Catalytic asymmetric total synthesis of (+)-yohimbine

Article abstract of DOI:10.1021/ol702781q

The total synthesis of (+)yohimbine was achieved in 11 steps and 14% overall yield. The absolute configuration was established through a highly enantioselective thiourea-catalyzed acyl-Pictet-Spengler reaction, and the remaining 4 stereocenters were set simultaneously in a substrate-controlled intramolecular Diels Alder reaction.

Full text of DOI:10.1021/ol702781q

ORGANIC
LETTERS
2008
Vol. 10, No. 5
745-748
Catalytic Asymmetric Total Synthesis of
)-Yohimbine
(+
Dustin J. Mergott, Stephan J. Zuend, and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
jacobsen@chemistry.harVard.edu
Received November 16, 2007
ABSTRACT
The total synthesis of (
highly enantioselective thiourea-catalyzed acyl-Pictet
substrate-controlled intramolecular Diels Alder reaction.
+
)-yohimbine was achieved in 11 steps and 14% overall yield. The absolute configuration was established through a
−Spengler reaction, and the remaining 4 stereocenters were set simultaneously in a
−
Yohimbine (1) is an important member of the monoterpenoid
indole alkaloids, a large class of natural products that features
synthetically challenging structures with diverse biological
activity.1 Total syntheses of 1 and related alkaloids have
relied on either of two strategies (Scheme 1).2-4 One
â-carboline ABC-ring system, followed by annulation to set
the D and E rings (3 f 1). This strategy has been used less
frequently, especially in asymmetric syntheses, owing to the
(1) For reviews, see: (a) Brown, R. T. In The Chemistry of Heterocyclic
Compounds; Saxton, J. E., Ed.; John Wiley and Sons: New York, 1983;
Vol. 25, Part 4, pp 147-199. (b) Baxter, E. W.; Mariano, P. S. In
Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.;
Springer-Verlag: New York, 1992; Vol. 8, pp 197-319. (c) Sza´ntay, C.;
Honty, K. In The Chemistry of Heterocyclic Compounds; Saxton, J. E.,
Ed.; John Wiley and Sons: New York, 1994; Vol. 25, Part 4 Suppl., pp
161-216. (d) Goldberg, M. R.; Robertson, D. Pharmacol. ReV. 1983, 35,
143-180.
Scheme 1. General Strategies Employed in Previous Syntheses
of Yohimbine and Related Alkaloids
(2) For the first total synthesis of yohimbine, see: (a) van Tamelen, E.
E.; Shamma, M.; Burgstahler, A. W.; Wolinsky, J.; Tamm, R.; Aldrich, P.
E. J. Am. Chem. Soc. 1958, 80, 5006-5007. (b) van Tamelen, E. E.;
Shamma, M.; Burgstahler, A. W.; Wolinsky, J.; Tamm, R.; Aldrich, P. E.
J. Am. Chem. Soc. 1969, 91, 7315-7333.
(3) For other total syntheses of yohimbine, see: (a) To¨ke, L.; Honty,
K.; Sza´ntay, C. Chem. Ber. 1969, 102, 3248-3259. (b) Stork, G.;
Guthikonda, R. N. J. Am. Chem. Soc. 1972, 94, 5109-5110. (c) Kametani,
T.; Kajiwara, M.; Takahashi, T.; Fukumoto, K. Heterocycles 1975, 3, 179-
182. (d) Brown, R. T.; Pratt, S. B. J. Chem. Soc., Chem. Commun. 1980,
165-167. (e) Wenkert, E.; St. Pyrek, J.; Uesato, S.; Vankar, Y. D. J. Am.
Chem. Soc. 1982, 104, 2244-2246. (f) Miyata, O.; Hirata, Y.; Naito, T.;
Ninomiya, I. J. Chem. Soc., Chem. Commun. 1983, 1231-1232. (g) Blasko´,
G.; Knight, H.; Honty, K.; Sza´ntay, C. Liebigs Ann. Chem. 1986, 655-
663. (h) Martin, S. F.; Ru¨eger, H.; Williamson, S. A.; Grzejszczak, S. J.
Am. Chem. Soc. 1987, 109, 6124-6134. (i) Hirai, Y.; Terada, T.; Okaji,
Y.; Yamazaki, T.; Momose, T. Tetrahedron Lett. 1990, 31, 4755-4756.
