Enantioselective organocatalytic michael/aldol sequence: Anticancer natural product (+)-trans-dihydrolycoricidine

Article abstract of DOI:10.1002/anie.201403065

A total synthesis of the anticancer natural product (+)-trans- dihydrolycoricidine is reported from α-azidoacetone and cinnamaldehyde precursors. Key elements include an asymmetric organocatalytic sequence proceeding by a regiospecific secondary-amine-catalyzed synMichael addition followed by an intramolecular aldol reaction. The sequence results in the formation of an advanced intermediate, containing three stereogenic centers, in one step which and was converted into the title compound in eight steps.

Full text of DOI:10.1002/anie.201403065

Angewandte
Chemie
DOI: 10.1002/anie.201403065
Natural Products
Enantioselective Organocatalytic Michael/Aldol Sequence: Anticancer
Natural Product (+)-trans-Dihydrolycoricidine**
James McNulty* and Carlos Zepeda-Velꢀzquez
Abstract: A total synthesis of the anticancer natural product
(+)-trans-dihydrolycoricidine is reported from a-azidoacetone
and cinnamaldehyde precursors. Key elements include an
asymmetric organocatalytic sequence proceeding by a regio-
specific secondary-amine-catalyzed syn Michael addition fol-
lowed by an intramolecular aldol reaction. The sequence
results in the formation of an advanced intermediate, contain-
ing three stereogenic centers, in one step which and was
converted into the title compound in eight steps.
product 6, including the 3-deoxy analogue 7. Anticancer
investigations of these analogues demonstrated that 6 con-
stitutes the minimum anticancer pharmacophore in the
series.[2l–p] Additionally, the 1-10b-styryl double bond in
narciclasine (3) is associated with unwanted cytochrome P450
activity,[2q] thus highlighting the importance of 5 and 6 toward
developing a potent and selective anticancer agent.
Natural (+)-trans-dihydrolycoricidine (6) has been the
subject of four previous total syntheses.[4] We were inspired by
recent enantioselective organocatalytic approaches toward
six-membered carbocycles[5a] to develop a stepwise [3+3]-
type Michael/aldol sequence,[5b–g] involving an a-nitrogen-
substituted acetone moiety reacting with an unsaturated
aldehyde, as a possible rapid entry to the amaryllidaceae core.
Such an approach would also open a valuable asymmetric
entry to aminocyclitols, a large and expanding class of
compounds with diverse biological activities.[6] In our retro-
synthetic analysis (Scheme 1), we envisioned that 6 would be
A
maryllidaceae alkaloids[1,2] have occupied the attention of
natural product and synthetic chemists[3] for many years in
view of the biological activity displayed, including potent
anticancer and antiviral activities, as well as the presence of
synthetically challenging, densely functionalized aminocycli-
tol cores.[1,2] The lycorane isocarbostyrils 1–6 (Figure 1)
including pancratistatin (1), narciclasine (3), and (+)-trans-
dihydrolycoricidine (6), have attracted particular interest
because of the potent and selective nanomolar anticancer
activity demonstrated.[3] Several research groups described
the systematic synthesis of deoxy analogues of the natural
Scheme 1. Retrosynthetic analysis of (+)-trans-dihydrolycoricidine. The
natural-product numbering system is employed. PG=protecting
group, Moc=methoxycarbonylamino, Ts=p-toluenesulfonyl.
derived from the methoxycarbonyl-substituted aminocyclitol
8, produced from the cyclohexene 9 by epoxidation and 2,3-
diaxial diol formation. The critical synthesis of 9 via the aldol
intermediate 10 would hinge upon the development of
a successful regiocontrolled syn-stereoselective Michael addi-
tion of a suitable nitrogen-functionalized acetone (12a/b)
with the cinnamaldehdye 11a.
Figure 1. Structures of the bioactive amaryllidaceae alkaloids 1–6 and
non-natural 3-deoxy derivative 7.
