Rapid assembly of the salvileucalin B norcaradiene core

Article abstract of DOI:10.1021/ol902848k

(Chemical Equation Presentation) Preparation of the polycyclic core of the cytotoxic natural product salvileucalin B is described. The key feature of this synthetic strategy is a copper-catalyzed intramolecular arene cyclopropanation to provide the central norcaradiene. These studies lay the foundation for continued investigations toward an enantioselective total synthesis of 1

Full text of DOI:10.1021/ol902848k

ORGANIC
LETTERS
2
010
Vol. 12, No. 4
80-783
Rapid Assembly of the Salvileucalin B
Norcaradiene Core
7
Sergiy Levin, Roger R. Nani, and Sarah E. Reisman*
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, DiVision of
Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125
reisman@caltech.edu
Received December 10, 2009
ABSTRACT
Preparation of the polycyclic core of the cytotoxic natural product salvileucalin B is described. The key feature of this synthetic strategy is
a copper-catalyzed intramolecular arene cyclopropanation to provide the central norcaradiene. These studies lay the foundation for continued
investigations toward an enantioselective total synthesis of 1.
Plants of the SalVia genus have a rich history in traditional
medicine. Indeed, the name SalVia derives from the Latin
The isolation of a norcaradiene-containing natural product
is striking, as it is well-known that simple norcaradienes
undergo facile electrocyclic ring-opening to provide the
1
word salVare, which means, “to heal”. Isolation studies
targeting SalVia plants have yielded a wealth of structurally
intriguing, biologically active natural products, including the
4
corresponding cycloheptatrienes. Studies have shown that
5
6
sterically or electronically biased, as well as geometrically
2
7
potent hallucinogen salvinorin A. Recently, studies aimed
constrained norcaradienes (such as that found in 1) can be
at identifying novel diterpenoids as potential medicinal leads
stable at room temperature. The electrocyclic ring-opening
of norcaradiene 1 would produce two bridgehead olefins
within a strained [4.3.1]bicycle, and is therefore anticipated
to be highly unfavorable.
resulted in the isolation of three new compounds from SalVia
3
leucantha that possess unusual structures. Of particular
interest is the compound salvileucalin B (1), which exhibits
promising cytotoxicity against A549 (human lung adeno-
carcinoma) and HT-29 (human colon adenocarcinoma) cells,
and comprises an unusual norcaradiene core embedded
within the polycyclic carbon skeleton. The structural assign-
ment of compound 1 was confirmed by single-crystal X-ray
diffraction.
In considering a synthesis of 1, we were intrigued by the
possibility of employing a late-stage intramolecular cyclo-
propanation reaction of a tricyclic arene such as 2 to directly
form the norcaradiene core. Since the initial report by
Buchner and Curtius in 1885 detailing the thermolysis of
8
ethyl diazoacetate in benzene, the cyclopropanation of
(
1) Ulubelen, A. Sage: The Genus SalVia, Medicinal and Aromatic
(4) Maier, G. Angew. Chem., Int. Ed. 1967, 6, 402.
(5) Prinzbach, H.; Fischer, U.; Cruse, R. Angew. Chem., Int. Ed. 1966,
5, 251.
Plants, Industrial Profiles; Kintzios, S. E., Ed.; Harwood Academic
Publishers: Amsterdam, The Netherlands, 2000; Vol. 14.
(
2) Ortega, A.; Blount, J. F.; Manchand, P. S. J. Chem. Soc., Perkin
(6) Ciganek, E. J. Am. Chem. Soc. 1967, 89, 1454.
Trans. 1 1982, 10, 2505.
3) Aoyagi, Y.; Yamazaki, A.; Nakatsugawa, C.; Fukaya, H.; Takeya,
K.; Kawauchi, S.; Izumi, H. Org. Lett. 2008, 10, 4429.
(7) (a) Schreiber, J.; Leimgruber, W.; Pesaro, M.; Schudel, P.; Threlfall,
T.; Eschenmoser, A. HelV. Chim. Acta 1961, 44, 540. (b) Darms, R.;
Threlfall, T.; Pesaro, M.; Eschenmoser, A. HelV. Chim. Acta 1963, 46, 2893.
