Mechanistically Inspired Route toward Hexahydro-2H-chromenes via Consecutive [4 + 2] Cycloadditions

Article abstract of DOI:10.1021/acs.orglett.6b01742

Utilizing two robust C-C bond-forming reactions, the Baylis-Hillman reaction and the Diels-Alder reaction, we report a highly enantio-, regio-, and diastereoselective synthesis of hexahydro-2H-chromenes via two sequential [4 + 2] cycloadditions. These tandem and formal cycloadditions have also been performed as a "one-pot" sequence to access the corresponding heterocycles constituting up to five contiguous stereocenters in excellent yields and stereoselectivity.

Full text of DOI:10.1021/acs.orglett.6b01742

Letter
pubs.acs.org/OrgLett
Mechanistically Inspired Route toward Hexahydro‑2H‑chromenes via
Consecutive [4 + 2] Cycloadditions
Kumar Dilip Ashtekar,† Xinliang Ding,† Edmond Toma, Wei Sheng, Hadi Gholami, Christopher Rahn,
Paul Reed, and Babak Borhan*
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
S
* Supporting Information
ABSTRACT: Utilizing two robust C−C bond-forming reactions, the
Baylis−Hillman reaction and the Diels−Alder reaction, we report a
highly enantio-, regio-, and diastereoselective synthesis of hexahydro-
2H-chromenes via two sequential [4 + 2] cycloadditions. These
tandem and formal cycloadditions have also been performed as a
“one-pot” sequence to access the corresponding heterocycles
constituting up to five contiguous stereocenters in excellent yields and stereoselectivity.
The approach described above requires a facile strategy for the
lthough the synthesis of hexahydro-2H-chromenes (4) can
1
Abe achieved through a number of strategic disconnections, synthesis of dihydropyrans with the general structure depicted in
3 in high enantioselectivity. A number of groups, including ours,
have addressed this requirement.2 Our endeavor in this field
commenced with the early discovery for the mechanistically
guided synthesis of substituted dihydropyrans.2e As shown in
Scheme 1, we circumvent the rate-limiting proton transfer
associated with the Baylis−Hillman reaction of enones and
allenoates (path A, 2d → 2e),3 by utilizing acyclic enones (1) as
secondary electrophiles. The relatively fast intramolecular
trapping of the oxyanion 2f siphons the reaction toward
formation of the corresponding dihydropyran 3 in high yields
and enantioselectivity via path B (modified Baylis−Hillman
route4). We predicted that a similar transformation initiated with
a symmetric chalcone (such as 1, Scheme 1) would yield the
required diene 3 for the proposed Diels−Alder reaction.
Furthermore, we surmised that the enantioenriched C4
substituent in 3 would serve as a stereochemical driver in the
concomitant [4 + 2] cycloaddition. The conjugated diene motif
in 3 displays a unique integration of two key features: (a) the
extended cross-conjugation of the pyranyl oxygen atom (O1)
results in an electronic bias that may allow regioselective trapping
of a unsymmetrically substituted dienophile and (b) the
nucleophilic carbon (C5) and the stereochemical driver (C4
substituent), both being part of a conformationally rigid cyclic
framework, may allow an easy access to diastereoselective [4 + 2]
cycloadditions. The latter hypotheses were readily examined by
subjecting a model substrate, dibenzalacetone 1a, to the catalytic
asymmetric formal [4 + 2] cycloaddition under an optimized set
of conditions (Scheme 2). Initial screening with several chiral
amines revealed A and B as optimum catalysts for the synthesis of
oxatriene 3a-(S) and 3a-(R), respectively. Using catalyst A under
solvent-free conditions, oxatriene 3a-(S) was obtained in 98%
yield and 98% ee. Subsequent treatment of this oxatriene with
we sought to explore a rapid assembly, as depicted retrosyntheti-
cally in Scheme 1. The enantioenriched precursor diene (3),
required for the concomitant Diels−Alder reaction, would be
obtained via a chiral amine catalyzed modified Baylis−Hillman
reaction of allenoate 2 with chalcone 1 that precedes a formal [4 +
2] cycloaddition. The latter strategy provides an expedient route
toward substituted hexahydro-2H-chromenes with high stereo-
selectivity via two consecutive [4 + 2] cycloaddition reactions.