(j) Aube´, J.; Ghosh, S.; Tanol, M. J. Am. Chem. Soc. 1994, 116, 9009-
9018.
approach relies on the generation of the DE-ring system,
followed by cyclization to form the C ring (2 f 1). This
strategy has been effective; however, control of the C(3)
stereogenic center has presented significant difficulties. A
second approach involves formation of the tetrahydro-
(4) For general reviews of synthetic approaches toward yohimbine
alkaloids, see refs 1a-c. See also: Kuehne, M. E.; Muth, R. S. J. Org.
Chem. 1991, 56, 2701-2712.
10.1021/ol702781q CCC: $40.75
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lack of general methods for preparation of enantioenriched
tetrahydro-â-carbolines (rings A-C). We have recently re-
ported a thiourea-catalyzed asymmetric acyl-Pictet-Spengler
reaction for the enantioselective synthesis of such ring
systems.5-7 A further challenge lies in the diastereoselective
formation of the D and E rings. An intramolecular Diels-
Alder (IMDA) reaction appears ideally suited to address this
challenge, and several indole alkaloids have been prepared
through such an approach.8,9 Herein we report an analysis
of the requisite IMDA reaction for the synthesis of yohim-
bine, and a concise, completely stereocontrolled synthesis
of 1 that relies on a successful Pictet-Spengler/IMDA
strategy.
withdrawing groups and Lewis acids has been shown to
increase selectivity for the trans (i.e., endo) isomer.10 Despite
the extensive body of knowledge about the stereoselectivity
of the IMDA reaction,11,12 the system of interest in our study
represents a challenging case: the planar AB ring system
and the nitrogen atom at the C-D ring fusion lead to
distortions from well-defined chair cyclohexane conforma-
tions of the C and D rings. Given that the stereochemical
outcome in the cyclization of 4 represented a key and open
question in this plan, we turned to computational methods
both to better understand the accessible conformations of
IMDA substrates and to guide our efforts to develop
stereoselective variants.
Our synthetic plan relied on the generation of a chiral
building block such as 4 or 5 via the acyl-Pictet-Spengler
reaction, which establishes the absolute configuration at C(3)
(Scheme 2). Construction of the DE-ring system, and the
Computations were performed using model substrates 4a
and 5 (P ) H, P′ ) Me) for both at the B3LYP/6-311+G-
(d,p)//B3LYP/6-31G(d) level of density functional theory.13,14
Diels-Alder reactions with substrate 4a are asynchronous,
and the transition structures (TSs) have C(15)-C(20) bond
lengths of ∼2.0 Å and C(16)-C(17) bond lengths of ∼2.7
Å (Figure 1). TSs in which the incipient D-ring adopts a
Scheme 2. Retrosynthetic Analysis
remaining four stereocenters present in yohimbine, was then
envisioned via an IMDA reaction (4 or 5 f 1). IMDA
reactions using simple 1,6,8-nonatriene and 1,7,9-decatriene
derivatives often display poor trans/cis selectivity across the
ring fusion, but activation of the dienophile with electron-
Figure 1. Relative energies of IMDA transition structures 8a-f
calculated for model substrate 4a. TSs 8c and 8d lead to a
cycloadduct with the relative configuration of 1.
(5) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
10558-10559. (b) Raheem, I. T.; Thiara, P. V.; Peterson, E. A.; Jacobsen,
E. N. J. Am. Chem. Soc. 2007, 129, 13404-13405. For other approaches
to asymmetric catalysis of the Pictet-Spengler reaction, see: (c) Seayad,
J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086-1087. (d)
Wanner, M. J.; van der Haas, R. N. S.; de Cuba, K. R.; van Maarseveen,
J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2007, 46, 7485-7487.
(6) For a total synthesis of (+)-harmicine using a catalytic asymmetric
Pictet-Spengler-type cyclization, see ref 5b.
(7) For asymmetric allylations of dihydro- â-carbolines using stoichio-
metric allylating reagents, see: (a) Wu, T. R.; Chong, J. M. J. Am. Chem.
Soc. 2006, 128, 9646-9746. (b) Nakamura, M.; Hirai, A.; Nakamura, E. J.
Am. Chem. Soc. 1996, 118, 8489-8490.
(8) (a) Yamaguchi, R.; Otsuji, A.; Utimoto, K. J. Am. Chem. Soc. 1988,
110, 2186-2187. (b) Meyers, A. I.; Highsmith, T. K.; Buonora, P. T. J.