(
1
0.1021/ol902848k  2010 American Chemical Society
Published on Web 01/20/2010

arenes has been the focus of numerous investigations.
Thermal Buchner reactions generally provide the ring-opened
cycloheptatriene products as mixtures of isomers. With the
with propargyl bromide provided the corresponding triyne,
which, after exposure to Pd(PPh (2.5 mol %) in the
presence of AcOH, smoothly delivered tricycle 10 in 78%
3 4
)
4
1
8,19
advent of transition metal-catalyzed decomposition of sta-
yield (54% yield over the two-step sequence).
Krapcho
9
20
bilized diazo compounds, several methodological studies
dealkoxycarbonylation of tricycle 10 was followed by
saponification with potassium hydroxide to give carboxylic
acid 11. Subsequent conversion to the acid chloride and
have demonstrated that isomerically pure cycloheptatrienes
can be isolated in synthetically useful yields from an
appropriate diazo precursor and arene with use of Cu and
2
1
homologation with use of the Arndt-Eistert protocol
1
0-12
Rh catalysts.
Despite the prevalence of cycloheptane
furnished carboxylic acid 12 in 75% yield. The R-diazo
ketone 14 was prepared in good yield by treatment of the
acid chloride derived from carboxylic acid 12 with an
ethereal solution of diazomethane.
containing natural products, the Buchner reaction is still
1
3
under-utilized in total synthesis endeavors.
Access to 1 via cyclopropanation of 2 requires the
chemoselective intramolecular reaction of a metal-carbenoid
With R-diazo ketone 14 in hand, a number of metal
catalysts were evaluated for their ability to promote the
formation of norcaradiene 18. Whereas Rh catalysts favored
(
derived from the R-diazo carbonyl of 2) with the arene
II
π-system, in preference to highly favorable C-H insertion
1
4
reactions at the adjacent, activated benzylic proton sites.
the formation of C-H insertion products (Table 1, entries
In addition, cyclopropanation to give 1 requires formation
of a fully substituted cyclopropane. In this context, the
cyclopropanation of 2 provides an interesting case study of
the factors influencing benzylic C-H insertion versus arene
cyclopropanation. In a synthetic sense, it is envisioned that
arene 2 could easily arise from the cycloisomerization of
triyne 3, which in turn could derive from the union of
fragments 4, 5, and 6. Reported herein are our initial forays
into the execution of this synthetic plan (Scheme 1).
Table 1. Catalysts Screened for Cyclopropanation of R-Diazo
Ketone 14
1
5
a
b
entry
catalyst
Rh(OAc)
method
% yield
Scheme 1
.
Retrosynthetic Analysis of Salvileucalin B
1
2
3
4
5
6
7
8
4
A
A
A
B
B
B
B
B
14
1
5
30
50 (73)
40
Rh(cap)
Rh(tfa)
Cu(acac)
Cu(tfacac)
Cu(hfacac)
Cu(TMHD)
Cu(TBS)
4
4
2
c
2
2
2
28
11
2
a
Method A: [14] ) 0.01 M, [cat.] ) 0.001 M, CD
Cl , 100 °C (microwave),
min. Determined by H NMR analysis of crude reaction mixture, using
2 2
Cl , 22 °C, 12 h.
Method B: [14] ) 0.01 M, [cat.] ) 0.001 M, CD
2
2
b
1
1
c
an internal standard. Isolated yield, slow addition of 14, DCE, reflux.
2
2
1
2
-3), Cu(acac) provided more promising levels of cy-
II
clopropanation (entry 4). Further screening of several Cu
catalysts revealed that the yields of norcaradiene 18 were
II
highly catalyst dependent, with relatively electron-poor Cu
salts providing the best results (entries 5-8). Although
conducting the reactions in a microwave reactor proved
useful in the context of catalyst screening, improved yields
(
8) (a) Buchner, E.; Curtius, T. Chem. Ber. 1885, 18, 2377. (b) Buchner,
E.; Curtius, T. Chem. Ber. 1896, 29, 106.
9) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
(
Whereas an enantioselective synthesis of 1 would require
an asymmetric alkylation reaction to prepare triyne 3, for
the purpose of rapidly accessing the R-diazo carbonyl
compounds of interest, the compounds in this study were
prepared as racemates. Thus, our model studies commenced
with the alkylation of commercially available dimethyl
propargyl malonate with TBS-protected propargyl bromide
for Organic Synthesis with Diazo Compounds; John Wiley & Sons: New
York, 1998.
(
10) For reviews including discussions of arene cyclopropanation, see:
(
a) Ye, T.; Mckervey, M. A. Chem. ReV. 1994, 94, 1091. (b) Merlic, C. A.;
Zechman, A. L. Synthesis 2003, 8, 1137.
11) Early examples employing copper, see: (a) Scott, L. T. J. Chem.
(
Soc., Chem. Commun. 1973, 882. (b) Scott, L. T.; Minton, M. A.; Kirms,
M. A. J. Am. Chem. Soc. 1980, 102, 6311.
(12) Early examples employing rhodium, see : (a) Anciaux, A. J.; Hubert,
A. J.; Noels, A. F.; Petiniot, N.; Teyssie, P. J. Chem. Soc., Chem. Commun.
1
6
8
,
followed by acid-mediated cleavage of the silyl ether
1
980, 765. (b) Anciaux, A. J.; Demonceau, A.; Noels, A. F.; Hubert, A. J.;
1
7
to give diyne 9 in 87% yield (Scheme 2). Alkylation of 9
Warin, R.; Teyssie, P. J. Org. Chem. 1981, 46, 873.
Org. Lett., Vol. 12, No. 4, 2010
781

were obtained for substrate 14 by using a slow addition
protocol. Thus, syringe pump addition of 14 to a solution of
N-nitrosourea) to provide R-diazo ketone 15 in 63% yield.
R-Diazo ꢀ-ketoester 16 was prepared from acid 12 by a two-
step procedure consisting of conversion to the ketoester,
2
5
Cu(tfacac)
2
in dichloroethane at reflux cleanly provided
1
norcaradiene 18 in 73% isolated yield. Notably, the H NMR
spectrum of 18 shows no evidence of the corresponding
cycloheptatriene at room temperature.
followed by diazo transfer with p-ABSA. Alternatively,
R-diazo ꢀ-ketonitrile 17 was prepared by treatment of methyl
ester 13 with R-lithio-acetonitrile followed by diazo transfer
II
26
There are several reports of Rh catalysts providing good
with N-imidazole sulfonyl azide in the presence of pyridine.
2
7
yields of Buchner products; however, these systems generally
Whereas R-diazo carbonyls 15 and 16 heavily favored
dimerization and C-H insertion pathways when using a
lack benzylic protons, or geometrically disfavor C-H
23
28
insertion. In systems where C-H insertion is geometrically
variety of catalysts and conditions, more promising results
II
favorable, Cu catalysts provide improved selectivity for
were realized with R-diazo ꢀ-ketonitrile 17 (Table 2).
2
4
cyclopropanation. Although we were pleased with our
ability to prepare norcaradiene 18, more functionalized
norcaradienes were required to facilitate the implementation
of an endgame strategy toward salvileucalin B (1). In
particular, it was envisioned that use of R-diazo ꢀ-ketoester
Table 2. Cyclopropanation of Functionalized Diazo Substrates
1
6 or R-diazo ꢀ-ketonitrile 17 (Scheme 2) would provide
Scheme 2. Synthesis of Arene Cyclopropanation Substrates
a
b
entry
R
catalyst
Cu(acac)
product
% yield
,
c d
1
2
3
4
5
a
Me (15)
2
19
20
21
21
21
7
CO
2
Me (16)
Cu(hfacac)
Cu(TBS)
2
<2
14
6
CN (17)
CN (17)
CN (17)
2
Cu(tfacac)
Cu(hfacac)
2
d
2
66 (64)
[
sub] ) 0.01 M, [cat.] ) 0.001 M, CD
min. Determined by H NMR analysis of crude mixture, using an internal
standard. Slow addition of 15, DCE, reflux. Isolated yield.
