A torquoselective 6π electrocyclization approach to reserpine alkaloids

Article abstract of DOI:10.1021/ol302265z

A highly torquoselective thermal triene 6π electrocyclization controls the relative stereochemistry between the C3 and C18 stereocenters of the dodecahydroindolo[2,3-a]benzo[g]quinolizine skeleton of reserpine-type alkaloids. Employing a tandem cross-coup

Full text of DOI:10.1021/ol302265z

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5388–5391
A Torquoselective 6π Electrocyclization
Approach to Reserpine Alkaloids
Gregg A. Barcan, Ashay Patel, K. N. Houk, and Ohyun Kwon*
Department of Chemistry and Biochemistry, University of California, Los Angeles,
607 Charles E. Young Drive East, Los Angeles, California 90095-1569, United States
ohyun@chem.ucla.edu
Received August 14, 2012
ABSTRACT
A highly torquoselective thermal triene 6π electrocyclization controls the relative stereochemistry between the C3 and C18 stereocenters of
the dodecahydroindolo[2,3-a]benzo[g]quinolizine skeleton of reserpine-type alkaloids. Employing a tandem cross-coupling/electrocyclization
protocol allowed us to form the requisite triene and ensure its subsequent cyclization. A novel low-temperature dibromoketene acetal Claisen
rearrangement established the requisite exocyclic dienylbromide precursor for the palladium-catalyzed cross-coupling reaction.
The reserpine-type alkaloids, possessing the dodecahydro-
indolo[2,3-a]benzo[g]quinolizine skeleton, are the most
structurally complex of the indole alkaloids (Figure 1). These
compounds exhibit significant CNS activity and are key
components of herbal medicines that have been used for
centuries. Sixteen naturally occurring reserpine alkaloids
have been isolated; among them, several have been prepared,
along with a variety of semisynthetic derivatives.1,2 The most
common synthetic strategies toward reserpine alkaloids are
“bottom-up” approaches, involving preparation of the fused
D/E-ring system with subsequent installation of the C3
stereocenter in the process of C2ꢀC3 bond formation.3aꢀh
Figure 1. Reserpine-type alkaloids.
(1) Szantay, C.; Blasko, G.; Honty, K.; Dornyei, G. In The Alkaloids
Chemistry and Pharmacology; Brossi, A., Ed.; Academic Press: Orlando,
FL, 1986; Vol. 27, Chapter 2.
(2) (a) Chen, F.-E.; Huang, J. Chem. Rev. 2005, 105, 4671. (b) Healy,
“Top-down” approaches, involving either C3ꢀC14 or
D.; Savage, M. Br. J. Psychiat. 1998, 172, 376. (c) Bleuler, M.; Stoll,
C14ꢀC15 bond formation with concomitant generation
C20 stereocenters, have been employed less frequently.3iꢀl
W. A. Ann. N.Y. Acad. Sci. 1955, 61, 167.
(3) (a) Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.;
Kierstead, R. W. J. Am. Chem. Soc. 1956, 78, 2023. (b) Pearlman,
of the C3 stereocenter and establishment of the C15 and
B. A. J. Am. Chem. Soc. 1979, 101, 6404. (c) Wender, P. A.; Schaus,
J. M.; White, A. W. J. Am. Chem. Soc. 1980, 102, 6157. (d) Martin, S. F.;
Grzejszczak, S.; Rueeger, H.; Williamson, S. A. J. Am. Chem. Soc. 1985,
107, 4072. (e) Stork, G. Pure Appl. Chem. 1989, 61, 439. (f) Baxter, E. W.;
Labaree, D.; Ammon, H. L.; Mariano, P. S. J. Am. Chem. Soc. 1990, 112,
7682. (g) Gomez, A. M.; Lopez, C.; Fraser-Reid, B. J. Org. Chem. 1995,
60, 3859. (h) Hanessian, S.; Pan, J.; Carnell, A.; Bouchard, H.; Lesage, L.
J. Org. Chem. 1997, 62, 465. (i) Beke, D.; Szantay, C. Chem. Ber. 1962,
95, 2132. (j) Szantay, C.; Toke, L. Tetrahedron Lett. 1963, 4, 251. (k)
Szantay, C.; Toke, L.; Kalaus, G. J. Org. Chem. 1967, 32, 423. (l) Naito,
T.; Hirata, Y.; Miyata, O.; Ninomiya, I.; Inoue, M.; Kamiichi, K.; Doi,
M. Chem. Pharm. Bull. 1989, 37, 901.
Asanalternative tothesestrategies, wewereintriguedby
the idea of the C3 center exerting remote stereocontrol
across the fused D/E-ring system during the formation of
the C18 stereocenter. Because C18 is the most remote
stereocenter from C3 on the benzo[g]quinolizine scaffold,
we were aware of the potential difficulty of this 1,6-relay
of stereochemical information and sought to identify an
appropriate reaction manifold for such a strategy.
r
10.1021/ol302265z
Published on Web 10/05/2012
2012 American Chemical Society

The thermal 6π electrocyclization of all-carbon-containing
trienes is an underutilized, yet highly powerful, reac-
tion with the capacity to generate two new stereocenters.