Scheme 1. (Top) Retrosynthetic Strategy for the Synthesis of
Hexahydro-2H-chromenes. (Bottom) Paths A and B
Represent a Simplified Mechanistic Picture of the Canonical
a
vs the Modified Baylis−Hillman Pathway
a
Possible resonance structures of the amine−allenoate adduct are
Received: June 15, 2016
shown in the dashed box with 2a being the major contributor.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01742
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Preliminary Results for Consecutive [4 + 2]
Cycloadditions under Optimized Conditions Using
a c
−
Dibenzalacetone (1a) as a Test Substrate
a
b
c
Isolated yields. Ratios were determined by HPLC analysis. Reaction
was performed using 1 g (4.3 mmol) of 1a.
maleic anhydride 4a furnished the stereopentad 5aa as a single
diastereomer in 78% yield. This offers an alternate approach to
previous explorations5 directed toward controlling stereo-
selectivity in cycloadditions of dienes bearing an allylic chiral
center.6
Figure 1. (a) Two diastereomeric transition states TS-1 and TS-2
calculated at the B3LYP/6-31G*/SM8(toluene) level of theory. The
bonds highlighted in red color depict the unfavorable gauche
interactions in TS-2. (b) Three possible transition states associated
with the [4 + 2] cycloaddition of 3a-(S) and 4a. TS-3(endo) is favored by
2.8 kcal/mol over TS-4(exo) and by 1.8 kcal/mol over TS-5(endo). The
fourth possible TS involving an exo approach of 4a from the same face as
the C4-Ph substituent cannot be calculated due to severe steric clash
between the approach dienophile and the aromatic ring.
Intrigued by the levels of stereoinduction, especially in the
latter cycloaddition, we decided to probe the origins of
stereoselectivity by employing quantum chemical computational
analysis of the transition states (TS) at the B3LYP/6-31G*/SM8
(toluene) level of theory.7 Hydroquinidine (instead of catalyst A)
was employed to reduce the computational expense. In
accordance with the previous findings,2e the diastereomeric
transition state TS-1 (Figure 1a), which provides the product 3a-
(S), was favored by 2.7 kcal/mol (corresponding to er = 99:1).
The steric congestion (gauche interactions highlighted by bonds
in red color) and the diminished electrostatic stabilization (as
determined by the COδ−···δ+NR4 distance) in TS-2 make it
energetically less favorable than TS-1. The computational
analysis corroborates the experimental observation in the initial
[4 + 2] cycloaddition (98% ee using the hydroquinidine based
catalyst-A, see the SI for details). We next examined the
stereoinduction associated with the Diels−Alder reaction of 3a-
(S) with maleic anhydride 4a. In agreement with the
experimentally observed endo-selectivity,5e,8 TS-3endo was found
to be more favored over TS-4exo by 2.8 kcal/mol (Figure 1b). TS-
4exo also suffers from the electrostatic repulsion between the π-
cloud of the C4 phenyl substituent in 3a-(S) and the electron
density on the proximal carbonyl of 4a (see the SI for details).
Furthermore, the corresponding TS-5endo that involves the
approach of dienophile 4a from the sterically hindered face of
the diene is disfavored over TS-3endo by 1.8 kcal/mol (see dashed
box in Figure 1b). Although the B3LYP/6-31G* level of theory
underestimates the energetics of secondary interactions in the
Diels−Alder reaction,9 it clearly depicts the correct energetic
trend as observed experimentally.10 Overall, the stereochemistry
at C4, obtained from the Baylis−Hillman reaction, governs the
stereospecificity in the concomitant Diels−Alder reaction.
The mechanistic nuances underlying the modified Baylis−
Hillman reaction of allenoates (primary electrophile) with
dibenzalacetone (secondary electrophile) are more complex
than the simplified picture depicted in Scheme 1, leading to the
following central question. Despite the possibility for the
formation of several theoretical adducts (based on the relative
reactivity of the primary and secondary electrophile), which
factor governs the formation of 3 as the predominant product?