[*] Dr. J. McNulty, C. Zepeda-Velꢀzquez
Department of Chemistry and Chemical-Biology
McMaster University
Considering the reactivity of a-nitrogen-functionalized
carbonyl compounds in organocatalytic processes, Alexakis
and co-workers reported the Michael addition of a-NH-
tosylacetone derivatives to nitroalkenes, a reaction that was
shown to proceed with syn stereoselectivity.[7a] Barbas and co-
workers described the generation of enamines from a-
azidoketones and trapping with imines as a route to chiral
1280 Main Street West, Hamilton, Ontario, L8S 4M1 (Canada)
E-mail: jmcnult@mcmaster.ca
Homepage: //www.chemistry.mcmaster.ca/mcnulty/index.html
[**] We thank NSERC and CONACyT for financial support of this work
and Dr. Hilary A. Jenkins for X-ray analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403065.
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Table 1: Selected studies on optimization of the reaction parameters.[a]
1,2- and 1,4-diamines.[7b] A few other examples of organo-
catalytic reactions involving a-nitrogen-containing carbonyl
derivatives are known.[7c–f] A synthesis of six-membered
carbocycles from a suitable a-nitrogen-functionalized car-
bonyl compound, involving a regiocontrolled Michael/aldol
sequence as we envisioned (Scheme 1), has not been
reported. Alonso and co-workers have recently reported
a synthesis of pancratistatin (1) by employing the Michael
addition of a symmetrical 1,3-dioxyketone to a doubly
activated a-nitro-unsaturated aldehyde.[3o] Herein, we report
our initial findings and success in developing this Michael/
aldol sequence and an asymmetric synthesis of natural
(+)-trans-dihydrolycoricidine (6).
The study was initiated through investigation of a possible
organocatalytic sequence using a-N-tosylacetone (12a) react-
ing with the model acceptor cinnamaldehyde (11b; Scheme 2)
Entry
Catalyst
Substrate
Yield [%][b]
ee [%][c]
d.r.[d]
n.d.
n.d.
n.d.
4:1
5:1
17:1
>20:1
>20:1
>20:1
>20:1
>20:1
1
2
3
4
5
6
7
8
13b
13c
16a
13a
13c/DIPEA
13b/16a
13c/16a
13c/16b
13d/16a
13d/16a
13d/16a
11b
11b
11b
11b
11b
11b
11b
11b
11b
11a
11a
n.r.
n.r.
n.r.
64
29
60
48
50
52
56
65
n.d
n.d.
n.d.
29
90
6
93
91
9
92[e]
>98[f]
>98[f]
10
11[g]
[a] Unless noted, the reaction was conducted with 11a/11b (0.50 mmol),
12b (0.75 mmol, 1.5 equiv), cat. (10 mol%) for 32 h at RT. [b] Yield of
isolated product. [c] The ee values were determined by HPLC, and the
absolute configuration was assigned based on the X-ray crystal structure
Scheme 2. Possible reaction sequence leading to the dimeric adduct
14.[11]
1
of 20.[11] [d] The d.r. values of 18a/18b were determined by H NMR
in dichloromethane with the catalyst 13. While reaction was
slow, a 1:1 adduct was indeed formed in low yield (14% upon
isolated). This product proved to be the compound 14
(confirmed by X-ray analysis), the product of dimerization
of the intermediate Michael addition adduct. No trace of the
cyclohexane 15 was observed. We had envisioned a sequence
in which the immediate Michael adduct A (Scheme 2) would
undergo intramolecular proton transfer, thus leading to C,
which would cyclize through the aldol process to yield 15. We
attributed formation of 14 to the presence of the acidic NH
constituent in A, which leads to B, thus leading to 14 upon
hydrolysis. These results immediately served to direct our
attention to the corresponding possibility using the azidoace-
tone 12b. The reaction of 11b and 12b was investigated using
a variety of secondary-amine catalysts and reaction condi-
tions. The use of l-proline (13b) or the prolinol silyl ether 13c
(Jørgensenꢀs type) alone failed to generate the cyclohexane
derivative in water or organic media (dichloromethane,
toluene etc.; Table 1, entries 1 and 2). On the basis of the
initial observations that led to 14, we considered that a basic
entity might be required to effect proton shuttling (e.g., azido
analogue of A to C in Scheme 2), thus permitting the
sequential Michael/aldol sequence. While use of a chiral
tertiary amine alone proved ineffective (entry 3), to our
spectroscopy and HPLC. [e] ent-18a was obtained. [f] ent-17a was
obtained. [g] 11a (4.7 mmol) and 12b (4.5 mmol) 24 h at RT. Ar=(2,3-
methylenedioxy)phenyl, DIPEA=N,N-diisopropylethylamine, TMS=tri-
methylsilyl.
