Seebach's conjunctive reagent enables double cyclizations

Article abstract of DOI:10.1021/ol100845z

(Figure presented) When ketones flanked on both sides by nucleophilic atoms react with Seebach's nitropropenyl pivaloate reagent, direct couplings take place to give two new ring systems and three bonds. Cis-ring fusions are observed in unions leading to 5,5-, 5,6-, and 6,6-bicycles. Densely functionalized and rigid frameworks may be rapidly formed by the chemistry described herein.

Full text of DOI:10.1021/ol100845z

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2746-2749
Seebach’s Conjunctive Reagent Enables
Double Cyclizations
Brent D. Chandler, Jason T. Roland, Yukai Li, and Erik J. Sorensen*
Department of Chemistry, Princeton UniVersity, Frick Chemical Laboratory,
Princeton, New Jersey 08544
ejs@princeton.edu
Received April 13, 2010
ABSTRACT
When ketones flanked on both sides by nucleophilic atoms react with Seebach’s nitropropenyl pivaloate reagent, direct couplings take place
to give two new ring systems and three bonds. Cis-ring fusions are observed in unions leading to 5,5-, 5,6-, and 6,6-bicycles. Densely
functionalized and rigid frameworks may be rapidly formed by the chemistry described herein.
The general idea outlined in Figure 1 is attractive as a
strategy for achieving a double cyclization in the course of
Scheme 1. Strategy for Synthesizing the Core Architecture of
Citrinadin B Featuring the Concept of Double Cyclization
an intermolecular union. The impressive synthesis of the
adamantane skeleton by Stetter and Thomas1 offers an
excellent example of a bimolecular union with three bond
formations and is one of several examples showing the value
of conjunctive reagents in syntheses of new rings.2-6
Our laboratory was drawn to the concept shown in Figure
1 as we considered the problem of synthesizing the penta-
cyclic structure of the scarce, cytotoxic, marine-derived
natural product citrinadin B (1) (Scheme 1).7,8 By mentally
excising the structural elements highlighted in compound 1
(Scheme 1), we imagined a direct construction of the
Figure 1. Concept for “double cyclization”: Nu ) nucleophilic
atom; X ) cation-stabilizing heteroatom; Y ) anion-stabilizing
functional group.
(5) For the use of 2-bromoethyl-3-(trimethylsilylmethyl)buta-1,3-diene
in tandem annulations, see: Trost, B. M.; Remuson, R. Tetrahedron Lett.
1983, 24, 1129
.
(6) For uses of 2-nitro-3-pivaloyloxypropene to achieve ring annulations,
see: (a) Seebach, D.; Missbach, M.; Calderari, G.; Eberle, M. J. Am. Chem.
Soc. 1990, 112, 7625. (b) Lapierre, J. M.; Gravel, D. Tetrahedron Lett.
1991, 32, 2319. (c) Eberle, M.; Missbach, M.; Seebach, D. Org. Synth.
(1) Stetter, H.; Thomas, H. G. Angew. Chem., Int. Ed. 1967, 6, 554.
(2) For ring annulations via the reactions of dimethyl γ-bromomesa-
conate with enamines of cyclic ketones, see: Nelson, R. P.; Lawton, R. G.
1993, 8, 332
.
J. Am. Chem. Soc. 1966, 88, 3884
(3) For a one-pot synthesis of adamantane derivatives via a bimolecular
coupling with four bond formations, see: Takagi, R.; Miwa, Y.; Matsumura,
.
(7) Mugishima, T.; Tsuda, M.; Kasai, Y.; Ishiyama, H.; Fukushi, E.;
Kuwabata, J.; Watanabe, M.; Akao, K.; Kobayashi, J. J. Org. Chem. 2005,
70, 9430
.
S.; Ohkata, K. J. Org. Chem. 2005, 70, 8587
(4) For a ring annulation with three bond formations in a synthesis of
clusianone, see: Qi, J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2007, 129, 12682
.
