Total Synthesis and Structural Elucidation of (-)-Cephalezomine G

Article abstract of DOI:10.1021/acs.orglett.9b00036

The first asymmetric synthesis and configurational elucidation of (-)-cephalezomine G was achieved. The highly functionalized Cα-substituted proline derivative was prepared from d-proline as the only chiral source via a C → N → C chirality transfer method

Full text of DOI:10.1021/acs.orglett.9b00036

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis and Structural Elucidation of (−)-Cephalezomine G
Hongjun Jeon, Hyunkyung Cho, and Sanghee Kim*
College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
S
* Supporting Information
ABSTRACT: The first asymmetric synthesis and configurational
elucidation of (−)-cephalezomine G was achieved. The highly
functionalized Cα-substituted proline derivative was prepared
from D-proline as the only chiral source via a C → N → C
chirality transfer method consisting of stereoselective N-allylation
and [2,3]-Stevens rearrangement. The azaspiranic tetracyclic
backbone was constructed using ring-closing metathesis and the
Friedel−Crafts reaction. Two contiguous hydroxyl groups were
introduced in the later stages.
Cephalotaxus alkaloids have been fascinating synthetic targets
for several decades due to their interesting structures and
biological activities.1−3 The principal structural feature of this
family of alkaloids is an azaspiranic tetracyclic backbone
(Figure 1), which comprises a benzazepine ring system (rings
cephalezomine A was isolated, several other alkaloids were
also isolated including cephalezomines G and H.8 They are
unique compared to other Cephalotaxus alkaloids in that their
C-2 carbons present a lower oxidation state. The structure of
cephalezomine H was proposed as the 2β,3α-anti-diol, but it
was revised as the β,β-syn-diol 5 by the first total synthesis by
Ishibashi.9 The structure of cephalezomine G was initially
proposed as the α,α-syn-diol 6.8 It is interesting to note that 6
was synthesized before the isolation of cephalezomine G from
a natural source.10 Later, the structure of cephalezomine G was
reproposed by the Ishibashi group as the 2α,3β-anti-diol 7
based on the 1H−1H NMR coupling constant.9 The
reproposed structure of cephalezomine G has not yet been
validated. Thus, this uncertainty necessitates clarification.
Cephalezomine G characteristically contains four contiguous
stereogenic centers in the cyclopentane D ring, one of which is
a tetrasubstituted carbon atom bearing a nitrogen substituent.
The selective installation of these stereogenic centers would be
a major synthetic challenge, especially considering the sterically
encumbered nature of the D ring. In addition, the efficient
construction of the embedded azaspirocycle system is also
demanding. We herein describe the configurational elucidation
of (−)-cephalezomine G and its first total synthesis relying on
our recently reported chirality transfer method for the
asymmetric synthesis of α-substituted proline derivatives.11
We planned to synthesize both the originally proposed and
reproposed structures of cephalezomine G, 6 and 7, for
unambiguous structural validation. After disconnection of the
B ring via intramolecular Friedel−Crafts cyclization, we
identified olefinic compound I as a possible platform to obtain
stereochemicial diversity of two hydroxyl groups (Scheme 1).
We envisioned accessing I from Cα-substituted proline
derivative II through construction of a cyclopentene ring by
way of a ring-closing metathesis (RCM) reaction. The proline
derivative II was expected to be asymmetrically prepared from
Figure 1. Structures of Cephalotaxus alkaloids (1−7) and their
azaspiranic tetracyclic backbone.
A and B) and a 1-azaspiro[4.4]nonane unit (rings C and D).
More than 70 compounds have been isolated to date.1e
A
representative member of this family is (−)-cephalotaxine (1),
which was isolated from Cephalotaxus harringtonii in 1963.4
One of its naturally occurring ester derivatives, homoharring-
tonine (2), was approved by the FDA in 2012 as a drug for the
treatment of chronic myeloid leukemia.5 The other represen-
tative member is drupacine (3), which is a C-11 oxygenated
analogue of cephalotaxine (1).6 Cephalezomine A (4) has a
drupacine-type skeleton and the same oxygenated side chain as
homoharringtonine.7 From the same plant from which
Received: January 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00036
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
BuOK in THF for the [2,3]-Stevens rearrangement,15 the
desired exo product 12 was obtained as the major diastereomer
(dr >97:3).14 The reaction conditions led to partial
deacetylation of the product. Complete deacetylation was
achieved upon basic workup affording catechol 12 in 84%
yield. Treatment of rearrangement product 12 with dibromo-
methane produced methylenedioxy compound 13. The
enantiomeric ratio of 13 (93:7)16 was essentially the same as
the diastereomeric ratio of 11, which indicates that the
diastereopurity of the N-quaternization product was com-
pletely transmitted to the enantiopurity of the [2,3]-Stevens
rearrangement product.