To address this question, the identity of stable intermediates that
arise during the reaction of 1a with 2, catalyzed by quinuclidine C
(an achiral surrogate of catalysts A and B), were investigated by
ESI-MS (Figure 2). A nucleophilic attack of the Lewis base
catalyst C on allenoate 2 generates the zwitterionic intermediate
2/C. The resulting enolate can attack another molecule of 2 to
furnish the intermediate 22/C. Sequential additions of 2 will yield
the trimeric adduct 23/C and higher oligomers that constitute
several polymeric adducts in equilibrium. This is indeed
supported by ESI-MS analysis of a preincubated mixture of C
and 2 (Figure 2b). When this mixture was treated with the
secondary electrophile 1a, intermediates 1a-2/C en route to
product 3a and higher order adduct 1a-22/C were observed
(Figure 2c).11 This study suggests that the reaction of 1a, 2, and C
indeed yields a mixture of several adducts in equilibrium;
however, the irreversibility associated with the ring-closure step
(see dashed box, Figure 2a) adventitiously siphons the
equilibrium mixture to the desired cycloadduct 3a.
To explore the scope of this reaction, a series of substituted
dibenzalacetones (1a−p) were reacted with allenoate 2 under
solvent-free conditions (see Table 1). Catalysts A and B (see
B
DOI: 10.1021/acs.orglett.6b01742
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Substrate Scope for Enantioselective Synthesis of
Substituted Oxatrienes
a
b
entry
1
R
cat. product time (h) yield (%) ee (%)
c
Ph
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
3a-S
3a-R
3b-S
3b-R
3c-S
3c-R
3d-S
3d-R
3e-S
3e-R
3f-S
40
8
98
74
60
65
98
87
25
20
75
68
43
57
78
71
95
95
66
32
99
89
58
36
27
32
76
69
98
87
90
82
96
88
94
76
88
82
94
72
92
88
88
78
94
72
90
84
91
88
95
78
92
72
90
67
94
58
90
72
d
d
2
o-OMeC6H4
m-OMeC6H4
p-OMeC6H4
o-MeC6H4
p-MeC6H4
o-FC6H4
60
60
12
12
60
60
40
10
60
60
48
48
30
30
40
40
25
25
48
48
48
48
40
40
72
72
72
72
36
36
3
d
d
4
5
d
d
6
Figure 2. (a) Equilibrium mixture of putative intermediates in the
Baylis−Hillman reaction of 1a and 2. For simplicity, intermediates
arising only from the γ-attack of the enolate are shown. (b) ESI-MS
spectrum of a reaction mixture (preincubated for 30 min) constituting of
a 1:2 ratio of C and allenoate 2. (c) ESI-MS spectrum obtained after 1 h
upon addition of 1a to the mixture of C and 2.
3f-R
3g-S
3g-R
3h-S
3h-R
3i-S
7
8
o-BrC6H4
p-BrC6H4
o-ClC6H4
p-ClC6H4
2-furyl
9
3i-R
3j-S
Scheme 2) were employed to access either enantiomer of the
corresponding oxatrienes 3a−p. Overall, catalyst A displayed
better efficiency and stereoinduction over catalyst B. Regardless
of the electronics of the substituents attached; i.e., electron-
donating aryl (entries 2−6 and 13), electron-withdrawing aryl
(entries 7−12), and even aliphatic substituents (entries 14−16),
excellent enantioinduction was observed with catalyst A.12 The
X-ray crystal structures of derivatives of 3b-(S) and 3j-(S)
provided unequivocal evidence for the absolute stereochemistry
of the products obtained using catalyst A (see Scheme 3, dashed
box). These results also corroborated the quantum chemical
computational analysis (Figure 1a) that revealed the absence of a
gauche interaction (sterics) in TS-1 is responsible for favoring the
(S)-enantiomer.
