Asymmetric total synthesis of Lepadiformine C using memory of chirality in an intramolecular ester enolate michael addition

Article abstract of DOI:10.1021/acs.orglett.6b03550

The asymmetric synthesis of lepadiformine C was achieved using D-proline as the only chiral source. The synthetic strategy features the use of the principle of memory of chirality in an intramolecular Michael addition to construct the bicyclic intermediate without the aid of external chiral sources. A brief mechanistic rationale is presented to account for the stereochemical outcome.

Full text of DOI:10.1021/acs.orglett.6b03550

Letter
pubs.acs.org/OrgLett
Asymmetric Total Synthesis of Lepadiformine C Using Memory of
Chirality in an Intramolecular Ester Enolate Michael Addition
Seokwoo Lee, Minsik Bae, Jinkyung In, Jae Hyun Kim, and Sanghee Kim*
College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea
S
* Supporting Information
ABSTRACT: The asymmetric synthesis of lepadiformine C was
achieved using D-proline as the only chiral source. The synthetic
strategy features the use of the principle of “memory of chirality” in
an intramolecular Michael addition to construct the bicyclic
intermediate without the aid of external chiral sources. A brief
mechanistic rationale is presented to account for the stereochemical
outcome.
epadiformine C (1, Figure 1) is a tricyclic marine alkaloid
with a perhydropyrrolo[1,2-j]quinoline ring system. This
Scheme 1. Retrosynthetic Analysis of Lepadiformine C (1)
L
Figure 1. Structures of lepadiformines (1−3).
alkaloid was isolated from the tunicate Clavelina moluccensis
together with its congeners, lepadiformine A (2) and B (3),
each of which has a hydroxymethyl group at C-13.1 Despite
only a few reported biological effects,1b,c these tricyclic alkaloids
have been the subject of extensive synthetic studies due to their
intriguing structural features.2−4 The construction of the
tricycle framework characterized by the trans-1-azadecalin A/
B ring and the AC spiro-cyclic ring system is the primary
synthetic challenge posed by the lepadiformines. While the total
synthesis of lepadiformine A has been published numerous
times,3 only a few total syntheses have been reported for
lepadiformine C.4 In this paper, we report the stereoselective
asymmetric synthesis of lepadiformine C (1) using the amino
acid D-proline as the only chiral source.
have reported the total synthesis of (−)-penibruguieramine A
using the MOC phenomenon.8b MOC was utilized during the
intramolecular aldol reaction of proline ester 7 to afford the
bicyclic product 8 with the correct absolute and relative
configuration required to proceed to the natural product
(Scheme 2a). Successful examples of MOC in the intra-
molecular Michael addition of α-amino ester enolates have
been reported by Kawabata, in which a bulky N-tert-
butoxycarbonyl (Boc) group is essential for the generation of
Scheme 2. Previously Reported Related MOC Phenomena
As outlined in Scheme 1, we envisioned that the intra-
molecular Michael addition5 of proline ester 4 would provide
bicyclic compound 5, putting in place the substituents
necessary for the formation of the A ring of lepadiformine C
(1). If the central chirality in the proline moiety of 4 was
transformed into the axial chirality in the enolate intermediate
6, and the transient axial chirality was transferred back to
central chirality in product 5, the asymmetric synthesis could be
achieved from D-proline without the aid of external chiral
sources.
The use of “memory of chirality” (MOC) is an attractive
strategy for asymmetric synthesis.6,7 However, MOC has thus
far found limited applications in total synthesis.8 Recently, we
Received: November 28, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03550
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the axial chirality in the enolate intermediate (Scheme 2b).9
Based on these precedents, we anticipated a successful MOC in
the intramolecular Michael reaction of proline ester 4.
