Enantioselective Multicomponent Condensation Reactions of Phenols, Aldehydes, and Boronates Catalyzed by Chiral Biphenols

Article abstract of DOI:10.1021/acs.orglett.5b02954

Chiral diols and biphenols catalyze the multicomponent condensation reaction of phenols, aldehydes, and alkenyl or aryl boronates. The condensation products are formed in good yields and enantioselectivities. The reaction proceeds via an initial Friedel-Crafts alkylation of the aldehyde and phenol to yield an ortho-quinone methide that undergoes an enantioselective boronate addition. A cyclization pathway was discovered while exploring the scope of the reaction that provides access to chiral 2,4-diaryl chroman products, the core of which is a structural motif found in natural products.

Full text of DOI:10.1021/acs.orglett.5b02954

Letter
pubs.acs.org/OrgLett
Enantioselective Multicomponent Condensation Reactions of
Phenols, Aldehydes, and Boronates Catalyzed by Chiral Biphenols
Keith S. Barbato, Yi Luan, Daniele Ramella, James S. Panek, and Scott E. Schaus*
Center for Molecular Discovery, Boston University, 24 Cummington Mall, Boston, Massachusetts 02215, United States
S
* Supporting Information
ABSTRACT: Chiral diols and biphenols catalyze the multi-
component condensation reaction of phenols, aldehydes, and alkenyl
or aryl boronates. The condensation products are formed in good
yields and enantioselectivities. The reaction proceeds via an initial
Friedel−Crafts alkylation of the aldehyde and phenol to yield an
ortho-quinone methide that undergoes an enantioselective boronate
addition. A cyclization pathway was discovered while exploring the scope of the reaction that provides access to chiral 2,4-diaryl
chroman products, the core of which is a structural motif found in natural products.
and chiral boron ate complex forms the product in a
stereoselective fashion.
ortho-Quinone methides (oQMs) are reactive intermediates with
wide-ranging applications in organic synthesis.1 As transient
species, they have been exploited in biomimetic syntheses as
heterodiene partners in Diels−Alder reactions.2 The propensity
to rearomatize prompts nucleophilic additions at the methide
carbon, which has frequently been exploited asymmetrically
within the past decade.3 The formation of metal-coordinated
oQM complexes and bench stable conjugated oQMs have
enabled their use in synthesis.4,5 More typically, however, oQMs
are short-lived species, making their detection and utility in
synthesis challenging.6 Therefore, in situ synthesis of the oQM
would be an attractive approach to alleviate any issues involved in
constructing a reactive intermediate.
Herein, we report a multicomponent condensation reaction to
form oQMs through a bimolecular process involving a phenol
and an aldehyde mediated by boronates and catalyzed by chiral
phenols resulting in an enantioselective nucleophilic addition to
the methide carbon. Enantioselective additions of boronates to
oQMs catalyzed by chiral biphenols provide access to chiral
motifs that appear in natural products and drugs.7 For instance,
myristinin A is a potent inhibitor of DNA polymerase β and
contains a chiral diaryl methane within its chroman core.8 Other
notable examples include myristicyclin A, dracoflavans C and D,
and cochinchinenins B and C.9−11 Methods to form oQMs
typically require oxidation, acid/base chemistry, photolysis, or
thermolysis.12 Asymmetric, multicomponent reactions (MCR)
provide access to structural complexity within a single trans-
formation.13 A convergent approach in constructing this moiety
leads to higher process efficiency.14 Despite these potential
benefits, there are currently no examples of an asymmetric
multicomponent reaction utilizing oQM chemistry.15 The
efficiency of a possible MCR led us to investigate using boronates
to mediate oQM formation.16 Our investigations to develop a
multicomponent strategy began with an electron-rich phenol, an
aldehyde, and a styrenyl boronate. Mediated by the boronate, a
Friedel−Crafts hydroxyalkylation reaction occurs to yield a
dioxaborin intermediate.17 Nucleophilic attack by an activated
Experiments were designed to evaluate chiral diol catalysts in
the reaction (Table 1, entries 1−3). 1,1′-Bi-2-naphthol (BINOL)
derived catalysts containing substituents at the 3,3′ positions led
to higher enantioselectivities (Table 1, entries 4−6). In
agreement with our previous studies, (R)-3,3′-Br2-BINOL was
identified as the catalyst for further evaluation giving the best
combination of yield and enantioselectivity.7 Higher concen-
trations improved the yield but resulted in lower enantiose-
lectivity (Table 1, entries 7−9). A temperature of 80 °C was
found to be ideal for promoting the condensation while
maintaining enantioselectivity. As such, other high boiling
solvents were examined, but did not yield product (Table 1,
entries 10 and 11). Use of trifluorotoluene resulted in a higher
yield, but the enantioselectivity was lower; likely due to an
increase in a competing uncatalyzed background reaction rate
(Table 1, entry 12). We rationalized that the boronate ester
group would have an important influence on the selectivity of the
reaction.18 It was found that changing the ethyl group to an
isopropyl group led to a higher enantiomeric ratio (Table 1, entry
13). By adjusting the concentration and catalyst loading, we
identified conditions resulting in a 70% yield and a 95:5
enantiomeric ratio (Table 1, entry 14). These reaction
conditions proved optimal to explore the scope of the reaction
(Figure 1).
A wide range of aldehydes and boronates could be used in the
reaction, but the phenol needed to be electron-rich in order to
promote the Friedel−Crafts alkylation reaction. Halogen
substitution at the 4-position of the aldehyde was well tolerated,
providing high enantioselectivity (4b, 4c). Electron-rich
aldehydes maintained selectivity, however, in lower yield (4d).
Conversely, electron-deficient substitution resulted in lower
enantioselectivity, but higher yield (4e) supporting the
Received: October 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02954
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Chiral Diols in the Multicomponent Boronate
a
Condensation Reaction
b
c
entry catalyst 6 (mol %) concn [M]
R
yield [%]
er
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
6f
6f
6f
6f
6f
6f
6f
6f
15
15
15
15
15
20
20
20
20
20
20
20
10
15
0.3
0.3
0.3
0.3
0.3
0.2
0.4
0.8
0.8
0.2
0.2
0.2
0.2
0.3
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
i-Pr
i-Pr
77
51
96
100
77
55
78
94
50
−
50:50
85:15
57:43
80:20
91:9
94:6
92:8
88:12
86:14
−
d
e
f
10
11
12
13
14
g
h
−
−
75
51
70
92:8
95:5
95:5
a
Reactions were run at 80 °C with 0.4 mmol of phenol, 0.8 mmol of
aldehyde, and 0.8 mmol of boronate for 24 h in toluene unless
b
c
otherwise indicated. Yield of isolated product. Enantiomeric ratios
(er) determined by HPLC analysis using a chiral stationary phase.
d
e
Reaction was run for 48 h. Reaction was run at 60 °C for 24 h.
f
g
h
Ethanol used as solvent. 1,4-Dioxane used as solvent. Tri¯uor-
otoluene used as solvent.
hypothesis of a rate-determining Friedel−Crafts alkylation.
Heterocyclic aldehydes could be used in the reaction; 2-
thenaldehyde gave a quantitative yield (4f). Comparison of 4f
to the previously reported compound confirmed the absolute
stereochemistry of the product and is consistent with the
reported oQM mechanistic model of enantioselectivity.7 2-
Naphthaldehyde was tolerated in the reaction; however, sterics
limited the reactivity of 1-naphthaldehyde (4g, 4h). Notably,
ortho-substitution improved the selectivity in the case of 2-
bromobenzaldehyde (4i).
A similar observation was made with 2-methylbenzaldehyde,
suggesting a steric interaction during the enantio-determining
event (4j). The boronate constituents were evaluated in the
reaction, and each were prepared from the boronic acid
precursor.19 Both styrenyl and aryl boronates performed well
in the reaction (4k, 4l, 4m). Despite being less nucleophilic,
electron-deficient boronate also afforded the product with good
results (4n). The furanyl boronate was evaluated in the reaction
proving to be highly reactive; it resulted in quantitative yield with
low selectivity due to a competitive uncatalyzed background
reaction (4o). Finally, the use of aliphatic hexenyl boronate
resulted in excellent yield and enantioselectivity (4p). Phenol
Figure 1. Multicomponent boronate condensation reactions.
substitution was investigated; 3-methoxyphenol and 3,4-
dimethoxyphenol both gave high yields and enantioselectivity
(4q, 4r). Substrate combinations were tested and indicate this
would likely work well for others (4s−4u). In the course of
evaluating reaction components in the MCR, an unanticipated
reaction pathway was identified. Using 4-methoxystyrenyl
boronate afforded the 2,4-diarylchroman structure as the major
product (5a). Identification of the chroman encouraged us to
explore preferential chemoselectivity for the cyclization pathway.
We initiated studies to evaluate catalysts that would promote
chemo-, enantio-, and diastereoselective formation of the
chroman (Table 2).
Of the chiral diol catalysts assessed, (R)-3,3′-I2BINOL (6g)
was found to give the best combination of yield and
enantioselectivity (Table 2, entry 4). Next, we turned our
attention to the reaction conditions. We hypothesized that the
B
DOI: 10.1021/acs.orglett.5b02954
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Chroman Formation
product 4v
yield [%]
product
4v er
product 5a
yield [%]
product
5a er
entry catalyst 6
1
2
3
4
5
6
7
8
9
6c
6d
6f
22
46
22
31
37
39
5
70:30
66:33
80:20
82:18
21:79
89:11
−
28
33
55
59
16
50
69
72
40
60:40
60:40
79:21
87:13
49:51
81:19
84:16
85:15
99:1
6g
6h
6i
b
c
6g
6g
6g
d
−
−
−
−
de
,
a
Reactions were run at 80 °C with 0.4 mmol of phenol, 0.8 mmol of
aldehyde, and 0.8 mmol of boronate for 24 h in toluene (0.3 M) unless
otherwise indicated. Diastereomeric ratios were 2:1 as determined by
1H NMR unless otherwise indicated. Enantiomeric ratios are reported
Figure 2. MCR chroman synthesis.
b
for the major diastereomer. (S)-Enantiomer of catalyst used. Mesityl
c
= 2,4,6-trimethyl ofbenzene. Reaction was run in sealed tube at 120
cyclization step facilitated by the catalyst; a matched cyclization
to afford the syn product was confirmed by 1D NOE. We have
developed a mechanistic model consistent with our observations
(Scheme 1). Boron-mediated Friedel−Crafts hydroxyalkylation
d
°C for 24 h. Reaction was run in a sealed tube at 80 °C for 24 h and
e
then 150 °C for 1 h. Product was recrystallized from hot hexanes. The
1
diastereomeric ratio was >20:1 as determined by H NMR.
electron-rich nature of the styrene component under acidic
conditions at higher temperatures facilitated the cyclization
process. To test this hypothesis, the reaction was run in a sealed
tube at 120 °C. A significant shift in chemoselectivity was
observed, yielding the chroman product in 69% yield (Table 2,
entry 7). We found that an increase in temperature for a brief
time following the standard reaction conditions afforded the
chroman product and maintained modest levels of selectivity
(Table 2, entry 8). It was later determined that recrystallization
from hot hexanes afforded the product with enhanced diastereo-
and enantioselectivity (Table 2, entry 9). A few substrates are
illustrated to show the potential of this reaction type (Figure 2).
As postulated, electron-rich π-conjugation displayed a
propensity to cyclize (5a−5e), while electron-neutral styrene
remained slow with regard to chroman formation, even at higher
temperatures (5f). This observation led us to believe that the
cyclization proceeds through protonation of the electron-rich
olefin with subsequent nucleophilic attack of the phenol oxygen.
Experiments were designed to further investigate the nature of
the cyclization. Enantioenriched addition product (S)-4v (81:19
er) was isolated and subjected to reaction conditions used to
afford the chroman product: 15 mol % (R)-3,3′-I2-BINOL,
benzaldehyde, and boronate 3b, omitting phenol 1a, at 150 °C
for 24 h. Chroman (S,S)-5a was isolated in a 90:10 enantiomeric
ratio. The result demonstrates a stepwise pathway leading to the
formation of the chromans and enhanced selectivity in the
Scheme 1. Proposed Mechanism for the Asymmetric
Boronate MCR
condensation of the phenol and aldehyde in complex 7 is most
likely rate limiting. There is no product formation at lower
temperatures, also consistent with observations made in the
literature.17 Next, boronate complex 8 dissociates and ligand
transfer occurs rapidly forming product 9, the enantiodetermin-
ing event. This is consistent with our earlier studies in which
enantioselective additions of boronates to oQMs occur at low
temperatures.7 The facile nature of this dissociation−ligand
transfer also explains why there is no observation of a dioxaborin
intermediate during the reaction.20 The cyclization is initiated by
protonation of the electron-rich olefin. A resonance-stabilized
C
DOI: 10.1021/acs.orglett.5b02954
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(7) Luan, Y.; Schaus, S. E. J. Am. Chem. Soc. 2012, 134, 19965.
intermediate 10 is produced and quickly trapped by subsequent
attack of the phenol oxygen to provide 11.
(8) (a) Sawadjoon, S.; Kittakoop, P.; Kirtikara, K.; Vichai, V.;
Tanticharoen, M.; Thebtaranonth, Y. J. Org. Chem. 2002, 67, 5470.
(b) Deng, J. Z.; Starck, S. R.; Li, S.; Hecht, S. M. J. Nat. Prod. 2005, 68,
1625.
(9) Lu, Z.; Van Wagoner, R. M.; Pond, C. D.; Pole, A. R.; Jensen, J. B.;
Blankenship, D.; Grimberg, B. T.; Kiapranis, R.; Matainaho, T. K.;
Barrows, L. R.; Ireland, C. M. Org. Lett. 2014, 16, 346.
In summary, an enantioselective multicomponent reaction was
developed that provides access to chiral di- and triaryl methane
products with high levels of yield and selectivity. We observed an
unanticipated cyclization pathway, which yielded chiral 2,4-diaryl
chromans. Further studies of this reaction are underway and
involve optimizing the stereocontrol of the cyclization process as
well as exploring its utility in natural product synthesis.
(10) Arnone, A.; Nasini, G.; Vajna de Pava, O. J. Nat. Prod. 1997, 60,
971.
(11) Zhu, Y.; Zhang, P.; Yu, H.; Wang, M.-W.; Zhao, W. J. Nat. Prod.
2007, 70, 1570.
ASSOCIATED CONTENT
* Supporting Information
■
(12) (a) Cavitt, S. B.; Sarrafizadeh, H.; Gardner. J. Org. Chem. 1962, 27,
1211. (b) Bolon, D. A. J. Org. Chem. 1970, 35, 715. (c) Selenski, C.;
Pettus, T. R. R. Quinomethanes. Science of Synthesis; Georg Theieme
Verlag: 2006; Vol. 28, section 4.28.12.1. (d) Lumb, J.-P.; Choong, K. C.;
Trauner, D. J. Am. Chem. Soc. 2008, 130, 9230. (e) Kumbaraci, V.;
Ergunes, D.; Midilli, M.; Begen, S.; Talinli, N. J. Heterocycl. Chem. 2009,
46, 226. (f) Bai, W.-J.; David, J. G.; Feng, Z.-G.; Weaver, M. G.; Wu, K.-
L.; Pettus, T. R. R. Acc. Chem. Res. 2014, 47, 3655.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02954.
Synthetic procedures, chiral HPLC analysis, character-
ization and spectral data for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
(13) Yus, M.; Ramon, D. J. Angew. Chem., Int. Ed. 2005, 44, 1602.
(14) Westermann, B.; Brauch, S.; van Berkel, S. S. Chem. Soc. Rev. 2013,
42, 4948.
■
*E-mail: seschaus@bu.edu.
Notes
(15) (a) El Kaim, L. E.; Grimaud, L.; Oble, J. Org. Biomol. Chem. 2006,
4, 3410. (b) Lawrence, A. L.; Adlington, R. M.; Baldwin, J. E.; Lee, V.;
Kershaw, J. A.; Thompson, A. L. Org. Lett. 2010, 12, 1676. (c) Rama, V.;
Kanagaraj, K.; Pitchumani, K. Tetrahedron Lett. 2012, 53, 1018.
(d) Yoshioka, E.; Kohtani, S.; Miyabe, H. Molecules 2014, 19, 863.
(16) (a) Wu, T. R.; Shen, L.; Chong, J. M. Org. Lett. 2004, 6, 2701.
(b) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2005, 127, 3244. (c) Lou,
S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2006, 128, 12660.
(d) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2007, 129, 4908. (e) Lou,
S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398.
(f) Barnett, D. S.; Moquist, P. N.; Schaus, S. E. Angew. Chem., Int. Ed.
2009, 48, 8679. (g) Moquist, P. N.; Kodama, T.; Schaus, S. E. Angew.
Chem. 2010, 122, 7250. (h) Barnett, D. S.; Schaus, S. E. Org. Lett. 2011,
13, 4020. (i) Lundy, B. J.; Jansone-Popova, S.; May, J. A. Org. Lett. 2011,
13, 4958. (j) Turner, H. M.; Patel, J.; Niljianskul, N.; Chong, J. M. Org.
Lett. 2011, 13, 5796.
(17) (a) Peer, H. G. Recl. Trav. Chim. Pays-Bas 1960, 79, 825.
(b) Nagata, W.; Okada, K.; Aoki, T. Synthesis 1979, 1979, 365. (c) Lau,
C. K.; Williams, H. W. R.; Tardiff, S.; Dufresne, C.; Scheigetz, J.;
Belanger, P. C. Can. J. Chem. 1989, 67, 1384. (d) Lau, C. K.; Chambers,
J. D.; Crawford, J.; Williams, H. W. R.; Dufresne, C.; Scheigetz, J.;
Bernstein, M. A. Can. J. Chem. 1992, 70, 1717. (e) Olson, B. S.; Trauner,
D. Synlett 2005, 4, 700. (f) Lumb, J.-P.; Trauner, D. J. Am. Chem. Soc.
2005, 127, 2870. (g) Zheng, H.; Hall, D. G. Tetrahedron Lett. 2010, 51,
4256. (h) Sharifi, A.; Abaee, M. S.; Mirzaei, M.; Naimi-Jamal, M. R. Asian
J. Chem. 2010, 22, 6519.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by the NIH (R01 GM078240 and
P50 GM067041).
■
REFERENCES
■
(1) (a) Beaudry, C. M.; Malerich, J. P.; Trauner, D. Chem. Rev. 2005,
105, 4757. (b) Rokita, S. E. Quinone Methides: Wiley: 2009. (c) Willis, N.
J.; Bray, C. D. Chem. - Eur. J. 2012, 18, 9160.
(2) (a) Ungaro, R.; Arduini, A.; Bosi, A.; Pochini, A. Tetrahedron 1985,
41, 3095. (b) Selenski, C.; Pettus, T. R. R. J. Org. Chem. 2004, 69, 9196.
(c) Batsomboon, P.; Phakhodee, W.; Ruchirawat, S.; Ploypradith, P. J.
Org. Chem. 2009, 74, 4009. (d) Zhao, J.-J.; Sun, S.-B.; He, S.-H.; Wu, Q.;
Shi, F. Angew. Chem., Int. Ed. 2015, 54, 5460. (e) Hsiao, C.-C.; Raja, S.;
Liao, H.-H.; Atodiresei, I.; Rueping, M. Angew. Chem., Int. Ed. 2015, 54,
5762.
(3) (a) Zhang, Y.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 3076.
(b) Alden-Danforth, E.; Scerba, M. T.; Lectka, T. Org. Lett. 2008, 10,
4951. (c) Jensen, K. H.; Panthak, T. P.; Zhang, Y.; Sigman, M. S. J. Am.
Chem. Soc. 2009, 131, 17074. (d) Green, J. C.; Pettus, T. R. R. J. Am.
Chem. Soc. 2011, 133, 1603. (e) Pathak, T. P.; Sigman, M. S. J. Org.
Chem. 2011, 76, 9210. (f) Green, J. C.; Brown, E. R.; Pettus, T. R. R. Org.
Lett. 2012, 14, 2929. (g) El-Sepelgy, O.; Haseloff, S.; Alamsetti, S. K.;
Schneider, C. Angew. Chem., Int. Ed. 2014, 53, 7923. (h) Hsiao, C.-C.;
Liao, H.-H.; Rueping, M. Angew. Chem., Int. Ed. 2014, 53, 13258.
(i) Yeung, C. S.; Ziegler, R. E.; Porco, J. A.; Jacobsen, E. N. J. Am. Chem.
Soc. 2014, 136, 13614. (j) Wang, Z.; Ai, F.; Wang, Z.; Zhao, W.; Zhu, G.;
Lin, Z.; Sun, J. J. Am. Chem. Soc. 2015, 137, 383. (k) Saha, S.; Schneider,
C. Org. Lett. 2015, 17, 648. (l) Saha, S.; Schneider, C. Chem. - Eur. J.
2015, 21, 2348. (m) Saha, S.; Alamsetti, S. K.; Schneider, C. Chem.
Commun. 2015, 51, 1461. (n) Li, M.-L.; Chen, D.-F.; Luo, S.-W.; Wu, X.
Tetrahedron: Asymmetry 2015, 26, 219. (o) Caruana, L.; Mondatori, M.;
Corti, V.; Morales, S.; Mazzanti, A.; Fochi, M.; Bernardi, L. Chem. - Eur. J.
2015, 21, 6037.
(18) (a) Roy, C. D.; Brown, H. C. J. Organomet. Chem. 2007, 692, 784.
(b) Roy, C. D.; Brown, H. C. Monatsh. Chem. 2007, 138, 879.
(19) Hall, D. G. Boronic Acids: Preparation and Applications in Organic
Synthesis, Medicine and Materials, 2nd ed.; Wiley-VCH: Weinheim,
Germany, 2005.
(20) A model for enantioselectivity has been proposed based on the
calculation of a cyclic BINOL-boronate structure; however, the
transition state energy required to access the seven-membered reactive
boronate nucleophile has never been calculated. Grayson, M. N.;
Goodman, J. M. J. Org. Chem. 2015, 80, 2056−2061.
(4) (a) Kopach, M. E.; Harman, W. D. J. Am. Chem. Soc. 1994, 116,
6581. (b) Amouri, H.; Besace, Y.; Le Bras, J. J. Am. Chem. Soc. 1998, 120,
6171. (c) Amouri, H.; Vaissermann, J. Organometallics 2000, 19, 1740.
(d) MacIntosh, A. D.; Yang, H.; Pike, R. D.; Sweigart, D. A. J. Organomet.
Chem. 2012, 719, 14.
(5) (a) Jurd, L. Tetrahedron 1977, 33, 163. (b) Roitman, J. N.; Jurd, L.
Tetrahedron 1978, 34, 57.
(6) Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367.
D
DOI: 10.1021/acs.orglett.5b02954
Org. Lett. XXXX, XXX, XXX−XXX