e
10
11
12
13
14
15
16
3j-R
3k-S
3k-R
3l-S
3l-R
3m-S
3m-R
3n-S
3n-R
3o-S
3o-R
3p-S
3p-R
1-naphthyl
n-propyl
d
d
d
d
,
,
,
,
f
f
f
f
28 (52)
24 (50)
29 (87)
23 (80)
48
isopropyl
Me
26
As a proof of principle, we briefly explored the ability of these
oxatrienes to govern regio- and stereoinduction in the Diels−
Alder reaction. Scheme 3 summarizes the results of 11
cycloaddition reactions of dienes 3a-(S), 3b-(S), 3c-(S), and
3j-(S) with an illustrative set of dienophiles 4a−d. Dienophiles 4a
and 4b exhibited exclusive diastereoselective addition, whereas 4c
and 4d displayed excellent regioselection. Furthermore, these
sequential transformations (Baylis−Hillman reaction followed
by a concomitant Diels−Alder reaction) were also performed
efficiently as a “one-pot” domino reaction (see Scheme 3 for
products 5aa and 5ab). As anticipated, the cross-conjugation of
the endocyclic oxygen (O1) not only enhances the HOMO
energy of the diene motif in 3 but also generates an electronic bias
that allows regiospecific trapping of the dienophiles 4c and 4d,
thus validating the initial hypothesis. Of interest is the reaction of
3a with 4d, which led to an isomeric mixture of products 5ad and
6ad in nearly equimolar ratios. Fortuitously, upon treatment with
DBU in refluxing DCM, the mixture was cleanly converted to
yield the endocyclic product 6ad in high diastereo- and
regioselectivity. Unlike the products of other Diels−Alder
reactions depicted in Scheme 3, 6ad (and for that matter 5ad)
is the result of an exo [4 + 2] cycloaddition (see SI for
stereochemical assignment based on NMR studies). Although we
see no evidence of the endo product during the course of the
a
b
Isolated yields. Ratios were determined by HPLC analysis using
c
chiral stationary phase columns. Reaction was performed on a 1 g
scale of 1a. Longer reaction times led to degradation of allenoate 2,
and incomplete conversion of dienones was observed. Reaction was
performed on a 0.5 g scale of 1j. Numbers in parentheses refer to yield
d
e
f
based on recovered starting material.
reaction, we cannot exclude the possibility of either epimerization
at C6 or a reversible Diels−Alder process that ultimately settles
for the thermodynamic product.
In summary, a two-step process is reported for the synthesis of
hexahydro-2H-chromenes. The asymmetric Baylis−Hillman
reaction provides the dihydropyrans in high stereoselectivity.
The ensuing Diels−Alder reaction is also under strict regio- and
stereochemical control. The C4 stereocenter, established during
the initial [4 + 2] cycloaddition, is the stereochemical driver,
whereas the cross-conjugation of pyranyl oxygen (O1) aids to
generate an electronic bias for the observed regioselectivity in the
Diels−Alder reaction. This methodology provides a comple-
mentary approach to control the stereochemistry in Diels−Alder
reactions of chiral dienes:5b,f,h,i unlocking opportunities toward
expanding the repertoire of stereo- and regioselective reactions of
chiral dienes.
C
DOI: 10.1021/acs.orglett.6b01742
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Diels−Alder Reaction of Substituted Oxatrienes
REFERENCES
■
a e
−
3a−c,j with Illustrative Dienophiles 4a−d
(1) (a) de Benneville, P. L.; Connor, R. J. Am. Chem. Soc. 1940, 62, 283.
(b) Griffiths, D. V.; Wilcox, G. J. Chem. Soc., Perkin Trans. 2 1988, 431.
(c) Hanaki, N.; Ishihara, K.; Kaino, M.; Naruse, Y.; Yamamoto, H.
Tetrahedron 1996, 52, 7297. (d) Ishihara, K.; Hanaki, N.; Yamamoto, H.
J. Chem. Soc., Chem. Commun. 1995, 1117. (e) Jones, D. N.; Khan, M. A.;
Mirza, S. M. Tetrahedron 1999, 55, 9933.
(2) (a) Wang, X.; Fang, T.; Tong, X. Angew. Chem., Int. Ed. 2011, 50,
5361. (b) Yang, H.-B.; Yuan, Y.-C.; Wei, Y.; Shi, M. Chem. Commun.
2015, 51, 6430. (c) Yao, W.; Dou, X.; Lu, Y. J. Am. Chem. Soc. 2015, 137,
54. (d) Zhang, S.; Luo, Y.-C.; Hu, X.-Q.; Wang, Z.-Y.; Liang, Y.-M.; Xu,
P.-F. J. Org. Chem. 2015, 80, 7288. (e) Ashtekar, K. D.; Staples, R. J.;
Borhan, B. Org. Lett. 2011, 13, 5732.
(3) (a) Huang, G. T.; Lankau, T.; Yu, C. H. J. Org. Chem. 2014, 79,
1700. (b) Evans, C. A.; Miller, S. J. J. Am. Chem. Soc. 2003, 125, 12394.
(4) The sequence of events highlighted in path B is akin to the Baylis−
Hillman reaction (thus referred to as the modified BH) that has been
interrupted with an intramolecular cyclization, prior to the elimination of
the amine catalyst, which regenerates the olefin.
