 (2ϫC), 162.2 (C) ppm. IR (KBr): ν = 55.4 (CH3), 55.96 (CH3), 55.98 (CH3), 90.8 (CH), 91.0 (CH), 105.1
˜
2936, 2837, 1732, 1608, 1587, 1515, 1457, 1277, 1248, 1226, 1204,
(C), 113.7 (CH), 127.0 (CH), 130.1 (CH), 131.2 (C), 133.0 (C),
1156, 1126 cm–1. HRMS (ESI): calcd. for C47H47N2O10 [M + H]+ 136.4 (C), 141.5 (C), 150.5 (C), 159.01 (C), 159.09 (C) 159.13 (C),
799.3225; found 799.3241.
162.0 (C) ppm. IR (KBr): ν = 2930, 2838, 1710, 1606, 1587, 1514,
˜
1459, 1390, 1283, 1245, 1225, 1204, 1154, 1127, 808 cm–1. HRMS
(ESI): calcd. for C28H32NO4 [M + H]+ 462.2275; found 462.2279.
(6R,12R)-4,10-Bis(4-fluorophenyl)-2,8-bis(2,4,6-trimethoxyphenyl)-
5,6,11,12-tetrahydro-6,12-methanocycloocta[1,2-b:5,6-bЈ]dipyridine
1,7-Dioxide (1c): Purified by column chromatography (EtOAc/ (6R,12R)-2,8-Bis(2,4,6-trimethoxyphenyl)-5,6,11,12-tetrahydro-
MeOH/TEA, 97:3:3) to afford 1c as an off-white solid (190 mg, 6,12-methanocycloocta[1,2-b:5,6-bЈ]dipyridine 1,7-Dioxide (3): Puri-
49 %), m.p. Ͼ 250 °C. [α]D = +202 (c 1.0, CHCl3). 1H NMR fied by column chromatography (EtOAc/MeOH/TEA, 95:5:3) to
(CDCl3): δ = 2.19 (s, 2 H), 3.16 (dd, J = 18.0, 5.7 Hz, 2 H), 3.23 afford 3 as an off-white solid (140 mg, 47 %), m.p. Ͼ 250 °C.
1
(d, J = 18.0 Hz, 2 H), 3.62 (s, 6 H), 3.72 (s, 6 H), 3.83 (s, 6 H), [α]D = +484 (c 1.0, CHCl3). H NMR (CDCl3): δ = 2.16 (s, 2 H),
4.22 (br. s, 2 H), 6.18 (s, 4 H), 7.03 (s, 2 H), 7.06 (t, J = 8.7 Hz, 4
3.19 (dd, J = 17.8, 5.7 Hz, 2 H), 3.33 (d, J = 17.8 Hz, 2 H), 3.75
H), 7.29–7.35 (m, 4 H) ppm. 13C NMR (CDCl3): δ = 27.90 (CH2), (s, 12 H), 3.85 (s, 6 H), 4.14 (br. s, 2 H), 6.12 (s, 4 H), 6.94 (d, J =
27.95 (CH2), 31.8 (CH), 55.4 (CH3), 55.9 (CH3), 91.0 (CH), 91.1 8.0 Hz, 2 H), 7.07 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR (CDCl3): δ
(CH), 104.4 (C), 115.3 (d, J = 21.5 Hz, CH), 127.9 (CH), 130.7 (d, = 27.4 (CH), 28.4 (CH2), 32.1 (CH2), 55.4 (CH3), 55.9 (CH3), 56.0
J = 8.1 Hz, CH), 130.8 (C), 134.2 (d, J = 3.4 Hz, C), 136.7 (C), (CH3), 90.7 (CH), 90.8 (CH), 104.6 (C), 125.3 (CH), 126.4 (CH),
142.0 (C), 149.2 (C), 159.0 (C), 159.1 (C), 162.32 (C), 162.36 (d, J
133.4 (C), 142.5 (C), 149.4 (C), 159.0 (C), 159.2 (C), 162.3 (C) ppm.
6366
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6359–6369

Enantioselective Ring Opening of meso-Epoxides
IR (KBr): ν = 2936, 2839, 1730, 1710, 1614, 1587, 1226, 1205, 1464, 1419, 1231, 1165, 1130 cm–1. HRMS (ESI): calcd. for
˜
1157, 1127 cm–1. HRMS (ESI): calcd. for C33H35N2O8 [M + H]+
587.2388; found 587.2388.
C12H15O4 [M + H]+ 223.0965; found 223.0974.
