Enantioselective total synthesis of (+)-reserpine

Article abstract of DOI:10.1021/ol400046n

A catalytic, enantioselective synthesis of (+)-reserpine is reported. The route features a highly diastereoselective, chiral catalyst-controlled formal aza-Diels-Alder reaction between a 6-methoxytryptamine-derived dihydro-β-carboline and an enantioenriched α-substituted enone to form a key tetracyclic intermediate. This approach addresses the challenge of setting the C3 stereogenic center by using catalyst control. Elaboration of the tetracycle to (+)-reserpine includes an intramolecular aldol cyclization and a highly diastereoselective hydrogenation of a sterically hindered enoate.

Full text of DOI:10.1021/ol400046n

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Enantioselective Total Synthesis
of (þ)-Reserpine
Naomi S. Rajapaksa, Meredeth A. McGowan, Matthew Rienzo, and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge,
Massachusetts 02138, United States
jacobsen@chemistry.harvard.edu
Received January 8, 2013
ABSTRACT
A catalytic, enantioselective synthesis of (þ)-reserpine is reported. The route features a highly diastereoselective, chiral catalyst-controlled
formal aza-DielsꢀAlder reaction between a 6-methoxytryptamine-derived dihydro-β-carboline and an enantioenriched R-substituted enone to
form a key tetracyclic intermediate. This approach addresses the challenge of setting the C3 stereogenic center by using catalyst control.
Elaboration of the tetracycle to (þ)-reserpine includes an intramolecular aldol cyclization and a highly diastereoselective hydrogenation of a
sterically hindered enoate.
Reserpine (1) has represented an iconic target for or-
ganic synthesis since its isolation six decades ago.1 The
stereochemically complex pentacyclic structure of this
indole alkaloid continues to serve as a forum for exploring
the frontiers of stereoselective synthesis and has inspired
Scheme 1. Synthetic Strategy Common to All Previous
Successful Approaches to Reserpine
€
(1) Muller, J.; Schlittler, E.; Bein, H. Experientia 1952, 8, 338.
(2) (a) For a review of synthetic efforts directed toward reserpine, see:
Chen, F.-E.; Huang, J. Chem. Rev. 2005, 105, 4671. For more recent
approaches, see: (b) Barcan, A. G.; Patel, A.; Houk, K. N.; Kwon, O.
Org. Lett. 2012, 14, 5388. (c) Yar, M.; Arshad, M.; Akhtar, M. N.;
Shahzad, S. A.; Khan, I. U.; Khan, Z. A.; Ullah, N.; Ninomiya, I. Eur. J.
Org. Chem. 2012, 3, 26. (d) Huang, J.; Chen, F.-E. Helv. Chim. Acta
2007, 90, 1366.
some of the most important work in the history of the
field.2 Despite the scopeof this effort, eachof the successful
approaches to this molecule has relied on the same funda-
mental strategy, namely, a late-stage generation of the
C-ring and its embedded C3 stereocenter from a 2,3-seco-
derivative (2, Scheme 1).3
This approach is generally complicated by preferential
formation of the C3 center with the undesired, thermo-
dynamically favored relative stereochemistry.4 This limita-
tionwas overcome ina notable and most elegant manner in
the Stork synthesis, wherein the desired C3 configuration
(3) (a) Woodward, R. B.; Bader, F. E.; Bickel, H.; Kierstead, R. W.
Tetrahedron 1958, 2, 1. (b) Woodward, R. B.; Bader, F. E.; Bickel, H.;
Frey, A. J.; Kierstead, R. W. J. Am. Chem. Soc. 1956, 78, 2023. (c)
Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W.
J. Am. Chem. Soc. 1956, 78, 2657. (d) Pearlman, B. A. J. Am. Chem. Soc.
1979, 101, 6398. (e) Wender, P. A.; Schaus, J. M.; White, A. W. J. Am.