Another concern for this MOC-Michael reaction strategy is
the resulting diastereoselectivity. A computational study
indicated that the desired trans-Michael adduct 5 is not
thermodynamically favored over the cis-isomer (see Supporting
Information (SI)), which suggested that the reaction should be
carried out under kinetic control for the formation of the trans
isomer. We postulated kinetically relevant transition states for
this reaction (vide infra) and eventually designed the Michael
substrate 9 (Scheme 3).
a
Table 1. Reaction Conditions for Michael Addition of 9
b
c
entry
base (equiv)
temp
time
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
NaOtBu (1.1)
KOtBu (1.1)
LiOtBu (1.1)
NaOtBu (3)
NaOtBu (0.5)
NaOtBu (1.1)
NaOtBu (1.1)
NaOtBu (1.1)
NaOEt (1.1)
NaHMDS (3)
rt
10 min
3 h
82
45
0
88
88
−
89
89
92
95
98
89
94
rt
rt
12 h
10 min
2 h
rt
71
69
76
62
23
77
48
rt
0 °C
−20 °C
−40 °C
rt
2 h
Scheme 3. Synthesis of Michael Substrate 9
12 h
72 h
12 h
1 h
d
10
−78 °C
a
Reactions were performed with 9 (50 mg, 0.15 mmol) at a substrate
b
1
concentration of 0.01 M in DMF. Yield was estimated from the H
c
analysis. Enantiomeric excess was determined by chiral HPLC
analysis of thioamide derivative from 13. THF was used as the
d
reaction solvent.
Our study commenced with the preparation of substrate 9
for the key Michael reaction. The known acid 1010 with a tert-
butyl enoate group was readily prepared from commercial γ,δ-
unsaturated acid 11 via sequential ozonolysis and Wittig
olefination. The obtained acid 10 was condensed with L-proline
ethyl ester (12) instead of the less common D-enantiomer. The
HOBt/EDCI-mediated coupling afforded 9 without erosion of
enantiomeric purity.
With compound 9 in hand, we investigated the intra-
molecular Michael reaction with the aim of obtaining of the
desired diastereo- and enantioselective outcome. In addition to
the envisioned intramolecular Michael reaction, 9 can also
undergo other competitive intra- and intermolecular side
reactions, including Dieckmann-type condensations,11 due to
the presence of multiple enolizable carbonyl groups. Thus, a
judicious choice of base and reaction conditions was necessary
to obtain the desired product.
Various bases and conditions were screened; the results are
listed in Table 1. A promising result was obtained when
substrate 9 was treated with tert-butoxide as a base. The
reaction with 1.1 equiv of NaOtBu at rt in DMF rapidly yielded
the bicyclic compound 13 as a single diastereomer in 82% yield
(entry 1). The reaction took place also when KOtBu was used
as a base (entry 2), but the yield of 13 was significantly lower
because of the formation of substantial amounts of polar side
products which were difficult to characterize. When LiOtBu was
used, no reaction occurred and only starting material was
recovered (entry 3). These results indicated the marked
influence of the countercation on the success of intramolecular
Michael reaction. This countercation effect may be due to the
subtle difference in basicity between alkali metal tert-
butoxides.12 The trans relative stereochemistry of 13 was
determined by 2D NMR analysis (see SI). The enantiomeric
excess of 13 was determined to be 88% by chiral HPLC analysis
upon conversion to a UV-active thioamide derivative (see SI
and Scheme 6). This result indicated that MOC was exerted
during the intramolecular Michael addition of 9.
DMF only led to a lower enantiomeric purity and yield (see
SI). When the temperature was decreased, the enantiomeric
purity of the product increased (entries 6−8), albeit to the
detriment of the reaction rate and yield; the enantiomeric
purity of the reaction with NaOtBu at −20 °C was greater than
95% with a yield of 62%. NaOEt also yielded the desired 13
without significant loss of yield (entry 9). On the other hand,
the strong base NaHMDS resulted in an intractable mixture of
side products and a low yield of product 13, although the
reaction at −78 °C delivered the product in high (94%) ee
(entry 10).13
To understand the stereochemical outcome of the intra-
molecular Michael addition of 9, we performed additional
experiments. Resubjection of trans Michael product 13 to the
reaction conditions resulted in no change in the product
profile; the enantiomeric purity of 13 remained unchanged, and
the cis diastereomer was not formed (see SI). This result
suggested that the above Michael reaction is irreversible.14 We
analyzed the remaining substrate in the incomplete reaction
mixture from the reaction of entry 6 in Table 1 and found that
the proline stereocenter of the stating material was not
racemized (see SI). The deuterium level at the proline
stereocenter remained the same (Scheme 4a). These results
suggested that any ester enolate intermediate is rapidly
converted to the Michael product. When the reaction was
performed in the presence of an external proton source, the
enantiomeric purity of product was significantly reduced. For
example, the enantiomeric purity of the product from the
reaction in DMF/tBuOH (1:1) at rt was only 65% (Scheme
4b). Based on these observations together with the obtained
MOC results, a Michael reaction mechanism was proposed as
depicted in Scheme 5. The axially chiral enolate 14-I (with an
arbitrary enolate geometry) is formed selectively over 14-II via
the favored conformer 9-I with minimized 1,3-allylic strain. The
transient ester enolate 14-I undergoes Michael addition prior to
the racemization of axial chirality. The reaction via conformer
14-III, which leads to the formation of the cis-isomer, is less
favorable due to steric repulsion between the proline moiety
and the tert-butyl enoate group.
