Highly functionalized donor-acceptor cyclopropanes applied toward the synthesis of the Melodinus alkaloids

Article abstract of DOI:10.1016/j.tetlet.2014.09.016

Abstract A series of highly substituted vinylcyclopropanes were prepared and examined as reaction partners in a palladium-catalyzed (3+2) cycloaddition with nitrostyrenes. Described herein are our efforts to synthesize an elusive 1,1-divinylcyclopropane by several distinct approaches, and to apply surrogates of this fragment toward the synthesis of the Melodinus alkaloids.

Full text of DOI:10.1016/j.tetlet.2014.09.016

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly functionalized donor–acceptor cyclopropanes applied toward
the synthesis of the Melodinus alkaloids
⇑
Alexander F. G. Goldberg, Robert A. Craig II , Nicholas R. O’Connor , Brian M. Stoltz
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology,
1200 E California Boulevard, MC 101-20, Pasadena, CA 91125, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of highly substituted vinylcyclopropanes were prepared and examined as reaction partners in a
palladium-catalyzed (3+2) cycloaddition with nitrostyrenes. Described herein are our efforts to synthe-
size an elusive 1,1-divinylcyclopropane by several distinct approaches, and to apply surrogates of this
fragment toward the synthesis of the Melodinus alkaloids.
Received 14 August 2014
Revised 28 August 2014
Accepted 3 September 2014
Available online xxxx
Ó 2014 Elsevier Ltd. All rights reserved.
Dedicated to Professor Harry H. Wasserman
(1920–2013); a dear friend and mentor
Keywords:
Cycloaddition
Cyclopropanes
Stereoselective synthesis
Melodinus alkaloids
Claisen rearrangement
The Melodinus alkaloids are a class of dihydroquinolinone
natural products related to the Aspidosperma alkaloids through
an oxidative rearrangement of dehydrotabersonine (1,
Scheme 1).1,2 Despite their lack of known biological activity,3,4
the structural complexity of the Melodinus alkaloids and the pros-
pects of preparing non-natural derivatives for biological evaluation
were both extremely appealing to our lab.
acid oxidation state. Accordingly, after disconnection of the E ring
via benzylic C–H insertion, we envisioned that the D and B rings of
7 could be formed by substrate-controlled diastereoselective ring-
closing metathesis and lactamization steps of divinylcyclopentane
8 (Scheme 2). This intermediate could arise, in turn, from nitrocycl-
opentane 9, the product of a transition metal catalyzed, intermo-
lecular formal (3+2) cycloaddition between a trans-b-nitrostyrene
(10) and divinylcyclopropane 11.10
At the outset of our synthetic efforts, we examined several
possible approaches toward the synthesis of the desired divinylcy-
clopropane (11, Scheme 3). The geminal vinyl groups could poten-
tially be installed through substitution of 1,1-dihalocyclopropane
12,11 itself generated from a dihalocarbene 13 and methylidene
dimethylmalonate (14).12 Alternatively, the two vinyl groups could
be formed by elimination from cyclopropane 15, derived from the
reaction of olefin 17 with a malonate-derived carbenoid (16).
Finally, we envisioned utilizing an SN20 displacement of alkylidene
cyclopropane 18 with a vinyl nucleophile. This cyclopropane could
be synthesized from allene 19.
In the case of (+)-scandine (3),1 (+)-meloscandonine (4),5 and
others,6 three of the four contiguous stereocenters on the charac-
teristic central cyclopentane ring are quaternary. To date, the only
members of the family to have been synthesized are meloscine (5)
and epimeloscine (6), both of which possess only two quaternary
stereocenters on the central C ring.7–9 It is hypothesized that (+)-
scandine (3) is the biosynthetic precursor to the other Melodinus
alkaloids.2 Thus, we began to pursue the synthesis of scandine
(3), which could allow access to the related dihydroquinolinone
natural products.
