Organic Letters
Letter
2
4. Fortunately, the enol-ether functionality of 24 also can be
point for the examination. Lithium naphthalenide was first
examined, but unfortunately the desired spiro-α-aminocyclo-
pentanone 26 was not observed (Table 1, entry 1). To identify
a matched combination, a variety of arenes were screened as
parterns with lithium on this platform. To our delight, a small
amount of the product 26 (7%) was detected when 2,6-di-tert-
butylnaphthalene was applied (Table 1, entry 2). According to
the general properties of lithium arenides, we suspected that a
reductant milder than lithium naphthalenide might be
preferred. The parallel tests of reductive couplings showed
that lithium acenaphthalenide was too feeble to promote the
reaction, and lithium 1,1′-binaphthylide seemed to be too
powerful and resulted in messy reaction (Table 1, entries 3 and
4, respectively). Alternatively, the reaction with lithium
diphenylide gave us a promising result and delivered an
improved yield (37%) of the product 26 (Table 1, entry 5). A
noticeable improvement was found in the reaction when using
lithium 4,4′-di-tert-butylbiphenylide (LiDBB), affording a
satisfying yield (74%) of the spiro-α-aminocyclopentaone 26
as a single diastereoisomer. It is worth noting here that the C4
stereochemistry of 26 was indirectly determined by a
comparison with the literature data of 11 in a late stage
(Scheme 2). We speculate that the chelation of lithium ion
regarded as a special protecting form for both the ketone-
carbonyl group (of the six-membered ring) and the hydroxyl
group (of the linear chain); therefore, it was suitable for the
next transformation. Based on our observation, a continuously
sequential operation was finally optimized for the preparation
of 24 and 25. First, the mixture of 23a and 23b was treated
with 0.3 equiv of boron trifluoride in DCM at 0 °C to rt. It was
found that the enol-ether was formed completely while one of
the two N-Boc groups of 23a or 23b was also removed. The
removal of the remaining N-Boc group was carried out by a
further treatment with trifluoroacetic acid. However, the
purification of the free amine 24 via silica gel chromatography
was found to be inefficient. To save the material, a solution of
the unpurified amine 24 DCM was directly applied to the next
step after neutralization and drying. The spontaneous
formation of the cyclic imine in 25 took place slowly but
efficiently when the above solution was heated at 40 °C. To
avoid the side reactions brought by long-time heating, the
reaction was interrupted after three days, and the expected
imine 25 was separated. Usually, 56−66% of the amine 24 can
be converted into the corresponding imine 25, with a recovery
yield of 87−97%. The recovered amine 24 was redissolved in
DCM and heated for the second batch of the crop. After two
additional recycles, the combined overall yield of imine 25
Scheme 2. Total Synthesis of the Fawcettimine Class
14
could be increased to 82% over two steps.
With the cyclic imine 25 in hand, we started to explore the
crucial intramolecular reductive imine−ester coupling (Table
1
). Although several electrochemical approaches were reported
a
Imine−Ester Coupling of 25
b
entry
arene
naphthalene
2,6-di-tert-butylnaphthalene
acenaphthene
1,1′-binaphthyl
diphenyl
4,4′-di-tert-butylbiphenyl
4,4′-di-tert-butylbiphenyl
4,4′-di-tert-butylbiphenyl
temperature (°C)
26 (%)
c
1
−80
n.d.
7
d
2
−80 to −40
−80 to −40
−80 to −60
−80 to −55
−60
d
3
n.r.
n.d.
37
56
74
84
c
4
d
5
d
6
d
7
−80
−98
d
with the ester carbonyl and the steric effect of the α-amino
radical finally led to the observed stereoselectivity. The
detailed mechanism for the subsequent C−C bond formation,
either by an anionic or free-radical process, remains to be
explored. Further optimization showed that lower temper-
atures could further increase the yields (Table 1, entries 6−8),
and the final reaction temperature was determined to be −98
8
a
Reactions were performed at a set concentration of 25 (0.020 M),
b
and lithium arenide (0.25 M) in THF was added. Isolated yields.
c
d
Lithium arenide (0.3 equiv) was added. Lithium arenide (3.0 equiv)
was added; n.d. stands for not detected, and n.r. stands for no
reaction.
°
C.
To simplify the procedure for the scaled-up preparation, the
for similar intramolecular couplings of aromatic imines and
1
5
esters, few have been explored on the corresponding aliphatic
system, especially a complex aliphatic system that contains
multiple continuous stereocenters. As a category of powerful
reductants involving single-electron processes, lithium-arenides
were employed in some challenging C−C bond forma-
purification of product 26 was waived after completing the
reductive coupling of 25 under the optimized conditions.
Instead, the resulting reaction mixture was treated with
concentrated aqueous hydrochloric acid (Scheme 2). A
mixture of 27a and 27b (4:1, 2.2 g) was afforded in an 84%
yield. The subsequent reaction of 27a and 27b with
methanesulfonyl chloride and N,N-diisopropylethylamine in
DCM delivered the first natural fawcettimine-type alkaloid
1
1,16
tions.
Due to the uncertainty of the reductive C−C
coupling between an aliphatic imine and an ester, metal−
arene-based conditions were chosen by us as a feasible starting
3
580
Org. Lett. 2021, 23, 3578−3583
Huang, Bing-Bing