delight, it was determined that the catalyst 13a, containing
a basic pyrrolidyl side chain, provided the necessary turnover
and reasonable yields of the cyclohexane derivatives 18a and
18b, which were isolated as a 4:1 ratio of diastereomers
(entry 4). The diastereomers 18a and 18b were readily
separated on silica gel and a single-crystal X-ray structural
determination on rac-18a confirmed the regiospecificity and
syn stereoselectivity of the Michael addition and the overall
relative stereochemistry on the cyclohexane ring (Table 1).
Resolution of rac-18a was also readily accomplished using
HPLC (see the Supporting Information). The use of the
prolinol catalyst 13c in the presence of an external, nonchiral
base (DIPEA) also gave the desired cyclohexanone in
moderate yield and high ee value, but with a low d.r. value
on the aldol step (entry 5). We next determined that the use of
13b and an added chiral tertiary base such as the quinidine
16a allowed conversion with a much higher d.r. value
(entry 6), but low ee value. While the use of 13b and 16a
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(entry 6) had a marked effect on the d.r. value of the reaction,
the ee value (6%) was unacceptable.
the natural anticancer agent (+)-trans-dihydrolycoricidine
(6).
From these results (Table 1, entries 1–6) we hypothesized
that to achieve high ee and d.r. values, the use of 13c in
conjunction with a bulky chiral cinchona base might be
required. We therefore investigated a series of combinations
of chiral secondary amines in the presence of a bulky basic
tertiary amine cocatalysts with stunning results. While neither
the prolinol catalyst 13c/13d nor the quinidine 16a or quinine
16b alone provided significant turnover, we were delighted to
find that dual catalysis provided 18a in 48–50% yield upon
isolation, and also now with high d.r. values (> 20:1) and
greater than 90% ee (entries 7 and 8). The absolute stereo-
chemistry of the product (see below) proved to be governed
only by 13c, with either enantiomer of the quinine increasing
the selectivity on the aldol reaction alone (d.r.). Switching to
the secondary amine antipode 13d yielded ent-18a (compare
entries 7 and 9) in similar yield and stereoselectivity as before.
Finally, the same process conducted on the methylenedioxy-
substituted cinnamaldehyde 11a, available in one step from
piperonal,[8] proved even more stereoselective and the desired
cyclohexane ent-17a (entry 10) was isolated in 56% yield and
with greater than 98% ee. The reaction also proved highly
effective on scale up (65% yield upon isolation), thus
providing reliable access to greater than 500 mg quantities
of the desired stereoisomer ent-17a (entry 11).
The absolute configuration of ent-17a was determined as
depicted in Scheme 3. The azido group was reduced and the
resulting cyclohexylamine protected in situ with DMDC as
the methoxycarbonylamino (Moc) derivative 19. Reduction
of the 4-oxo group to the C4 equatorial alcohol and
bis(benzoylation) of the resulting 2,4-diol with 4-bromoben-
zoylchloride gave the derivative 20. A single-crystal X-ray
diffraction analysis confirmed the relative and absolute
stereochemistry as depicted (Scheme 3). Thus it was defini-
tively shown that use of the (R)-(+)-stereoisomer of prolinol
silyl ether catalyst 13d provided the Michael/aldol cyclo-
adduct having the correct absolute configuration as found in
We finally turned our attention to completion of the
synthesis of 6, as outlined in Scheme 4. The adduct ent-17a,
obtained as described (Table 1, entry 11), was converted into
the methoxycarbamate 19 as before. Treatment with meth-
Scheme 4. Reagents and conditions: Yields of isolated products are
indicated. e) MsCl (1.30 equiv), DIPEA (3.0 equiv), CH2Cl2, 08C!RT,
10 h, 95%. f) LiHAl(OtBu)3 (3.0 equiv), THF, 08C!RT, 7 h, 85%.
