Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

Article abstract of DOI:10.3762/bjoc.10.261

Pd-catalyzed enantioselective alkylation in conjunction with further synthetic elaboration enables the formal total syntheses of a number of "classic" natural product target molecules. This publication highlights recent methods for setting quaternary and tetrasubstituted tertiary carbon stereocenters to address the synthetic hurdles encountered over many decades across multiple compound classes spanning carbohydrate derivatives, terpenes, and alkaloids. These enantioselective methods will impact both academic and industrial settings, where the synthesis of stereogenic quaternary carbons is a continuing challenge.

Full text of DOI:10.3762/bjoc.10.261

Formal total syntheses of classic natural product target
molecules via palladium-catalyzed enantioselective alkylation
Yiyang Liu, Marc Liniger, Ryan M. McFadden, Jenny L. Roizen, Jacquie Malette,
Corey M. Reeves, Douglas C. Behenna, Masaki Seto, Jimin Kim, Justin T. Mohr,
Scott C. Virgil and Brian M. Stoltz*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 2501–2512.
Warren and Katharine Schlinger Laboratory of Chemistry and
Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, 1200 E. California
Boulevard, Pasadena, CA, USA
doi:10.3762/bjoc.10.261
Received: 11 August 2014
Accepted: 09 October 2014
Published: 28 October 2014
Email:
Brian M. Stoltz* - stoltz@caltech.edu
Associate Editor: S. Bräse
* Corresponding author
© 2014 Liu et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
enantioselective alkylation; natural products; palladium
Abstract
Pd-catalyzed enantioselective alkylation in conjunction with further synthetic elaboration enables the formal total syntheses of a
number of “classic” natural product target molecules. This publication highlights recent methods for setting quaternary and tetra-
substituted tertiary carbon stereocenters to address the synthetic hurdles encountered over many decades across multiple compound
classes spanning carbohydrate derivatives, terpenes, and alkaloids. These enantioselective methods will impact both academic and
industrial settings, where the synthesis of stereogenic quaternary carbons is a continuing challenge.
Introduction
Catalytic enantioselective allylic alkylation has emerged as a carissone [9], cassiol [10], chamigrenes [11], and liphagal [12].
powerful method for the construction of building blocks bearing Other labs have also utilized our method in natural product total
quaternary carbon and fully substituted tertiary centers [1,2]. A synthesis [13,14]. Often, it is the case that a new technology
recent addition developed by our laboratory is the allylic alkyl- that allows the synthesis of building blocks will open up new
ation of nonstabilized enolate precursors to form α-quaternary avenues to complex structures of long standing interest [15,16].
carbonyl compounds (Scheme 1) [3]. Once the key stereocenter Herein we detail the application of this asymmetric chemistry in
is set by this chemistry, further elaboration allows access to formal total syntheses of “classic” natural product targets
many bioactive small molecules. In our lab alone, this palla- across a range of compound families by strategic selection of
dium-catalyzed alkylation has enabled the enantioselective total allylic alkylation substrates and subsequent product transforma-
syntheses of dichroanone [4], elatol [5], cyanthiwigins [6-8], tions.
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contiguous all-carbon quaternary centers, two of which are
stereogenic. Being a hydrocarbon, (−)-thujopsene (10) has few
natural handles for retrosynthetic analysis. Inspired by the
complexity of this relatively small natural product, several total
syntheses of racemic 10 have been reported [25-29] along with
at least two enantioselective routes [30-32].
One enantiospecific total synthesis of (+)-thujopsene (10) by
Srikrishna and Anebouselvy began with (R)-carvone (11)
(Scheme 2) [33]. During the total synthesis, the authors
prepared carboxylic acid (+)-12 over a 14-step sequence. We
planned to intercept the antipode of (+)-12 using the palladium-
catalyzed enantioselective alkylation chemistry described
above.
Scheme 1: Three classes of Pd-catalyzed enantioselective allylic
alkylations.
Results and Discussion
A) Thujopsene
The Japanese hiba tree, Thujopsis dolabrata has been used for
centuries as decoration and within traditional architecture [17].
The plant is a member of the order Cupressaceae, and its
fragrant wood oil contains numerous sesquiterpenes including
mayurone (8) [18,19], widdrol (9) [20], and (−)-thujopsene (10)
(Figure 1) [21,22]. The wood oil is a potent dust mite deterrent;
thus, in addition to its ornamental value, the hiba tree also
Scheme 2: Srikrishna and Anebouselvy’s approach to (+)-thujopsene.
provides and environmentally benign means of pest control We commenced a formal total synthesis of (−)-thujopsene (10)
[23,24].
with the goal of improved efficiency compared to the Srikr-
ishna/Anebouselvy route and to use enantioselective palladium
catalysis to install the initial stereocenters (Scheme 3). Treat-
ment of 16 with LiHMDS in THF, followed by allyl chlorofor-
mate, furnished the known carbonate 17 in high yield [34]. This
substrate smoothly undergoes palladium-catalyzed enantiose-
lective decarboxylative allylation in the presence of (S)-t-Bu-
PHOX (5), giving allyl ketone (−)-18 in 94% yield and 91% ee
[34]. Treatment of the ketone (−)-18 with MeMgBr at 23 ºC
provided a mixture of two diastereomeric alcohols 19A and 19B
in 94% yield. Without separation, the diastereomers were
Figure 1: Selected natural products from Thujopsis dolabrata.