In planning a concise synthesis, we chose to exploit elements of
symmetry found within the target natural product. In particular,
the quaternary stereocenter at C(20) bears two olefinic substitu-
ents, and C(16) bears two carbon substituents in the carboxylic
We first examined the use of a 1,1-dihalocyclopropane (e.g., 12)
toward divinylcyclopropane 11 (Pathway A, Scheme 3). The syn-
thesis and reactions of these building blocks have been extensively
researched.12 1,1-Dihalocyclopropanes are known to react with
dialkyl cuprates,13 trialkyl zincates,14 manganates,15 or magne-
sates16 to yield alkylated cyclopropyl metals, which can react with
⇑
Corresponding author. Tel.: +1 (626)395 6064; fax: +1 (626)564 9297.
E-mail address: stoltz@caltech.edu (B.M. Stoltz).
These authors contributed equally.
http://dx.doi.org/10.1016/j.tetlet.2014.09.016
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Goldberg, A. F. G.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.016

2
A. F. G. Goldberg et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Scheme 1. Proposed biosynthesis of the Melodinus alkaloids.
Scheme 2. Retrosynthetic analysis of scandine (3).
Scheme 3. Retrosynthetic analyses of cyclopropane 11.
an electrophile to deliver products with geminal substitution. Fur-
thermore, the cyclopropyl metal intermediates can be used in
metal-catalyzed cross-coupling reactions with vinyl halides to
deliver vinylcyclopropanes.15
Due to the highly reactive nature of methylidene dimethylmal-
onate (14),17 we sought to first examine the vinylation of
gem-dihalocyclopropanes using a reduced substrate. Accordingly,
acrylate derivative 20 was prepared by a known procedure and
protected as a silyl ether (21, Scheme 4).18 Olefin 21 was then
cyclopropanated using phase-transfer catalysis to afford gem-dib-
romocyclopropane 22.
Unfortunately, efforts to directly vinylate cyclopropane 22
failed (Scheme 5). A Stille coupling with tetravinyltin was unsuc-
cessful, as was the palladium-catalyzed cross coupling of the
in situ-generated organomanganate with vinyl bromide.15b An
attempt at a bis-alkynylation using Sonogashira coupling was also
Please cite this article in press as: Goldberg, A. F. G.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.016

A.F.G. Goldberg et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Scheme 4. Synthesis of reduced gem-dihalocyclopropane 22.
under acidic conditions,21 however, one hydroxyl group under-
went an undesired lactonization to give bicyclic lactone 33. This
product was mesylated and eliminated to yield vinylcyclopropane
35. Although an interesting structure, we were not able to advance
lactone 35 to divinylcyclopropane diester 11.
Finally, we examined
a route to the divinylcyclopropane
through SN20 displacement of a substituted alkylidenecyclopropane
(Pathway C, Scheme 3). De Meijere and coworkers have demon-
strated that vinylcyclopropanes and methylenecyclopropanes with
allylic leaving groups will react under palladium catalysis to form a
common palladium allyl intermediate, which can then be
alkylated.22
We sought to prepare an analogous alkylidenecyclopropane
bearing the necessary methyl ester functionalities. Beginning with
the known homoallenyl acetate 36,23 we screened cyclopropana-
tion conditions using diazodimethylmalonate (29), examining sev-
eral catalysts, carbenoid precursor equivalents, and addition times
(Scheme 8). On our first attempt (entry 1), we were able to isolate
the desired alkylidenecyclopropane (37) in 42% yield, although an
excess of allene 36 was required. While using an excess of the
diazo compound lowered the yield (entry 2), increasing the
catalyst loading and the equivalents of the diazo improved the
yield to 58% (entry 3). Increasing or decreasing the slow addition
rate of the diazo reagent had a detrimental effect on the yield
(entries 4 and 5). Changing the catalyst to the electron-poor trifluo-
roacetate complex resulted in a mixture of products (entry 6), and
use of the electron-rich caprolactamate complex gave low conver-
sion of the starting material (entry 7). Microwave heating of a neat
mixture of the reaction components (entry 8) afforded consider-
ably shortened reaction times, however, the yield was not
improved. Finally, the use of Du Bois’ catalyst (Rh2(esp)2) gave
the highest isolated yield (80% yield, entry 9), with a short reaction
time, low catalyst loading, and no need for syringe-pump addition
of the diazodimethylmalonate.24
Scheme 5. Efforts to substitute dibromocyclopropane 22.
unfruitful. Since no desired substitution products were observed
with this substrate, we did not pursue this route further and we
shifted our focus to an alternative approach.
