Collective Asymmetric Total Synthesis of C-11 Oxygenated Cephalotaxus Alkaloids

Article abstract of DOI:10.1002/anie.202101766

While numerous studies pertaining to the total synthesis of Cephalotaxus alkaloids have been reported, only two strategies have been reported to date for the successful synthesis of the C-11 oxygenated subset, due to the additional synthetic challenge posed by the remote C-11 stereocenter. Herein, we report the collective asymmetric total synthesis of C-11 oxygenated Cephalotaxus alkaloids using a chiral proline both as a starting material and as the only chirality source. A tetracyclic advanced intermediate was synthesized in a highly stereoselective manner from l-proline in 8 steps involving sequential chirality transfer steps such as a diastereoselective N-alkylation, stereospecific Stevens rearrangement and intramolecular Friedel–Crafts reaction via an unusual O-acyloxocarbenium intermediate. From a common intermediate, the asymmetric total synthesis of six C-11 oxygenated Cephalotaxus alkaloids was completed by a series of oxidation state adjustments.

Full text of DOI:10.1002/anie.202101766

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 12060–12065
International Edition:
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doi.org/10.1002/anie.202101766
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Total Synthesis
Hot Paper
Collective Asymmetric Total Synthesis of C-11 Oxygenated
Cephalotaxus Alkaloids
Jae Hyun Kim+, Hongjun Jeon+, Choyi Park, Soojun Park, and Sanghee Kim*
Abstract: While numerous studies pertaining to the total
synthesis of Cephalotaxus alkaloids have been reported, only
two strategies have been reported to date for the successful
synthesis of the C-11 oxygenated subset, due to the additional
synthetic challenge posed by the remote C-11 stereocenter.
Herein, we report the collective asymmetric total synthesis of
C-11 oxygenated Cephalotaxus alkaloids using a chiral proline
both as a starting material and as the only chirality source. A
tetracyclic advanced intermediate was synthesized in a highly
stereoselective manner from l-proline in 8 steps involving
sequential chirality transfer steps such as a diastereoselective
N-alkylation, stereospecific Stevens rearrangement and intra-
molecular Friedel–Crafts reaction via an unusual O-acylox-
ocarbenium intermediate. From a common intermediate, the
asymmetric total synthesis of six C-11 oxygenated Cephalo-
taxus alkaloids was completed by a series of oxidation state
adjustments.
Introduction
For half a century, Cephalotaxus alkaloids have been
popular synthetic targets due to their intriguing structures and
biological activities.[1] The alkaloids of this family have several
interesting biological activities, including antileukemic and
antitumor activities. The characteristic structural feature of
these alkaloids is an azaspiranic tetracyclic scaffold (Fig-
ure 1). More than 70 compounds have been isolated from
natural sources so far.[1b] The first isolated and most repre-
sentative member of this family is (À)-cephalotaxine (1).[2]
Figure 1. The structures of representative Cephalotaxus alkaloids and
the C-11 oxygenated subset members.
One of its naturally occurring ester derivatives, homohar-
ringtonine (2), was approved by the FDA in 2012 as an
antileukemia drug.[3] The other representative member is
drupacine (3) which was isolated from Cephalotaxus harring-
tonia.[4] Unlike cephalotaxine (1), this alkaloid possesses an
oxygen function at C-11. 11-Hydroxycephalotaxine (4), which
is readily converted to 3 under acidic conditions, was also
isolated from the same plant from which 3 was isolated.[4] To
date, ten C-11 oxygenated Cephalotaxus alkaloids have been
isolated, including three ester derivatives of 3 (5–7)[5] and an
N-oxide derivative cephalancetine B (8).[6] A dimeric alkaloid
cephalancetine D (9)[6] and pentacyclic cephalocyclidin A
(10)[7] also belong to this subset. Recently, torreyafargesine A
(11) and 11-hydroxycephalotaxinone hemiketal (12) were
identified from Torreya fargesii Franch as new members of the
C-11 oxygenated subset.[8] The major structural differences
among these alkaloids are the oxidation patterns on their
backbone. The biological activities of this subset of alkaloids
have not yet been thoroughly explored presumably because of
the limited supply from nature.