(−)-Thujopsene (10) has attractive features to the synthetic rapidly carried through a three-step sequence of hydroboration/
chemist. Its tricyclo[5.4.0.01,3]undecane skeleton contains three oxidation, terminal alcohol silylation, and tertiary alcohol dehy-
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Scheme 3: Formal total synthesis of (−)-thujopsene.
dration, affording methylene cyclohexane (−)-20. Treatment of
this silyl ether with Jones reagent simultaneously cleaved the
silyl group and oxidized the resulting alcohol, furnishing
carboxylic acid (−)-12 in 65% yield. With this enantioenriched
acid in hand, the formal total synthesis of (−)-thujopsene (10) is
completed in only 9 steps from trimethylcyclohexanone 16.
B) Quinic acid
(−)-Quinic acid (21) [35,36] serves as a useful chiral building
block that has been employed in numerous syntheses [37],
including our own syntheses of (+)- and (−)-dragmacidin F [38-
41], and the initial commercial-scale synthesis of Tamiflu [42].
In Renaud’s formal total synthesis of (−)-quinic acid (21) [35],
a key carboxylic acid 22 was accessed, intercepting Novak’s
older synthesis of the natural product (Scheme 4) [36]. To
begin, Renaud transformed the chiral glycolic acid ketal 23
Scheme 4: Renaud’s formal total synthesis of (−)-quinic acid.
(enantioenriched to 80% ee) to the more elaborate diene 24 via enabled alkylation via a metalloenamine. On acidic work-up,
two diastereoselective alkylations. After a sequence of three imine hydrolysis furnished an alkylated dioxanone in good
reactions including removal of the pinacolone portion of the yield. The targeted silyl enol ether 26 was prepared by thermo-
auxiliary, carboxylic acid 22 could be accessed. Novak’s syn- dynamic silylation in 66% yield [43]. Optimal conversions and
thesis applied a bromolactonization of 22 to build in the requi- enantioselectivities were achieved from triethylsilyl enol ether
site syn relationship between the carboxylate group and the 26 on exposure to [Pd(dmdba)2] (5 mol %), (S)-t-BuPHOX (5,
3-hydroxy group, ultimately leading to quinic acid.
5.5 mol %), and diallyl carbonate (1.05 equiv) at 25 °C, in
PhMe with an equivalent of Bu4NPh3SiF2 (TBAT) [43]. Recog-
Unlike the allylic alkylations in Scheme 1, which form all- nizing that enantioenriched α,ω-dienes could be transformed
carbon stereocenters, we envisioned a unique modification of into cycloalkenes with a stereocenter remote to the olefin [44],
the silyl enol ether version to access nonracemic tertiary alco- chiral diene 27 was submitted to ring closing metathesis to
hols (Scheme 5) [43]. The planned modification would involve generate 28 in 90% yield and 92% ee [43]. Cyclohexene 28
the use of dioxanone-derived substrates instead of the prototyp- readily undergoes acetonide cleavage and periodic acid oxi-
ical cycloalkanone-derived ones. To demonstrate this new tech- dation to provide carboxylic acid (S)-22 [43], completing the
nology in the context of formal total synthesis, we chose to formal synthesis of (−)-quinic acid (21). Additionally, one could
intercept the acid 22 in the Renaud and Novak routes to quinic in principle also access the less commercially abundant
acid (21). Conversion of dioxanone 25 to a cyclohexylimine antipode (+)-quinic acid (21) using the catalyst (R)-t-Bu-PHOX.
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Scheme 5: Formal total synthesis of (−)-quinic acid.
C) Dysidiolide
Dysidiolide (29, Scheme 6) was isolated from the marine
sponge Dysidea etheria and found to have inhibitory activity
toward protein phosphatase cdc25, with an IC50 value of
9.4 µM [45]. This enzyme is a member of the protein family re-
sponsible for dephosphorylation of cyclin-dependent kinases
[46]. Thus, inhibitors of cdc25 might allow for targeted cell-
cycle disruption [45]. The relative stereochemistry of
dysidiolide (29) was determined via single-crystal X-ray
diffraction analysis, revealing a molecule with six stereocenters,
two of which are quaternary carbons [45]. Several groups have
reported total syntheses of this natural product [47-53], three of
which are enantioselective [54-56].
In Danishefsky’s approach to racemic dysidiolide, the cyclo-
hexene ring of 30 was installed via diastereoselective
Diels–Alder reaction of a transient dioxolenium dienophile and
chiral vinylcyclohexene 31 [48]. Triene 31 was prepared from
α-quaternary ketone (±)-32 in racemic form. We anticipated the
interception of (−)-32 [57] in Danishefsky’s route using
enantioselective palladium-catalyzed allylic alkylation to set the
quaternary stereocenter.