Furthermore, if the starting triene possesses a stereogenic
center, the newly generated stereocenters could be formed
in a highly diastereoselective manner. Nevertheless, the
electrocyclization of all-carbon trienes has received rela-
tively little attention in the synthesis of small molecules
when compared with other pericyclic reactions, such as the
DielsꢀAlder and Claisen reactions.4
presence of the C3 stereocenter would allow the C18
stereocenter to be formed in a stereocontrolled manner
through a torquoselective 6π electrocyclization (Scheme 1).
This unique approach stands in stark contrast to previous
synthetic strategies toward the synthesis of reserpine
alkaloids and hinges upon a seldom-explored remote
1,6-stereoselective 6π electrocyclization.4d
Although the literature does not offer an extensive
discussion of remote stereocontrol in the context of 6π
electrocyclization, we reasoned that a suitably constrained
scaffold, such as that of the triene 1, should allow the C3
stereocenter to influence the stereoselectivity of this trans-
formation (Scheme 1).4b While optimistic for the possibi-
lity of stereochemical control, we lacked any established
models to predict the diastereoisomer favored upon elec-
trocyclization. If successful, however, this synthetic strat-
egy would provide the pentacycle 2 possessing the requisite
ABCDE skeleton in a stereodefined manner. Upon re-
moval of R1, the exposed hydroxyl functionality could be
inverted readily, if necessary, and the resultant R,β-unsa-
turated ester contained in the E-ring could act as a handle
for elaboration to (()-reserpine and related alkaloids.
Scheme 1. Remote Stereochemical Induction via Thermal
Torquoselective 6π Electrocyclization
Scheme 2. Retrosynthesis of the Key Triene 1a
As a part of our growing interest in novel 6π electro-
cyclizations5 and a research program in nucleophilic phos-
phine catalysis for the synthesis of heterocycles and
carbocycles,6 we became interested in the potential of these
transformations to meet the goals of our synthetic strategy
for remote 1,6-stereoinduction. We envisioned that the
(4) For notable early examples of thermal torquoselective all-carbon
6π electrocyclizations, see: (a) Trost, B. M.; Shi, Y. J. Am. Chem. Soc.
1992, 114, 791. (b) Dauben, W. G.; Williams, R. G.; McKelvey, R. D.
J. Am. Chem. Soc. 1973, 95, 3932. (c) Corey, E. J.;Hortmann, A. G. J. Am.
Chem. Soc. 1963, 85, 4033. For recent examples, see: (d) Hayashi, R.;
Walton, M. C.; Hsung, R. P.; Schwab, J. H.; Yu, X. Org. Lett. 2010, 12,
5768. (e) Jung, M. E.; Min, S.-J. Tetrahedron 2007, 63, 3682. (f) Benson,
C. L.; West, F. G. Org. Lett. 2007, 9, 2545. (g) Sunnemann, H. W.; de
Meijere, A. Angew. Chem., Int. Ed. 2004, 43, 895. For recent examples of
all-carbon 6π electrocyclizations of achiral molecules, see: (h) Togeum, S.-
M. T.; Hussain, M.; Malik, I.; Villinger, A.; Langer, P. Tetahedron Lett.
2009, 50, 4962. (i) Alvararez-Manzaneda, E.; Chahboun, R.; Cabrera, E.;
Alvarez, E.; Haidour, A.; Ramos, J. M.; Alvarez-Manzaneda, R.; Hma-
mouchi, M.; Es-Samti, H. Chem. Commun. 2009, 592. (j) Suffert, J.; Salem,
B.; Klotz, P. J. Am. Chem. Soc. 2001, 123, 12107. (k) von Zezschwitz, P.;
Petry, F.; de Meijere, A. Chem.;Eur. J. 2001, 7, 4035. For a review on
asymmetric electrocyclic reactions, see: (l) Thompson, S.; Coyne, A. G.;
Knipe, P. C.; Smith, M. D. Chem. Soc. Rev. 2011, 40, 4217. For recent
discussions on all-carbon 6π electrocyclizations, see: (m) Tantillo, D.
