Spirodiepoxide-based cascades: Direct access to diverse motifs

Article abstract of DOI:10.1021/ol201101e

Allene epoxide formation/opening reaction sequences enabled direct access to diverse products. Described here are a single flask procedure for allene preparation and allene oxidation/derivatization reactions that give, among others, diendiol, diyndiol, α′-hydroxy-γ-enone, dihydrofuranone, butenolide, and δ-lactone products.

Full text of DOI:10.1021/ol201101e

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3352–3355
Spirodiepoxide-Based Cascades: Direct
Access to Diverse Motifs
Rojita Sharma,† Madhuri Manpadi,† Yue Zhang,† Hiyun Kim,† Novruz G. Ahkmedov,‡
and Lawrence J. Williams*,†
Department of Chemistry and Chemical Biology, Rutgers, The State University of New
Jersey, Piscataway, New Jersey 08854, United States, and C. Eugene Bennett
Department of Chemistry, 406 Clark Hall, Prospect Street, West Virginia University,
Morgantown, West Virginia 26506, United States
lawjw@rci.rutgers.edu
Received April 26, 2011
ABSTRACT
Allene epoxide formation/opening reaction sequences enabled direct access to diverse products. Described here are a single flask procedure for
allene preparation and allene oxidation/derivatization reactions that give, among others, diendiol, diyndiol, R0-hydroxy-γ-enone, dihydrofuranone,
butenolide, and δ-lactone products.
Here we report a simplified procedure for allene
synthesis and several unprecedented spirodiepoxide-
based transformations with heteronucleophiles and car-
bon nucleophiles as well as ambiphilic reagents. Our aim
is to develop a framework for spirodiepoxide reactivity,
to demonstrate the strategic advantages that allene
oxidation offers in complex molecule synthesis, and to
identify reactions that give access to diverse structural
motifs.1 This disclosure is focused on simple proce-
dures, novel cascade sequences, and diversity oriented
transformations.
There are many methods for allene synthesis.2 Cuprate
addition to activated propargyl alcohol derivatives is mild
and probably the most general, convergent, and reliable
method available.3 A three-step sequence is usually em-
ployed: (1) a propargyl alcohol is assembled, (2) the
hydroxyl of the substrate is converted to a suitable leaving
group, and (3) copper mediated SN20 substitution is then
€
(3) (a) Hoffmann-Roder, A.; Krause, N. Metal-Mediated Synthesis
of Allenes. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K.,
Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2004; Vol. 1, pp
52ꢀ70 and references therein. (b) Ogasawara, M.; Hayashi, T. Transi-
tion Metal-Catalyzed Synthesis of Allenes. In Modern Allene Chemistry;
Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA:
Weinheim, 2004; Vol. 1, pp 107ꢀ110 and references therein. (c) Ohno, H.;
Nagaoka, Y.; Tomioka, K. Enantioselective Synthesis of Allenes. In
Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH
Verlag GmbH & Co. KGaA: Weinheim, 2004; Vol. 1, pp 141ꢀ151 and
references therein.
† Rutgers, The State University of New Jersey.
‡ West Virginia University.
(1) (a) Joyasawal, S.; Lotesta, S. D.; Akhmedov, N. G.; Williams,
L. J. Org. Lett. 2010, 12, 988. (b) Zhang, Y.; Cusick, J. R.; Shangguan,
N.; Katukojvala, S.; Inghrim, J.; Emge, T. J.; Williams, L. J. J. Org.
Chem. 2009, 74, 7707. (c) Ghosh, P.; Zhang, Y.; Emge, T. J.; Williams,
L. J. Org. Lett. 2009, 11, 4402. (d) Ghosh, P.; Cusick, J. R.; Inghrim, J.;
Williams, L. J. Org. Lett. 2009, 11, 4672. (e) Wang, Z. H.; Shangguan,
N.; Cusick, J. R.; Williams, L. J. Synlett 2008, 2, 213. (f) Kolakowski,
R. V.; Williams, L. J. Tetrahedron Lett. 2007, 48, 4761. (g) Ghosh, P.;
Lotesta, S. D.; Williams, L. J. J. Am. Chem. Soc. 2007, 129, 2438. (h)
Shangguan, N.; Kiren, S.; Williams, L. J. Org. Lett. 2007, 9, 1093. (i)
Lotesta, S. D.; Kiren, S. K.; Sauers, R. R.; Williams, L. J. Angew. Chem.,
Int. Ed. 2007, 46, 15. (j) Katukojvala, S.; Barlett, K. N.; Lotesta, S. D.;
Williams, L. J. J. Am. Chem. Soc. 2004, 126, 15348. (k) D.; Hou, Y.;
Williams, L. J. Org. Lett. 2007, 9, 869.