Chem. Soc. 1980, 102, 6157. (f) Wender, P. A.; Schaus, J. M.; White,
A. W. Heterocycles 1987, 25, 263. (g) Martin, S. F.; Grzejszczak, S.;
Rueger, H.; Williamson, S. A. J. Am. Chem. Soc. 1985, 107, 4072. (h)
Martin, S. F.; Rueger, H.; Williamson, S. A.; Grzejszczak, S. J. Am.
Chem. Soc. 1987, 109, 6124. (i) Stork, G. Pure Appl. Chem. 1989, 61, 439.
(j) Gomez, A. M.; Lopez, J. C.; Fraser-Reid, B. J. Org. Chem. 1994, 59,
4048. (k) Gomez, A. M.; Lopez, J. C.; Fraser-Reid, B. J. Org. Chem.
1995, 60, 3859. (l) Chu, C.-S.; Liao, C.-C.; Rao, P. D. Chem. Commun.
1996, 1537. (m) Hanessian, S.; Pan, J. W.; Carnell, A.; Bouchard, H.;
Lesage, L. J. Org. Chem. 1997, 62, 465. (n) Mehta, G.; Reddy, D. S.
J. Chem. Soc., Perkin Trans. 1 2000, 1399. (o) Sparks, S. M.; Shea, K. J.
Org. Lett. 2001, 3, 2265. (p) Sparks, S. M.; Gutierrez, A. J.; Shea, K. J.
J. Org. Chem. 2003, 68, 5274. (q) Stork, G.; Tang, P. C.; Casey, M.;
Goodman, B.; Toyota, M. J. Am. Chem. Soc. 2005, 127, 16255.
(4) (a) Zhang, L.-H.; Gupta, A. K.; Cook, J. M. J. Org. Chem. 1989,
54, 4708. (b) Lounasmaa, M.; Berner, M.; Tolvanen, A. Heterocycles
1998, 48, 1275.
r
10.1021/ol400046n
XXXX American Chemical Society

was installed through a kinetically controlled cyclization of
an amino-nitrile 2,3-seco-derivative.3i,q,5
R-methoxy group of aldehyde 7 then served to direct a
chelation-controlled diastereoselective allylation, thereby
installing the adjacent C18 stereogenic center and provid-
ing vinyl bromide 9 as a single diastereomer.11 Finally,
elaboration to enone 4 was accomplished via protection of
the C18 alcohol, followed by lithiumꢀhalogen exchange and
subsequent addition into N-methoxy-N-methylacetamide.
Scheme 2. Retrosynthetic Analysis of (þ)-Reserpine
Scheme 3. Stereoselective Synthesis of Enone 4
We envisioned an alternative approach to the reserpine
framework focused on specifically targeting control over
the C3 stereogenic center by means of a stereoselective
formal aza-DielsꢀAlder (FADA) reaction between two
fragments of comparable size (3 and 4, Scheme 2).6
Although high levels of substrate-induced stereocontrol
were deemed unlikely in such a coupling reaction, we
were encouraged by the prospect of selectively introducing
the key C3 stereocenter through the use of the chiral
catalyst-controlled formal FADA reaction discovered re-
cently in our laboratories.7 Herein, we describe the success-
ful application of the asymmetric FADA methodology
to a catalytic enantioselective total synthesis of (þ)-
reserpine.8
The synthetic efforts toward the requisite enone compo-
nent 4 began with a highly selective alcoholic kinetic
resolution of racemic terminal epoxide 5. The differentially
protected 4-carbon triol 6 was obtained in 96% ee through
the use of oligomeric cobalt salen catalyst 8,9 employing
benzyl alcohol as the nucleophile (Scheme 3). This proce-
dure proved more efficient and reliable in our hands than
routes originating from malic acid,10 particularly when
applied on multigram scale. Elaboration of protected
alcohol 6 to aldehyde 7 was accomplished in a three-step
sequence consisting of methylation of the secondary alco-
hol, subsequent hydrogenolysis of the benzyl ether, and
Swern oxidation of the resulting primary alcohol. The
The key coupling of enone 4 and 6-methoxytryptamine-
derived dihydro-β-carboline 37 to generate tetracyclic ke-
tone 11 was then examined under a series of conditions
(Scheme 4). The FADA reaction could be carried out with
a small excess of enone 4 (1.2 equiv) relative to imine 3 only
with primary amine catalysts, consistent with previous obser-
vations employing simple, hindered enone derivatives.12
The degree of intrinsic substrate-induced diastereocontrol
was evaluated using achiral amine promoters. With stoi-
chiometric n-hexylamine,13 ketones 11 and 12, which con-
tain a trans-relationship between the newly formed C3 and
C20 stereocenters, were generated in a 1:1 diastereomeric
ratio (dr) (entry 1). In contrast, high levels of chiral
catalyst-controlled diastereoselectivity were observed in
the presence of 20 mol % aminothiourea 10,7 providing
the desired diastereomer 11 in 76% isolated yield. Notably,
the enantiomeric primary aminothiourea ent-10 induced a
reversal of diastereoselectivity in the FADA reaction to
afford ketone 12 selectively (entry 3).