Angew. Chem., Int. Ed. 2009, 48, 31. (n) Bishop, L. M.; Barbarow, J. E.;
Bergman, R. B.; Trauner, D. Angew. Chem., Int. Ed. 2008, 47, 8100. (o) Yu,
T.-Q.; Fu, Y.; Liu, L.; Guo, Q.-X. J. Org. Chem. 2006, 71, 6157.
a Ns = o-nitrobenzenesulfonyl.
We envisioned efficient access to 1 through cross-
coupling of a suitable pseudometal with the vinyl bromide
3, which could be derived from the appropriately functiona-
lized ester 4 (Scheme 2). We planned to generate the R,R-
dihaloester 4 from the allylic alcohol 5 through [3,3]-
sigmatropic rearrangement of the corresponding dihaloke-
tene acetal. Based upon our previous experience with
heterocycle formation through phosphine catalysis, we
expected a relatively straightforward elaboration of the
allylic alcohol 5 from the [4 þ 2] annulation product 6.6b
The [4 þ 2] annulation between the imine 7 and the
butadienoate 8 in the presence of catalytic PBu3 proceeded
uneventfully (Scheme 3);7 we isolated the tetrahydropyr-
idine 9 as a yellow crystalline solid after removal of the Boc
group in toluene under reflux in the presence of silica gel.
(5) (a) Creech, G. S.; Kwon, O. J. Am. Chem. Soc. 2010, 132, 8876. (b)
Henry, C. E.; Kwon, O. Org. Lett. 2007, 9, 3069.
(6) (a) Fan, Y. C.; Kwon, O. Phosphine Catalysis. In Science of
Synthesis; List, B., Ed.; Asymmetric Organocatalysis, Vol. 1, Lewis Base and
Acid Catalysts; Georg Thieme: Stuttgart, 2012; pp 723ꢀ782. (b) Villa,
R. A.; Xu, Q.; Kwon, O. Org. Lett. 2012, 14, 4634. (c) Tran, Y. S.;
Martin, T.; Kwon, O. Chem.;Asian J. 2011, 6, 2101. (d) Khong, S. N.;
Tran, Y. S.; Kwon, O. Tetrahedron 2010, 66, 4760. (e) Lu, K.; Kwon, O.
Org. Synth. 2009, 86, 2012. (f) Sriramurthy, V.; Barcan, G. A.; Kwon, O.
J. Am. Chem. Soc. 2007, 129, 12928. (g) Tran, Y. S.; Kwon, O. J. Am.
Chem. Soc. 2007, 129, 12632. (h) Tran, Y. S.; Kwon, O. Org. Lett. 2005,
7, 4289. (i) Zhu, X.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716.
(7) See the Supporting Information for the synthesis of 7.
Org. Lett., Vol. 14, No. 21, 2012
5389

Scheme 3. Synthesis of the Cross-Coupling Partner 3 through Phosphine-Catalyzed [4 þ 2] Annulation and Dibromoketene Acetal
Claisen Rearrangement
Next, in a one-pot procedure, we prepared the tryptophol
10 through treatment of the indole 9 with oxalyl chlo-
ride at ambient temperature and subsequent BH3 SMe2-
this example is the first [3,3]-sigmatropic rearrangement
leading directly to highly functionalized R,R-dibromo-
esters.11 A number of amine and alkoxide bases facilitated
β-elimination from the R,R-dibromoester 4 to give the vinyl
bromides 3 in ∼2:1 dr, but with very low mass recoveries
(<40%). Ultimately, we found that potassium hexafluoroi-
sopropoxide, prepared in situ through the addition of 1 M
tBuOK to a solution of excess hexafluoroisopropanol (HFIP)
and [18]crown-6 at 0 °C, cleanly afforded the vinyl bromides
E-3 and Z-3 as a separable 2:1 mixture in 85% yield.12
For the formation of the requisite triene 1 for our
planned 6π electrocyclization, we initially speculated that
only Z-3 would be suitable for stereospecific cross-
coupling reaction to form the E-triene 1. We found, how-
ever, that we could employ both isomers under an opti-
mized sequence of Suzuki cross-coupling, photochemical
isomerization of the undesired triene, and electrocyclization
at 80 °C in benzene.13 Following this protocol, we obtained
the desired pentacycle in 54% yield as a single diastereo-
isomer, starting from a mixture of the two vinyl bromides
E/Z-3 (Scheme 4). X-ray crystallographic analysis revealed
the relative configuration of 2a. We suspect that the reac-
tion selectivity arises from an allylic interaction between the
methyl ester group and the adjacent D-ring methylene unit
in the transition state.4a,e Such interactions can be suffi-
ciently large to provide high levels of stereocontrol; studies
are currently ongoing in our laboratories to fully assess the
controlling element in this reaction.
