A stereoselective formal synthesis of leucascandrolide A

Article abstract of DOI:10.1021/ol200824r

A stereoselective formal synthesis of leucascandrolide A was accomplished through the tandem and organocatalytic oxa-Michael reactions, which were promoted by the gem-disubstituent effect, in conjunction with the dithiane coupling reaction.

Full text of DOI:10.1021/ol200824r

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2722–2725
A Stereoselective Formal Synthesis of
Leucascandrolide A
Kiyoun Lee, Hyoungsu Kim,† and Jiyong Hong*
Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
jiyong.hong@duke.edu
Received March 29, 2011
ABSTRACT
A stereoselective formal synthesis of leucascandrolide A was accomplished through the tandem and organocatalytic oxa-Michael reactions,
which were promoted by the gem-disubstituent effect, in conjunction with the dithiane coupling reaction.
The marine macrolide leucascandrolide A (1, Scheme 1)
was isolated from the calcareous sponge Leucascandra
caveolata by Pietra and co-workers.1 Leucascandrolide A
(1) is an extremely potent inhibitor of tumor cell prolifera-
tion(IC50 values: 71nM for KBand 357nMforP388)1 and
has attracted considerable interest from a number of
synthetic groups.2 Recently, Kozmin and co-workers
suggested that 1 may elicit its potent antiproliferative
activity via inhibition of mitochondrial ATP synthesis.3
With an interest in facilitating access to biologically im-
portant natural products with tetrahydropyrans,4 we
sought to develop an efficient and facile synthetic route
for 1 that would be amenable to the synthesis of analogues
for further biological studies. Herein, we report a stereo-
selective formal synthesis of 1 through the tandem and
organocatalytic oxa-Michael reactions in conjunction with
the dithiane coupling reaction.
Our retrosynthetic plan for 1 relies on the tandem and
organocatalytic oxa-Michael reactions for the stereo-
selective synthesis of the 2,6-cis-tetrahydropyran and
the 2,3-trans-2,6-trans-tetrahydropyran embedded in 1
(Scheme 1). Due to the poor thermodynamic stability
of 2,6-trans-tetrahydropyrans, we expected that the stereo-
selective synthesis of 2,3-trans-2,6-trans-tetrahydropyran 7
would be challenging.
† Current address: Ajou University, College of Pharmacy, Suwon 443-
749, Korea.
(1) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. Helv.
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S. D. J. Am. Chem. Soc. 2001, 123, 8420–8421. (c) Wang, Y.; Janjic, J.;
Kozmin, S. J. J. Am. Chem. Soc. 2002, 124, 13670–13671. (d) Wipf, P.;
Reeves, J. T. Chem. Commun. 2002, 2066–2067. (e) Fettes, A.; Carreira,
E. M. Angew. Chem., Int. Ed. 2002, 41, 4098–4101. (f) Paterson, I.;
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r
10.1021/ol200824r
Published on Web 04/29/2011
2011 American Chemical Society