Org. Chem. 1991, 56, 2960-2964. (c) Martin, S. F.; Benage, B.; Geraci,
L. S.; Hunter, J. E.; Mortimore, M. J. Am. Chem. Soc. 1991, 113, 6161-
6171.
(9) For other synthetic approaches to yohimbine, yohimbane, and
isoquinoline alkaolids that use IMDA reactions, see: (a) Leonard, J.;
Appleton, D.; Fearnley, S. P. Tetrahedron Lett. 1994, 35, 1071-1074. (b)
Sparks, S. M.; Gutierrez, A. J.; Shea, K. J. J. Org. Chem. 2003, 68, 5274-
5285. For a synthetic and theoretical study of IMDA reactions of various
azanona- and azadecatrienes, see (c) Tsirk, A.; Gronowitz, S.; Ho¨rnfeldt,
A.-B. Tetrahedron 1998, 54, 9529-9558.
chairlike conformation (8a-8e) are favored over boatlike
TSs (8f), and there is a significant preference for an
equatorial, rather than an axial, orientation of the substituent
at C3 (compare 8a and 8e). Thus, the dienophile facial
(10) For an example, see: Roush, W. R.; Essenfeld, A. P.; Warmus, J.
S. Tetrahedron Lett. 1987, 28, 2447-2450.
(11) For leading references to theoretical studies on IMDA reactions,
see: (a) Pearson, E. L.; Kwan, L. C. H.; Turner, C. I.; Jones, G. A.; Willis,
A. C.; Paddon-Row, M. N.; Sherburn, M. S. J. Org. Chem. 2006, 71, 6099-
6109. (b) Raimondi, L.; Brown, F. K.; Gonzalez, J.; Houk, K. N. J. Am.
Chem. Soc. 1992, 114, 4796-4804.
(12) For reviews on stereochemical aspects of IMDA reactions, see: (a)
Craig, D. Chem. Soc. ReV. 1987, 16, 167-238. (b) Roush, W. R. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, U. K., 1991; Vol.5, pp 513-550. For a review of IMDA reactions
in natural products synthesis, see: (c) Takao, K.; Munakata, R.; Tadano,
K. Chem. ReV. 2005, 105, 4779-4807.
746
Org. Lett., Vol. 10, No. 5, 2008

selectivity is expected to be high, leading to the C(3)-C(15)
cis stereoisomer. The calculations also indicate a preference
for an equatorial orientation of the substituent at N(4) with
respect to the forming D ring (8a and 8c vs 8b and 8d).
However, there is negligible endo/exo selectivity predicted
for TSs with an equatorial N(4) substituent (8a vs 8c). In
contrast, a significant preference for the endo pathway is
predicted among TSs with an axial N(4) substituent (compare
8b and 8d).
The synthesis began with the preparation of N-acetyl
tetrahydro-â-carboline 6 via the acyl-Pictet-Spengler
reaction.5a Condensation of tryptamine (9) with aldehyde
10,18 and treatment of the resulting imine 7 with acetyl
chloride and 2,6-lutidine in the presence of thiourea catalyst
11 (10 mol %) afforded 6 in 81% yield and 94% ee on gram
scale. Deacetylation of the amide was then accomplished by
treatment of 6 with lithium amidotrihydroborate,19 providing
enantioenriched tetrahydro â-carboline 12 in 74% yield.
The C(17)-C(21) diene side-chain was then installed in
one step via a reductive amination. Thus, treatment of 12
with aldehyde 13,20 HOBz, and NaBH3CN in benzene
afforded amine 14 in 55% yield. Protection of the indole
nitrogen by treatment of 14 with Cbz-Cl and KHMDS
afforded the corresponding N-Cbz indole in 92% yield.
Subsequent removal of the TBDPS group with TBAF gave
the corresponding alcohol in 85% yield.21 Oxidation of this
alcohol with SO3‚pyridine22 and treatment of the resulting
aldehyde with Ph3PdCHCO2Me provided IMDA substrate
4b in 79% yield over the two steps.