We turned our attention toward the formation of the desired
vinyl groups by elimination of two leaving groups (Pathway B,
Scheme 3). In this vein, we set out to prepare dimesylate 30 as a
divinylcyclopropane precursor (Scheme 6). Baylis–Hillman reac-
tion of methyl vinyl ketone (25) with acetaldehyde by a known
procedure furnished adduct 26 which was then reduced to afford
diol 27 as a mixture of diastereomers.19 Although this substrate
underwent mesylation cleanly, the product (28) was unstable as
a neat oil, and underwent spontaneous, rapid decomposition.20
Furthermore, when a solution of the dimesylate in dichlorometh-
ane was subjected directly to cyclopropanation with diazodimeth-
ylmalonate, a complex reaction mixture was observed and no
desired cyclopropane product (30) could be isolated.
With the desired alkylidenecyclopropane 37 in hand, we
examined an array of allylic substitution conditions with vinyl
nucleophiles, including those reported by de Meijere,22 as well as
other catalytic systems with vinyl alanes and cuprates (Scheme 9).
Unfortunately, in all cases, none of the desired divinylcyclopropane
11 was observed, and only ring-opened products were
obtained.25,26 It is possible that the diester functionality serves to
To avoid problems of substrate stability, we opted to protect
diol 27 as a disilyl ether (31, Scheme 7). This substrate was cyclo-
propanated efficiently using Du Bois’ catalyst to give cyclopropane
32, which was immediately subjected to alcohol deprotection
Scheme 6. Synthetic approach to elimination substrate 30.
Please cite this article in press as: Goldberg, A. F. G.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.016

4
A. F. G. Goldberg et al. / Tetrahedron Letters xxx (2014) xxx–xxx
At this stage, we considered that the use of a Claisen rearrange-
ment might offer an alternative pathway to install the desired qua-
ternary carbon on the cyclopropane (Scheme 11a).28 The use of
Claisen rearrangements to install vicinal quaternary centers is well
precedented.29 Furthermore, the relief of ring-strain (i.e., from
alkylidenecyclopropane to cyclopropane) was predicted to aid
the efficiency of the C–C bond formation. However, we envisioned
potential chemoselectivity and side-reactivity problems in the con-
version of Claisen product 40 to the desired divinylcyclopropane
(11). Particularly, conditions would be necessary that could reduce
the product carbonyl in the presence of the methyl esters and pre-
vent concomitant lactonization.
Accordingly, we turned to the Eschenmoser–Claisen reaction,
since numerous examples exist in the literature for chemoselec-
tive reduction of amides in the presence of esters,30 and the
resulting tertiary amines (42) would not be expected to react
with the pendent ester functionalities and can be converted to
olefins by means of the Cope31 or Hofmann32 elimination
(Scheme 11b).
Scheme 7. Vinylcyclopropane synthesis via diol 27.
We therefore treated alcohol 38 under typical reaction condi-
tions with dimethylacetamide dimethyl acetal, and observed the
formation of amide 43 in moderate yield (Scheme 12).33 The main
side product of the reaction was conjugated amide 44, likely
formed by base-promoted ring opening of the desired product,
and extensive screening of reaction temperatures and times could
not improve the yield of the desired vinylcyclopropane 43. Amide
43 was reduced with alane to dimethylamine 45 in 36% yield.
Efforts to eliminate the amine (45) to form the desired divinylcy-
clopropane (11) have been unsuccessful to date. Fortunately, our
efforts to this point provided three unique vinylcyclopropanes
(35, 43, and 45) which we could examine in the palladium-cata-
lyzed (3+2) reaction.