The key challenges associated with the synthesis of
Cephalotaxus alkaloids are the construction of the azaspiranic
tetracyclic core and the stereocontrolled functionalization of
the sterically encumbered cyclopentene D ring. Since the first
total syntheses of cephalotaxine (1) by Weinreb[9a] and
Semmelhack[9b] in 1972, a large number of groups have
[*] Dr. J. H. Kim,[+] Dr. H. Jeon,[+] C. Park, S. Park, Prof. Dr. S. Kim
College of Pharmacy, Seoul National University
1 Gwanak-ro, Gwanak-gu, Seoul 08826 (Republic of Korea)
E-mail: pennkim@snu.ac.kr
Dr. J. H. Kim[+]
College of Pharmacy, Kangwon National University
1 Kangwondaehak-gil, Chuncheon, Gangwon-do 24341 (Republic of
Korea)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.202101766.
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continued to investigate different approaches toward the total
synthesis of this family of alkaloids.[9,10] A number of elegant
total syntheses of cephalotaxine (1) and its relatives have
been accomplished. On the other hand, research into the
synthesis of the C-11 oxygenated subset of Cephalotaxus
alkaloids has made little progress, presumably because of the
additional synthetic challenge posed by the remote C-11
stereocenter. Only two successful total syntheses of this
subset of alkaloids have been reported: the first total syn-
thesis of racemic drupacine (3) and 11-hydroxycephalotaxine
(4) was disclosed by Fuchs in 1990,[11a] and the first asym-
metric synthesis of drupacine (3) was achieved by Stoltz in
2007, albeit with low stereoselectivity.[11b] Fuchs introduced
a C-11 hydroxyl group from tetracyclic lactam 13 through
two-step a-oxidation followed by stereoselective reduction of
the resulting a-keto lactam 14 (Scheme 1a). Stoltz employed
chiral mandelic acid 15 as the source of the C-11 hydroxyl
group (Scheme 1b).
Scheme 2. Retrosynthetic route for the C-11 oxygenated Cephalotaxus
alkaloids.
modification of the functional groups in a 1-azaspiro-
[4.4]nonane unit (C and D rings) of the target alkaloids
afforded A (Scheme 2). Deconstruction of the 1,3-cyclo-
pentanedione ring (D ring) of A by Dieckmann condensation
followed by ozonolysis led to B as a hypothetical intermedi-
ate. The presence of an ester function and a C-11 hydroxyl
group on the same face of structure B suggested a strategy
that would secure the C-11 stereocenter with the concomitant
formation of seven-membered B ring. The planned stereo-
controlled construction of B included the connection of these
functional groups and the intramolecular Friedel–Crafts
reaction of cyclic O-acyl hemiacetal C, which would involve
an O-acyloxocarbenium ion D as an intermediate. We
envisaged that the bicyclic system of D might impart complete
diastereoselectivity by permitting the approach of the aro-
matic nucleophile only from a specific face of the oxocarbe-
nium electrophile.
We planned asymmetrically accessing C from the bicyclic
l-proline derivative E based on the concept of C-N-C
chirality transfer[13] which comprises of diastereoselective N-
quaternization (E/F to G) and the subsequent stereospecific
[2,3]-Stevens rearrangement (G to C). According to this
retrosynthetic scheme, all of the stereochemistry in the target
alkaloids would be derived exclusively from a single stereo-
center of proline. Prior to this study, as an approach for the
conservation of chirality during a-substitution of proline, we
have developed a couple of C-N-C chirality transfer method-
s.[13c–e] For the high diastereoselectivity during the N-quater-
nization with allylic electrophiles, one method employed
a rigid nitrogen-fused bicyclic derivative H in which the
nitrogen lone-pair electrons were forced to be located on the
convex face.[13c] Unlike [5,5]-bicyclic compound H, the
designed [5,6]-bicyclic system E would be conformationally
flexible. Thus, unclear was the stereoselectivity in the N-
quaternization of E which was critical to conserve the
chirality of proline.