2
Cl
2
, 120 °C (microwave), 1
b
1
c
d
Although 17 was significantly less reactive than 14, 15, or
1
6, exposure to 10 mol % Cu(hfacac)
2
in dichloroethane at
2
9
8
0 °C for 3 h provided approximately 10% yield of the
desired norcaradiene, in addition to significant quantities of
unreacted starting material. After a survey of conditions,
cyclopropane 21 was obtained in 64% yield by heating a
2
solution of diazo substrate 17 and 10 mol % Cu(hfacac) in
dichloromethane to 120 °C for 1 min under microwave
irradiation. It is envisioned that nitrile 21 should allow for
elaboration to the southern lactone of salvileucalin B (1) in
a short reaction sequence.
At this time, the source of the divergent reactivity of diazo
substrates 14, 15, 16, and 17 is unclear. A simple comparison
of the cyclopropanation product yields from electronically
similar diazo ketones 14 and 15 (R ) H versus CH
3
), or,
diazo ester 16 and diazo nitrile 17 (R ) CO Me versus CN),
2
suggests that the steric profile of the metal carbenoid
intermediate may be important.
Concomitant to our studies on substrates 14-17, silyl
analogue 26 was also prepared. It was envisioned that the
silyl group could provide a useful handle for functionalization
of the northern portion of 1. Thus, R-diazo ꢀ-ketonitrile 26
was obtained by a short synthetic sequence from 9, which
norcaradienes with appropriate functionality for conversion
to the required γ-lactone.
To this end, additional R-diazo carbonyl compounds were
prepared from either carboxylic acid 12 or methyl ester 13,
each easily accessible from 11 by simply modifying the
2
0
began with Krapcho dealkoxycarbonylation followed by
3
0
silylation with alkynylsilyl bromide 22 to give triyne 23
(61% yield, 2 steps). Exposure of 23 to 1 mol % of
21
conditions of the Arndt-Eistert homologation. Carboxylic
acid 12 was converted to the corresponding acid chloride
and treated with diazoethane (generated in situ from N-ethyl-
1
9
RuCp*(cod)Cl smoothly provided arene 24 in 90% yield.
Notably, the cycloisomerization of 23 clearly indicates that
782
Org. Lett., Vol. 12, No. 4, 2010

the benefit of a “Thorpe-Ingold” effect from the gem-diester
Acknowledgment. We thank Dr. Scott Virgil and Dr.
Jennifer Roizen of the California Institute of Technology for
insightful discussions, as well as Prof. Brian Stoltz and the
Caltech Center for Catalysis and Chemical Synthesis for
access to analytical equipment. Financial support from the
California Institute of Technology is gratefully acknowl-
edged.
3
1
moiety is not required for cyclization. This result lends
support for proposed future work on an enantioselective
route, which will require the cyclization of a chiral substrate
bearing a tertiary center at C2 (salvileucalin numbering).
Homologation of arene 24 proceeded as before with use
2
1
of the Arndt-Eistert protocol to provide methyl ester 25,
which was converted in two steps to R-diazo ꢀ-ketonitrile
2
6. Heating a solution of 26 in the presence of 10 mol %
Cu(hfacac) to 150 °C under microwave irradiation for 2 min
provided cyclopropane 27 in 49% yield (Scheme 3). In this
Note Added after ASAP Publication. Scheme 3 con-
tained errors in the version published ASAP on January 20,
2010; the corrected version was posted to the web on January
2
2
2, 2010.
Supporting Information Available: Experimental pro-
Scheme 3
.