N,N-Dimethyl-3-oxo-3-(2,4,6-trimethoxyphenyl)propan-1-ammo-
nium Chloride (13b): Enone 11 (2.22 g, 10 mmol) was added to a
suspension of dimethylamine hydrochloride (2.0 g, 25 mmol) in
iPrOH (15 mL) and the reaction mixture was stirred at reflux tem-
perature for 1 h, then cooled in an ice bath. The precipitated solid
was filtered and washed with iPrOH to afford slightly yellow crys-
tals, which were suspended in iPrOH (10 mL) and heated at reflux
for 1 h, then cooled in an ice bath, and filtered. The obtained crys-
tals were washed with iPrOH and Et2O to yield 13b as colorless
1-(2,4,6-Trimethoxyphenyl)prop-2-en-1-one (11): Procedure A: To a
solution of 1,3,5-trimethoxybenzene (12, 1.68 g, 10 mmol) in dry
1,2-DCE (20 mL) at 0 °C 3-chloropropanoyl chloride (1.9 mL,
2.54 g, 20 mmol) was added, followed by TiCl4 (2.2 mL, 3.8 g,
20 mmol). The reaction mixture was warmed to r.t. and was stirred
for 20 h, then quenched with ice. The organic phase was washed
with H2O, 2% NaOH solution and brine, dried (Na2SO4), and the
solvents evaporated. The obtained residue was purified by column
chromatography on silica gel (petroleum ether/EtOAc, 8:2) to yield
13a, which was immediately subjected to elimination. The obtained
13a was dissolved in CH2Cl2 (20 mL), TEA (1.4 mL, 1 g, 10 mmol)
was added and the reaction mixture was stirred at r.t. overnight.
After evaporation, the obtained residue was suspended in EtOAc
and filtered. The filter cake was washed with EtOAc, the filtrate
was evaporated and the obtained residue was purified by column
chromatography (petroleum ether/EtOAc, 7:3) to afford enone 11
(0.96 g, 43%) as a yellowish solid.
1
solid (2.76 g, 91%), m.p. 180–182 °C. H NMR ([D6]DMSO): δ =
2.72 (s, 6 H), 3.20 (t, J = 6.8 Hz, 2 H), 3.31 (t, J = 6.8 Hz, 2 H),
3.76 (s, 6 H), 3.81 (s, 3 H), 6.28 (s, 2 H), 10.46 (br. s, 1 H) ppm.
13C NMR ([D6]DMSO): δ = 39.0 (CH2), 42.0 (CH3), 51.2 (CH2),
55.6 (CH3), 56.0 (CH3), 91.1 (CH), 111.6 (C), 157.8 (C), 162.5 (C),
199.3 (CO) ppm. IR (KBr): ν = 3010, 2966, 2846, 2557, 2512, 2444,
˜
1710, 1692, 1610, 1590, 1474, 1236, 1211, 1157, 1139, 1123,
814 cm–1. HRMS (ESI): calcd. for C14H22NO4 [M – Cl]+ 268.1534;
found 268.1540.
(6R,12R)-2,8-Bis(2,4,6-trimethoxyphenyl)-5,6,11,12-tetrahydro-
6,12-methanocycloocta[1,2-b:5,6-bЈ]dipyridine (15): Compounds 4
(609 mg, 4 mmol) and 13b (2.55 g, 8.4 mmol) were thoroughly
mixed and placed in a pressure screw-cap vial. TEA (1.7 mL,
1.23 g, 12 mmol) was added and the vial was sealed. The reaction
mixture was heated in a 180 °C oil bath for 30 min (WARNING:
formation of volatile compounds causes high pressure inside the
vial), then the mixture was cooled to r.t. and partitioned in EtOAc
(25 mL) and H2O (25 mL). The organic phase was washed with
water, brine, dried (Na2SO4), and the solvents evaporated. The ob-
tained brown foam was dissolved in EtOH (50 mL), hydroxylamine
hydrochloride (1.4 g, 20 mmol) was added and the reaction mixture
was heated to reflux for 1 h. Once cooled, reaction mixture was
concentrated under reduced pressure and to the obtained residue
CH2Cl2 was added, which resulted in the precipitation of unreacted
hydroxylamine hydrochloride. The suspension was filtered, the fil-
trate was washed with 5% NaOH solution and brine, dried
(Na2SO4), and the solvents evaporated. The obtained residue was
purified by column chromatography (petroleum ether/EtOAc/TEA,
35:65:3) to afford 15 as an off-white solid (690 mg, 31%), m.p.