With three highly functionalized vinylcyclopropanes in hand,
we set out to determine their compatibility with palladium-
catalyzed (3+2) cycloaddition conditions originally developed
by Tsuji.10 Under an array of conditions, no cyclopentane
products could be isolated (Scheme 13). In the case of dimeth-
ylamide substituted cyclopropane 43, the starting material was
isomerized in high yield to conjugated amide 44 as a mixture
of olefin isomers. Dimethylamine analog 45 and bicyclic
vinylcyclopropane 35 showed no reactivity, even at elevated
temperatures.
The isomerization of dimethylamide 43 is attributed to the
presence of acidic protons on the substrate: upon formation of
the palladium(II) allyl species (48), the pendant malonate acts as
a base, eliminating Pd(0) via deprotonation to give conjugated
amide 44 (Scheme 14).
Scheme 8. Cyclopropanation of homoallenyl acetate 36.
weaken the distal bond of the methylenecyclopropane, favoring
ring-opening rather than substitution.27 We did find, however, that
we could smoothly remove the acetate protecting group through a
two-step procedure from homoallenyl acetate 36 to furnish
primary allylic alcohol 38 in 94% yield (Scheme 10).
As for vinylcyclopropanes 35 and 45, we propose that the lack
of reactivity results from the demanding allylation step of the cat-
alytic cycle (Scheme 15). Although soft nucleophiles generally
attack the less substituted terminus of a palladium
p-allyl frag-
ment through an outer sphere mechanism, in the case of an unsub-
stituted vinylcyclopropane (i.e., 49, R = H), conformational effects
in the ring closure presumably override this innate selectivity,
resulting in addition of the nucleophile to the more highly substi-
tuted internal position34 of the allyl fragment. However, in the case
of our substituted vinylcyclopropanes (i.e., R – H), the steric
demand is possibly too high to form the desired cyclopentane
product (50) under these conditions.
Scheme 9. Attempted vinylation of diester cyclopropane 37.
In the course of our studies, Curran and Zhang completed the
total syntheses of ( )-meloscine (5), ( )-epimeloscine (6), and sev-
eral unnatural analogs by a route similar to our own original strat-
egy (Scheme 16).7d,i They were able to construct necessary
divinylcyclopropane 55 through a tandem oxidation-Wittig meth-
ylenation sequence from cyclopropane 53. After coupling of acid 55
with aniline 57, the core tetracycle 59 was formed via an intramo-
Scheme 10. Synthesis of primary allylic alcohol 38.
Please cite this article in press as: Goldberg, A. F. G.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.016

A.F.G. Goldberg et al. / Tetrahedron Letters xxx (2014) xxx–xxx
5
Scheme 11. Proposed Claisen rearrangement routes.
Scheme 12. Eschenmoser-Claisen rearrangement of 38.
Scheme 13. Palladium-catalyzed (3+2) cycloaddition attempts.
Scheme 14. Mechanistic rationale for the formation of amide 44.
lecular radical-mediated cycloaddition and quickly advanced to
epimeloscine (6) and meloscine (5). Scandine (3), the parent of
the natural product family, was not accessed via this route but
the similarity of their approach to our own original pathway, as
well as the challenges we faced in effecting a transition metal cat-
alyzed intermolecular (3+2) cycloaddition encouraged us to modify
our synthetic plan.
Scheme 15. Rationale for the lack of desired reactivity of highly substituted
vinylcyclopropanes.
Please cite this article in press as: Goldberg, A. F. G.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.016

6
A. F. G. Goldberg et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Scheme 16. Total syntheses of epimeloscine and meloscine by Curran and Zhang.7d
Scheme 17. Revised retrosynthetic analysis.