In contrast, computations of the IMDA reaction of model
substrate 5 predict a modest preference for boatlike rather
than chairlike TSs (Figure 2), leading to cycloadducts with
The IMDA reaction of triene 4b promoted by 4 equiv of
Sc(OTf)3 in CH3CN proceeded with unexpectedly high
selectivity, affording the cycloadduct 15 as a single diaste-
reomer in 87% yield. The relative configuration of 15 at C(3),
C(15), and C(20) is consistent with reaction through a cis,
endo TS analogous to 8c or 8d (Figure 1). Removal of both
the N-Cbz and C(17)-OBz protecting groups was then
accomplished by exposure to Cs2CO3 in MeOH/THF, giving
the corresponding alcohol in 80% yield. Finally, hydrogena-
tion of the C(18)-C(19) olefin yielded (+)-yohimbine (1)
in quantitative yield. Synthetic (+)-1 was identified by
Figure 2. Lowest energy IMDA transition structures using model
substrate 5.
C(3)-C(15) trans configuration. Endo TSs, which generate
a trans ring fusion, are significantly preferred over exo TSs
(see Supporting Information), presumably due to a preference
for the amide diene to adopt a C(20)-C(21) s-cis conforma-
tion.15 These calculations are consistent with experimental
results reported previously with related substrates.8,16
Despite the poor diastereoselectivity predicted for the
thermal cyclization of 4a (Figure 1, TSs 8a vs 8c), we
decided to investigate substrates akin to 4 for the synthesis
of (+)-yohimbine. The C(3) stereogenic center could be set
via a catalytic asymmetric acyl-Pictet-Spengler condensa-
tion, and this would in turn serve to set the configuration at
C(15) via TS 8a or 8c in the IMDA reaction. Control over
the C(20) stereocenter depends on the endo/exo selectivity
in the IMDA reaction, and we reasoned that this might in
principle be achieved by a chiral catalyst.17
1
comparison to a sample of natural (+)-1 by H NMR, 13C
NMR, and IR spectroscopy, as well as by high-resolution
MS and optical rotation.
Although the high C(3)-C(15) cis selectivity of the IMDA
reaction could be anticipated, the high endo/exo selectivity
was not predicted from our computations. The high dr is
not entirely attributable to the presence of a Lewis acid, as
thermally induced cyclization of 4b (70 °C, benzene)
provided a 6:1 mixture of endo/exo cyclodducts (∆∆Gq )
1.2 kcal/mol). Interestingly, N-unprotected analogues (i.e.,
N-H indoles) were found to undergo poorly selective
thermally induced cyclization (2-3:1 endo/exo selectivity
at 23 °C, ∆∆Gq ) 0.4-0.6 kcal/mol). To better understand
the role of the indole protecting group in enhancing diaste-
(13) B3LYP has been shown to reproduce experimentally observed
kinetic isotope effects in Diels-Alder reactions, suggesting that this method
yields accurate TS geometries: (a) Beno, B. R.; Houk, K. N.; Singleton,
D. A. J. Am. Chem. Soc. 1996, 118, 9984-9985. Although B3LYP usually
yields accurate endo/exo and dienophile facial selectivities, the MP2 method
has been suggested to be more accurate for calculating endo/exo selectivities
in some cases: (b) Bakalova, S. M.; Santos, A. G. J. Org. Chem. 2004, 69,
8475-8481. However, MP2 Diels-Alder TS geometries have been shown
to be significantly distorted from B3LYP TS geometries. Using substrate
4a, MP2 predicts dienophile facial selectivities that are inconsistent with
experiment, whereas B3LYP predicts a significant preference for the
experimentally observed isomer (Vide infra). A comparison of results using
B3LYP and MP2 with various basis sets is provided in the Supporting
Information.
(14) Calculations were carried out using Gaussian 98: Frisch, M. J.; et.
al. Gaussian 98; Gaussian, Inc.: Pittsburgh, PA, 2002.
(15) For discussions of conformational requirements of carbonyl dienes
in IMDA reactions, see: (a) Boeckman, R. K.; Demko, D. M. J. Org. Chem.
1982, 47, 1789-1792. (b) Martin, S. F.; Williamson, S. A.; Gist, R. P.;
Smith, K. M. J. Org. Chem. 1983, 48, 5170-5180.
(17) For previous efforts from this laboratory directed toward natural
product synthesis employing catalyst-controlled diastereoselective Diels-
Alder reactions, see: (a) Joly, G. D.; Jacobsen, E. N. Org. Lett. 2002, 4,
1795-1798. (b) Chavez, D. E.; Jacobsen, E. N. Org. Lett. 2003, 5, 2563-
2565. (c) Boezio, A. A.; Jarvo, E. R.; Lawrence, B. M.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2005, 44, 6046-6050. (d) Balskus, E. P.; Jacobsen,
E. N. Science 2007, 317, 1736-1740.
(18) Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc.