Scheme 1. Previous synthesis of drupacine (3).
In addition to their biological activities, our synthetic
interest in the C-11 oxygenated subset of Cephalotaxus
alkaloids arose from the possibility of using a chiral proline
both as a starting material and as the only chirality source to
generate all the requisite stereocenters, including the remote
C-11 stereocenter. In this report, we present our investiga-
tions toward the first and asymmetric total synthesis of
cephalancetine B (8), cephalocyclidin A (10), torreyafargesi-
ne A (11) and 11-hydroxycephalotaxinone hemiketal (12) as
well as the stereoselective asymmetric total synthesis of
drupacine (3) and 11-hydroxycephalotaxine (4).[12] One of the
keys to the success of this collective asymmetric synthesis was
the newly designed bicyclic proline derivative which imparted
almost complete stereoselectivity in the sequential chirality-
transfer steps and allowed the facile construction of seven-
membered B ring.
Results and Discussion
We designed a synthetic scheme starting from the amino
acid proline that would permit access to a maximal number of
C-11 oxygenated Cephalotaxus alkaloids. Retrosynthetic
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Assuming success in our synthetic plan especially the
chirality transferring transformations, synthetic efforts com-
menced with the preparation of the newly designed bicyclic
proline derivative 16 and its N-alkylation partner cinnamyl
halide 17 (Scheme 3a). The synthesis of cinnamyl halide 17
started from the condensation between piperonal (18) and an
anion formed by the Michael addition of methoxide to
acrylate 19.[14] Subsequent one-pot hydrolysis afforded cin-
namic acid 20, in which a C-2 methoxy group (natural product
numbering) was installed. Acid 20 was reduced to the
corresponding alcohol 21, which was brominated to afford
17 in good overall yield. The bicyclic proline derivative 16 was
prepared from l-proline in two steps. Reductive amination of
l-proline with 2,2-dimethoxyacetaldehyde (22) afforded 23 in
an almost quantitative yield. Various acid catalysts and
solvents were explored to generate bicyclic product 16 in
high diastereoselectivity and yield (see the Supporting
Information for details). The optimal result was obtained
when 23 was treated with BF3·OEt2 in MeCN. The major
isomer was obtained in a diastereomeric ratio of 10:1 and was
assigned as 16 with (S)-stereochemistry at the anomeric
center.[15] Our computational and experimental studies sug-
gested that this reaction is under thermodynamic control (see
the Supporting Information for details).
With two fragments 16 and 17 in hand, their ligation
through N-alkylation was investigated (Scheme 3b). The
reaction in MeCN without any additive at room temperature
was smooth and completely stereoselective, providing the
quaternary ammonium salt 24 as the only detectable diaste-
reomer in an excellent yield. The NOESY spectrum indicated
that 24 was formed as the cis-fused isomer as shown. To
understand the excellent stereoselectivity in the N-quaterni-
zation, we carried out a Density Functional Theory (DFT)
computational investigation (Figure 2). The computational
results revealed that the nitrogen-fused bicycle 16 slightly
favors the trans-fused conformer, while the energy barrier of
N-inversion in the trans-fused form was predicted to only be
5.1 kcalmolÀ1 (Figure 2a). These results suggested that bi-
cycle 16 is conformationally rather flexible, as we had initially
expected (see the Supporting Information for details). On the
other hand, the obtained product cis-24 is thermodynamically
more favored than its trans isomer (Figure 2b). The computed
transition state energy for cis-24 (TS 1) is lower than that for
trans-24 (TS 2). This energy profile suggested that the kinetics
Scheme 3. Stereoselective synthesis of advanced intermediate 30.