g) mCPBA (2.0 equiv), NaHCO3 (2.0 equiv), CH2Cl2, RT, 24 h, 22a
59%, 22b 16%. h) NaOBz (0.06 equiv), H2O, 958C, 16 h, 93%.
i) Ac2O (6.0 equiv), py, RT, 16 h, 87%. j) Tf2O (5.0 equiv), DMAP
(3.0 equiv), CH2Cl2, 08C!RT, 16 h, 52%. k) K2CO3 (0.10 equiv),
MeOH/H2O (1:9), RT, 16 h, 92%. MsCl=methanesulfonyl chloride,
mCPBA=meta-chloroperbenzoic acid, Tf=trifluoromethanesulfonyl,
THF=tetrahydrofuran.
anesulfonyl chloride in the presence of Hꢁnigꢀs base effected
dehydration to give the cyclohexanone 21 in 95% yield.
Chemoselective reduction of the carbonyl group in 21 using
lithium tri-tert-butoxyaluminium hydride gave the equatorial
alcohol 9 (85%). Epoxidation of 9 was accomplished using
mCPBA, thus yielding a mixture of the b-epoxide 22a and a-
epoxide 22b in a 4:1 ratio.[9] The epoxides could be easily
separated on silica gel and were isolated in 59% (22a) and
16% (22b) yields and independently characterized. Stereo-
selective opening of the epoxides was achieved as expect-
ed,[2 m] through either axial attack at C2 (22a) or C3 (22b),
thus giving the same 2,3,4-triol 23 in 96% yield (from 22a).
The triol derivative was protected as the triacetate 24 without
incident, and 24 cyclized following the Banwell[10] modifica-
tion of the Bischler–Napieralski reaction to give 25 in 52%
yield and greater than 98% ee (see Table S1 in the Supporting
Information). Finally, removal of the acetate protecting
groups yielded natural 6 in 92% yield from 25. Overall, 6
was obtained in nine chemical steps from 12b and 11a, with
an overall yield of 12% and greater than 98% ee. While the
absolute configuration was determined as described in
Scheme 3, optical rotation and all other spectroscopic char-
acterization data for (+)-trans-dihydrolycoricidine (6) were in
accord with published values (see Tables S2 and S3 in the
Supporting Information).[4]
Scheme 3. Reagents and conditions: Yields of isolated products are
indicated.[11] a) 13d (10 mol%) and 16a (10 mol%), CH2Cl2, RT, 24 h,
65%. b) DMDC (3.0 equiv), H2, 10% Pd/C (0.075 equiv), 50 psi,
MeOH, RT, 16 h, 82%. c) Me4NHB(OAc)3 (4.0 equiv), acetonitrile/
AcOH (96:4), RT, 12 h, 77%. d) p-BrBzCl (3.0 equiv), DMAP
(0.10 equiv), py, 08C, 8 h, 71%. Bz=benzoyl, DMAP=4-dimethyl-
aminopyridine, DMDC=dimethyl dicarbonate.
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S. Sauvage, G. Van Goietsnoven, V. Megalizzi, D. Lamoral-
Theys, O. Debeir, S. Spiegl-Kreinecker, W. Berger, V. Mathieu,
C. Decaestecker, R. Kiss, Mol. Cancer Ther. 2009, 8, 1739 – 1750;
l) J. McNulty, R. Mo, Chem. Commun. 1998, 933 – 935; m) J.
McNulty, J. Mao, R. Gibe, R. Mo, S. Wolf, G. R. Pettit, D. L.
Herald, M. R. Boyd, Bioorg. Med. Chem. Lett. 2001, 11, 169 –
In conclusion, we have developed a nine-step total
synthesis of the anticancer natural product (+)-trans-dihy-
drolycoricidine (6) from readily available starting materials.