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Rona, P.; Crabbe, P. J. Am. Chem. Soc. 1969, 91, 3289. (c) Tadema, G.;
Vermeer, P.; Meijer, J.; Brandsma, L. Recl. Trav. Chim. Pays-Bas 1976,
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95, 66. (d) Alexakis, A.; Commerc-on, A.; Villieras, J.; Normant, J. F.
Tetrahedron Lett. 1976, 17, 2313. (e) Moreau, J.-L.; Gaudemar, M. J.
Organomet. Chem. 1976, 108, 159. (f) Marek, I.; Mangeney, P.; Alexakis,
A.; Normant, J. F. Tetrahedron Lett. 1986, 27, 5499. (g) Alexakis, A.;
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8042. (h) Daeuble, J. F.; McGettigan, C.; Stryker, J. M. Tetrahedron
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Lett. 1990, 31, 2397. (i) Ansorge, K.; Polborn, K.; Muller, T. J. J.
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(2) (a) Krause, N., Hashmi, A. S. K., Eds. Modern Allene Chemistry,
Vol. 1; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany,
2004. (b) Brummond, K. M.; DeForrest, J. E. Synthesis 2007, 6, 795.
r
10.1021/ol201101e
Published on Web 06/07/2011
2011 American Chemical Society

applied to give the allene.4 We use an abbreviated variant
that does not require purification, or even isolation, of the
intermediates (Table 1). The combination of an alkyne
with a base; sequential addition of an aldehyde or ketone,
methanesulfonyl chloride, and triethylamine; and then
exposure of the reaction mixture to a cuprate reagent gives
the desired allene directly. The use of triethylamine for
propargyl activation is not strictly necessary. However,
this additive was found to improve reproducibility. Upon
addition of the propargyl mesylate mixture to the cuprate
reagent, low temperature conditions were found to sup-
press the SN2 product and favor SN20 product formation.
In total, this sequential component coupling procedure5
produces minimal waste, requires ∼5 h of reaction time,
and is efficient for a range of substituents, including aryl
(Table 1, entries 1, 2, 10, 14ꢀ16, and 20), silyl (Table 1,
entries 7, 9, 11, and 16), halo (Table 1, entries 12ꢀ20), and
R-branched alkyl (Table 1, entries 4, 6, 17, and 19) groups.6
and/or simple epoxides are summarized in Tables 2ꢀ4.
Dimethyldioxirane (DMDO) rapidly converts allenes to
spirodiepoxides via sequential oxygen delivery (IfIII,
eq 1). The first epoxidation is reliably selective for 1,
3-disubstituted allenes and for trisubstituted allenes. This
oxidation simultaneously sets the absolute configuration
and alkene geometry of the allene oxide, II, with high
fidelity (dr >20:1), and although the selectivity of the
second oxidation (fIII) may be near 1:1, for suitable
substrates the stereoselectivity is excellent (>20:1). For
all experiments described here, the allene was oxidized in
DMDO/chloroform solutions7 and then exposed to the
conditions indicated without isolation and purification of
the intermediate spirodiepoxide.
Table 2 lists data for heteronucleophile addition to
spirodiepoxides that suggest this electrophile, though highly
reactive, is probably best thought of as relatively soft.