Reagents and conditions: a) i. 18 (1.0 equiv), NaH (1.8 equiv), MeOH
(1.8 equiv), 19 (1.5 equiv), THF, 08C to rt, 16 h; ii. NaOH(aq), reflux,
30 min, 80%; b) i. ClCO2Et (1.0 equiv), Et3N (1.0 equiv), THF, 08C,
30 min; ii. NaBH4 (4.0 equiv), MeOH, 08C, 1 h, 82%; c) PBr3
(1.5 equiv), Et2O, 08C, 1 h, 95%; d) 22 (1.0 equiv), NaBH(OAc)3
(1.0 equiv), CH2Cl2, 08C to rt, 16 h, 98%; e) BF3·OEt2 (8.0 equiv),
MeCN, 08C to rt, 20 h, 86% (10:1 d.r.); f) 16 (1.0 equiv), 17
(1.05 equiv), MeCN, rt, 24 h, 96%; g) DBU (1.5 equiv), CH2Cl2, À788C,
1 h, 85% (10:1 d.r., 98% ee); h) MsOH (10 equiv), CH2Cl2, 08C to
reflux, 5 h, 75%; i) NBS (2.5 equiv), 1,4-dioxane/H2O (9:1), rt, 1.5 h,
90%; j) O3, CH2Cl2, À788C, 1 h, then Me2S (10 equiv), rt, 16 h, 41%
(81% brsm); k) KOtBu (1.0 equiv), THF, 08C, 1 h, then Me2SO4
(5.0 equiv), rt, 16 h, 57%. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
MsOH=methanesulfonic acid; NBS=N-bromosuccinimide.
Figure 2. DFT computational investigations calculated at the B3LYP/6–
31+G(d) level of theory. A) Energy profiles of 16 in MeCN. B) Energy
profiles for the diastereoselective N-quarternization of 16 with 17.
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of the N-quaternization of 16 are most likely controlled by the
system, and in situ etherification of enolate intermediate with
Curtin–Hammett principle (see the Supporting Information
dimethyl sulfate afforded 30 as the only regioisomer.
for details).[16]
Having constructed the carbon framework of Cephalo-
taxus alkaloids, we sought to streamline our total synthesis
(Scheme 4). The target subset of C-11 oxygenated alkaloids
differ in their oxidation patterns. Thus, chemo- and regiose-
lective oxidation state adjustments were investigated to
convert the advanced intermediate 30 to the target alkaloids.
First, the oxidation state of the C-1 atom of 30 was reduced to
give 31 via a two-step sequence involving hydrogenation using
Adamꢀs catalyst and base-promoted b-elimination. According
to NMR analysis, the obtained product 31 predominantly
existed in a hemiketal form. The reduction of the lactam
moiety of 31 using RhH(CO)(PPh3)3 and phenylsilane[21]
afforded 11-hydroxycephalotaxinone hemiketal (12). De-
tailed NMR analysis revealed that 12 existed as an 8:1
mixture of hemiketal and ketone forms in CDCl3.[22] Torreya-
When 24 was treated with 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) in CH2Cl2 at À788C for the [2,3]-Stevens
rearrangement, 25 was obtained as the major diastereomer
(dr= 10:1).[17] The configuration of 25 was determined to be
(4R,5R) by X-ray crystallographic analysis of 26 (see the
Supporting Information for details) after the Friedel–Crafts
reaction (vide infra) and confirmed later by total synthesis.
The [2,3]-Stevens rearrangement proceeded via an exo
transition state as shown and this can be rationalized by the
repulsion between the anomeric methoxy group and the
CH2OMe substituent in the endo transition state. The ee value
of 25 was 98%, which indicated that the Ca-chirality of the
proline derivative 16 was successfully conserved via the C-N-
C chirality transfer process.
