Acylammonium salts as dienophiles in diels-alder/lactonization organocascades

Article abstract of DOI:10.1021/ja501005g

α,I?-Unsaturated acylammonium salts, generated in situ from commodity acid chlorides and a chiral isothiourea organocatalyst, comprise a new and versatile family of chiral dienophiles for the venerable Diels-Alder (DA) cycloaddition. Their reactivity is unveiled through a highly diastereo- and enantioselective Diels-Alder/lactonization organocascade that generates cis- and trans-fused bicyclic I?- and I??-lactones bearing up to four contiguous stereocenters. Moreover, the first examples of DA-initiated, stereodivergent organocascades are described delivering complex scaffolds found in bioactive compounds. The origins of stereoselectivity are rationalized through computational studies. In addition, the utility of this methodology is demonstrated through a concise approach to the core structure of glaciolide and formal syntheses of fraxinellone, trisporic acids, and trisporols.

Full text of DOI:10.1021/ja501005g

Communication
pubs.acs.org/JACS
Acylammonium Salts as Dienophiles in Diels−Alder/Lactonization
Organocascades
Mikail E. Abbasov,† Brandi M. Hudson,‡ Dean J. Tantillo,‡ and Daniel Romo*,†
†Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, Texas 77842-3012, United States
‡Department of Chemistry, University of CaliforniaDavis, One Shields Avenue, Davis, California 95616, United States
S
* Supporting Information
demonstrated the full potential of chiral, triply reactive, α,β-
ABSTRACT: α,β-Unsaturated acylammonium salts, gen-
erated in situ from commodity acid chlorides and a chiral
isothiourea organocatalyst, comprise a new and versatile
family of chiral dienophiles for the venerable Diels−Alder
(DA) cycloaddition. Their reactivity is unveiled through a
highly diastereo- and enantioselective Diels−Alder/lacto-
nization organocascade that generates cis- and trans-fused
bicyclic γ- and δ-lactones bearing up to four contiguous
stereocenters. Moreover, the first examples of DA-initiated,
stereodivergent organocascades are described delivering
complex scaffolds found in bioactive compounds. The
origins of stereoselectivity are rationalized through
computational studies. In addition, the utility of this
methodology is demonstrated through a concise approach
to the core structure of glaciolide and formal syntheses of
fraxinellone, trisporic acids, and trisporols.
unsaturated acylammonium salts for the rapid assembly of
complex cyclopentanes8c and optically active γ-lactams and
piperidones.8d Inspired by these studies, we sought to explore
the reactivity of α,β-unsaturated acylammonium salts as
dienophiles in DA reactions anticipating that these inter-
mediates might emulate the electronic properties of activated
dienophiles.
To test the reactivity of α,β-unsaturated acylammonium salts
as dienophiles, we targeted the synthesis of cis- and trans-fused
bicyclic γ- and δ-lactones which are ubiquitous structural motifs
found in bioactive terpenoids and pharmaceuticals (Figure 1a).
ransformations that rapidly generate complex and
Tstructurally diverse molecular architectures are essential
components of modern organic chemistry.1 In this regard, the
Diels−Alder (DA) cycloaddition is arguably the most versatile
and powerful transformation in chemical synthesis.2 In
particular, catalytic asymmetric DA reactions are unparalleled
in their ability to rapidly and efficiently generate optically active,
architecturally complex, and densely functionalized heterocycles
and carbocycles from simple achiral substrates.3 Furthermore,
enantioselective organocatalytic DA variants have recently been
established using iminium,4 enamine,5 bifunctional acid−base
catalysis,6 and hydrogen-bonding catalysis.7 MacMillan and co-
workers employed both α,β-unsaturated aldehydes4a and
ketones4b in cycloadditions through iminium-activated chiral
dienophiles, whereas α,β-unsaturated aldehydes7b and indoli-
nones7c were activated through hydrogen-bonding catalysis by
Rawal and Barbas, respectively. Surprisingly, however, simple
acid chlorides have yet to be successfully employed in
organocatalyzed DA reactions. Herein, we report the first
enantioselective organocatalytic DA reactions with α,β-
unsaturated acid chlorides activated in situ by a chiral
isothiourea catalyst.
Figure 1. (a) Selected natural products and pharmaceuticals
containing or derived from cis- or trans-fused bicyclic γ- or δ-lactones.
(b) The described organocatalytic Diels−Alder/lactonization cascade
sequence.