Table 2, entry 1 shows that the spirodiepoxide reacts with
sodium benzenesulfinate to give the sulfone.8 No O-alky-
lation was observed in this case. Approximately stoichio-
metric sodium trifluoroethoxide adds efficiently (Table 2,
entry 2); however, trifluoroethanol does not add to the
spriodiepoxide under neutral conditions even in large
excess, in contrast to water and other alcohols.9ꢀ11 Base
is also required to effect spirodiepoxide opening with
indole. This takes place in the absence of an added Lewis
acid and occurs exclusively on the indole nitrogen (Table 2,
entry 3).12 The highly versatile haloketone functionality9
can be derived from spirodiepoxides as well. These reac-
tions proceed in servicable but capricious yield when
tetraalkylammonium salts are used (e.g., Table 2, entries
4ꢀ6).11 In contrast, lithium halide salts react rapidly and
reliably to give the haloketones in excellent yields (Table 2,
entries 7ꢀ9). The benefit of the lithium gegenion is espe-
cially noteworthy, since there are no reported examples of
Lewis acid promoted spirodiepoxide opening.
Table 1. Single Flask Allene Synthesisa
The addition of carbon nucleophiles to spirodiepoxides
is particularly appealing, and diverse CꢀC bond forming
reactions are given in Table3. As noted previously, cyanide
adds smoothly to spirodiepoxides to give the correspond-
ing nitrile derivative.1i The anion derived from acetonitrile
and LDA gave the homologous ketonitrile (Table 3, entry 1).
Although such anions are known to add to ketones, in this
case the reaction cleanly gives monoaddition and the
a Conditions: (1) n-BuLi (1.05 equiv), THF, ꢀ78 to 0 °C, 35 min; (2)
aldehyde/ketone (1.0 equiv), ꢀ78 to 0 °C, 0.5ꢀ2 h; (3) MsCl (1.05 equiv),
Et3N (1.05 equiv), 0 °C, 1ꢀ2 h; (4) R4CuCNLi, THF, ꢀ78 °C to rt, 1ꢀ3
h. b (R4)2CuLi was used instead of R4CuCNLi. c Ms2O was used instead
of MsCl.
(7) (a) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847.
(b) For photo of the experimental setup for this procedure, see ref 1i. (c)
Gilbert, M.; Ferrer, M.; Sanchez-Baeza, F.; Messeguer, A. Tetrahedron
1997, 53, 8643.
Reactions of allene-derived spirodiepoxides that deviate
from what would be expected based on earlier reports
(8) Meek, J. S.; Fowler, J. S. J. Org. Chem. 1968, 33, 3422.
(9) For example, see: Malosh, C. F.; Ready, J. M. J. Am. Chem. Soc.
2004, 126, 10240.
(10) Exceptions are known, see ref 1b, 1d, 1h, and 1i.
(11) Crandall, J. K.; Batal, D. J.; Sebesta, D. P.; Ling, F. J. Org.
Chem. 1991, 56, 1153. The history of the tetraalkyl ammonium reagent
appears to strongly influence reproducibility.
€
(5) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. The
authors make the distinction between multicomponent reactions
(MCRs) and sequential component reactions (SCRs). The transforma-
tions described in the present work are properly characterized as SCRs.
(6) Enantioenriched allenes are readily prepared from enantioen-
riched propargyl alcohols with this procedure, beginning at step 3,
Table 1.
(12) Cf. Westermaier, M.; Mayr, H. Chem.;Eur. J. 2008, 14, 1638.
Org. Lett., Vol. 13, No. 13, 2011
3353

Table 2. Simple Nucleophile Additiona
Table 3. Complex Nucleophile Additiona
a Step 1: DMDO, CHCl3, ꢀ40 °C, 30 min. b Step 2: PhSO2Na (1.5
equiv), 15-crown-5 (1.5 equiv), THF 0 °C to rt, 5 h. c Step 2: NaH (1.5
equiv), CF3CH2OH, 0 °C to rt, 1 h. d Step 2: n-BuLi (3.0 equiv), indole
(3.0 equiv), THF, ꢀ78 to 0 °C, 4 h. e Step 2: TBAF (2.0 equiv), THF, 0 °C
to rt, 4 h. f Step 2: Benzyltrimethylammonium chloride (2.0 equiv), THF,
0 °C to rt, 4 h. g Step 2: TBAB (2.0 equiv), THF, 0 °C to rt, 4 h. h Step 2:
LiX (X = Cl, Br; 3.0 equiv), THF, 0 °C to rt, 4 h, i Step 2: Lil (10.0 equiv),
CHCl3, 0 °C to rt, 4 h.
ketone is isolated. In contrast, ambiphilic isonitriles follow
a different course. The combination of n-butylisonitrile in
t-BuOH and the epoxidized allene led to the slow but
efficient formation of dihydrofuranone (Table 3, entry 2).