Scheme 1. Retrosynthetic Plan for Leucascandrolide A (1)
Scheme 2. Synthesis of 2,3-trans-2,6-trans-Tetrahydropyran 12a
with amine and acid (Table 1). The organocatalytic oxa-
Michael reaction7,8 of 8 in the presence of pyrrolidine
or piperidine at 25 °C dramatically promoted the oxa-
Michael reaction but afforded the undesired 2,3-cis-2,
6-cis-tetrahydropyran 12b as a single diastereomer
(entries 1 and 2). Surprisingly, when the reaction was
attempted at À40 °C, the stereoselectivity was reversed to
provide 2,3-trans-2,6-trans-tetrahydropyran 12a as the
major diastereomer (dr = 7À10:1, entries 3 and 4).9
Encouraged by these results, we decided to test chiral
organocatalysts to further improve the stereoselectivity
of the oxa-Michael reaction. When 8 was treated with
(S)-1310 at À40 °C, the organocatalytic oxa-Michael reac-
tion proceeded smoothly to provide 12a with excellent
stereoselectivity and yield (dr >20:1, 98%, entry 7). To the
best of our knowledge, this is the first report for the
synthesis of 2,3-trans-2,6-trans-tetrahydropyrans through
the oxa-Michael reaction of R,β-unsaturated aldehydes. It
is also noteworthy that both 2,3-trans-2,6-trans- and 2,
3-cis-2,6-cis-tetrahydropyrans could be prepared from the
The synthesis of 1 started with the preparation of 2,
3-trans-2,6-trans-tetrahydropyran 12a (Scheme 2). The
coupling of 9 and 105 proceeded smoothly to afford allyl
alcohol 11. The tandem allylic oxidation/oxa-Michael
reaction4b of 11 provided aldehyde 8 as the major product
(70%) due to the stereochemical mismatch between the C3
methyl group and the C6 alkyl group in 8A and 8B and
resulted in complete decomposition after the prolonged
reaction time (72 h).
We hypothesized that the iminium activation of the
conjugate acceptor in the oxa-Michael reaction would help
overcome the stereochemical mismatch in transition states
and promote the oxa-Michael step by increasing the
reactivity of aldehyde 8.6 To test this hypothesis, we
converted 8 to the corresponding iminium ion by treating
(8) For recent examples of the organocatalytic intermolecular oxa-
ꢀ
Michael reaction, see: (a) Bertelsen, S.; Diner, P.; Johansen, R. L.;
Jørgensen, K. A. J. Am. Chem. Soc. 2007, 129, 1536–1537. (b) Li, H.;
Wang, J.; E-Nunu, T.; Zu, L.; Jiang, W.; Wei, S.; Wang, W. Chem.
ꢀ
Commun. 2007, 507–509. (c) Sunden, H.; Ibrahem, I.; Zhao, G. L.;
ꢀ
Eriksson, L.; Cordova, A. Chem.;Eur. J. 2007, 13, 574–581. (d)
Rueping, M.; Sugiono, E.; Merino, E. Angew. Chem., Int. Ed. 2008,
47, 3046–3049. (e) Kotame, P.; Hong, B.-C.; Liao, J.-H. Tetrahedron
Lett. 2009, 50, 704–707. (f) Andersen, N. R.; Hansen, S. G.; Bertelsen, S.;
Jørgensen, K. A. Adv. Synth. Catal. 2009, 351, 3193–3198.
(9) The relative stereochemistry was determined by 2D NMR studies
(see the Supporting Information for details).
(10) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2005, 44, 794–797. (b) Hayashi, Y.; Gotoh,
H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212–4215.
(6) Ying, Y.; Kim, H.; Hong, J. Org. Lett. 2011, 13, 796–799.
(7) For examples of the organocatalytic intramolecular oxa-Michael
reaction, see: (a) Wang, H.-F.; Cui, H.-F.; Chai, Z.; Li, P.; Zheng, C.-W.;
Yang, Y.-Q.; Zhao, G. Chem.;Eur. J. 2009, 15, 13299–13303. (b) Dıez,
ꢀ~
ꢀ
D.; Nunez, M. G.; Beneitez, A.; Moro, R. F.; Marcos, I. S.; Basabe, P.;
Broughton, H. B.; Urones, J. G. Synlett 2009, 390–394.
Org. Lett., Vol. 13, No. 10, 2011
2723