(5) A related cyclizationof an amino-nitrile intermediate was recently
employed in the syntheses of C3-epimeric natural products venenatine
and alstovenine: Lebold, T. P.; Wood, J. L.; Deitch, J.; Lodewyk, M. W.;
Tantillo, D. J.; Sarpong, R. Nat. Chem. 2012,10.1038/nchem.1528.
(6) Analogous fragment couplings have been applied in the synthesis
ꢀ
ꢀ
of related alkaloids: (a) (()-Deserpidine: Szantay, C.; Blasko, G.;
ꢀ
ꢀ
+
Honty, K.; Baitz-Gacs, E.; Tamas, J.; Toke, L. Leibigs Ann. Chem.
1983, 8, 1292. (b) (()-Yohimbine congeners: Danishefsky, S.; Langer,
M. E.; Vogel, C. Tetrahedron Lett. 1985, 26, 5983. (c) Itoh, T.; Yokoya,
M.; Miyauchi, K.; Nagata, K.; Ohsawa, A. Org. Lett. 2006, 8, 1533. (d)
Nagata, K.; Ishikawa, H.; Tanaka, A.; Miyazaki, M.; Kanemitsu, T.;
Itoh, T. Heterocycles 2010, 81, 1791.
(11) The sequence of allylsilane addition and subsequent PMB protec-
tion was adapted from: Evans, D. A.; Rajapakse, H. A.; Stenkemp, D.
Angew. Chem., Int. Ed. 2002, 41, 4569.
(7) Lalonde, M. P.; McGowan, M. A.; Rajapaksa, N. S.; Jacobsen,
E. N. J. Am. Chem. Soc. 2013, 10.1021/ja310718f.
(8) The three previous reported syntheses of (ꢀ)-reserpine have relied
on either classical resolution or chiral pool approaches (refs 3i, 3j, and
3m).
(9) White, D. E.; Jacobsen, E. N. Tetrahedron: Asymmetry 2003, 14,
3633.
(12) No catalysis was observed with proline or related secondary
amine catalysts. The proline-catalyzed formal aza-DielsꢀAlder reaction
between dihydro-β-carboline and enones has been shown to require a
large excess of enone (30 equiv) relative to imine in those cases where
catalysis is observed: See refs 6c and 6d.
ꢀ
(10) Pattenden, G.; Gonzalez, M. A.; Little, P. B.; Millan, D. S.;
(13) Very low conversions (<10% after 6 d) were obtained using
20 mol % n-hexylamine and 20 mol % acetic acid.