With the key intermediate 25 in hand, we proceeded to
perform the intramolecular Friedel–Crafts reaction to con-
struct the seven-membered B ring and install the C-11
stereocenter. This transformation would involve an O-acy-
loxocarbenium ion (AOI), which is a very reactive subfamily
of the oxocarbenium ion class, as an intermediate. AOIs have
been less explored in organic synthesis than other oxocarbe-
nium ions, probably due to the lack of an efficient method for
AOI formation.[18] We expected that AOI intermediate 27
would be formed from 25 under acidic conditions, analogous
to the widely applied method for the formation of the N-
acyliminium ion from N-acyl hemiaminal ether. After some
trials, we found that the treatment of O-acyl hemiacetal 25
with MsOH as an acid catalyst in CH2Cl2 led to the formation
of 26 as the only regio- and stereoisomer, the identity of which
was confirmed by X-ray crystallography. This efficient seven-
membered ring formation reaction installed the oxygen
function at C-11 with the desired stereochemistry, presumably
through geometric constraints where only the Re face of
oxocarbenium moiety is accessible for nucleophilic attack as
shown in intermediate 27. The postulated AOI intermediate
27 was not observed during the reaction process apparently
because of the high reactivity and instability. However, the
lactone functionality in the product strongly suggested that
the reaction proceeded through the cyclic AOI intermediate
27.
With a route to 26 secured, we proceeded to construct the
D ring with two substituents at C-4 and C-5. Toward this end,
we employed Dieckmann condensation. Prior to the oxidative
cleavage of the methylene moiety of 26 to afford the bis-
carbonyl substrate for the Dieckmann ring closure, the
tertiary amine of 26 was oxidized to amide using NBS to
obtain 28 with almost perfect regioselectivity.[19] This step was
necessary in this stage to synthesize torreyafargesine A (vide
infra) and also to prevent the susceptible skeletal cleavage via
retro-Mannich type fragmentation; the cephalotaxine skel-
eton is susceptible to cleavage via retro-Mannich type
fragmentation when a carbonyl group was present at the C-
3 position.[9g,i,10a,11b,20] Ozonolysis of 28 in CH2Cl2 solvent at
À788C successfully afforded the desired ketone 29 along with
the recovered starting material (81% brsm). The KOtBu-
mediated Dieckmann ring closure of 29 yielded the tetracyclic
Scheme 4. Completion of the total synthesis of C-11 oxygenated
Cephalotaxus alkaloids. Reagents and conditions: a) PtO2, H2, EtOH, rt,
16 h; b) K2CO3 (5.0 equiv), MeOH, reflux, 5 h, 77% for 2 steps;
c) RhH(CO)(PPh3)3 (0.15 equiv), PhSiH3 (5.0 equiv), THF, rt, 1 h, 91%;
d) NaBH4 (30 equiv), MeOH, 08C to rt, 1 h, 89% (10:1 d.r.); e) LiAlH4
(12 equiv), THF, 08C to rt, 16 h, 72%; f) 1n HCl(aq)/THF (1:1), rt,
48 h, 78%; g) mCPBA (1.0 equiv), CH2Cl2, 08C, 30 min, 83%; h) PCC
(1.2 equiv), CH2Cl2, rt, 3 h, 65%; i) RhH(CO)(PPh3)3 (0.15 equiv),
PhSiH3 (5 equiv), THF, rt, 2 h, 65%; j) 1n HCl in 1,4-dioxane, rt,
30 min, 60%; k) LiAlH4 (4.3 equiv), THF, 08C, 30 min, 76%.
mCPBA=3-chloroperoxybenzoic acid; PCC=pyridinium chlorochro-
mate.
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fargesine A (11) could also be obtained from 31 by the
Acknowledgements
reduction of the hemiketal moiety using an excess amount of
NaBH4. From 11, a series of natural products were readily
accessible. The reduction of the lactam moiety of 11 afforded
11-hydroxycephalotaxine (4), which was converted to drupa-
cine (3) under acidic conditions. Treatment of mCPBA to 3
provided cephalancetine B (8).