We envisioned that this bicyclic architecture could be
constructed in a single operation by a Diels−Alder/
lactonization (DAL) cascade between acylammonium salts,
generated in situ from acid chlorides or carboxylic acids
(activated in situ) 1, a chiral tertiary amine organocatalyst, and
rationally designed dienes 2 (Figure 1b). We recognized the
potential for further stereochemical diversity if racemic dienes
bearing a pendant carbinol, e.g., ( )-2 (R6 ≠ R7), could
participate in an unprecedented DA-initiated, stereodivergent9
organocascade. This process could proceed through catalyst
The potential of α,β-unsaturated acylammonium catalysis
was first realized by Fu in asymmetric, net [3+2] annulations
leading to diquinanes.8a Building on this early work, Smith
recently employed mixed anhydrides as α,β-unsaturated
acylammonium precursors for the direct synthesis of
dihydropyranones and dihydropyridones.8b Furthermore, we
Received: January 31, 2014
Published: March 3, 2014
© 2014 American Chemical Society
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control during the DA step, independent of the resident
stereocenter, and the subsequent lactonization step would
generate diastereomeric lactones 3 with distinct topologies that
could facilitate chromatographic separation, a common
challenge for stereodivergent processes.
exo), while enantioselectivities ranged from 91 to 99% ee
(Scheme 1).
a
Scheme 1. Enantioselective DAL Organocascade
We initiated our studies of the DAL organocascade with a
Danishefsky diene 2a bearing a tethered tertiary alcohol to
minimize competitive acylation while providing greater
reactivity and synthetic versatility.10 In the absence of a
nucleophilic promoter, a significant background DAL proceeds
with ethyl fumaroyl chloride (1a) to afford an inseparable
mixture of endo/exo diastereomers of bicyclic γ-lactones 3a and
3a′ in 21% yield (Supporting Information (SI), Table S1).
A catalyst screen revealed that chiral isothioureas11 were
superior (Table 1a) with best results obtained using
a
Table 1. Selected Optimization Studies of the DAL
a
Yields refer to isolated, purified products; endo/exo ratios determined
by 1H NMR analysis; ee determined by chiral-phase HPLC.
†(−)-BTM (10 mol%) was used. ‡(+)-BTM (20 mol%) was used.
§(−)-BTM (5 mol%) was used.
Cis-fused bicyclic γ-lactones 3b−h were readily obtained
from (E)-dienes with both α- and β-substituted acid chlorides.
Use of crotonoyl chloride (1c) and methacryloyl chloride (1d)
led to less reactive acylammonium dienophiles, as reflected in
reduced yields of cycloadducts (−)-3g and (−)-3h; however,
enantioselectivity was maintained. Use of a (Z,Z)-configured
diene 2e produced the trans-fused bicyclic γ-lactone (+)-3i in
48% yield (99% ee) despite the unfavorable conformation that
typically impedes effective cycloaddition.13 Variation in tether
length of the pendant alcohol as in diene 2f (n = 1) afforded
the bicyclic δ-lactone (+)-3j in 54% yield (92% ee). Use of the
enantiomeric isothiourea catalyst, (+)-BTM, provided the
enantiomeric lactone (+)-3f in 71% yield (96% ee). Lowered
catalyst loadings of 10 and 5 mol% gave cis- and trans-fused
bicyclic γ-lactones (−)-3c and (+)-3i with similar levels of
enantioselectivity but diminished yields. In these cases, lower
yields were due to decomposition of dienes and irreversible
acylation of the tethered alcohol moiety leading to dienyl esters
(e.g., see SI, p S21). The preparative utility of the DAL was
demonstrated by two gram-scale reactions affording 1.4 g of
(−)-3c (68% yield) and 4.0 g of (−)-3d (84% yield).
Given the terminal lactonization step, we reasoned that a
stereodivergent resolution of a racemic diene possessing a
pendant stereogenic carbinol using the DAL strategy would be
feasible. Indeed, reaction of racemic diene ( )-2g bearing a
pendant, secondary alcohol delivered readily separable fused,
tricyclic γ-lactones (−)-3k (50% yield, 99% ee) and (−)-3k′ in
(35% yield, 99% ee) which are useful intermediates toward
compactin14 and forskolin.15 The stereochemistry of (−)-3k
and (−)-3k′ was assigned by X-ray analysis; in the latter case
following cleavage with 4-bromobenzylamine (Scheme 2a,
insets; Figures S1 and S2).
a
Yields of isolated, purified products; endo/exo ratios determined by
1H NMR analysis; ee determined by chiral-phase HPLC and only
shown for endo diastereomer (see SI for details). Reaction conditions:
(a) 1a, 2a, 2,6-lutidine, CH2Cl2; (b) 1b, 2b, (−)-BTM, CH2Cl2; (c)
1b, 2b, DTBP, (−)-BTM. DTBP = 2,6-di-tert-butylpyridine.
benzotetramisole, (−)-BTM.11b Extending addition times of
1a through syringe pump addition ensured high enantio-
selectivity (Table S1, entries 9, 11) presumably by enabling the
asymmetric DAL to compete effectively with the racemic
background pathway. Further optimization studies revealed that
endo/exo selectivity was highly dependent on the Brønsted base
and also that pendant primary alcohols were tolerated. Thus,
we next screened various Brønsted bases with diene 2b, acid
chloride 1b, and (−)-BTM as catalyst (Table 1b). Generally,
pyridine bases afforded superior levels of enantioselectivity
(Table S2, entries 6−15), while substantial steric bulk adjacent
to the pyridine nitrogen suppressed formation of the exo
diastereomer with concomitant reduction in yield (Table S2,
entry 8). Use of a shuttle base12 was successful and delivered 3b
in 64% yield (95% de, 99% ee). Finally, a solvent screen
revealed that chlorinated solvents provided the highest levels of
diastereo- and enantioselectivity (Table 1c; Table S3, entries
8−10).