Scheme 1. Retrosynthetic Route for the Originally Proposed
and Reproposed Structure of Cephalezomine G (6 and 7)
Having achieved the diastereo- and enantioselective syn-
thesis of substituted proline 13, we next focused on the
construction of the azaspirocycle system using an ester group
and olefin moiety. To this end, the sterically hindered tert-butyl
ester group of 13 was first reduced with LiAlH4 to the
corresponding primary alcohol (Scheme 3). We successfully
D-proline ester IV without the aid of external chiral sources by
the method that we developed recently.11 In this trans-
formation, the diastereoselective N-allylation with cinnamyl
bromide V was required to generate the quaternary ammonium
salt III exhibiting N-chirality. We previously found that high
diastereoselectivity was obtained when a 2,3-disubstituted
benzyl group was used as an N-substituent (R3). The
subsequent exo-selective [2,3]-Stevens rearrangement of III
would deliver the enantiomerically enriched proline derivative
II, having a relative stereochemistry required for an azaspiranic
tetracyclic backbone, by transferring the generated N-chirality
back to the α-carbon chirality.
Scheme 3. Synthesis of the Originally Proposed Structure of
Cephalezomine G (6)
Although cephalezomine G contains a methylenedioxy
group on the aromatic ring, we started our synthesis with
the known (E)-cinnamyl alcohol 8, containing a 3,4-diacetoxy
group (Scheme 2). This is because our previous study
Scheme 2. Construction of Cα-Substituted Prolinate via N-
Allylation and [2,3]-Stevens Rearrangement
converted the hydroxymethyl group of 14 to the allyl group in
16 via aziridinium intermediate17 15, the identity of which was
confirmed by X-ray crystallography. The RCM of diene 16 was
successfully performed with the Grubbs first generation
catalyst, furnishing the azaspirocycle 17.
The obtained RCM product 17 was subjected to
dihydroxylation conditions with OsO4 to generate cis-diol 18
as the only observable diastereomer. Without trifluoroacetic
acid, diol 18 was obtained only in very low yield (16%). For
the formation of the benzazepine ring system by intramolecular
Friedel−Crafts cyclization, a two-carbon unit was introduced
in two steps by removing the benzyl-type N-substituent
followed by reductive amination with 2,2-dimethoxy-
acetaldehyde (19) to afford acetal 20. Carbon−carbon bond
formation by Friedel−Crafts reaction was accomplished with
an excess of methanesulfonic acid to produce the correspond-
ing enamine intermediate, which was directly reduced in a one-
demonstrated that the cinnamyl aromatic ring having an
electron-withdrawing substituent shows better diastereoselec-
tivity in N-allylation compared to that with an electron-
donating substituent. Cinnamyl alcohol 8 was prepared in a
two-step process from caffeic acid, according to the literature.12
Bromination of cinnamyl alcohol 8 afforded cinnamyl bromide
9. N-Quaternization of 2,3-dimethylbenzyl D-proline tert-butyl
ester (10) was performed with the obtained cinnamyl bromide
9 in the presence of sodium iodide13 at −10 °C to afford
ammonium salt 11 in 76% yield with a good diastereomeric
ratio of 93:7.14 When ammonium salt 11 was treated with t-
B
DOI: 10.1021/acs.orglett.9b00036
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
pot process with a borane tert-butylamine complex to the
originally proposed cephalezomine G (6) in high yield.18
The H NMR spectrum of our synthetic compound 6 in
ment of 22 with diethylaminosulfur trifluoride (DAST) to
yield the seven-membered cyclic carbamate 23.19
1
The cyclic carbamate group of 23 was cleaved by the action
of phenyl lithium to give amino alcohol 24. Under several
standard conditions including KOH/EtOH and HCl, no
desired product was obtained.20 As in the synthesis of the
originally proposed structure of cephalezomine G (6), an
external two carbon source was introduced by reductive
amination with 19 to afford compound 25. Unlike the previous
case, acid-catalyzed Friedel−Crafts reaction of 25 yielded
benzyl ether 26 with concomitant deprotection of the TBS
group. The formation of 26 might result from the capture of
the oxonium intermediate by the C-3 hydroxyl group.
Reduction at the benzylic position of 26 was difficult probably
due to the incomplete orbital overlap between the C−O σ-
bond and the π-system of benzene.21 Thus, the C-3 hydroxyl
group was protected as a pivalate 27 to prevent its involvement
in the Friedel−Crafts reaction. Subsequent one-pot Friedel−
Crafts reaction and reduction gave benzazepine 28. Depro-
tection of the pivaloyl group of 28 with LiAlH4 finally led to
compound 7.
CD3OD did not match that of the natural product. Because
trifluoroacetic acid (TFA) was used as an HPLC eluent
additive during the isolation of natural products,8 the reported
data of natural cephalezomine G might represent those of the
1
TFA salt. Comparison of our H NMR spectrum of TFA salt
6′ to that reported in CD3OD revealed very little agreement.