(5) (a) Agopcan, S.; Celebi-Olcum, N.; Ucisik, M. N.; Sanyal, A.;
Aviyente, V. Org. Biomol. Chem. 2011, 9, 8079. (b) Atta-ur-Rahman;
Shah, Z. Stereoselective Synthesis in Organic Chemistry, 1st ed.; Springer-
Verlag: New York, 1993. (c) Fisher, M. J.; Hehre, W. J.; Kahn, S. D.;
Overman, L. E. J. Am. Chem. Soc. 1988, 110, 4625. (d) Galley, G.; Patzel,
M. J. Chem. Soc., Perkin Trans. 1 1996, 2297. (e) Gleiter, R.; Paquette, L.
A. Acc. Chem. Res. 1983, 16, 328. (f) Hamada, T.; Sato, H.; Hikota, M.;
Yonemitsu, O. Tetrahedron Lett. 1989, 30, 6405. (g) Nicolaou, K. C.;
Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int.
Ed. 2002, 41, 1668. (h) Siegel, C.; Thornton, E. R. Tetrahedron Lett.
1988, 29, 5225. (i) Tripathy, R.; Carroll, P. J.; Thornton, E. R. J. Am.
Chem. Soc. 1990, 112, 6743.
(6) (a) Giuliano, R. M.; Jordan, A. D.; Gauthier, A. D.; Hoogsteen, K. J.
Org. Chem. 1993, 58, 4979. (b) Jin, Z.; Yang, R.; Du, Y.; Tiwari, B.;
Ganguly, R.; Chi, Y. R. Org. Lett. 2012, 14, 3226. (c) Kirillov, N. F.;
Gavrilov, A. G.; Slepukhin, P. A.; Vakhrin, M. I. Russ. J. Org. Chem. 2013,
49, 717.
a
Diels−Alder reaction conditions for each dienophile are as follows:
dienophile 4a, 0.1 M toluene, reflux, 2−16 h; dienophile 4b, 0.1 M
toluene, reflux, 2 h; dienophile 4c, 0.1 M EtOH/DCM (1:1), 0 °C →
b
rt, 12 h; dienophile 4d, 0.1 M in toluene, reflux, 12 h. Diastereomeric
ratios (dr) were determined by 1H NMR analysis of the crude reaction
c
(7) (a) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56,
2257. (b) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213.
(c) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (d) Becke, A. D. J. Chem.
Phys. 1993, 98, 1372. (e) Raghavachari, K. Theor. Chem. Acc. 2000, 103,
361.
mixture. Regioselectivity (rs) and relative stereochemistry were
d
determined via NMR analysis of the purified product. Isolated yields.
e
Isolated yields for “one pot” consecutive transformations from 1a as a
starting material.
(8) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650.
(9) (a) Lewars, E. G. Computational Chemistry: Introduction to the
Theory and Applications of Molecular and Quantum Mechanics, 2nd ed.;
Springer-Verlag: New York, 2011; p 1. (b) Wise, K. E.; Wheeler, R. A. J.
Phys. Chem. A 1999, 103, 8279.
(10) An exhaustive analysis at the MP2 level of theory can be attempted
(requires longer time and higher computational expense) to capture the
precise energetics in the Diels−Alder reaction; however, our approach
utilizes the B3LYP/6-31G*analysis to map the reaction pathway and
compare the relative energies of the transition states involved at a
relatively low computational expense.
(11) The final ESI-MS spectrum displayed the same peaks regardless of
the order of addition of 1a, 2, and C. MS spectra obtained at longer time
points depict the anticipated difference in relative intensities of the
intermediates as the reaction progresses to yield more product.
Futhermore, for simplicity, Figure 2 depicts adducts that arise only
from γ-attack of the allene ester, whereas the actual mixture may
comprise equilibrating intermediates formed via γ and α attack.
(12) We have also explored the Baylis−Hillman reaction with
unsymmetrically substituted enones. The resulting products obtained
with modest selectivity of 2:3 were inseparable by analytical techniques
to evaluate the stereoinduction (see the Supporting Information for
details).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01742.
■
S
Experimental and DFT computational data (PDF)
X-ray crystallographic data for 5ba (CIF)
X-ray crystallographic data for 5ja (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: babak@chemistry.msu.edu.
Author Contributions
†K.D.A. and X.D. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous support was provided by the NIH (GM110525). We
are grateful to Dr. Daniel Holmes and Dr. Li Xie (MSU) for
assistance on NMR experiments.
D
DOI: 10.1021/acs.orglett.6b01742
Org. Lett. XXXX, XXX, XXX−XXX