The outcome is consistent with formation of nitrilium ion
intermediate IV (eq 2), cyclization to V, and then isomer-
ization of the olefin. This mild transformation is remark-
able, especially since spontaneous opening of conventional
epoxides with isonitriles is unknown.13
a Step 1: DMDO, CHCl3, ꢀ40 °C, 30 min. b Step 2: LDA (3.0 equiv),
CH3CN (3.0 equiv), ꢀ78 to 0 °C, 4 h. c Step 2: n-BuNC (10 equiv),
t-BuOH, rt, 2 d. d Step 2: Diethyl malonate (1.5 equiv), NaH (1.5 equiv),
0 °C to rt, 4 h. e Step 2: (EtO)2OPCH2CO2H (2.0 equiv), K2CO3 (6.0
equiv), 18-C-6 (2 equiv), rt, 4 h. f Step 2: LiCHCH2 (4.0 equiv), 0 °C to rt,
2 h. g Step 2: n-BuLi (4.0 equiv), HCCR (R = Bu, TMS; 4.0 equiv), ꢀ78
to 0 °C, 2 h. h Step 2: LiCHCH2 (4.0 equiv), 0 °C to rt, 1 h; HMPA
(20 equiv), 0 °C to rt, 1 h.
Conceptually similar to the isonitrile reaction, and as
shown in Table 3, entry 3, the use of diethyl malonate and
sodium hydride established new CꢀC, CꢀO, and new ring
connectivity;and a new stereocenter (dr 6:1).14 Table 3,
entry 4 demonstrates a different reaction cascade. Expo-
sure of the spirodiepoxide to2-(diethoxyphosphoryl)acetic
acid in the presence of K2CO3 and crown ether gave the
butenolide. In this case, the nascent tertiary alkoxide is
parlayed into a new CꢀC bond: upon addition of the
carboxylate to the spirodiepoxide resultant alkoxide VI
(eq 3) acts as base and generates the ylide, which then
effects ring closure to give butenolide VII.15
In previous work, organocuprates were necessary to
promote nucleophilic opening over eliminative opening.1d,g
However, we have found that vinyl and alkynyl lithium
(13) (a) Imi, K.; Yanagihara, N.; Utimoto, K. J. Org. Chem. 1987, 52,
1013. (b) Kern, O. T.; Motherwell, W. B. Chem. Commun. 2003, 24, 2988.
(c) The analogous reaction where neat DMF was used, instead of 30
equiv of n-butyl isonitrile, gave the formate addition product in 83%
yield; see Supporting Information for details.
(14) Cf. the reaction of malonates with epoxides: Van Zyl, G.; Van
Tamelen, E. E. J. Am. Chem. Soc. 1950, 72, 1357.
(15) The formation of a highly basic species by the release of ring
strain is well known, as in the Favorskii rearrangement. See: Guijarro,
D.; Yus, M. Curr. Org. Chem. 2005, 9, 1713.
3354
Org. Lett., Vol. 13, No. 13, 2011

reagents add directly and efficiently to spirodiepoxides in the
absence of copper(I) salts (Table 3, entries 5ꢀ7). This result
appears traceable to the reduced basicity of these organo-
lithium reagents in comparison to alkyl lithium reagents.
Unlike less reactive nucleophiles, these reagents add twice (cf.