The primary revision to our retrosynthesis involves using a
less, after reductive amination, acetylation, and ring-closing
metathesis, we were able to access the tetracyclic ABCD ring sys-
tem of the Melodinus alkaloids (72) in only six steps from commer-
cial sources.
monovinylcyclopropane (63) in the palladium-catalyzed (3+2)
cycloaddition, and appending the second vinyl group at a later
stage by C–H functionalization (Scheme 17).
In 2011, we disclosed our progress toward scandine, using the
palladium-catalyzed intermolecular (3+2) cycloaddition strategy
as planned in our revised retrosynthesis (Scheme 18).35 We were
able to synthesize monovinylcyclopropane 63 from dimethylmalo-
nate (64) and dibromide 65 via a known procedure.36 The subse-
quent palladium-catalyzed (3+2) cycloaddition of cyclopropane
63 and nitrostyrene 47 proceeded smoothly. Tandem reduction
and lactamization provided tricycle 67 as a 2:1 mixture of diaste-
reomers at C(20) in favor of the undesired stereoisomer. Neverthe-
In summary, efforts to synthesize and apply a 1,1-divinylcyclo-
propane toward the total synthesis of scandine are described. Fur-
thermore, we have applied a monovinylcyclopropane toward the
preparation of a tetracyclic precursor to scandine via a palla-
dium-catalyzed (3+2) cycloaddition. The remaining challenges to
overcome in the synthesis include E ring closure by benzylic C–H
insertion and installation of the C(20) vinyl group. Finally, the
derivatization of scandine to other members of the natural product
family will be examined.
Please cite this article in press as: Goldberg, A. F. G.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.016

A.F.G. Goldberg et al. / Tetrahedron Letters xxx (2014) xxx–xxx
7
Scheme 18. Assembly of the ABCD ring system.
9. Efforts towards the synthesis of Melodinus alkaloids have been reported: (a)
Schultz, A. G.; Dai, M. Tetrahedron Lett. 1999, 40, 645–648; (b) Denmark, S. E.;
Cottell, J. J. Adv. Synth. Catal. 2006, 348, 2397–2402.
Acknowledgments
The authors wish to thank NIH-NIGMS (R01GM080269-01),
Amgen, and Caltech for financial support. A.F.G.G. thanks the Nat-
ural Sciences and Engineering Research Council (NSERC) of Canada
for a PGS D scholarship. R.A.C. gratefully acknowledges the support
of this work provided by a fellowship from the National Cancer
Institute of the National Institutes of Health under Award Number
F31CA174359.
10. (a) Shimizu, I.; Ohashi, Y.; Tsuji, J. Tetrahedron Lett. 1985, 26, 3825–3828; (b)
Dieskau, A. P.; Holzwarth, M. S.; Plietker, B. J. Am. Chem. Soc. 2012, 134, 5048–
5051; (c) Trost, B. M.; Morris, P. J. Angew. Chem. Int. Ed. 2011, 50, 6167–6170;
(d) Trost, B. M.; Morris, P. J.; Sprague, S. J. J. Am. Chem. Soc. 2012, 134, 17823–
17831; (e) Mei, L.-y.; Wei, Y.; Xu, Q.; Shi, M. Organometallics 2012, 31, 7591–
7599; Selected recent reviews on the use of cyclopropanes in synthesis: (f)
Schneider, T. F.; Kaschel, J.; Werz, D. B. Angew. Chem. Int. Ed. 2014, 53, 5504–
5523; (g) Jiao, L.; Yu, Z.-X. J. Org. Chem. 2013, 78, 6842–6848; (h) Tang, P.; Qin,
Y. Synthesis 2012, 2969–2984; (i) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009,
36, 3051–3060; (j) De Simone, F.; Waser, J. Synthesis 2009, 3353–3374; (k)
Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117–3179; (l)
Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151–1196.
Supplementary data
11. Mathias, R.; Weyerstahl, P. Chem. Ber. 1979, 112, 3041–3053.
12. Fedoryn´ ski, M. Chem. Rev. 2003, 103, 1099–1132.
13. (a) Glick, H. C.; Likhotvorik, I. R.; Jones, M., Jr. Tetrahedron Lett. 1995, 36, 5715–
5718; (b) Thamattoor, D. M.; Jones, M., Jr.; Pan, W.; Shevlin, P. B. Tetrahedron
Lett. 1996, 37, 8333–8336; (c) Thamattoor, D. M.; Snoonian, J. R.; Sulzbach, H.