Scheme 6: Danishefsky’s approach to (±)-dysidiolide.
in EtOAc to furnish diketone 35 [34]. Chemoselective Wittig
mono-olefination of 35 provided ω-enone (−)-32, spectroscopi-
The formal total synthesis of (−)-dysidiolide (29) commenced cally identical to the material in Danishefsky’s racemic syn-
with known allyl β-ketoester 4 (Scheme 7), which was thesis. This formal synthesis shows the power of the enantiose-
converted to 2-allyl-2-methylcyclohexanone (2) in 85% yield lective allylic alkylation to access formerly racemic constructs
and 88% ee [58] with a catalytic amount of [Pd2(dba)3] and (S)- as single enantiomers; Danishefsky’s synthesis is now rendered
t-BuPHOX (5, Scheme 1). The allyl ketone was enriched to enantioselective.
98% ee via recrystallization of semicarbazone 33 [59]. Using
the Grubbs 2nd generation metathesis catalyst, allyl ketone (−)-2 D) Aspidospermine
was crossed with methyl vinyl ketone in 62% yield [34]. Reduc- The aspidosperma alkaloids have garnered much attention as
tion of enone 34 was achieved in the presence of Pd/C with H2 beautiful targets for the synthetic chemist. Most of the 250-plus
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Scheme 7: Formal total synthesis of (−)-dysidiolide.
compounds in this class share a pentacyclic core, from the clin-
ical anticancer therapeutics vincristine and vinblastine to the
simpler aspidospermidine [60]. To address the challenging syn-
thetic features of the aspidosperma alkaloids, many clever syn-
thetic approaches have been reported [61,62]. One popular
target in this family is aspidospermine (36, Scheme 8).
Although its medicinal potency is inferior to other members of
the class, this alkaloid has served as a proving ground for many
synthetic chemists.
In 1989, Meyers reported an enantioselective synthesis of the
(4aS,8aR,8S)-hydrolilolidone core 37 [63,64] present in aspi-
dospermine (36), and thus a formal total synthesis of the alka-
loid itself, intercepting Stork’s classic route [61]. One precursor
described in the core synthesis is enone 38, which bears the
quaternary stereocenter of the natural product. Contrasting
Scheme 8: Meyers’ approach to unnatural (+)-aspidospermine.
Meyers’ approach, which employed a chiral auxiliary as part of promotion (Scheme 9) [65]. The β-ketoester 42 was prepared
39, we thought a catalytic enantioselective alkylation strategy using a two-step sequence of acylation and alkylation, then
would be ideal for a formal total synthesis of natural (−)-aspi- treated with the (S)-t-Bu-PHOX catalyst system (with
dospermine (36) via the antipode of 38.
[Pd(dmdba)2]) to generate (+)-43 in 86% ee. The challenge of
installing the γ-stereocenter of the target 38 was addressed as
The formal synthesis began with 1,3-cyclohexanedione (40), follows: LiAlH4 treatment of (+)-43 gave exclusive 1,2-reduc-
which was converted to isobutyl vinylogous ether 41 under acid tion. When the crude product was hydrolyzed, β-elimination
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Scheme 9: Formal total synthesis of (−)-aspidospermine.
gave the desired enone 38. The overall formal synthesis repre-
sents a rare example of enantioselective Stork–Danheiser chem-
istry [66,67].
E) Rhazinilam
(−)-Rhazinilam (44) has been isolated from various plants
including Rhazya strica decaisne [68], Melodinus australis
[69], and Kopsia singapurensis [70]. Shortly after the first isola-
tion, its structure was elucidated by single crystal X-ray diffrac-
tion analysis [71]. It features a tetracyclic scaffold with a nine-
membered ring and an all-carbon quaternary stereocenter. This
alkaloid is a microtubule-disrupting agent that displays similar
cellular effects to paclitaxel [72,73]. Because of its biological
activities and potential pharmaceutical use, many groups have
pursued its total synthesis [74-77], including a number of
enantioselective syntheses [78-82].
Scheme 10: Magnus’ approach to (±)-rhazinilam.
In 2001, Magnus reported a total synthesis of rhazinilam in Magnus’ route. This formal synthesis demonstrates the utility of
racemic form (Scheme 10) [83]. In their approach, the first our recently developed asymmetric lactam alkylation chemistry.
retrosynthetic disconnection of the amide C–N bond in the nine-
membered ring led to tricyclic compound 45. The pyrrole ring F) Quebrachamine
of 45 was formed by intramolecular condensation of cinnamyl Quebrachamine (51) is an indole alkaloid isolated from the
amide 46, which is prepared via union of quaternary piperidi- Aspidosperma quebracho tree bark [60]. It has been found to
none 47 and cinnamyl electrophile 48. We envisioned that our possess adrenergic blocking activities for a variety of urogen-
allylic alkylation of lactam enolates would furnish enantioen- ital tissues [85]. Structurally, it features a tetracycle including
riched piperidinone 47, and thus a single enantiomer of an indole nucleus, a 9-membered macrocycle, and an all-carbon
rhazinilam may be prepared.