This work was supported by the Mid-Career Researcher
Program (NRF-2019R1A2C2009905) and Basic Science Re-
search Program (NRF-2020R1I1A1A01073065) of the Na-
tional Research Foundation of Korea (NRF) funded by the
Government of Korea (MSIP). We thank Prof. Dongjoo Lee
(Ajou University) for helpful discussions.
The pentacyclic alkaloid cephalocyclidin A (10) was also
accessible from 11, similar to the proposed biosynthetic
pathway.[7] The oxidation of the 11-hydroxy group of 11 using
PCC afforded 32 in a moderate yield (65%) along with
a small amount of compound 31 (11%). The reduction of the
lactam moiety of 32, using the identical reaction conditions
employed for the chemoselective reduction of 31, provided
33.[23] The acidic hydrolysis of the methyl enol ether of 33 was
accompanied by the desired intramolecular aldol reaction and
led to the formation of the pentacycle 34. Finally, cephalo-
cyclidin A (10) was obtained by the reduction of 34 using
LiAlH4. The spectral data and optical rotations of all obtained
compounds were in good agreement with those of natural
products. Overall, six C-11 oxygenated Cephalotaxus alka-
loids were synthesized from the common intermediate 31.
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkaloids ·asymmetric synthesis ·chirality transfer ·
collective synthesis ·total synthesis
[1] For reviews, see: a) H. Abdelkafi, B. Nay, Nat. Prod. Rep. 2012,
29, 845 –869; b) J. PØrard-Viret, L. Quteishat, R. Alsalim, J.
Royer, F. Dumas in The Alkaloids, Vol. 78 (Eds.: H.-J. Knçlker),
Academic Press, New York, 2017, pp. 205 –352.
[2] W. W. Paudler, G. I. Kerley, J. McKay, J. Org. Chem. 1963, 28,
2194 –2197.
[3] a) M. Wetzler, D. Segal, Curr. Pharm. Des. 2011, 17, 59 –64;
b) H. M. Kantarjian, S. M. OꢀBrien, J. Cortes, Clin. Lymphoma
Myeloma Leuk. 2013, 13, 530 –533.
Conclusion
[4] R. G. Powell, R. V. Madrigal, C. R. Smith, K. L. Mikolajczak, J.
Org. Chem. 1974, 39, 676 –680.
[5] a) I. Takano, I. Yasuda, M. Nishijima, Y. Hitotsuyanagi, K.
Takeya, H. Itokawa, Bioorg. Med. Chem. Lett. 1996, 6, 1689 –
1690; b) H. Morita, M. Arisaka, N. Yoshida, J. Kobayashi,
Tetrahedron 2000, 56, 2929 –2934.
[6] Y.-R. He, Y.-H. Shen, B. Li, L. Lu, J.-M. Tian, W.-D. Zhang,
Chem. Biodiversity 2013, 10, 584 –595.
[7] J. Kobayashi, M. Yoshinaga, N. Yoshida, M. Shiro, H. Morita, J.
Org. Chem. 2002, 67, 2283 –2286.
In conclusion, we have achieved stereoselective asym-
metric total synthesis of six C-11 oxygenated Cephalotaxus
alkaloids in 11–15 steps from l-proline (12–16 steps from
piperonal). The total number of steps from commercially
available materials are comparable to those reported for
asymmetric synthesis of Cephalotaxus alkaloids without an
oxygen at C-11. Our synthesis minimized the need for
protecting-group manipulations. l-Proline was utilized both
as a starting material and as the only chirality source to
generate all the requisite stereocenters. Key to the success of
this concise synthesis was a three-step sequential transforma-
tion of the proline derived nitrogen-fused bicycle 16 into the
far more complex ring structure 26 with chirality propagation.
