Organic Letters
Letter
similarly via the salt with (+)-S,S-di-p-toluoyl tartaric acid (see
ester 11 was synthesized from the bicyclic amine 10.6,7
A potentially simple synthesis of the azatetraquinane 1 from
the chiral α-amino acid 9 using an azomethine ylide-olefin
[3+2] cycloaddition step, e.g., 9 → 1 (Figure 2), is actually
extremely challenging because the scope of such additions is
trimethylsilyl acetamide (2 equiv) as a scavenger of water led
to a cleaner reaction and higher yields. Under optimum
the [3+2] cycloaddition reaction of racemic 9, paraformalde-
hyde, and 1-cyanocyclopentene afforded the racemic adduct 14
as a 90:10 mixture of anti- and syn-[3+2] adducts in 70% yield.
Scheme 3. An Expeditious Synthesis of the C2-Symmetric
anti-Azatetraquinane 1
Figure 2. Simple but hypothetical route for the synthesis of 1.
We devoted a very considerable amount of time and effort to
the synthesis of the tricyclic lactone 12 from the amino acid 9
(or ester 11) because that substance might serve as a useful
precursor for the azomethine ylide 13 (Figure 3), but to no
avail. The insolubility of the amino acid 9 in aprotic solvents is
one obstacle to the generation of lactone 12 or azomethine
ylide 13 from paraformaldehyde. The synthesis of the lactone
12 from various formaldehyde equivalents using a benzene-
The pure racemic anti-adduct 14 was readily obtained by flash
column chromatography on silica gel using hexane/acetone as
the eluent. Reductive decyanation of 14 with excess lithium in
liquid ammonia/THF at −78 °C occurred smoothly to give
the desired racemic anti-azatetraquinane 1 in 80% yield as
shown in Scheme 3.10 The achiral Cs-symmetric diastereomer
of 1 (Figure 4) having the terminal rings syn to one another
was similarly made from the (minor) diastereomer of 14 (see
Figure 3. Hypothetical [3+2] cycloaddition route for the conversion
of 9 to 1 in a single step.
Figure 4. Cs diastereomer of 1.
Enantiomerically pure R-amino acid 9 was analogously
converted into the chiral levorotatory tetracyclic nitrile 14 and
then into the chiral C2-symmetric dextrorotatory azatetraqui-
nane 1, as summarized in Scheme 3 and detailed in the
synthesized starting from S-amino acid 9.11,12
The stereochemistry of 14, with terminal rings anti to one
another in the major [3+2] cycloaddition product, follows
from its conversion to the C2-symmetric, chiral tetracyclic
product 1 rather than the diastereomer of 1 described above
having a terminal-ring-syn structure, which has Cs symmetry
The pre-transition state assembly for the formation of 14
may reasonably be represented by the approximation shown in
Figure 5 in which the cyano group projects away from (and is
exo to) the bicyclic ylide moiety.
An important takeaway from the success of the process
outlined in Scheme 3 is that cyano can be uniquely useful in
azomethine-ylide cycloadditions to CC, both serving as an
activating and removable group and broadening the range of
applicability.
The guidance provided by structure 14 led us to speculate
that the reaction of the R-amino acid 9, paraformaldehyde, and
1,2-dicyanocyclopentene (E) might be even more exo
In addition, the use of various literature procedures8 for
generating azomethine ylides failed to form 1 from excess
cyclopentene and 9, most likely because the azomethine ylide
13 is insufficiently reactive. The desired [3+2] cycloaddition
reaction also failed to take place with the more electrophilic
olefinic substrates 1-methoxycarbonyl cyclopentene, 2-cyclo-
pentenone, and cyclopentadiene under a variety of conditions.
Fortunately, it was possible to obtain the desired [3+2]
cycloaddition product 14 from 1-cyanocyclopentene9 and in
situ-generated azomethine ylide 13 in modest yield using
racemic amino acid, a tertiary amine, and paraformaldehyde at
reflux in benzene or toluene. More than 40 experiments were
performed to ascertain the most favorable conditions for the
synthesis of the amino nitrile adduct 14. Freshly sublimed
paraformaldehyde in a large excess in benzene at reflux worked
best and afforded higher yields of 14 than CH2O gas
(generated externally from paraformaldehyde and Amberlyst
sulfonic acid resin in diglyme at 80 °C and added as a slow
stream with N2 gas as the carrier) or the Eschenmoser-type
CH2O equivalent i-Pr2N+CH2Cl− or chloromethyl trifluor-
oethyl ether. Triisobutylamine and trimethallylamine were
superior to diisopropylethyl amine, and triethylamine was
nonviable as a tertiary amine component. The use of bis-
2259
Org. Lett. 2021, 23, 2258−2262