quaternary stereocenter. Due to its structural complexity and
biological activities, quebrachamine has received considerable
The formal synthesis of (+)-rhazinilam commenced with palla- attention from the chemistry community. A number of total
dium-catalyzed decarboxylative allylic alkylation of known syntheses have been reported [86-88], with several examples of
carboxy-lactam 49 to afford benzoyl-protected piperidinone 50 asymmetric syntheses [89-91].
in 97% yield and 99% ee (Scheme 11) [84]. Cleavage of the
benzoyl group under basic conditions furnished piperidinone In 2007, Amat reported an enantioselective total synthesis of
(+)-47 [84], which can be advanced to (+)-rhazinilam via quebrachamine (Scheme 12) [92]. In their planning, disconnec-
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Scheme 11: Formal total synthesis of (+)-rhazinilam.
tion at the macrocycle led to amide 52, which was prepared
from 3,3-disubstituted piperidine 53. The all-carbon quaternary
stereocenter in 53 was installed by double alkylation of lactam
55, using an auxiliary to control the stereoselectivity. We envi-
sioned that an alternative way of constructing this motif would
again make use of our recently developed palladium-catalyzed
asymmetric alkylation of lactam enolates.
Scheme 13: Formal total synthesis of (+)-quebrachamine.
furnished N-boc piperidine-alcohol (+)-53 [84], thus inter-
cepting an intermediate in Amat’s synthesis of quebrachamine.
G) Vincadifformine
Vincadifformine (59) was isolated in both enantioenriched and
Scheme 12: Amat’s approach to (−)-quebrachamine.
racemic forms from the leaves and roots of Rhazya stricta in
The formal synthesis of (+)-quebrachamine commenced with 1963 [93]. Not only is it a representative member of the Aspi-
benzoyl lactam 50 (Scheme 13), which was prepared in excel- dosperma alkaloid family, but it also holds particular signifi-
lent yield and ee by alkylation of carboxy-lactam 49 (see cance as a valuable precursor to pharmaceutically important
Scheme 11) [84]. Oxidative cleavage of the terminal double vincamine, vincamone, and cavinton [94-97]. The molecule has
bond and subsequent reduction with LiAlH4 afforded a fused pentacyclic framework with three contiguous stereocen-
N-benzylpiperidine-alcohol 56 [84]. Hydrogenolysis of the ters, two of which are all-carbon quaternary centers. The medic-
N-benzyl group and re-protection with di-tert-butyl dicarbonate inal relevance and structural complexity of vincadifformine
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have led to a large number of total syntheses [98-104],
including several enantioselective examples [105-108].
Recently, Pandey reported a highly efficient synthesis of (+)-
vincadifformine (Scheme 14) [106]. The key step in the syn-
thesis was an iminium ion cascade reaction that formed the
fused ring systems by coupling 3,3-disubstituted tetrahydropyri-
dine 57 with indole derivative 58. The former coupling partner
was derived from chiral α-quaternary lactam 60, which was
constructed using a chiral auxiliary strategy. We envisioned that
chiral lactam 60 could again be readily accessed by our palla-
dium-catalyzed enantioselective alkylation chemistry.
The formal synthesis of (−)-vincadifformine commenced with
ruthenium-catalyzed isomerization of the terminal olefin moiety
in unprotected piperidinone (+)-47 (made previously in the
formal synthesis of (+)-rhazinilam shown in Scheme 11) to
produce internal olefin 63 (Scheme 15) [109]. Ozonolysis of the
double bond furnished aldehyde 64, which was reduced under
Luche conditions to alcohol 65, a compound identical in struc-
ture and enantiomeric to the intermediate employed by Pandey
in the synthesis of (+)-vincadifformine.
Conclusion
The development of a series of Pd-catalyzed methods for
constructing stereogenic quaternary carbons has provided two
generations of building blocks (Scheme 16). The described
derivatization enabled the formal total syntheses of an array of
Scheme 15: Formal total synthesis of (−)-vincadifformine.
classic natural products including sugar derivatives, terpenes, enantiomer of this important substance. We have also inter-
and alkaloids, adding significantly to the growing list of uses cepted a key intermediate in Danishefsky’s synthesis of (±)-
for this powerful C–C bond construction. An efficient route to dysidiolide (29), rendering the former racemic route enantiose-
the sesquiterpenoid (−)-thujopsene (10) has been delineated, lective. Additionally, a rapid approach to a compound in
allowing access to the compound’s natural antipode. Our lab’s Meyers’ formal synthesis of (+)-aspidospermine (36) granted
novel approach to (−)-quinic acid (21) allowed access to either access to the natural product without the use of a chiral auxil-
Scheme 14: Pandey’s approach to (+)-vincadifformine.