(8) The Martin laboratory achieved a concise and stereocontrolled
synthesis of the spirooxindole ring system of citrinadin A; see: Pettersson,
.
M.; Knueppel, D.; Martin, S. F. Org. Lett. 2007, 9, 4623.
10.1021/ol100845z  2010 American Chemical Society
Published on Web 05/19/2010

citrinadin architecture by a merger of a functionalized
piperidine intermediate of type 2 with a three-carbon, “double
annulation” reagent 3 having electrophilic reactivity at the
terminal carbons and nucleophilic reactivity at the middle
carbon. This would be a pairing by complementary reactivity,
and it was our hope that we could identify an appropriate
reagent with the characteristics of the hypothetical construct
3. Implicit in this analysis was the assumption that an attack
of a nitro-stabilized anion on the keto group of 2 might be
reversible, thus potentially allowing control over the problem
of establishing the required relative stereochemistry at
carbons a and b, and that the methylamino group of citrinadin
B could be elaborated from a nitro group.
intrigued by the possibility that structurally rigid and
functionalized bicycles of the type shown as 8 (Scheme 2)
might arise by simple unions of compound 4 with ketones
flanked on both sides by nucleophilic atoms (e.g., 5). This
type of double cyclization could conceivably proceed by a
mechanism involving the following sequence of bond forma-
tions: (1) an intermolecular conjugate addition reaction with
concomitant elimination of pivaloate ion, (2) a ring-forming
conjugate addition reaction, and (3) a final transannular
carbonyl addition. Our aim was to evaluate the feasibility
of this scheme as a strategy for directly generating densely
functionalized, bicyclic compounds from acyclic inputs.
Rigid, functionalized molecules of type 8 have genuine value
in the construction of compound libraries.11
Our initial target was a bicyclo[3.3.0]octane framework
of type 8 (n ) 1; Nu ) aminoalkyl) because a double
cyclization, if it occurred, would produce a single diastere-
oisomer due to the well-known thermodynamic bias for a
cis ring fusion in [3.3.0] bicycles.12 In our search for reactants
of type 5, we encountered the symmetrical diaminoketone
9.13 When the bis-hydrochloride salt of this compound was
allowed to react with the NPP reagent 4 under the conditions
shown in Scheme 3, cis-fused bicyclic nitro alcohol 10 was
In the course of contemplating a suitable laboratory
surrogate for a reactive species having the properties of 3,
we encountered the 2-nitro-3-pivaloyloxypropene (NPP)
reagent 4 (Scheme 2) introduced by Seebach and Knochel.6,9
Scheme 2. Concept for “Double Cyclization”
Scheme 3
.
Direct Synthesis of Bicycle 10 and Chemical Proof
of Relative Stereochemistry
This three-carbon compound was shown to be a reactive
conjunctive or “linchpin” reagent1-6,10 to which new bonds
may be readily made to the terminal carbon atoms.
At the outset of our studies, uses of compound 4 as a
double-cyclization reagent were not described. We were
produced and isolated in 83% yield.14 The value of Seebach’s
NPP reagent for the facile production of three new bonds in
the course of a simple union was thus demonstrated.
Experimental support for the cis ring fusion shown in 10
was obtained by the outcome of the following sequence of
transformations: (1) a complete reduction of the nitro group
in compound 10 with Raney nickel in an atmosphere of
hydrogen and (2) conversion of the resulting amino alcohol
11 to carbamate 12 by the action of phosgene. The production
of 12 would be possible only if the amino and hydroxyl
groups in 11 were situated on the same side of the molecular
plane.
(9) Knochel, P.; Seebach, D. NouV. J. Chim. 1981, 5, 75. (b) Knochel,
P.; Seebach, D. Tetrahedron Lett. 1981, 34, 3223. (c) Seebach, D.; Knochel,
P. HelV. Chim. Acta 1984, 67, 261. (d) Knochel, P.; Seebach, D. Synthesis
1982, 1017. (e) Knochel, P.; Seebach, D. Tetrahedron Lett. 1982, 23, 3897.