However, the 1H and 13C NMR spectra of 6 in CDCl3 were in
good agreement with those previously reported for the α,α-syn-
diol 6.10
We assumed that the correct structure of cephalezomine G is
2α,3β-anti-diol 7, as proposed by the Ishibashi group.9 For
installation of the anti-stereochemistry of the C-2 and C-3
stereocenters, a number of trans-dihydroxylation reactions
́
were first attempted on azaspiranic substrate 17. The Prevost
type reactions were unsuccessful, and no product was
observed. Attempts for the epoxidation and opening of the
epoxide proved unsuccessful. The attempts to effect inversion
of configuration of the C-3 hydroxyl groups in 18 and 6,
through a reaction sequence of C-2 hydroxyl group protection
followed by SN2 type displacement at C-3 with nucleophiles,
were met with failure. We attributed these failures to the steric
congestion around the cyclopentene ring which prevents the
facile access of external nucleophiles from the β-face.
1H NMR spectra of our synthetic compound 7 did not
match those of the natural product. However, spectroscopic
data for its TFA salt 7′ were identical to those reported for the
natural product. The optical rotation sign and value obtained
for 7′ {[α]D20 = −46.9 (c 1.8, MeOH), lit.8 [α]D = −48 (c 1.8,
MeOH)} were also in good agreement, which confirmed that
the absolute configuration of natural (−)-cephalezomine G is
2S,3S,4S,5S.
In conclusion, we have achieved the first total synthesis and
structural elucidation of (−)-cephalezomine G by using our
recently developed chirality transfer method. D-Proline was the
only chiral source for this asymmetric synthesis. [2,3]-Stevens
rearrangement delivered the Cα-substituted proline with the
relative stereochemistry required for an azaspiranic tetracyclic
backbone. Two contiguous stereogenic centers bearing
hydroxyl groups were installed in the late stages. For the
introduction of a hydroxyl group in the sterically hindered face,
an internal N-Boc group was utilized. With this achievement as
a stepping stone, we are currently investigating asymmetric
synthesis of other Cephalotaxus alkaloids and their analogues,
and the results will be reported in due course.
To overcome this steric hindrance problem, we utilized the
nitrogen atom on the β-face to deliver an oxygen nucleophile
to the C-3 position in an intramolecular fashion. We chose the
N-Boc group as an internal nucleophile. Replacement of the
benzyl-type N-substituent in 18 with a Boc group was achieved
by hydrogenolysis in the presence of Boc2O to provide 21
(Scheme 4). Monoprotection of a less hindered C-2 hydroxyl
group in diol 21 was achieved with TBSOTf at low
temperature to give 22 as a major product with an isomeric
ratio of 5:1. The intramolecular nucleophilic substitution of the
C-3 hydroxyl group was successfully accomplished by treat-
Scheme 4. Completion of the Total Synthesis of
Cephalezomine G (7)
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00036.
Experimental procedures, analytical data, and copies of
1
the H and 13C NMR spectra for all new products
(PDF)
Accession Codes
CCDC 1864102 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
C
DOI: 10.1021/acs.orglett.9b00036
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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9601. (b) Isono, N.; Mori, M. J. Org. Chem. 1995, 60, 115.
(11) Cho, H.; Jeon, H.; Shin, J. E.; Lee, S.; Park, S.; Kim, S.
Asymmetric Synthesis of Cα-Substituted Prolines via Curtin−
Hammett Controlled Diastereoselective N-Alkylation. Chem. - Eur.
J. 2019, DOI: 10.1002/chem.201804965.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pennkim@snu.ac.kr.
ORCID
(12) (a) Zhu, Y.; Regner, M.; Lu, F.; Kim, H.; Mohammadi, A.;
Pearson, T. J.; Ralph, J. RSC Adv. 2013, 3, 21964. (b) De Lucia, D.;
Lucio, O.; Musio, B.; Bender, A.; Listing, M.; Dennhardt, S.;
Koeberle, A.; Garscha, U.; Rizzo, R.; Manfredini, S. Eur. J. Med. Chem.
2015, 101, 573.
Sanghee Kim: 0000-0001-9125-9541
Notes
The authors declare no competing financial interest.
(13) Sodium iodide was used for acceleration of the reaction.
(14) The diastereomeric ratio was determined by 1H NMR analysis.
(15) For a review of Stevens rearrangement of ammonium ylides,
see: Tetrahedron 2006, 62, 1046 and references therein.
ACKNOWLEDGMENTS
■
This work was supported by the Mid-Career Researcher
Program (Grant NRF-2016R1A2A1A05005375) of the Na-
tional Research Foundation of Korea (NRF) funded by the
Government of Korea (MSIP).
(16) The enantiomeric ratio of 13 was determined by chiral HPLC.
́
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S.; Bar, S. Tetrahedron: Asymmetry 2012, 23, 151.
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