Key features of the synthesis involve the regiospecific
organocatalytic addition of a-azidoacetone (12b) onto
Michael acceptors such as 3,4-methylenedioxycinnanmalde-
hyde (11a), by a syn-stereoselective process and subsequent
intramolecular aldol reaction, thus yielding highly function-
alized cyclohexanones such as 17a/18a (or enantiomers). The
process occurs with high enantioselectivity when employing
chiral prolinol silyl ether secondary amine catalysts, and high
d.r. values were achieved by use of a base as a cocatalyst. The
sequence may proceed through either enamine or iminum ion
activation. Further exploration of the scope and mechanism
of this sequence and application toward the synthesis of other
amaryllidaceae constituents and aminocyclitols is being
actively pursued in our laboratory. Demonstration of this
asymmetric Michael/aldol sequence from a-azocarbonyl
compounds and unsaturated aldehydes opens many possibil-
ities for the synthesis of related alkaloids. Perhaps, more
importantly, this methodology provides a rapid asymmetric
entry to the larger class of aminocyclitols, which display
therapeutic activities toward a wide range of targets.[6]
´
172; n) U. Rinner, H. L. Hillebrenner, D. R. Adams, T. Hudlicky,
G. R. Pettit, Bioorg. Med. Chem. Lett. 2004, 14, 2911 – 2914; o) J.
McNulty, V. Larichev, S. Pandey, Bioorg. Med. Chem. Lett. 2005,
15, 5315 – 5318; p) J. McNulty, J. J. Nair, C. Griffin, S. Pandey, J.
Nat. Prod. 2008, 71, 357 – 363; q) J. McNulty, A. Thorat, N.
Vergun, J. J. Nair, E. Makaji, D. J. Crankshaw, A. C. Holloway, S.
Pandey, J. Nat. Prod. 2011, 74, 106 – 108.
[3] For reviews and select synthetic studies on lycorane amaryllida-
ceae constituents, see: a) M. G. Banwell, N. Y. Gao, B. D.
Schwartz, L. V. White, Top. Curr. Chem. 2012, 309, 163 – 202;
´
b) U. Rinner, T. Hudlicky, Synlett 2005, 365 – 387; c) Y. Chapleur,
F. Chretien, S. Ibn-Ahmed, M. Khaldi, Curr. Org. Synth. 2006, 3,
169 – 185; d) M. Manpadi, A. Kornienko, Org. Prep. Proced. Int.
2008, 40, 107 – 161; e) S. Danishefsky, J. Y. Lee, J. Am. Chem.
´
Soc. 1989, 111, 4829 – 4837; f) X. R. Tian, T. Hudlicky, K.
Kçnigsberger, J. Am. Chem. Soc. 1995, 117, 3643 – 3644;
g) B. M. Trost, S. R. Pulley, J. Am. Chem. Soc. 1995, 117,
10143 – 10144; h) G. E. Keck, S. F. McHardy, J. A. Murry, J. Am.
´
Chem. Soc. 1995, 117, 7289 – 7290; i) T. Hudlicky, X. R. Tian, K.
Kçnigsberger, R. Maurya, J. Rouden, B. Fan, J. Am. Chem. Soc.
1996, 118, 10752 – 10765; j) T. J. Doyle, M. Hendrix, D. Van-
Derveer, S. Javanmard, J. Haseltine, Tetrahedron 1997, 53,
11153; k) P. Magnus, I. K. Sebhat, Tetrahedron 1998, 54, 15509 –
15524; l) P. Magnus, I. K. Sebhat, J. Am. Chem. Soc. 1998, 120,
5341 – 5342; m) J. H. Rigby, U. S. M. Maharoof, M. E. Mateo, J.
Am. Chem. Soc. 2000, 122, 6624 – 6628; n) H. Ko, E. Kim, J. E.
Park, D. Kim, S. Kim, J. Org. Chem. 2004, 69, 112 – 121; o) F.
Cagide-Fagꢂn, O. Nieto-Garcꢂa, H. Lago-Santomꢃ, R. Alonso, J.
Org. Chem. 2012, 77, 11377 – 11382.
Received: March 6, 2014
Revised: May 9, 2014
Published online: && &&, &&&&
Keywords: alkaloids · asymmetric synthesis · natural products ·
.
organocatalysis · total synthesis
[4] For previous total syntheses of (+)-trans-dihydrolycoricidine,
see: a) N. Chida, M. Jitsuoka, Y. Yoshiyuki, M. Ohtsuka, S.