To enhance the degree of chirality preservation, the reaction
conditions using NaOtBu were further optimized. Changing the
amount of NaOtBu did not alter the enantiomeric purity of
product (entries 4 and 5). Changing the solvent system from
B
DOI: 10.1021/acs.orglett.6b03550
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Exploratory Studies To Determine the
Intramolecular Michael Addition Mechanism
Scheme 6. Total Synthesis of Lepadiformine C (1)
Scheme 5. Proposed Mechanistic Route for the Michael
Addition
yield. The final task in completing the synthesis was the
removal of the enone functionality in the A ring. This was
accomplished expediently via three steps that included the
double bond hydrogenation of the enone, thioketalization, and
reduction of the thioketal with Raney nickel.18 The spectral and
optical rotation data of the synthetic lepadiformine C (1) were
in good agreement with those previously reported.1c,4
In this study, using the principles of “memory of chirality”
(MOC), we successfully achieved a concise asymmetric total
synthesis of lepadiformine C (1). Proline was the only chiral
source, and all stereocenters were established without the aid of
an external chiral influence. The key synthetic sequence was the
intramolecular Michael reaction of proline-amide 9, which
proceeded with a high level of chirality preservation and with
complete diastereoselectivity.
Having achieved the diastereo- and enantioselective intra-
molecular Michael reaction of proline ester 9, we next focused
on the total synthesis of lepadiformine C (1). To this end, the
enantiomer of bicyclic compound 13 was prepared in 93% ee
from ent-9 using the conditions in entry 6 of Table 1 (Scheme
6). For the introduction of the butyl group at C-2 (natural
product numbering), the amide group of ent-13 was first
converted to the thioamide with Lawesson’s reagent.
Methylation of thioamide 15 and treatment of the resulting
thioiminium salt with n-butyl cuprate, followed by reduction of
iminium intermediate 16 with NaCNBH3, afforded indolizidine
17 as a single diastereomer in 62% yield over three steps.15 The
diastereofacial selectivity is a consequence of the preferred axial
attack of the hydride on the half-chair iminium intermediate
16.16
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03550.
■
S
Copies of 1H and 13C NMR spectra of all new
compounds and preparation of starting materials
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pennkim@snu.ac.kr.
ORCID
The A ring was constructed from the two ester groups on 17.
The tert-butyl ester group was reduced with Superhydride to
the corresponding primary alcohol 18, and the sterically
hindered C-10 ester group was converted to a methyl ketone
Sanghee Kim: 0000-0001-9125-9541
Notes
The authors declare no competing financial interest.
group with (trimethylsilyl)methyllithium to give 19.17
A
ACKNOWLEDGMENTS
This work was supported by the Mid-Career Researcher
Program (NRF-2016R1A2A1A05005375) of the National
Parikh−Doering oxidation of the primary alcohol in 19,
followed by an acid-catalyzed intramolecular aldol condensa-
tion, afforded the desired tricyclic product 20 in good overall
■
C
DOI: 10.1021/acs.orglett.6b03550
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Watt, C. I. F. Chem. Soc. Rev. 1992, 21, 237. (b) Shirakawa, E.; Zhang,
X.; Hayashi, T. Angew. Chem., Int. Ed. 2011, 50, 4671.
Research Foundation of Korea (NRF) grant funded by the
Korea government (MSIP). This work was also supported by
B a s i c S c i e n c e R e s e a r c h P r o g r a m ( N R F -
2016R1A6A3A01013304) through the NRF funded by the
Ministry of Education.
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D
DOI: 10.1021/acs.orglett.6b03550
Org. Lett. XXXX, XXX, XXX−XXX