3
mediated reduction of the intermediate glyoxylic acid
chloride. The use of bases commonly employed under
classical Fukuyama conditions for nosyl deprotection led
to partial decomposition of 10 and low yields. We found,
however, that addition of potassium thiophenoxide
(PhSK) as a preformed salt led to clean removal of the
o-nosyl protecting group in excellent yield. Formation of
ring C in 11 was facilitated by the intramolecular alkyla-
tion of the resulting secondary amine in the presence of
PPh3 and I2. Protection of the indole N-atom with Boc2O
and subsequent DIBAL-mediated reduction of the ester
gave the key allylic alcohol 5 in 88% yield. Overall, this
route provided efficient access to 5 in eight steps from the
imine 7 on a multigram scale.
We prepared a variety of dimethylorthoacetates con-
taining R-halogen atoms with the intention of exploiting
a JohnsonꢀClaisen rearrangement for the preparation
of the R,R-dibromoester 4.8 Despite our best efforts, we
were unable to facilitate the desired [3,3]-sigmatropic
rearrangement employing these substituted orthoesters.9
Fortunately, access to 4 could be achieved through [3,3]-
sigmatropic rearrangement of the dibromoketene acetal
generated through dehydrobromination of the acetal 19.10
Remarkably, rearrangement occurred spontaneously after
elimination of HBr at ꢀ78 °C, providing the desired R,R-
dibromoester4 in88% yield. To the best of our knowledge,
Although we could functionalize 2a through conjugate
addition to the R,β-unsaturated ester, the yields and
(8) (a) Keegstra, M. A. Tetrahedron 1992, 48, 2681. (b) McElvain,
S. M.; Waters, P. M. J. Am. Chem. Soc. 1942, 64, 1963.
(9) Lounasmaa, M.; Hanhinen, P.; Jokela, R. Tetrahedron 1995, 51,
8623.
(10) McElvain, S. M.; Kundiger, D. Org. Synth. 1943, 23, 45.
(11) For examples of Claisen rearrangements of difluoro- or dichloro-
substituted vinyl ethers, leading to difluoro-esters, -ketones, and -alde-
hydes and dichloroaldehydes, see: (a) Christopher, A.; Brandes, D.;
Kelly, S.; Minehan, T. Org. Lett. 2006, 8, 451. (b) Yuan, W.; Berman,
R. J.; Gelb, M. H. J. Am. Chem. Soc. 1987, 109, 8071. (c) Welch, J. T.;
Samartino, J. S. J. Org. Chem. 1985, 50, 3663. (d) Metcalf, B. W.; Jarvi,
E. T.; Burkhart, J. P. Tetrahedron Lett. 1985, 26, 2861.
(12) The geometry of the olefin was assigned based on X-ray crystal-
lographic analysis of Z-3 (see Supporting Information for details).
(13) For a discussion of selective photochemical isomerization of all-
carbon trienes followed by thermal 6π electrocyclization, see: von Essen,
R.; von Zezschwitz, P.; Vidovic, D.; de Meijere, A. Chem.;Eur. J. 2004,
10, 4341. This sequence was ideal because the vinyl bromides E-3 and
Z-3 both underwent Suzuki cross-coupling with low levels of stereospeci-
ficity, providing inseparable mixtures of 2a and the undesired triene in
approximately 2:1 and 3:1 ratios, respectively. Boronate 20 was prepared
according to: Regan, C. F. Ph.D Dissertation, University of California, Los
Angeles, CA, 2009, see Supporting Information for details.
5390
Org. Lett., Vol. 14, No. 21, 2012

22 as the sole product in 55% yield and 20:1 dr. Surpris-
ingly, photoisomerization was unnecessary in this case:
we obtained the cyclization product in similar yield
directly from the cross-coupling reaction.15
Scheme 4. Torquoselective Suzuki/6π Electrocyclization
Deprotection of the acetonide with InCl3 and water in
MeCN provided an oxidatively sensitive and unstable
hydroxy ketoester.16 Reduction of the ketone under H2 in
the presence of PtO2 provided the trans diol 23 in 70% yield
as a single diastereoisomer. Advancing 23 to (()-reserpine
would require selective benzoylation of the R-hydroxyl
group, deprotection of the Boc group, reduction (from the
R face) of the olefinic bond at the D/E-ring junction,18
inversion of the relative configuration of the vicinal diol
through a benzoate walk,19 and O-methylation.