Table 3, entry 1), initially to the spirodiepoxide and then to
the carbonyl produced upon spirodiepoxide opening. In each
instance, a single diastereomer was obtained, indicative of
stereoselective carbonyl addition. This outcome appears
readily understood in terms of steric congestion. It is likely
that, upon spirodiepoxide opening, the lithium alkoxide is
involved in chelation with the carbonyl of VIII (eq 4). The
Table 4. Nucleophile Additiona
combination of steric congestion and the comparatively
small alkynyl and alkenyl substituents favor π-facial addi-
tion, as drawn, to giveIX.16 Exposure of the divinyl addition
reaction mixture of Table 3, entry 5 to HMPA, instead of the
workup conditions that gave the diendiol product, effected
the formation of the cis-olefin shown in Table 3, entry 8. The
facility of this EvansꢀCope rearrangement17 is consistent
with solvent destabilization of the vicinal tertiary lithium
alkoxides. Reaction by way of conformers that avoid syn-
pentane interactions accounts for the cis-olefin geometry as
shown for X (eq 5).18
a Step 1: DMDO, CHCl3, ꢀ40 °C, 30ꢀ120 min. b Step 2: LiX (X =
Br, I; 10.0 equiv), CHCl3, 0 °C to rt, 2 h. c Step 2: n-BuNC (30 equiv),
t-BuOH, rt, 5 d. d Step 2: (EtO)2OPCH2CO2H (2.0 equiv), K2CO3 (6.0
equiv), 18-C-6 (6.0 equiv), rt, 4 h.
conditions as before. The yields for these substrates are
excellent and parallel the yields of the simpler allene.
Importantly, the reactions described in Tables 1ꢀ4 have
been run on scales ranging from ∼20 mg to >1 g. As noted
above in eq 1, despite the sometimes low selectivity in the
second oxidation, the first oxidation stereoselectivity is
excellent. As such, the first oxidation for the entries in
Table 4 was >20:1, and where relevant, the second oxida-
tion was modest (dr ∼3:2). Nevertheless, the overall
structural complexity achieved for these reactions is
remarkable.19
The motifs accessed and tabulated in this report were
obtained in one or two flask procedures. The combina-
tion of alkynes, aldehydes, and cuprates gives allenes
directly and in good yield. In a second maneuver, allene
epoxidation and subsequent reaction give diverse pro-
duct motifs of considerable use in complex molecule
synthesis and the search for bioactive compounds.
These data underscore the distinct reactivity and con-
sequences of allene oxidation/derivatization for chemi-
cal synthesis.
Taken together, Tables 2 and 3 demonstrate the conver-
sion of a single allene to a diverse range of products via
oxidation/derivatization reactions. To further demonstrate
a diversity-focused methodology, we evaluated three other
allenes in four of the reactions described in Tables 2 and 3.
The allenes were taken from Table 1, entries 2, 3, and 8, and
include those with aromatic and common heterofunction-
ality. The transformations examined were the oxidation/
bromide and oxidation/iodide additions (Table 4, entries 1
and 2) and the oxidation/dihydrofuranone and oxidation/
butenolide cascades (Table 4, entries 3 and 4) under the same
(16) Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828.
(b) Cram, D. J.; Greene, F. D. J. Am. Chem. Soc. 1953, 75, 6005. (c)
Cram, D. J.; Wilson, D. R. J. Am. Chem. Soc. 1963, 85, 1245. (d)
Fleming, I.; Hill, J. H. M.; Parker, D.; Waterson, D. J. Chem. Soc.,
Chem. Commun. 1985, 318. (e) Mengel, A.; Reiser, O. Chem. Rev. 1999,
99, 1191. The π-facial selectivity of ketones of this type have not been
evaluated previously.
Acknowledgment. Financial support from the NIH
(GM-078145) and preliminary experiments by Jennifer In-
grhim (Bristol-Myers Squibb) are gratefully acknowledged.
(17) Evans, D. A.; Golob, A. M. J. Am. Chem. Soc. 1975, 97, 4765. (b)
Evans, D. A.; Baillargeon, D. J.; Nelson, J. V. J. Am. Chem. Soc. 1978,
100, 2242. (c) Paquette, L. A. Tetrahedron 1997, 53, 13971.
(18) The cis olefin product is also consistent with the stereochemical
assignments of the products of entries 5ꢀ7 (Table 3).
Supporting Information Available. Synthetic methods
and characterization data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(19) Reagent-controlled diastereoselective allene oxidation will
be described separately (Hu, G.; Williams, L. J. Manuscript in
preparation).
Org. Lett., Vol. 13, No. 13, 2011
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