This complexity-generating sequence involved an N-allyla-
tion, [2,3]-Stevens rearrangement, and intramolecular Frie-
del–Crafts reaction via an unusual AOI intermediate. The
azaspiranic tetracyclic scaffold of Cephalotaxus alkaloids was
readily constructed from 26. Using 30 as an advanced
intermediate, the total synthesis of six target alkaloids was
completed without problem of skeletal cleavage by a series of
selective oxidation state adjustments. This synthesis presents
a good example of divergent total syntheses of complex
natural products and an attractive strategy in terms of chiral
economy. The concise synthetic route to C-11 Cephalotaxus
alkaloids would enable investigations into their biological
activities, which have been relatively less explored. Further
applications of the proline-derived nitrogen-fused bicycle 16
and its related acyclic amino acid derivatives to the synthesis
of complex molecules are underway in our group.
[8] M. Wang, X.-D. Zhang, Y.-L. Peng, Z.-H. Li, H.-L. Ai, P. Li, T.
Feng, J.-K. Liu, Phytochem. Lett. 2018, 28, 42 –46.
[9] For selected racemic syntheses, see: a) J. Auerbach, S. M.
Weinreb, J. Am. Chem. Soc. 1972, 94, 7172 –7173; b) M. F.
Semmelhack, B. P. Chong, L. D. Jones, J. Am. Chem. Soc. 1972,
94, 8629 –8630; c) M. E. Kuehne, W. G. Bornmann, W. H.
Parsons, T. D. Spitzer, J. F. Blount, J. Zubieta, J. Org. Chem.
1988, 53, 3439 –3450; d) T. P. Burkholder, P. L. Fuchs, J. Am.
Chem. Soc. 1988, 110, 2341 –2342; e) H. Ishibashi, M. Okano, H.
Tamaki, K. Maruyama, T. Yakura, M. Ikeda, J. Chem. Soc.
Chem. Commun. 1990, 1436 –1437; f) F. G. Fang, M. E. Maier,
S. J. Danishefsky, J. Org. Chem. 1990, 55, 831 –843; g) X. Lin,
R. W. Kavash, P. S. Mariano, J. Am. Chem. Soc. 1994, 116, 9791 –
9792; h) S. Suga, M. Watanabe, J.-I. Yoshida, J. Am. Chem. Soc.
2002, 124, 14824 –14825; i) J. D. Eckelbarger, J. T. Wilmot, M. T.
Epperson, C. S. Thakur, D. Shum, C. Antczak, L. Tarassishin, H.
Djaballah, D. Y. Gin, Chem. Eur. J. 2008, 14, 4293 –4306; j) W.-
D. Z. Li, W.-G. Duo, C.-H. Zhuang, Org. Lett. 2011, 13, 3538 –
3541; k) H. Liu, J. Yu, X. Li, R. Yan, J.-C. Xiao, R. Hong, Org.
Lett. 2015, 17, 4444 –4447; l) P. Gouthami, R. Chegondi, S.
Chandrasekhar, Org. Lett. 2016, 18, 2044 –2046.
[10] For selected asymmetric syntheses, see: a) N. Isono, M. Mori, J.
Org. Chem. 1995, 60, 115 –119; b) L. F. Tietze, H. Schirok, J. Am.
Chem. Soc. 1999, 121, 10264 –10269; c) L. Planas, J. PØrard-
Viret, J. Royer, J. Org. Chem. 2004, 69, 3087 –3092; d) J. D.
Eckelbarger, J. T. Wilmot, D. Y. Gin, J. Am. Chem. Soc. 2006,
128, 10370 –10371; e) T. Taniguchi, S. Yokoyama, H. Ishibashi, J.
Org. Chem. 2009, 74, 7592 –7594; f) H. Jeon, Y. Chung, S. Kim, J.
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Org. Chem. 2019, 84, 8080 –8089; g) H. Jeon, H. Cho, S. Kim,
[18] For selected reports on AOI-involved reactions, see: a) D.