2002, 124, 11102-11113.
(19) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D.
J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511. A modified
version of the reported procedure was used. See the Supporting Information
for details.
(20) Becher, J. Org. Synth. 1980, 59, 79-83.
(16) For other discussions of boatlike transition structures in IMDA
reactions, see: (a) Coe, J. W.; Roush, W. R. J. Org. Chem. 1989, 54, 915-
930. (b) Tantillo, D. J.; Houk, K. N.; Jung, M. E. J. Org. Chem. 2001, 66,
1938-1940.
(21) Trifluoroethanol was used as solvent for this transformation to
suppress transfer of the N-carbobenzyloxy group to the liberated alcohol.
(22) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-
5507.
Org. Lett., Vol. 10, No. 5, 2008
747

Scheme 3. Total Synthesis of (+)-Yohimbine
reoselectivity, we applied DFT methods to model substrate
the C(3)-C(15) side chain (red arrow, Figure 3). Although
it is likely that the relative distribution of TSs 16a-d will
be further influenced by the structure of the indole and C(17)
protecting groups and by solvent and Lewis acid,24 the data
in Figures 1 and 3 suggest a basis for the observed high
diastereoselectivity in the IMDA reaction.
4c (P ) CO2Me, P′ ) Me) to help characterize IMDA TSs.
Comparison of computed TSs 16a-16d with 8a-8d
reveals a plausible explanation for moderately enhanced
endo/exo selectivities with protected indole substrates (Figure
3). TSs with equatorial N(4) substituents with respect to the
We have developed a concise and stereoselective synthesis
of (+)-yohimbine (1) that features an enantioselective acyl-
Pictet-Spengler reaction, a reductive amination to install the
diene side chain, and an exceptionally diastereoselective
IMDA reaction (see Scheme 3). The brevity and efficiency
of this synthesis (11 steps, 14% overall yield) highlights the
utility of enantioenriched tetrahydro-â-carboline building
blocks now readily accessible via asymmetric catalysis.
Alternative stereochemical outcomes to IMDA reactions of
aza-decatrienes related to 4 and 5 could lead to efficient
routes to both natural and unnatural congeners of the
yohimbane alkaloid family.25
Acknowledgment. This work was supported by the NIH
(GM-59316) and by fellowship support to SJZ from the ACS
and Roche.
Supporting Information Available: Complete experi-
mental procedures, characterization data, H NMR spectra
for all isolated products, geometries and energies of calcu-
lated TSs, and complete ref 14. This material is available
free of charge via the Internet at http.//pubs.acs.org.
Figure 3. Relative energies of IMDA transition structures 16a-d
calculated for model substrate 4c. TSs 16c and 16d lead to a
cycloadduct with the relative configuration of 1.
1
incipient D ring display a small preference for endo TS 16c
compared with exo TS 16a. In addition, TSs with axial N(4)
substituents are accessible, and N(4)-axial, endo TS 16d
is substantially more stable than N(4)-axial, exo TS 16b.
The carbamate CdO of the protecting group displays a
strong preference to be coplanar with the aromatic ring of
the indole (blue arrow, Figure 3),23 leading to repulsive
nonbonding interactions between the protecting group and
OL702781Q
(24) Quantitative understanding of the role of the Lewis acid represents
a particularly complex problem. The requirement for a large excess of
Sc(OTf)3 raises the possibility that multiple equivalents bind to the substrate,
and indeed 4b contains four Lewis basic sites. The most Lewis basic site
is the tertiary amine; whereas binding to this site should not substantially
affect the IMDA activation energy, it will likely lead to a reduced preference
for TS 16a compared with 16b-d, because the pseudo-axial conformation
of C(19) blocks binding of large Lewis acids. The relative energies of TSs
16a-d with BH3 bound to the tertiary amine are: 16a‚BH3: 10.0 kcal/
mol; 16b‚BH3: 3.8; 16c‚BH3: 3.6; 16d‚BH3: 0.0.
(23) The energetic cost of rotating the carbamate CdO out of the indole
aromatic plane is ca. 10 kcal/mol. See the Supporting Information for details.
(25) Reserpine, for example, shares the same pentacyclic core as
yohimbine but is epimeric at the 3, 16, and 20 positions.
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Org. Lett., Vol. 10, No. 5, 2008