M.; Hadad, C. M. J. Org. Chem. 1999, 64, 5886–5895.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.09.
016.
14. Harada, T.; Katsuhira, T.; Hattori, K.; Oku, A. J. Org. Chem. 1993, 58, 2958–2965.
15. (a) Inoue, R.; Shinokubo, H.; Oshima, K. Tetrahedron Lett. 1996, 37, 5377–5380;
(b) Kakiya, H.; Inoue, R.; Shinokubo, H.; Oshima, K. Tetrahedron 2000, 56, 2131–
2137.
16. Inoue, A.; Kondo, J.; Shinokubo, H.; Oshima, K. Chem. Eur. J. 2002, 8, 1730–1740.
17. De Keyser, J.-L.; De Cock, C. J. C.; Poupaert, J. H.; Dumont, P. J. Org. Chem. 1988,
53, 4859–4862.
References and notes
1. (a) Bernauer, K.; Englert, G.; Vetter, W. Experientia 1965, 21, 374–375; (b)
Bernauer, K.; Englert, G.; Vetter, W.; Weiss, E. Helv. Chim. Acta 1969, 52, 1886–
1905; (c) Cannon, J. R.; Croft, K. D.; Matsuki, Y.; Patrick, V. A.; Toia, R. F.; White,
A. H. Aust. J. Chem. 1982, 35, 1655–1664.
2. Szabó, L. F. ARKIVOC 2007, vii, 280–290.
18. Villieras, J.; Rambaud, M. Synthesis 1982, 924–926.
3. Some species of the Melodinus genus are used in Chinese folk medicine to treat
rheumatic disease and childhood meningitis, see: Guo, L.-W.; Zhou, Y.-L.
Phytochemistry 1993, 34, 563–566.
4. Bach and coworkers propose that the lack of biological activity may be
attributed ‘to the fact that the incorporated lactam moiety strongly impairs with
the passage of melodan structures through biological membranes’. See Ref. 7h
5. (a) Plat, M.; Hachem-Mehri, M.; Koch, M.; Scheidegger, U.; Potier, P.
Tetrahedron Lett. 1970, 11, 3395–3398; (b) Rodier, N.; Mauguen, Y.; Hachem-
Mehri, M.; Plat, M. Acta Crystallogr. 1978, B34, 232–237.
19. König, C. M.; Harms, K.; Koert, U. Org. Lett. 2007, 9, 4777–4779.
20. Although the mesylate appeared to be stable in solution, upon removal of
solvent in vacuo, the clear oil was observed (after 15–30 min under high-
vacuum) to exotherm and effervesce vigorously, quickly becoming a black tar.
21. Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc. 2004, 126,
15378–15379.
22. Stolle, A.; Ollivier, J.; Piras, P. P.; Salaün, J.; de Meijere, A. J. Am. Chem. Soc. 1992,
114, 4051–4067.
23. (a) Qi, L.; Meijler, M. M.; Lee, S.-H.; Sun, C.; Janda, K. D. Org. Lett. 2004, 6, 1673–
1675; (b) Molander, G. A.; Cormier, E. P. J. Org. Chem. 2005, 70, 2622–2626.
24. González-Bobes, F.; Fenster, M. D. B.; Kiau, S.; Kolla, L.; Kolotuchin, S.;
Soumeillant, M. Adv. Synth. Catal. 2008, 350, 813–816.
6. Daudon, M.; Hachem Mehri, M.; Plat, M. M.; Hagaman, E. W.; Wenkert, E. J. Org.
Chem. 1976, 41, 3275–3278. and references therein.
7. Four racemic syntheses (a/b, c, d, e/f) and one enantioselective synthesis (g/h) of
meloscine (5) have been reported to date, as have several syntheses of unnatural
meloscine analogs: (a) Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Org.