Org. Lett. 2019, 21, 1121 –1124; h) X. Ju, C. M. Beaudry, Angew.
Chem. Int. Ed. 2019, 58, 6752 –6755; Angew. Chem. 2019, 131,
6824 –6827.
Lebœ uf, A. Simonneau, C. Aubert, M. Malacria, V. Gandon, L.
Fensterbank, Angew. Chem. Int. Ed. 2011, 50, 6868 –6871;
Angew. Chem. 2011, 123, 7000 –7003; b) A. Monaco, A. E.
Aliev, S. T. Hilton, Chem. Eur. J. 2015, 21, 13909 –13912;
c) M. R. Barone, A. M. Jones, Org. Biomol. Chem. 2017, 15,
10010 –10015; d) X. Li, R. G. Carter, Org. Lett. 2018, 20, 5541 –
5545.
[11] a) T. P. Burkholder, P. L. Fuchs, J. Am. Chem. Soc. 1990, 112,
9601 –9613; b) Q. Liu, E. M. Ferreira, B. M. Stoltz, J. Org. Chem.
2007, 72, 7352 –7358.
[12] Prior to isolation and characterization from natural sources,
Powell et al. synthesized 12, starting from drupacine (3). See
ref.[4].
[13] For reports on the asymmetric Ca-alkylation of proline deriv-
atives using the C-N-C chirality transfer strategy, see: a) K. W.
Glaeske, F. G. West, Org. Lett. 1999, 1, 31 –34; b) P. Tuzina, P.
Somfai, Org. Lett. 2009, 11, 919 –921; c) H. Cho, J. E. Shin, S.
Lee, H. Jeon, S. Park, S. Kim, Org. Lett. 2018, 20, 6121 –6125;
d) H. Cho, H. Jeon, J. E. Shin, S. Lee, S. Park, S. Kim, Chem. Eur.
J. 2019, 25, 2447 –2451; e) H. Cho, J. Kim, J. H. Kim, Y. Song, S.
Kim, Adv. Synth. Catal. 2020, 362, 2941 –2946.
[14] E. Ciganek, J. Org. Chem. 1995, 60, 4635 –4637.
[15] The stereochemistry of 16 was deduced from the X-ray crystallo-
graphic analysis of its analog. See the Supporting Information
for details.
[19] a) A. Picot, X. Lusinchi, Synthesis 1975, 109 –111; b) R. H.
Furneaux, G. J. Gainsford, J. M. Mason, P. C. Tyler, Carbohydr.
Res. 2004, 339, 1747 –1751.
[20] X. Lin, R. W. Kavash, P. S. Mariano, J. Org. Chem. 1996, 61,
7335 –7347.
[21] S. Das, Y. Li, C. Bornschein, S. Pisiewicz, K. Kiersch, D.
Michalik, F. Gallou, K. Junge, M. Beller, Angew. Chem. Int. Ed.
2015, 54, 12389 –12393; Angew. Chem. 2015, 127, 12566 –12570.
[22] The existence of 12 as a mixture of hemiketal and ketone forms
in CDCl3 was not discussed in previous reports, refs. [4] and [8].
[23] Like 12, compounds 32 and 33 exist as mixtures of hemiketal and
ketone forms in CDCl3. See the Supporting Information for
details.
[16] a) J. I. Seeman, Chem. Rev. 1983, 83, 83 –134; b) J. I. Seeman, J.
Chem. Educ. 1986, 63, 42 –48.
[17] The N-quaternization of the anomeric isomer of 16 was also
diastereoselective, whereas the subsequent [2,3]-Stevens rear-
rangement was notably less selective. See the Supporting
Information for details.
Manuscript received: February 4, 2021
Accepted manuscript online: March 17, 2021
Version of record online: April 16, 2021
Angew. Chem. Int. Ed. 2021, 60, 12060 –12065
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