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Scheme 16: Two generations of building blocks.
iary. Finally, we have demonstrated the application of lactam thank the Caltech Minorities Undergraduate Research Fellow-
alkylation products in the catalytic asymmetric syntheses of (+)- ship program, PREM program, Eli Lilly, the Resnick Sustain-
rhazinilam (44), (+)-quebrachamine (51), and (−)-vincadif- ability Institute at Caltech (fellowship for Y. L.), and the Swiss
formine (59). The powerful catalytic enantioselective allylic National Science Foundation (SNSF, fellowship for M. L.). Dr.
alkylation will undoubtedly enable new synthetic endeavors in Michael L. Krout and Dr. David E. White are acknowledged for
the context of both academic and industrial research.
preliminary experimental work related to their results. Dr.
Michael Takase (Caltech) and Larry Henling (Caltech) are
gratefully acknowledged for X-ray crystallographic structural
determination.
Supporting Information
Supporting information features experimental procedures,
characterization data of synthesized compounds, copies of
1H and 13C NMR spectra, and single crystal structure data.
References
1. Trost, B. M.; Jiang, C. Synthesis 2006, 369–396.
doi:10.1055/s-2006-926302
2. Mohr, J. T.; Stoltz, B. M. Chem. – Asian J. 2007, 2, 1476–1491.
doi:10.1002/asia.200700183
Supporting Information File 1
Experimental data, NMR spectra and X-ray data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-261-S1.pdf]
3. Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marinescu, S. C.;
Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novák, Z.; Krout, M. R.;
McFadden, R. M.; Roizen, J. L.; Enquist, J. A., Jr.; White, D. E.;
Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M.
Chem. – Eur. J. 2011, 17, 14199–14223.
doi:10.1002/chem.201003383
Acknowledgements
We are grateful to NIH (R01GM080269), Amgen, the Gordon
4. McFadden, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128,
7738–7739. doi:10.1021/ja061853f
and Betty Moore Foundation, and Caltech for funding. We also
2509

Beilstein J. Org. Chem. 2014, 10, 2501–2512.
5. White, D. E.; Stewart, I. C.; Grubbs, R. H.; Stoltz, B. M.
J. Am. Chem. Soc. 2008, 130, 810–811. doi:10.1021/ja710294k
6. Enquist, J. A., Jr.; Stoltz, B. M. Nature 2008, 453, 1228–1231.
doi:10.1038/nature07046
34. Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126,
15044–15045. doi:10.1021/ja044812x
35. Rapado, L. P.; Bulugahapitiya, V.; Renaud, P. Helv. Chim. Acta 2000,
83, 1625–1632.
7. Enquist, J. A., Jr.; Virgil, S. C.; Stoltz, B. M. Chem. – Eur. J. 2011, 17,
9957–9969. doi:10.1002/chem.201100425
doi:10.1002/1522-2675(20000705)83:7<1625::AID-HLCA1625>3.0.C
O;2-W
8. Enquist, J. A., Jr.; Stoltz, B. M. Nat. Prod. Rep. 2009, 26, 661–680.
doi:10.1039/B811227B
36. Wolinsky, J.; Novak, R.; Vasilev, R. J. Org. Chem. 1964, 29,
3596–3598. doi:10.1021/jo01035a038
9. Levine, S. R.; Krout, M. R.; Stoltz, B. M. Org. Lett. 2009, 11, 289–292.
doi:10.1021/ol802409h
37. Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini, G. P.;
Zanirato, V. Tetrahedron: Asymmetry 1997, 8, 3515–3545.
doi:10.1016/S0957-4166(97)00471-0
10. Petrova, K. V.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2009, 11, 293–295.
doi:10.1021/ol802410t
38. Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126,
9552–9553. doi:10.1021/ja046695b
11. White, D. E.; Stewart, I. C.; Seashore-Ludlow, B. A.; Grubbs, R. H.;
Stoltz, B. M. Tetrahedron 2010, 66, 4668–4686.
doi:10.1016/j.tet.2010.04.128
39. Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127,
5970–5978. doi:10.1021/ja050586v
12. Day, J. J.; McFadden, R. M.; Virgil, S. C.; Kolding, H.; Alleva, J. L.;
Stoltz, B. M. Angew. Chem., Int. Ed. 2011, 50, 6814–6818.
doi:10.1002/anie.201101842
40. Garg, N. K.; Stoltz, B. M. Chem. Commun. 2006, 3769–3779.
doi:10.1039/B605929E
41. Garg, N. K.; Caspi, D. D.; Stoltz, B. M. Synlett 2006, 3081–3087.
doi:10.1055/s-2006-951492
13. Wei, Y.; Zhao, D.; Ma, D. Angew. Chem., Int. Ed. 2013, 52,
12988–12991. doi:10.1002/anie.201307788
42. Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.;
Chapman, H. H.; Kelly, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.;
Prisbe, E. J.; Schultze, L. M.; Yu, R. H.; Zhang, L. J. Org. Chem.