Ogawa, Heterocycles 1996, 43, 1385 – 1390; b) T. Fujimura, M.
Shibuya, K. Ogasawara, Y. Iwabuchi, Heterocycles 2005, 66,
[1] a) J. W. Cook, J. D. Loudon in The Alkaloids, Vol. 2 (Eds.:
R. H. F. Manske, H. L. Holmes), Academic Press, New York,
1952, pp. 331 – 352; b) W. C. Wildman in The Alkaloids, Vol. 11
(Ed.: R. H. F. Manske), Academic Press, New York, 1968,
pp. 307 – 405; c) S. F. Martin in The Alkaloids, Vol. 30 (Ed.: A.
Brossi), Academic Press, New York, 1987, pp. 251 – 376; d) Z.
Jin, Nat. Prod. Rep. 2013, 30, 849 – 868; e) A. Evidente, A. S.
Kireev, A. R. Jenkins, A. E. Romero, W. F. A. Steelant, S.
van Slambrouck, A. Kornienko, Planta Med. 2009, 75, 501 – 507.
[2] For isolation and biological activity studies on isocarbostyrils,
see: a) G. R. Pettit, V. Gaddamidi, G. M. Cragg, D. L. Herald, Y.
Sagawa, J. Chem. Soc. Chem. Commun. 1984, 1693 – 1694;
b) G. R. Pettit, V. Gaddamidi, G. M. Cragg, J. Nat. Prod. 1984,
47, 1018 – 1020; c) G. R. Pettit, V. Gaddamidi, D. L. Herald, S. B.
Singh, G. M. Cragg, J. M. Schmidt, F. E. Boettner, M. Williams,
Y. Sagawa, J. Nat. Prod. 1986, 49, 995 – 1002; d) G. R. Pettit III,
R. A. Backhaus, M. R. Boyd, A. W. Meerow, J. Nat. Prod. 1993,
56, 1682 – 1687; e) B. Gabrielsen, T. P. Monath, J. W. Huggins,
D. F. Kefauver, G. R. Pettit, G. Groszek, M. Hollingshead, J. J.
Kirsi, W. M. Shannon, E. M. Schubert, J. DaRe, B. Ugarkar, M.
Ussery, M. J. Phelan, J. Nat. Prod. 1992, 55, 1569 – 1581; f) A.
McLachlan, N. Kekre, J. McNulty, S. Pandey, Apoptosis 2005, 10,
619 – 630; g) N. Kekre, C. Griffin, J. McNulty, S. Pandey, Cancer
Chemother. Pharmacol. 2005, 10, 619 – 630; h) S. Pandey, N.
Kekre, J. Naderi, J. McNulty, Artif. Cells Blood Substitutes
Biotechnol. 2005, 33, 279 – 295; i) P. Siedlakowski, A. McLachla
nBurgess, C. Griffin, S. Tirumalai, J. McNulty, S. Pandey, Cancer
Biol. Ther. 2008, 7, 376 – 384; j) L. Ingrassia, F. Lefranc, J.
Dewelle, L. Pottier, V. Mathieu, S. Spiegl-Kreinecker, S.
Sauvage, M. El Yazidi, M. Dehoux, W. Berger, E. van Quaque-
beke, R. Kiss, J. Med. Chem. 2009, 52, 1100 – 1114; k) F. Lefranc,
´
167 – 173; c) J. Collins, U. Rinner, M. Moser, T. Hudlicky, I.
Ghiviriga, A. E. Romero, A. Kornienko, D. Ma, C. Griffin, S.
Pandey, J. Org. Chem. 2010, 75, 3069 – 3084; d) S. L. Poe, J. P.
Morken, Angew. Chem. 2011, 123, 4275 – 4278; Angew. Chem.
Int. Ed. 2011, 50, 4189 – 4192. For (ꢀ)-trans-dihydrolycoricidine,
˝
see: e) G. Szꢄntꢅ, L. Hegedus, L. Mattyasovszky, A. Simon, ꢆ.