In conclusion, we have obtained highly functionalized
pentacyclic intermediates en route to the preparation of
reserpine-type alkaloids. Our synthetic sequence relies on a
phosphine-catalyzed [4 þ 2] annulation, a novel dibromo-
keteneacetalClaisen rearrangement, and a cross-coupling/
torquoselective 6π electrocyclization cascade. In particu-
lar, we have demonstrated that the torquoselective triene
6π electrocyclization is an extremely efficient method for
remote 1,6-transfer of chirality from C3 to C18 in the
synthesis of reserpine alkaloids. We are currently assessing
the stereochemistry-controlling elements in these reactions
and their potential for further synthetic applications.
diastereoselectivities of these reactions were generally very
poor, providing all four possible diastereoisomers. We
reasoned that deprotection of the benzyl group would
allow a hydroxyl-directed reaction to provide better con-
trol over the stereoselectivity. Unfortunately, our efforts at
removing this protecting group under a variety of conditions
gave undesired products, including those from reduction of
the R,β-unsaturated ester and elimination of the benzyloxy
substituent resulting in aromatization of the E-ring. Con-
sidering the difficulty we encountered installing the requisite
functionality onto 2a, we sought to install all of the E-ring
alkoxy groups of reserpine in a single step through our
tandem cross-coupling/6π electrocyclization. We envi-
sioned that this approach would require a 1,2-dialkoxyvinyl
pseudometal to undergo the cross-coupling reaction. From
an exploration of the literature, we identified the dioxole 21
as a potentially suitable candidate (Scheme 5).14
Acknowledgment. This study was funded by the NIH
(R01GM071779 and P41GM081282) and the NSF
(Equipment Grant CHE-1048804). We thank Christian
Bustillos for support in the preparation of synthetic inter-
mediates and Prof. Hongchao Guo (China Agricultural
University) for providing the allenoate 8 (synthesized in
the National Key Technologies R&D Program of China,
2012BAK25B03, CAU).
Scheme 5. Torquoselective Negishi/6π Electrocyclization
Note Added after ASAP Publication. Reference 13 was
incomplete in the version published ASAP October 5,
2012; the correct version reposted October 12, 2012.
Supporting Information Available. Experimental pro-
cedures; characterization data; copies of 1H and 13C
NMR spectra; crystallographic data for 2a and Z-3
(CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Although the conversion of 21 into a variety of vinyl
boronic esters (e.g., pinacol and diisopropyl) proceeded
well, their instability during purification limited our op-
tions for optimization of the Suzuki/6π electrocyclization
cascade. Instead, following treatment of 21 with nBuLi
and exposure to anhydrous ZnCl2, we could facilitate a
Negishi/6π electrocyclization cascade upon heating E/Z-3
under reflux in THF in the presence of Pd(PPh3)4. To the
best of our knowledge, this transformation marks the first
use of 21 as a highly oxidized partner in cross-coupling
chemistry. The optimized conditions provided the acetonide
(15) For a recent discussion of isomerization during Pd-catalyzed
cross-coupling reactions, see: Ling, G.-P.; Voigtritter, K. R.; Cai, C.;
Lipshutz, B. H. J. Org. Chem. 2012, 77, 3700 and references therein.
(16) Pfrengle, F.; Dekaris, V.; Schefzig, L.; Zimmer, R.; Reissig,
H.-U. Synlett 2008, 19, 2965.
(17) The relative stereochemistry was assigned by NOESY 1H NMR
spectroscopy of the corresponding acetonide; see the Supporting
Information.
(18) (a) Winstein, S.; Buckles, R. E. J. Am. Chem. Soc. 1943, 65, 613.
(b) Buchanan, J. G.; Edgar, A. R. Carbohydr. Res. 1976, 49, 289. (c)
Jaconsen, S.; Mols, O. Acta Chim. Scand. 1981, 35, 169. (d) Binkley, R. W.;
Sivik, M. R. J. Org. Chem. 1986, 51, 2619. (e) Bloomfield, G. C.; Ritchie,
T. J.; Wriggleworth, R. J. Chem. Soc., Perkin Trans. 1 1992, 1229.
(19) (a) Lounasmaa, M.; Jokele, R. Tetrahedron 1990, 46, 615. (b)
Paivio, E.; Berner, M.; Tolvanen, A.; Jokela, R. Heterocycles 2000, 10, 2241.
(14) (a) Lett R.; Melnyk, O. (Roussel Uclaf, France) U.S. Patent
5,723,638, March 3, 1998. (b) Posner, G. H.; Nelson, T. D. Tetrahedron
1990, 46, 4573.
The authors declare no competing financial interest.
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