114 °C. [α]D = +300 (c 1.0, CHCl3). 1H NMR (CDCl3): δ = 2.31
(s, 2 H), 3.09 (d, J = 16.9 Hz, 2 H), 3.28 (dd, J = 16.9, 5.6 Hz, 2
H), 3.58 (br. s, 2 H), 3.72 (s, 12 H), 3.84 (s, 6 H), 6.20 (s, 4 H), 7.01
(d, J = 7.8 Hz, 2 H), 7.32 (d, J = 7.8 Hz, 2 H) ppm. 13C NMR
(CDCl3): δ = 28.2 (CH2), 35.3 (CH), 36.8 (CH2), 55.4 (CH3), 55.9
(CH3), 91.1 (CH), 112.5 (C), 125.4 (CH), 128.0 (C), 137.13 (CH),
Procedure B: POCl3 (9.32 mL, 15.3 g, 100 mmol) was added drop-
wise over 45 min to a solution of 1,3,5-trimethoxybenzene (12,
8.41 g, 50 mmol) in DMF (20 mL) at 0 °C. The reaction mixture
was stirred at 0 °C for 1 h, then poured into H2O (50 mL) and solid
K2CO3 (≈ 40 g) was added in small portions until the mixture was
slightly basic (pH 9–10). The solid precipitate was filtered, washed
with H2O and dried to yield 2,4,6-trimethoxybenzaldehyde as col-
orless crystals (9.61 g, 98 %), m.p. 118–120 °C. 1H NMR
(300 MHz, CDCl3): δ = 3.87 (s, 3 H), 3.88 (s, 6 H), 6.08 (s, 2 H),
10.35 (s, 1 H) ppm, in agreement with the literature data.[41]
1-(2,4,6-Trimethoxyphenyl)prop-2-en-1-ol (14): Vinylmagnesium
bromide (1 m solution in THF, 44 mL) was added dropwise over
20 min to a suspension of 2,4,6-trimethoxybenzaldehyde (7.85 g,
40 mmol) in THF (60 mL) at 0 °C. The reaction mixture was stirred
at 0 °C for 1 h, then warmed to r.t. and NH4Cl (2m, 50 mL) and
Et2O (50 mL) was added. The organic phase was separated, washed
with H2O and brine, dried (Na2SO4), and the solvents evaporated.
The obtained residue was purified by column chromatography on
silica gel (petroleum ether/EtOAc, 8:2), followed by recrystalli-
zation from hexane to afford 14 as a colorless solid (7.48 g, 83%),
1
m.p. 81–83 °C. H NMR (CDCl3): δ = 3.78 (d, J = 11.4 Hz, 1 H),
3.81 (s, 3 H), 3.82 (s, 6 H), 5.02 (ddd, J = 10.3, 1.6, 1.6 Hz, 1 H),
5.15 (ddd, J = 17.1, 1.6, 1.6 Hz, 1 H), 5.57 (ddt, J = 11.3, 5.5,
1.5 Hz, 1 H), 6.14 (s, 2 H), 6.16 (ddd, J = 17.1, 10.3, 5.5 Hz, 1
H) ppm, in agreement with the literature data.[42]
151.8 (C), 158.9 (C), 159.1 (C), 161.1 (C) ppm. IR (KBr): ν = 2932,
˜
1-(2,4,6-Trimethoxyphenyl)prop-2-en-1-one (11): IBX (6.72 g,
24 mmol) was added to a stirred solution of 14 (4.49 g, 20 mmol)
in THF (60 mL), and to the resulting suspension DMSO (7.1 mL,
7.8 g, 0.1 mol) was added. The reaction mixture was stirred at r.t.
for 2 h, then H2O (40 mL) and EtOAc (40 mL) was added and the
mixture was filtered through a pad of Celite. The organic phase
was washed with saturated solution of NaHCO3 and brine, dried
(Na2SO4), and the solvents evaporated. The obtained residue was
purified by column chromatography on silica gel (petroleum ether/
EtOAc, 7:3), followed by recrystallization from Et2O to afford 11
2836, 1710, 1609, 1587, 1458, 1225, 1204, 1155, 1127 cm–1. HRMS
(ESI): calcd. for C33H35N2O6 [M + H]+ 555.2490; found 555.2482.