Chem. 1989, 54, 1236–1238; (b) Overman, L. E.; Robertson, G. M.; Robichaud, A.
J. J. Am. Chem. Soc. 1991, 113, 2598–2610; (c) Hayashi, Y.; Inagaki, F.; Mukai, C.
Org. Lett. 2011, 13, 1778–1780; (d) Zhang, H.; Curran, D. P. J. Am. Chem. Soc. 2011,
133, 10376–10378; (e) Feldman, K. S.; Antoline, J. F. Org. Lett. 2012, 14, 934–937;
(f) Feldman, K. S.; Antoline, J. F. Tetrahedron 2013, 69, 1434–1445; (g) Selig, P.;
Bach, T. Angew. Chem., Int. Ed. 2008, 47, 5082–5084; (h) Selig, P.; Herdtweck, E.;
Bach, T. Chem. Eur. J. 2009, 15, 3509–3525; (i) Zhang, H.; Jeon, K. O.; Hay, E. B.;
Geib, S. J.; Curran, D. P.; LaPorte, M. G. Org. Lett. 2014, 16, 94–97.
25. In all attempts, the resulting 1H NMR spectra showed the disappearance of the
diagnostic cyclopropyl methylene peaks (1.5–2 ppm), and only vinylic peaks
were observed. A tentative assignment of these products is shown here:
26. Other leaving groups were examined including diethylphosphate and
mesylate. Neither compound could be successfully advanced to the desired
divinylcyclopropane.
8. A biomimetic semisynthesis of (+)-scandine from 18,19-dehydrotabersonine
has been reported: Hugel, G.; Lévy, J. J. Org. Chem. 1986, 51, 1594–1595.
Please cite this article in press as: Goldberg, A. F. G.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.016

8
A. F. G. Goldberg et al. / Tetrahedron Letters xxx (2014) xxx–xxx
27. Danishefsky, S. Acc. Chem. Res. 1979, 12, 66–72.
31. Kürti, L.; Czakó, B. Cope Elimination. In Strategic Applications of Named Reactions
in Organic Synthesis; Elsevier: London, U.K., 2005; pp 96–97.
28. Kürti, L.; Czakó, B. Claisen Rearrangement. In Strategic Applications of Named
Reactions in Organic Synthesis; Elsevier: London, U.K., 2005; pp 88–89.
29. Peterson, E. A.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11943–
11948.
30. (a) Ashby, E. C.; Sanders, J. R.; Claudy, P.; Schwartz, R. J. Am. Chem. Soc. 1973, 95,
6485–6486; (b) Das, S.; Addis, D.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem. Soc.
2010, 132, 1770–1771; (c) Fairbanks, A. J.; Carpenter, N. C.; Fleet, G. W. J.;
Ramsden, N. G.; de Bello, I. C.; Winchester, B. G.; Al-Daher, S. S.; Nagahashi, G.
Tetrahedron 1992, 48, 3365–3376; (d) Burkhardt, E. R.; Matos, K. Chem. Rev.
2006, 106, 2617–2650.
32. Kürti, L.; Czakó, B. Hofmann Elimination. In Strategic Applications of Named
Reactions in Organic Synthesis; Elsevier: London, U.K., 2005; pp 206–207.
33. Kürti, L.; Czakó, B. Eschenmoser-Claisen Rearrangement. In Strategic
Applications of Named Reactions in Organic Synthesis; Elsevier: London, U.K.,
2005; pp 156–157.
34. Tsuji, J. Palladium Reagents and Catalysts: Innovations in Organic Synthesis; John
Wiley & Sons: Chichester, England, 1995.
35. Goldberg, A. F. G.; Stoltz, B. M. Org. Lett. 2011, 13, 4474–4476.
36. Parsons, A. T.; Campbell, M. J.; Johnson, J. S. Org. Lett. 2008, 10, 2541–2544.
Please cite this article in press as: Goldberg, A. F. G.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.016