Cyclopropanation of Silyl Analogue 26
1
13
cedures and spectral data ( H and C NMR, IR, and HRMS)
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL902848K
(13) For relevant synthetic studies, see : (a) King, G. R.; Mander, L. N.;
Monck, J. C.; Zhang, H. J. Am. Chem. Soc. 1997, 119, 3828. (b) Morris,
J. C.; Mander, L. N.; Hockless, D. C. R. Synthesis 1998, 455.
(
14) (a) Padwa, A.; Austin, D. J.; Hornbuckle, S. F.; Semones, M. A.;
Doyle, M. P.; Protopopova, M. N. J. Am. Chem. Soc. 1992, 114, 1874. (b)
Padwa, A.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle, M. P.;
Protopopova, M. N.; Winchester, W. R.; Tran, A. J. Am. Chem. Soc. 1993,
1
15, 8669.
(
15) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. Chem. ReV. 1996,
9
6, 635.
(
(
(
16) Schore, N. E.; Najdi, S. D. J. Org. Chem. 1987, 52, 5296.
17) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2003, 125, 12143.
18) Negishi, E.; Harring, L. S.; Owczarczyk, Z.; Mohamud, M. M.;
Ay, M. Tetrahedron Lett. 1992, 33, 3243.
19) Yamamoto, Y.; Arakawa, T.; Ogawa, R.; Itoh, K. J. Am. Chem.
Soc. 2003, 125, 12143.
20) (a) Krapcho, A. P.; Mundy, B. P. Tetrahedron 1970, 26, 5437. (b)
(
(
Krapcho, A. P.; Lovey, A. J. Tetrahedron Lett. 1973, 14, 957. (c) Krapcho,
A. P. Synthesis 1982, 805.
(
21) (a) Arndt, F.; Eistert, B. Org. React. 1942, 1, 38. (b) Organic
Syntheses; Wiley & Sons: New York, 2004; Collect. Vol. 10, p 194.
1
(
22) The H NMR spectra of the crude reaction mixtures indicate
significant quantities of isomeric C-H insertion products; however, due to
the complexity of the spectra, ratios of cylopropanation to C-H insertion
were not determined.
(
23) (a) McKervey, M. A.; Tuladhar, S. M.; Twohig, M. F. J. Chem.
case, the use of the microwave reactor significantly improved
the efficiency of the reaction; heating under similar conditions
in an oil bath to 80 °C for 6 h provided less than 5% yield
of the desired cyclopropanation product.
Soc., Chem. Commun. 1984, 129. (b) Kennedy, M.; McKervey, M. A.;
Maguire, A. R.; Tuladhar, S. M.; Twohig, M. F. J. Chem. Soc., Perkin
Trans. 1 1990, 1047.
(
24) Rogers, D. H.; Morris, J. C.; Roden, F. S.; Frey, B.; King, G. R.;
Russkamp, F. W.; Bell, R. A.; Mander, L. N. Pure Appl. Chem. 1996, 68,
The studies outlined here describe a synthetic approach
that provides rapid access to the norcaradiene core of
515.
(
25) Brooks, D. W.; Lu, L. D.-L.; Masamune, S. Angew. Chem., Int.
Ed. 1979, 18, 72.
II
salvileucalin B. Whereas Rh catalysts favor C-H insertion
(
26) Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797.
II
II
products, selection of an appropriate Cu catalyst provides
(27) Exposure of R-diazo ketone 15 to Cu catalysts did not appear to
result in significant formation of the corresponding Bamford-Stevens enone
product.
synthetically useful quantities of the required norcaradiene.
These cyclopropanation reactions provide access to fully
substituted cyclopropanes, and support for the viability of
the synthetic strategy outlined in Scheme 1 for the synthesis
of salvileucalin B (1). Application of this strategy to an
enantioselective synthesis of 1 is the focus of ongoing work
in our laboratory.
(28) The most promising result for each substrate 15 and 16 is shown
in Table 2.
1
(
(
29) Determined by H NMR analysis of the crude reaction mixture.
30) Petit, M.; Chouraqui, G.; Aubert, C.; Malacria, M. Org. Lett. 2003,
5
, 2037.
(
31) (a) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc.,
Perkin Trans. 1 1915, 1981. (b) Sammes, P. G.; Weller, D. J. Synthesis
1995, 1205. (c) Jung, M. E.; Pizzi, G. Chem. ReV. 2005, 105, 1735.
Org. Lett., Vol. 12, No. 4, 2010
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