Methylation of 16 followed by the coupling with 64b
proceeded smoothly to set the stage for the key tandem
allylic oxidation/oxa-Michael reaction. The tandem
oxa-Michael reaction of 5 (MnO2, CH2Cl2, 25 °C, 12
h) stereoselectively provided the desired 2,6-cis-tetrahy-
dropyran aldehyde 4 (dr >20:1 86%).4b,9 It is note-
worthy that the synthesis of both the 2,3-trans-2,6-
trans- and 2,6-cis-tetrahydropyrans through the same
type of reaction has been achieved only once in the
synthesis of 1.2l
Table 1. Organocatalytic Oxa-Michael Reaction for the
Stereoselective Synthesis of 2,3-trans-2,6-trans Tetrahydropyr-
an 12a
Scheme 3. Synthesis of Bis-Tetrahydropyran 4
temp
time
(h)
yield
(%)a
entry
amine
(°C)
drb
1
2
3
4
5
6
7
8
pyrrolidine
piperidine
pyrrolidine
piperidine
(S)-13
25
25
1
1
98
98
94
96
96
97
98
95
12b only
12b only
7:1
À40
À40
0
5
24
3
10:1
6:1
(S)-13
À20
À40
0
6.5
13
3
10:1
(S)-13
>20:1
1.5:1
(R)-13
a Combined yield of the isolated 12a and 12b. b The diastereomeric
ratio (12a/12b) was determined by integration of the 1H NMR of the
crude product.
common substrate through oxa-Michael reactions de-
pending on reaction temperature and the secondary amine
catalyst.
With the key 2,3-trans-2,6-trans-tetrahydropyran 12a in
hand, we turned our attention to the stereoselective synth-
esis of 4-hydroxy epoxide 16 for our second dithiane
coupling reaction (Scheme 3). Desulfurization of the 1,3-
dithiane group in 12a with Raney Ni, ParikhÀDoering
oxidation, and Brown asymmetric allylation11 provided
homoallyl alcohol 14. Direct epoxidation of homoallyl
alcohol 14 (VO(acac)2, TBHP, CH2Cl2, 0 to 25 °C) pro-
vided epoxide 16, but in no stereoselectivity (dr = 1:1).12
After an extensive investigation of epoxidation conditions,
we adopted the IBr-induced cyclization of a homoallylic
carbonate.13 Boc protection of 14, iodocyclization, and
methanolysis afforded the desired 4-hydroxy epoxide 16
with excellent stereoselectivity (dr = 16:1, 71%).
Having successfully assembled both the tetrahydro-
pyran units in leucascandrolide A (1), we embarked on
the final stage of the synthesis of 1 (Scheme 4). The
installation of the C17 appendage in a stereoselective
manner has been problematic in the previous syntheses
of 1. The direct addition of various vinyl groups to
aldehydes provided the corresponding alcohols, but in
low to modest stereoselectivities (dr = 1À6:1).2a,b,d,g,l,p,q
To solve this challenge, we decided to utilize the (À)-
MIB-catalyzed asymmetric vinylation reaction pre-
viously reported by Walsh and co-workers because of
the great success of the reaction in this area.14
(11) (a) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105,
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Sandri, S. J. Org. Chem. 1982, 47, 4626–4633. (c) Bartlett, P. A.;
Meadows, J. D.; Brown, E. G.; Morimoto, A.; Jernstedt, K. K. J.
Org. Chem. 1982, 47, 4013–4018. (d) Duan, J. J.-W.; Smith, A. B., III. J.
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(14) (a) Nugent, W. A. Chem. Commun. 1999, 1369–1370. (b) Chen,
Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 12225–
12231. (c) Garcia, C.; Libra, E. R.; Carroll, P. J.; Walsh, P. J. J. Am.
Chem. Soc. 2003, 125, 3210–3211. (d) Lurain, A. E.; Walsh, P. J. J. Am.
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P. J.; Nugent, W. A. Org. Synth. 2005, 82, 87–92.
2724
Org. Lett., Vol. 13, No. 10, 2011

delight, the (À)-MIB-catalyzed asymmetric vinylation
reaction of 18 (4-methyl-1-pentyne, Cy2BH, Et2Zn, (À)-
MIB, toluene, À5 °C, 1.5 h) afforded the desired (17R)-
alcohol 19 with excellent stereoselectivity (dr = 32:1).15
Acetal deprotection of 19 smoothly provided the corre-
sponding hydroxy aldehyde which was spontaneously
transformed into macrolactol 20 (49% for two steps
from 18) as previously observed by Kozmin and co-
workers.2c Deprotection of the dithiane group in 20,
PCC oxidation,2c and NaBH4 reduction2l accomplished
the synthesis of leucascandrolide A macrolactone (3),
constituting a formal synthesis of leucascandrolide
A (1).2c
Scheme 4. Completion of the Formal Synthesis of Leucascan-
drolide A (1)
In summary, the stereoselective formal synthesis of
leucascandrolide A (1) was accomplished through the
oxa-Michael reaction promoted by the gem-disubstituent
effect. We demonstrated that both the 2,6-cis- and 2,
3-trans-2,6-trans-tetrahydropyrans embedded in leucas-
candrolide A (1) can be assembled through the tandem
and organocatalytic oxa-Michael reactions with excellent
stereoselectivities. We also showed that the (À)-MIB-
catalyzed asymmetric vinylation reaction is a highly effec-
tive method for the stereoselective installation of the C17
stereocenter. Our efficient synthetic route established by
the tandem and organocatalytic oxa-Michael reactions in
conjunction with the dithiane coupling reaction would be
applicable to the synthesis of analogues of 1 for further
biological studies.
Acknowledgment. This work was supported by Duke
University. We are grateful to the NCBC (Grant No. 2008-
IDG-1010) for funding of NMR instrumentation.
Compound 4 was transformed into 18 via acetal forma-
tion, PMB deprotection, and TPAP oxidation. To our
Supporting Information Available. General experimen-
tal procedures including spectroscopic and analytical
data along with copies of 1H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) The diastereomeric ratio was determined by HPLC separation
(PhenomenexLuna C18 (5 μm, 4.60 mm  250 mm), flow rate: 1 mL/min,
80% MeOH in H2O) of the crude product (see the Supporting Informa-
tion for details).
Org. Lett., Vol. 13, No. 10, 2011
2725