1998, 63, 4545–4550. doi:10.1021/jo980330q
14. Xu, Z.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2013, 135,
19127–19130. doi:10.1021/ja4115192
15. Hu, Q.-Y.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126,
13708–13713. doi:10.1021/ja046154m
43. Seto, M.; Roizen, J. L.; Stoltz, B. M. Angew. Chem., Int. Ed. 2008, 47,
6873–6876. doi:10.1002/anie.200801424
16. Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A., III;
Sharpless, K. B.; Walker, F. J. Science 1983, 220, 949–951.
doi:10.1126/science.220.4600.949
44. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956. doi:10.1021/ol990909q
17. Inamori, Y.; Morita, Y.; Sakagami, Y.; Okabe, T.; Ishida, N.
Biocontrol Sci. 2006, 11, 49–54. doi:10.4265/bio.11.49
18. Chetty, G. L.; Dev, S. Tetrahedron Lett. 1965, 6, 3773–3776.
doi:10.1016/S0040-4039(01)99562-0
45. Gunasekera, S. P.; McCarthy, P. J.; Kelly-Borges, M.
J. Am. Chem. Soc. 1996, 118, 8759–8760. doi:10.1021/ja961961+
46. Millar, J. B. A.; Russel, P. Cell 1992, 68, 407–410.
doi:10.1016/0092-8674(92)90177-E
19. Itô, S.; Endo, K.; Honma, H.; Ota, K. Tetrahedron Lett. 1965, 6,
3777–3781. doi:10.1016/S0040-4039(01)99563-2
20. Oh, I.; Yang, W.-Y.; Park, J.; Lee, S.; Mar, W.; Oh, K.-B.; Shin, J.
Arch. Pharmacal Res. 2011, 34, 2141–2147.
47. Boukouvalas, J.; Cheng, Y.-X.; Robichaud, J. J. Org. Chem. 1998, 63,
228–229. doi:10.1021/jo972208h
48. Magnuson, S. R.; Sepp-Lorenzino, L.; Rosen, N.; Danishefsky, S. J.
J. Am. Chem. Soc. 1998, 120, 1615–1616. doi:10.1021/ja9740428
49. Miyaoka, H.; Kajiwara, Y.; Yamada, Y. Tetrahedron Lett. 2000, 41,
911–914. doi:10.1016/S0040-4039(99)02175-9
doi:10.1007/s12272-011-1218-5
21. Yano, M. J. Soc. Chem. Ind., Jpn. 1913, 16, 443–463.
22. Uchida, S. J. Soc. Chem. Ind., Jpn. 1928, 31, 501–503.
23. Miyazaki, Y. Mokuzai Gakkaishi 1996, 42, 624–626.
24. Hiramatsu, Y.; Miyazaki, Y. J. Wood Sci. 2001, 47, 13–17.
doi:10.1007/BF00776639
50. Takahashi, M.; Dodo, K.; Hashimoto, Y.; Shirai, R. Tetrahedron Lett.
2000, 41, 2111–2114. doi:10.1016/S0040-4039(00)00078-2
51. Paczkowski, R.; Maichle-Mössmer, C.; Maier, M. E. Org. Lett. 2000, 2,
3967–3969. doi:10.1021/ol006742e
25. Dauben, W. G.; Ashcraft, A. C. J. Am. Chem. Soc. 1963, 85,
3673–3676. doi:10.1021/ja00905a032
52. Miyaoka, H.; Yamada, Y. Bull. Chem. Soc. Jpn. 2002, 75, 203–222.
doi:10.1246/bcsj.75.203
26. Büchi, G.; White, J. D. J. Am. Chem. Soc. 1964, 86, 2884–2887.
doi:10.1021/ja01068a024
53. Demeke, D.; Forsyth, C. J. Tetrahedron 2002, 58, 6531–6544.
doi:10.1016/S0040-4020(02)00663-4
27. Mori, K.; Ohki, M.; Kobayashi, A.; Matsui, M. Tetrahedron 1970, 26,
2815–2819. doi:10.1016/S0040-4020(01)92857-1
28. McMurry, J. E.; Blaszczak, L. C. J. Org. Chem. 1974, 39, 2217–2222.
doi:10.1021/jo00929a017
54. Corey, E. J.; Roberts, B. E. J. Am. Chem. Soc. 1997, 119,
12425–12431. doi:10.1021/ja973023v
55. Miyaoka, H.; Kajiwara, Y.; Hara, Y.; Yamada, Y. J. Org. Chem. 2001,
66, 1429–1435. doi:10.1021/jo0015772
29. Branca, S. J.; Lock, R. L.; Smith, A. B., III. J. Org. Chem. 1977, 42,
3165–3168. doi:10.1021/jo00439a012
56. Jung, M. E.; Nishimura, N. Org. Lett. 2001, 3, 2113–2115.
doi:10.1021/ol016073k
30. Johnson, C. R.; Barbachyn, M. R. J. Am. Chem. Soc. 1982, 104,
4290–4291. doi:10.1021/ja00379a060
57. Das, P. P.; Lysenko, I. L.; Cha, J. K. Angew. Chem., Int. Ed. 2011, 50,
9459–9461. doi:10.1002/anie.201104331
31. Lee, E.; Shin, I.-J.; Kim, T.-S. J. Am. Chem. Soc. 1990, 112, 260–264.
doi:10.1021/ja00157a041
58. Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2005, 44, 6924–6927.