(f) Seebach, D.; Calderari, G.; Knochel, P. Tetrahedron 1985, 41, 4861
.
(10) For selected examples of conjunctive reagents (also known as
“linchpin” or “multiple coupling” reagents), see: (a) Corey, E. J.; Seebach,
D. Angew. Chem., Int. Ed. 1965, 4, 1075. (b) Seebach, D.; Corey, E. J. J.
Org. Chem. 1975, 40, 231. (c) Trost, B. M.; Vincent, J. E. J. Am. Chem.
Soc. 1980, 102, 5680. (d) Trost, B. M.; Curran, D. P. J. Am. Chem. Soc.
1981, 103, 7380. (e) Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1979,
101, 6429. (f) Harre, M.; Raddatz, P.; Walenta, R.; Winterfeldt, E. Angew.
Chem., Int. Ed. 1982, 21, 480. (g) For a review of tandem vicinal
difunctionalizations, see: Chapdelaine, M. J.; Hulce, M. Org. React. (N.Y.)
1990, 38, 225. (h) Piers, E.; Yeung, B. W. A.; Fleming, F. F. Can. J. Chem.
1993, 71, 280. (i) Trost, B. M.; Ghadiri, M. R. Bull. De la Soc. Chim. Fr.
1993, 130 (3), 433. (j) Hoye, T. R.; North, J. T.; Yao, L. J. J. Am. Chem.
Soc. 1994, 116, 2617. (k) Tietze, L. F.; Geissler, H.; Gewert, J. A.; Jakobi,
U. Synlett 1994, 511. (l) Smith, A. B., III.; Boldi, A. M. J. Am. Chem. Soc.
1997, 119, 6925. (m) Lipshutz, B. H.; Bulow, G.; Fernandez-Lazaro, F.;
Kim, S.-K.; Lowe, R.; Mollard, P.; Stevens, K. L. J. Am. Chem. Soc. 1999,
121, 11664. (n) Lipshutz, B. H.; Clososki, G. C.; Chrisman, W.; Chung,
D. W.; Ball, D. B.; Howell, J. Org. Lett. 2005, 7, 4561. (o) Smith, A. B.,
III; Wuest, W. M. Chem. Commun. 2008, 5883. (p) Devarie-Baez, N. O.;
(11) (a) Carell, T.; Wintner, E. A.; Bashir-Hashemi, A.; Rebek, J., Jr.
Angew. Chem., Int. Ed. 1994, 33, 2059. (b) Carell, T.; Wintner, E. A.; Rebek,
J., Jr. Angew. Chem., Int. Ed. 1994, 33, 2061.
(12) Wiberg, K. B. Angew. Chem. 1986, 98, 312.
(13) De Michelis, C.; Rocheblave, L.; Priem, G.; Chermann, J. C.; Kraus,
J. L. Bioorg. Med. Chem. 2000, 8, 1253.
(14) Additional bases could also effect unions of compound 9 with NPP
reagent 4. See the Supporting Information for details.
Kim, W.-S.; Smith, A. B., III; Xian, M. Org. Lett. 2009, 11, 1861
.
Org. Lett., Vol. 12, No. 12, 2010
2747

In the course of our studies, we also reacted the known
diamine derivative 1315 with NPP reagent 4 under the
conditions shown in Scheme 4. While there is no opportunity
Scheme 5. Syntheses of Compounds 20 and 23 from a Common
Precursor and their Reactions with NPP Reagent 4a
Scheme 4
.
Synthesis of an 8-Membered Ring by Bimolecular
Union
for a double cyclization in this particular instance, the
8-membered ring diazacycle 14 could be isolated, albeit in
a low yield, after purification by silica gel chromatography.