General Procedure for the Enantioselective Opening of meso-Epox-
ides with Silicon Tetrachloride: SiCl4 (43 μL, 64 mg, 0.375 mmol)
was added to a solution of catalyst (25 μmol, 10 mol-%), epoxide
16 (0.25 mmol) and DIPEA (0.13 mL, 97 mg, 0.75 mmol) in dry
CH2Cl2 (2.5 mL) at –78 °C. The reaction mixture was stirred at
–78 °C for 24 h, then poured into a cooled (0 °C) mixture of satu-
rated aqueous solution of KF and K2HPO4 (1:1, 2.5 mL). The re-
as yellow crystals (2.96 g, 67%), m.p. 72–74 °C. 1H NMR (CDCl3): sulting mixture was filtered through a pad of Celite, and the or-
δ = 3.76 (s, 6 H), 3.84 (s, 3 H), 5.88 (dd, J = 10.3, 1.3 Hz, 1 H),
6.05 (dd, J = 17.4, 1.3 Hz, 1 H), 6.12 (s, 2 H), 6.58 (dd, J = 17.4,
ganic phase was washed with brine, dried (Na2SO4), and the sol-
vents evaporated. In the case of 16f–16h, the obtained residues were
10.3 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 55.4 (CH3), 55.8 (CH3), subjected to column chromatography to yield 1,2-diaryl-2-chloro-
90.6 (CH), 110.9 (C), 129.3 (CH), 138.4 (CH2), 158.9 (C), 162.5 ethanols 17f–17h. In the case of 16a–16e and 16i, the obtained
(C), 194.7 (CO) ppm. IR (KBr): ν = 2944, 2843, 1663, 1611, 1586,
residue was dissolved in CH2Cl2 (2.5 mL), then 4-dimethyl-
˜
Eur. J. Org. Chem. 2015, 6359–6369
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6367

A. Nenisˇkis, S. Stoncˇius
FULL PAPER
[15] V. Simonini, M. Benaglia, T. Benincori, Adv. Synth. Catal.
2008, 350, 561–564.
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and 4-nitrobenzoyl chloride (93 mg, 0.5 mmol) were added. The
reaction mixture was stirred at r.t. for 2 h, then quenched with
H2O, stirred for additional 15 min and extracted with EtOAc
(20 mL). The organic phase was washed with 10% HCl, brine, satu-
rated NaHCO3 solution (ϫ2) and brine, dried (Na2SO4), and the
solvents evaporated. The obtained residue was purified by column
chromatography to yield corresponding 4-nitrobenzoates 18a–18e,
21i, and 23i (for further details see the Supporting Information).
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Supporting Information (see footnote on the first page of this arti-
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[19] C. J. Wallentin, E. Orentas, E. Butkus, K. Wärnmark, Synthesis
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1
copies of H and 13C NMR spectra of new compounds, and chiral
HPLC traces are provided.
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[20] a) E. Butkus, S. Stoncius, A. Zilinskas, Chirality 2001, 13, 694–
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698; b) E. Butkus, A. Zilinskas, S. Stoncˇius, R. Rozenbergas,
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Acknowledgments
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[21] a) S. Stoncius, E. Butkus, A. Zilinskas, K. Larsson, L.
ˇ
This research was funded by the European Social Fund under the
Global Grant Measure (VP1-3.1-SMM-07-K-01-030). Mr. L.
Taujenis, Department of Analytical and Environmental Chemistry,
Vilnius University, is acknowledged for performing the HRMS
analyses.
Öhrström, U. Berg, K. Wärnmark, J. Org. Chem. 2004, 69,
5196–5203; b) S. Stoncˇius, E. Orentas, E. Butkus, L. Öhrström,
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[27]
Formation of the analogous phenolic by-product was noted
earlier in the synthesis of METHOX, see footnote 64 in ref.[18b]
In the case of 2a, a small amount of rather unstable over-oxi-
dated phenolic by-product 2A was isolated as a mixture of two
atropoisomers, owing to the restricted rotation about the bond
linking pyridine N-oxide and 3-hydroxy-2,4,6-trimethoxy-
phenyl units (see Supporting Information).
H.-R. Bjørsvik, G. Occhipinti, C. Gambarotti, L. Cerasino,
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1276–1283.
Three separate experiments consistently produced 18a in 66–
72% yields and 47% ee.
Apparently allene-derived bisphosphine oxide L7 (Figure 1)
also produces rearranged alcohol 20i; see footnote 21 in ref.[10]
a) T. J. Gerteisen, D. C. Kleinfelter, J. Org. Chem. 1971, 36,
3255–3259; b) M. A. Loreto, L. Pellacani, P. A. Tardella,
Synth. Commun. 1981, 11, 287–293; c) G. Gargaro, M. A. Lor-
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[35]
[36]
The ratio of 4-nitrobenzoates 21i:23i in the crude reaction mix-
tures was about 6.5:1 and about 1:4.4 in the case of 1b and 3,
respectively, as determined from GC analysis. The isolated
yields of 23i, however, were rather low as a result of partial
loss of rather volatile nortricyclanol 22i during the work-up
procedures and complicated purification of 23i.
Unsatisfactory results were obtained if the ring opening of 16i
was performed in acetonitrile or chloroform. In the presence
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Published Online: August 20, 2015
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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