32. Zhang, C. X.; Fang, L. J.; Bi, F. Q.; Li, Y. L. Chin. Chem. Lett. 2008,
19, 256–258. doi:10.1016/j.cclet.2008.01.009
doi:10.1002/anie.200502018
59. Mohr, J. T.; Krout, M. R.; Stoltz, B. M. Org. Synth. 2009, 86, 194–211.
60. Saxton, J. E. Alkaloids of the Aspidospermine Group. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, 1998; Vol.
51, pp 2–198.
33. Srikrishna, A.; Anebouselvy, K. J. Org. Chem. 2001, 66, 7102–7106.
doi:10.1021/jo0105484
2510

Beilstein J. Org. Chem. 2014, 10, 2501–2512.
61. Stork, G.; Dolfini, J. E. J. Am. Chem. Soc. 1963, 85, 2872–2873.
doi:10.1021/ja00901a061
86. Coldham, I.; Burrell, A. J. M.; White, L. E.; Adams, H.; Oram, N.
Angew. Chem., Int. Ed. 2007, 46, 6159–6162.
doi:10.1002/anie.200701943
62. Ban, Y.; Sato, Y.; Inoue, I.; Nagai, M.; Oishi, T.; Terashima, M.;
Yonematsu, O.; Kanaoka, Y. Tetrahedron Lett. 1965, 6, 2261–2268.
doi:10.1016/S0040-4039(00)70368-6
87. Bajtos, B.; Pagenkopf, B. L. Eur. J. Org. Chem. 2009, 1072–1077.
doi:10.1002/ejoc.200801154
63. Meyers, A. I.; Berney, D. J. Org. Chem. 1989, 54, 4673–4676.
doi:10.1021/jo00280a040
88. Hsu, S.-W.; Cheng, H.-Y.; Huang, A.-C.; Ho, T.-L.; Hou, D.-R.
Eur. J. Org. Chem. 2014, 3109–3115. doi:10.1002/ejoc.201400064
89. Temme, O.; Taj, S.-A.; Andersson, P. G. J. Org. Chem. 1998, 63,
6007–6015. doi:10.1021/jo9807417
64. Lawton, G.; Saxton, J. E.; Smith, A. J. Tetrahedron 1977, 33,
1641–1653. doi:10.1016/0040-4020(77)80177-4
65. Spessard, S. J.; Stoltz, B. M. Org. Lett. 2002, 4, 1943–1946.
doi:10.1021/ol025968+
90. Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H. J. Am. Chem. Soc.
2002, 124, 4628–4641. doi:10.1021/ja017863s
91. Sattely, E. S.; Meek, S. J.; Malcolmson, S. J.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 943–953.
doi:10.1021/ja8084934
66. Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775–1776.
doi:10.1021/jo00949a048
67. Bennett, N. B.; Hong, A. Y.; Harned, A. M.; Stoltz, B. M.
Org. Biomol. Chem. 2012, 10, 56–59. doi:10.1039/C1OB06189E
68. Banerji, A.; Majumder, P. L.; Chatterjee, A. G. Phytochemistry 1970,
9, 1491–1493. doi:10.1016/S0031-9422(00)85265-6
69. Linde, H. H. A. Helv. Chim. Acta 1965, 48, 1822–1842.
doi:10.1002/hlca.19650480803
92. Amat, M.; Lozano, O.; Escolano, C.; Molins, E.; Bosch, J.
J. Org. Chem. 2007, 72, 4431–4439. doi:10.1021/jo070397q
93. Smith, G. F.; Wahid, M. A. J. Chem. Soc. 1963, 4002–4004.
doi:10.1039/JR9630004002
94. Szántay, C. Pure Appl. Chem. 1990, 62, 1299–1302.
doi:10.1351/pac199062071299
70. Thoison, O.; Guénard, D.; Sévenet, T.; Kan-Fan, C.; Quirion, J.-C.;
Husson, H. P.; Deverre, J.-R.; Chan, K. C.; Potier, P. C. R.
Acad. Sci. Paris II 1987, 304, 157–160.
95. Danieli, B.; Lesma, G.; Palmisano, G.; Gabetta, B.
J. Chem. Soc., Chem. Commun. 1981, 908–909.
doi:10.1039/C39810000908
71. Abraham, D. J.; Rosenstein, R. D.; Lyon, R. L.; Fong, H. H. S.
Tetrahedron Lett. 1972, 13, 909–912.