The production of an 8-membered ring by this direct union
provides circumstantial support for the mechanistic scenario
outlined in Scheme 2. A reduction of compound 14 with
Raney nickel in an atmosphere of hydrogen afforded the
more stable triamine derivative 15.
In the wake of the successful double cyclization shown
in Scheme 3, we investigated the behavior of carbon-based
nucleophiles in this process with a view toward the problem
of constructing both 5,5- and citrinadin-like 5,6-fused ring
systems. To this end, R-chloro ketone 18 (Scheme 5) was
prepared in three straightforward steps from benzylamine
(16) and epi-chlorohydrin (17) and subsequently reacted with
the stabilized enolate of dimethyl malonate. Cleavage of the
Boc carbamate with HCl then afforded hydrochloride salt
19. The expectation was that the relatively low pKa’s of the
ammonium ion and malonate groupings in 19 would permit
a base-mediated generation of a species with the chemical
character of the hypothetical “double nucleophile” shown
in Figure 1; such a species would be unveiled in the presence
of Seebach’s NPP reagent as a prelude for a union with three
new bond formations.
After some experimentation, we found that exposure of a
cold (-78 °C) solution of compound 19 and NPP reagent 4
in THF to the combined action of DABCO and sodium
hexamethyldisilazide resulted, after warming to room tem-
perature, in the formation of the desired bicyclic system 20.16
Compound 20 was isolated in 70% yield, and we did not
observe a trans-fused diastereoisomer. Not surprisingly, we
could also utilize chloromethyl ketone 18 as a building block
in a synthesis of the functionalized oxindole 22 (Scheme 5).
Our interest in the citrinadin synthesis problem prompted
the decision to alkylate the sodium enolate derived from the
oxindole derivative 21 with chloromethyl ketone 18. After
the desired carbon-carbon bond formation, the nitrogen-
bound Boc group was cleaved with HCl in ether, affording
a Boc ) tert-BuOCO; TPAP ) tetra-n-propylammonium perruthenate;
NMO ) N-methylmorpholine N-oxide; DABCO ) 1,4-diazabicyclo[2.2.2]octane;
NaHMDS ) sodium hexamethyldisilazide. Compounds 20 and 23 were
produced in racemic form. Two diasterereomers of 23, epimeric at the starred
carbon, were isolated in a 1.9:1 ratio favoring the compound shown.
HCl salt 22. Under the conditions shown, the desired union
of compound 22 with the NPP reagent 4 was achieved in
67% yield; this union produced tetracycle 23 as the major
component of a 1.9:1 mixture of diastereoisomers, epimeric
at the starred carbon atom. Again, the ring fusion stereo-
chemistry of the bicyclo[3.3.0]substructural element was
exclusively cis.
It was also possible to annulate two rings onto a preexisting
piperidine framework (Scheme 6). Compounds 28 and 30
were constructed from the same bromomethyl ketone 26,
which was available from methyl vinyl ketone (24) and
alkenyl carbamate 2517 by a three-step sequence featuring
an intermolecular olefin cross-metathesis and a ring-forming
conjugate addition reaction. As in the syntheses shown in
Scheme 6, straightforward enolate alkylations were used to
gain access to the multifunctional cyclization substrates 27
and 29. Both of these compounds reacted with NPP reagent
4 under the conditions indicated to give products 28 and 30;
each product was isolated as 1:1 and 2:1 mixture of separable
diastereoisomers, respectively, epimeric at the starred centers.
(15) Teyssot, M.-L.; Fayolle, M.; Philouze, C.; Dupuy, C. Eur. J. Org.
Chem. 2003, 54.
(16) The use of a stronger base (NaHMDS) in the generation of
compounds 20 and 28 was required to afford the desired double cyclization.
In the absence of this added base, compounds of type 6 shown in Scheme
2 are isolated.
(17) Michael, F. E.; Cochran, B. M. J. Am. Chem. Soc. 2006, 128, 4246.