˝
Simon, I. Bitter, G. Tꢅth, L. Toke, I. Kꢄdas, Tetrahedron 2009, 65,
8412 – 8417; For (ꢁ)-trans-dihydrolycoricidine see: f) G. Szꢄntꢅ,
˝
L. Hegedus, L. Mattyasovszky, A. Simon, ꢆ. Simon, I. Kꢄdas,
Tetrahedron Lett. 2009, 50, 2857 – 2859.
[5] a) S. Goudedranche, W. Raimondi, X. Bugaut, T. Constantieux,
D. Bonne, Synthesis 2013, 1909 – 1930; b) C. Grondal, M. Jeanty,
D. Enders, Nat. Chem. 2010, 2, 167 – 178; c) Ł. Albrecht, H.
Jiang, K. A. Jørgensen, Angew. Chem. 2011, 123, 8642 – 8660;
Angew. Chem. Int. Ed. 2011, 50, 8492 – 8509; d) H. Pellissier,
Adv. Synth. Catal. 2012, 354, 237 – 294; e) A. Carlone, M.
Marigo, C. North, A. Landa, K. A. Jørgensen, Chem.
Commun. 2006, 4928 – 4930; f) J. Alemꢄn, V. Marcos, L.
Marzo, J. L. G. Ruano, Eur. J. Org. Chem. 2010, 4482 – 4491;
g) S. Duce, M. Jorge, I. Alonso, J. L. G. Ruano, M. B. Cid, Org.
Biomol. Chem. 2011, 9, 8253 – 8260.
[6] For a summary of current and potential therapeutic amino-
cyclitols, see: J. A. Griffen, J. C. White, G. Kociok-Kohn, M. D.
Lloyd, A. Wells, T. C. Arnot, S. E. Lewis, Tetrahedron 2013, 69,
5989 – 5997.
[7] a) S. Belot, S. Sulzer-Mosse, S. Kehrli, A. Alexakis, Chem.
Commun. 2008, 4694 – 4696; b) N. S. Chowdari, M. Ahmad, K.
Albertshofer, F. Tanaka, C. F. Barbas III, Org. Lett. 2006, 8,
4
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Chemie
2839 – 2842; c) K. Albertshofer, R. Thayumanavan, N. Utsumi, F.
Tanaka, C. F. Barbas III, Tetrahedron Lett. 2007, 48, 693 – 696;
d) Y. Hayashi, K. Obi, Y. Ohta, D. Okamura, H. Ishikawa,
Chem. Asian J. 2009, 4, 246 – 249; e) Y.-Z. Liu, R.-L. Cheng, P.-F.
Xu, J. Org. Chem. 2011, 76, 2884 – 2887; f) Z. Shi, P. Yu, P. J.
Chau, G. Zhong, Adv. Synth. Catal. 2009, 351, 2797 – 2800.
[8] J. McNulty, C. Zepeda-Velꢄzquez, D. McLeod, Green Chem.
2013, 15, 3146 – 3149.
[10] a) M. G. Banwell, C. J. Cowden, R. W. Gable, J. Chem. Soc.
Perkin Trans. 1 1994, 3515; b) M. G. Banwell, B. D. Bissett, S.
Busato, C. J. Cowden, D. C. R. Hockless, J. W. Holman, R. W.
Read, A. W. Wu, J. Chem. Soc. Chem. Commun. 1995, 2551 –
2553.
[11] CCDC 987917 (14), CCDC 985658 (18a), and CCDC 984484
(20) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
[9] H. B. Henbest, R. A. L. Wilson, J. Chem. Soc. 1957, 1958 – 1964.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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.
Angewandte
Communications
Communications
Natural Products
J. McNulty,*
C. Zepeda-Velꢁzquez
&&&& — &&&&
Enantioselective Organocatalytic
Michael/Aldol Sequence: Anticancer
Natural Product (+)-trans-
Dihydrolycoricidine
Taking steps: A stepwise organocatalytic
Michael addition/aldol sequence is de-
scribed involving secondary-amine-cata-
lyzed regioselective addition of azidoace-
tone to cinnamaldehyde derivatives fol-
lowed by intramolecular aldolization. Ap-
plication of this route to aminocyclitols is
demonstrated by a short, asymmetric
synthesis of the anticancer natural prod-
uct (+)-trans-dihydrolycoricidine.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!