The scope of the DAL was studied under optimized
conditions with dienes 2b−f and commercially available acid
chlorides 1a−d possessing varying electronic and steric
properties. Diastereoselectivities were consistent (>19:1 endo/
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lactone (−)-4 corresponding to the core of glaciolide,16a
a
a
Scheme 2. Stereodivergent DAL Organocascades
degraded and rearranged diterpenoid, via regioselective α-
methylation. Direct α-selenylation of silyl enol ether (−)-3h
followed by oxidative elimination delivered enone (−)-5, an
intermediate previously employed as a racemate toward
fraxinellonone,16b and the fungal pheromones, trisporic acids
and trisporols.16c
To understand the origins of the enantio- and diastereo-
selectivity induced by (−)-BTM, all four possible transition
state structures (TSSs) for the catalyzed DAL were compared
to each other and to background DA cycloadditions proceeding
directly with acid chloride. Analysis of the lowest energy
conformations of each TSS indicates a kinetic preference (1−2
kcal/mol) for endo approach (Figure 2) and an even larger
a
Yields and ratios of isolated, purified products; ee determined by
chiral-phase HPLC. Insets are single crystal X-ray structures in
ORTEP format (50% probability; TIPS and 4-bromobenzyl groups are
removed for clarity). Reaction conditions: 4-BrC6H4CH2NH2, THF,
23 °C, 36 h (73%). †Reaction performed with carboxylic acid 1e
activated in situ by TsCl (SI, p S35).
Figure 2. Calculated transition structures for the DA step of the DAL
optimized at the M06‑2X/6‑31G(d) level with an implicit solvent
model [SMD (dichloromethane)]. Gibbs free energies in kcal/mol
shown are relative to the reactants. Selected bond distances are shown
(Å).
During optimization studies, we noted the profound impact
of the Brønsted base on endo/exo selectivities, and sought
access to trans-fused bicyclic lactones through judicious
combination of a Lewis and Brønsted base to enhance exo
selectivity. Indeed, use of 2,6-lutidine (3.0 equiv) with
(−)-BTM and diene 2b altered the endo/exo selectivity to
furnish readily separable cis- and trans-fused bicyclic γ-lactones
(−)-3c (37%, 99% ee) and (+)-3c′ (35%, 99% ee) (Scheme
1b). We cannot speculate regarding the origins of this Brønsted
base dependence at this time, however we are investigating this
phenomena further through both experimentation and
computation. We also studied in situ activated carboxylic
acids in this context, to expand the substrate repertoire of the
DAL, and found that activation of mono-ethyl fumarate (1e)
with TsCl afforded (−)-3c and (+)-3c′ with identical
enantiopurity but slightly reduced yields. The absolute
configuration of bicyclic γ-lactone (+)-3c′ was determined by
X-ray anomalous dispersion (Figure S3). These data, in
conjunction with detailed 2D NMR analysis and both predicted
and calculated (vide infra) lowest energy transition states,
enabled assignment of relative and absolute configurations of
cycloadducts 3b−j.
preference (>5 kcal/mol) for approach of diene from the
bottom face of the dienophile opposite the phenyl substituent
of (−)-BTM, leading to the observed major enantiomer (SI, pp
S49−S130).
This selectivity model is predicated on a preference for a
close contact between the carbonyl oxygen and sulfur atom of
the catalyst restricting rotation about the C−N bond of the
acylammonium salt (see inset, Scheme 4). Such a preference is
indeed found in isolation (2.81 Å) and in the TSSs (2.81 and
2.77 Å, endo/exo, respectively). The apparent S−O attraction
for isothiourea catalysts17 appears in this case to be driven by a
combination of orbital interactions (probed with NBO; Figures
S9 and S10), in particular, lone pairS ↔ σ*C−H/σC−H
interactions that disfavor the alternative conformation with a
Scheme 4. Postulated Reaction Pathway for the DAL
We next sought to demonstrate the utility of the
enantioenriched lactones obtained through the DAL (Scheme
3). Bicyclic γ-lactone (−)-3d was converted to α,α-dimethyl-
Scheme 3. Synthetic Utility of Bicyclic γ-Lactones
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* Supporting Information
Experimental and characterization details for all new com-
pounds, computational data, crystallographic data, HPLC
traces, and NMR spectra. This material is available free of
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AUTHOR INFORMATION
■
Corresponding Author
romo@tamu.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support from NSF (CHE-1112397 to D.R.; CHE-030089 with
XSEDE to D.J.T.) and the Robert A. Welch Foundation (A-
1280 to D.R.), ACS PRF (52801-ND4 to D.J.T.), and partial
support from NIH (GM 052964 to D.R.) and the U.S.
Department of Education (GAANN Fellowship to B.M.H), is
gratefully acknowledged. Drs. Nattamai Bhuvanesh and Joe
Reibenspies (Center for X-ray Analysis, TAMU) secured
structural data, and Dr. Bill Russell (Laboratory for Biological
Mass Spectrometry, TAMU) provided mass data.
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