96. Sápi, J.; Szabó, L.; Baitz-Gács, E.; Kalaus, G.; Szántay, C.
Tetrahedron 1988, 44, 4619–4629.
doi:10.1016/S0040-4039(01)84471-3
72. Alazard, J.-P.; Millet-Paillusson, C.; Boyé, O.; Guénard, D.;
Chiaroni, A.; Riche, C.; Thal, C. Bioorg. Med. Chem. Lett. 1991, 1,
725–728. doi:10.1016/S0960-894X(01)81056-8
doi:10.1016/S0040-4020(01)86164-0
97. Calabi, L.; Danieli, B.; Lesma, G.; Palmisano, G.
J. Chem. Soc., Perkin Trans. 1 1982, 1371–1379.
doi:10.1039/P19820001371
73. Edler, M. C.; Yang, G.; Jung, M. K.; Bai, R.; Bornmann, W. G.;
Hamel, E. Arch. Biochem. Biophys. 2009, 487, 98–104.
doi:10.1016/j.abb.2009.05.014
98. Kutney, J. P.; Chan, K. K.; Failli, A.; Fromson, J. M.; Gletsos, C.;
Nelson, V. R. J. Am. Chem. Soc. 1968, 90, 3891–3893.
doi:10.1021/ja01016a069
74. Kholod, I.; Vallat, O.; Buciumas, A.-M.; Neier, R. Heterocycles 2011,
82, 917–948. doi:10.3987/REV-10-SR(E)2
99. Laronze, P. J.-Y.; Laronze-Fontaine, J.; Lévy, J.; Le Men, J.
Tetrahedron Lett. 1974, 15, 491–494.
See for a review.
75. Ratcliffe, A. H.; Smith, G. F.; Smith, G. N. Tetrahedron Lett. 1973, 14,
5179–5184. doi:10.1016/S0040-4039(01)87657-7
76. Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2000, 122, 6321–6322.
doi:10.1021/ja0003223
doi:10.1016/S0040-4039(01)82252-8
100.Kuehne, M. E.; Roland, D. M.; Hafter, R. J. Org. Chem. 1978, 43,
3705–3710. doi:10.1021/jo00413a015
101.Barsi, M.-C.; Das, B. C.; Fourrey, J.-L.; Sundaramoorthi, R.
J. Chem. Soc., Chem. Commun. 1985, 88–89.
doi:10.1039/C39850000088
77. Bowie, A. L., Jr.; Hughes, C. C.; Trauner, D. Org. Lett. 2005, 7,
5207–5209. doi:10.1021/ol052033v
78. Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124,
6900–6903. doi:10.1021/ja026130k
102.Yoshida, K.; Nomura, S.; Ban, Y. Tetrahedron 1985, 41, 5495–5501.
doi:10.1016/S0040-4020(01)91349-3
79. Banwell, M. G.; Beck, D. A. S.; Willis, A. C. ARKIVOC 2006, No. 3,
163–174.
103.Kalaus, G.; Greiner, I.; Kajtár-Peredy, M.; Brlik, J.; Szabó, L.;
Szántay, C. J. Org. Chem. 1993, 58, 1434–1442.
doi:10.1021/jo00058a025
80. Liu, Z.; Wasmuth, A. S.; Nelson, S. G. J. Am. Chem. Soc. 2006, 128,
10352–10353. doi:10.1021/ja0629110
104.Kobayashi, S.; Peng, G.; Fukuyama, T. Tetrahedron Lett. 1999, 40,
1519–1522. doi:10.1016/S0040-4039(98)02667-7
105.Kuehne, M. E.; Podhorez, D. E. J. Org. Chem. 1985, 50, 924–929.
doi:10.1021/jo00207a002
81. Gu, Z.; Zakarian, A. Org. Lett. 2010, 12, 4224–4227.
doi:10.1021/ol101523z
82. Sugimoto, K.; Toyoshima, K.; Nonaka, S.; Kotaki, K.; Ueda, H.;
Tokuyama, H. Angew. Chem., Int. Ed. 2013, 52, 7168–7171.
doi:10.1002/anie.201303067
106.Pandey, G.; Kumara, P. C. Org. Lett. 2011, 13, 4672–4675.
doi:10.1021/ol201892j
83. Magnus, P.; Rainey, T. Tetrahedron 2001, 57, 8647–8651.
doi:10.1016/S0040-4020(01)00859-6
107.Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C.
Nature 2011, 475, 183–188. doi:10.1038/nature10232
108.Zhao, S.; Andrade, R. B. J. Am. Chem. Soc. 2013, 135,
13334–13337. doi:10.1021/ja408114u
84. Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.;
Stoltz, B. M. Nat. Chem. 2012, 4, 130–133. doi:10.1038/nchem.1222
85. Deutsch, H. F.; Evenson, M. A.; Drescher, P.; Sparwasser, C.;
Madsen, P. O. J. Pharm. Biomed. Anal. 1994, 12, 1283–1287.
doi:10.1016/0731-7085(94)00066-2
109.Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A.
Angew. Chem., Int. Ed. 2002, 41, 4732–4734.
doi:10.1002/anie.200290031
2511

Beilstein J. Org. Chem. 2014, 10, 2501–2512.
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