Org. Lett., Vol. 12, No. 12, 2010
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could selectively stabilize a cis-locked, bicyclic nitro alco-
hol.18 When compound 31 was allowed to react with
DABCO and NPP reagent 4 in acetonitrile, cis-fused, bicyclic
nitro alcohol 32 was selectively produced in 67% yield
(Scheme 7). The relative stereochemical assignment of
Scheme 6. Syntheses of Compounds 28 and 30 from a Common
Precursor and Their Reactions with NPP Reagent 4a
Scheme 7. Synthesis of Cis-Fused Bisaminobicyclo[4.4.0]decane
compound 32 was determined by reduction of the nitro
group, followed by a subsequent conversion of the resulting
amino alcohol to the corresponding cyclic carbamate (see
Supporting Information). Thus, in all cases examined so far,
we have observed a preference for the formation of cis-fused,
bicyclic nitro alcohols in reactions of the type outlined in
Scheme 2.
The complex, pentacyclic framework of citrinadin B (1)
inspired the retrosynthetic analysis shown in Scheme 1. The
studies described herein demonstrated that Seebach’s nitro-
propene 4, a compound with a proven utility as a conjunctive
reagent in organic synthesis, is also a convenient double
annulation reagent. Much of the impact of this chemistry
derives from the discovery that new bonds may be made to
all three of the carbon atoms of NPP reagent 4 in direct
couplings of compounds having an appropriate placement
of nucleophilic and electrophilic atoms. Furthermore, these
cyclizations demonstrate a strong preference for the cis-fused
configuration in all systems studied to date. Thus, the NPP
reagent is an attractive building block for rapid formations
of complex ring systems. Our preliminary studies also
suggest that medium-ring formations may be possible in the
course of simple unions with the NPP reagent. Further studies
are needed to delineate the scope of that aspect of the
reactivity of Seebach’s NPP reagent.
a NBS ) N-bromosuccinimide; TFA ) trifluoroacetic acid; DABCO
) 1,4-diazabicyclo[2.2.2]octane. Compounds 28 and 30 were produced in
racemic form. Two diasterereomers of 28, epimeric at the starred carbon,
were isolated in a 1:1 ratio. Two diastereomers of 30, epimeric at the starred
carbon, were isolated in a 2:1 ratio favoring the compound shown.
The constitution of pentacycle 30 is clearly related to that
found in citrinadin B. At the outset of our studies, we were
cognizant of the possibility that we might change the relative
dispositions of the hydroxyl and nitro groups in compounds
28 and 30 by a retro-Henry/Henry process. If feasible, this
tactic would afford materials having the type of trans-fused
ring system found in the citrinadins. In practice, however,
compounds 28 and 30 were found to be impervious to the
action of basic reagents, and, as of this writing, we have
been unable to isomerize the cis ring fusions in these
compounds to trans by a retro-Henry/Henry mechanism.
While the cis ring fusions found in compounds 10, 20,
23, 28, and 30 were anticipated on thermodynamic grounds,
we were less certain about the stereochemical outcome of a
double cyclization leading to a bicyclo[4.4.0]decanyl nitro
alcohol. Trans-fused decalins are generally more stable than
their cis-fused isomers, but we were mindful that an internal
hydrogen bond between adjacent hydroxyl and nitro groups
Acknowledgment. We gratefully acknowledge the Na-
tional Institute of General Medical Sciences (GM074763),
Princeton University, and the Merck Research Laboratories
for supporting this work. We also thank the NIH for a
postdoctoral fellowship (5 F32 GM078900 to J.T.R.).
Supporting Information Available: Experimental pro-
cedures and full characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL100845Z
(18) Support for a bonding interaction between proximate hydroxyl and
nitro groups may be found in the significantly lower boiling point of
o-nitrophenol (216 °C) in relation to p-nitrophenol (279 °C). Norwitz, G.;
Nataro, N.; Keliher, P. N. Anal. Chem. 1986, 58, 639.
Org. Lett., Vol. 12, No. 12, 2010
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