Plowright, A. T.; Tornos, J. A.; Ye, T. Org. Biomol. Chem. 2003, 1, 4173.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 4. Diastereoselective Thiourea-Catalyzed Formal aza-DielsꢀAlder Reactions
The closure of the E-ring to complete the carbon skele-
ton of reserpine was effected by an intramolecular aldol
Scheme 5. Completion of the Synthesis of (þ)-Reserpine
reaction of keto-aldehyde 15 (Scheme 5). Intermediate 15
was obtained in two steps from FADA adduct 11 through
cleavage of the primary TBS ether with pyridine-buffered
HF and oxidation of the resulting primary alcohol with the
DessꢀMartin periodinane. Treatment of crude aldehyde
15 with piperidine and catalytic TsOH resulted in an
intramolecular enamine aldol reaction to afford C15 ter-
tiary alcohol 16 as a single diastereomer. Pinnick oxidation
of aldehyde 16 to the corresponding carboxylic acid fol-
lowed by esterification with diazomethane provided methyl
ester 17.
Having efficiently accessedthe pentacyclicframeworkof
reserpine by means of the thiourea-catalyzed FADA reac-
tion and a subsequent aldol cyclization, the key remaining
challenge involved reduction of the hindered C15 alcohol
of 17 with introduction of the desired cis-fusion at the
D- and E-ring junction. While attempts to obtain the desired
reduction product directly through radical deoxygenation
were not fruitful, an elimination/reduction strategy proved
successful. Regioselective elimination to R,β-unsaturated
ester 18 was induced via trifluoroacetylation of alcohol 17
and subsequent elimination with DBU. After extensive
evaluation of both homogeneous and heterogeneous cat-
alytic systems under a range of conditions, cationic iridium
complex 20,14 bearing the noncoordinating BArF counter-
anion, was identified as uniquely effective in the reduction
of enoate 18.15 In addition, hydrogenation proceeded with
a significant degree of facial selectivity (6:1 dr), ultimately
affording the desired saturated ester 19 in 44% isolated
yield (81% based on recovered olefin 18). The stereoche-
mical assignment of compound 19 was confirmed by X-ray
crystallographic analysis.
E-ring. Thus, treatment of 19 sequentially with TfOH
and sodiumꢀmercury amalgam resulted in cleavage of
the PMB ether and tosyl protective groups, respectively.
The resulting C18 secondary alcohol was esterified using
previously reported conditions to deliver reserpine ((þ)-1).3i
The enantioselective total synthesis of reserpine was
accomplished in 19 steps in the longest linear sequence
from racemic epoxide 5. The convergent approach relied
on chiral catalysts to provide access to coupling component
4 and to address the historically problematic installation
With the fully elaborated pentacycle in hand, comple-
tion of the synthesis required only a global deprotection
and installation of the trimethoxybenzoyl ester on the
(14) (a) Vazquez-Serrano, L. D.; Owens, B. T.; Buriak, J. M. Inorg.
€
Chim. Acta 2006, 359, 2786. (b) Wustenberg, B.; Pfaltz, A. Adv. Synth.
Catal. 2008, 350, 174.
(15) Attempts to effect this transformation by means of conjugate
reductions resulted instead in elimination of the C17 methoxy group.
Org. Lett., Vol. XX, No. XX, XXXX
C

of the C3 stereogenic center. Further application of the
aminothiourea-catalyzed formal aza-DielsꢀAlder reac-
tion in the synthesis of complex alkaloids of both natural
and synthetic origin is anticipated.
supported by the National Science Foundation/Department
of Energy under Grant No. NSF/CHE 0822838. Use of
the Advanced Photon Source was supported by the
U.S. Department of Energy, Office of Science, Office of
Basic Energy Sciences, under Contract No. DE-AC02-
06CH11357.
Acknowledgment. This work was supported by the
NIGMS (GM-43214, GM-59316, and GM-69721) and
by predoctoral fellowship support to N.S.R. from
Boehringer Ingelheim and to M.A.M. from Eli Lilly. We
thank Dr. Shao-Liang Zheng at the Center for Crystallo-
graphic Studies at Harvard University for X-ray data collec-
tion and structure determination. We thank Dr. Yu-Sheng
Chen at ChemMatCARS, APS, for his assistance with
single-crystal data. ChemMatCARS Sector 15 is principally
Supporting Information Available. Complete experi-
1
mental procedures, characterization data, H and 13C
NMR spectra of all isolated intermediates, and crystal-
lographic data for compound 19. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX