Solvent-dependent divergent functions of Sc(OTf)3 in stereoselective epoxide-opening spiroketalizations

Article abstract of DOI:10.1021/ol500853q

A stereocontrolled synthesis of benzannulated spiroketals has been developed using solvent-dependent Sc(OTf)₃-mediated spirocyclizations of exo-glycal epoxides having alcohol side chains. In THF, the reaction proceeds via Lewis acid catalysis under kinetic control with inversion of configuration at the anomeric carbon. In contrast, in CH₂Cl ₂, Bronsted acid catalysis under thermodynamic control leads to retention of configuration. The reactions accommodate a variety of aryl substituents and ring sizes and provide stereochemically diverse spiroketals.

Full text of DOI:10.1021/ol500853q

Letter
pubs.acs.org/OrgLett
Solvent-Dependent Divergent Functions of Sc(OTf)3 in
Stereoselective Epoxide-Opening Spiroketalizations
Indrajeet Sharma,† Jacqueline M. Wurst,‡ and Derek S. Tan*,†,‡
†Molecular Pharmacology & Chemistry Program, ‡Tri-Institutional PhD Program in Chemical Biology, and Tri-Institutional Research
Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 422, New York, New York 10065, United States
S
* Supporting Information
ABSTRACT: A stereocontrolled synthesis of benzannulated
spiroketals has been developed using solvent-dependent Sc-
(OTf)3-mediated spirocyclizations of exo-glycal epoxides having
alcohol side chains. In THF, the reaction proceeds via Lewis acid
catalysis under kinetic control with inversion of configuration at
the anomeric carbon. In contrast, in CH2Cl2, Brønsted acid
catalysis under thermodynamic control leads to retention of
configuration. The reactions accommodate a variety of aryl
substituents and ring sizes and provide stereochemically diverse
spiroketals.
enzannulated spiroketal natural products exhibit a broad
array of biological activities.1 Examples include the matrix
Thus, the requisite benzannulated exo-glycal epoxide
substrates were synthesized from salicylaldehydes 1 via alkyne
additions to form propargyl alcohols 2a−h (Figure 1).15 Au(I)-
mediated cycloisomerization, previously restricted to aromatic
alkynes,15,16 then afforded exo-glycals 5a−h. Diastereoselective
anti-epoxidation with dimethyldioxirane (DMDO)17 provided
exo-glycal epoxides 6a−h. Interestingly, these epoxides were
B
metalloproteinase inhibitor berkelic acid,2 the fungal cell wall
glucan synthase inhibitory papulacandins,3 and the anti-
inflammatory aquilarinoside A.4 Bisbenzannulated spiroketals
include the rubromycin family of human telomerase and HIV
reverse transcriptase inhibitors,5 the DNA helicase inhibitor
heliquinomycin, and the antibiotic purpuromycin, which
inhibits aminoacyl-tRNA synthesis by a novel mechanism
involving direct binding to the tRNA substrate.6 Notably, the
benzannulated spiroketal core is essential for telomerase
inhibition in the rubromycin family.7 Numerous approaches
to the synthesis of benzannulated spiroketals have been
reported.8,9 Despite these notable advances, most strategies
rely upon thermodynamically controlled reactions that often
lead to stereoisomeric mixtures at the anomeric carbon.1
We have previously developed stereocontrolled approaches
to aliphatic spiroketals using stereocomplementary kinetic
spirocyclization reactions of endo-glycal epoxides that proceed
with either inversion or retention of configuration at the
anomeric carbon, independent of thermodynamic preferen-
ces.10 We have also extended this approach to benzannulated
spiroketals via incorporation of aromatic rings on the cyclizing
side chain.11 Unfortunately, this approach provides low
diastereoselectivity in spirocyclization reactions with phenolic
nucleophiles (45:55 to 58:42 dr).11
To address this problem, we envisioned an alternative entry
to phenolic spiroketals involving stereoselective spirocycliza-
tions of benzannulated exo-glycal epoxides (dihydrobenzofuran
spiroepoxides). Spirocyclizations of exocyclic enol ether
epoxides have apparently not been explored previously,
although classical acid-catalyzed spiroketalizations of the parent
exocyclic enol ethers are well-known,12 and the corresponding
epoxides13 have been used in intermolecular alcohol
additions.14
Figure 1. Synthesis of exo-glycal epoxide substrates 6a−h.
Received: March 21, 2014
Published: April 17, 2014
© 2014 American Chemical Society
2474
dx.doi.org/10.1021/ol500853q | Org. Lett. 2014, 16, 2474−2477

Organic Letters
Letter
stable upon warming to rt, in stark contrast to the
corresponding endo-glycal epoxides, which cyclize spontane-
ously at −35 °C.18
spirocyclization reactions depending upon solvent selection
(THF vs CH2Cl2, entry 9 vs 10).
It is known that metal triflates can serve as a mild source of
triflic acid.21 Thus, we carried out mechanistic studies to
differentiate between the Lewis and Brønsted acid activities of
Sc(OTf)3. Inclusion of the noncoordinating Brønsted base, 2,6-
di-tert-butyl-4-methylpyridine (DTBMP),21a in the reaction in
THF did not affect diastereoselectivity (entry 8 vs 12).
Treatment with ScCl3 at rt also led to complete stereoselectivity
for the contrathermodynamic spiroketal 7a (entry 13). In
contrast, spirocyclization with TfOH afforded a diastereomeric
mixture favoring the retention product 8a (entry 14). Taken
together, these results suggest that Sc(OTf)3 acts as a Lewis
acid in THF at reduced temperatures, catalyzing formation of
the contrathermodynamic spiroketal 7a under kinetic control.
We next carried out the analogous experiments in CH2Cl2
where, upon warming to rt, Sc(OTf)3 favors the retention
product 8a (entry 11). In contrast, inclusion of DTBMP
resulted in a diastereomeric mixture favoring the inversion
product 7a (entry 15). However, spirocyclization with TfOH
provided the retention product 8a exclusively (entry 16).
Treatment with both TfOH and DTBMP afforded a
diastereomeric mixture of spiroketals, similar to the result
observed with Sc(OTf)3 and DTBMP (entry 17 vs 15).
Collectively, these results suggest that Sc(OTf)3 acts as a mild
source of Brønsted acid in CH2Cl2 at rt, catalyzing formation of
the thermodynamically favored spiroketal 8a under equilibrium
control.
We then investigated the scope of these stereocomplemen-
tary Sc(OTf)3-catalyzed spirocyclization reactions. Substrates
with longer side chains (6b, 6c) and various aryl substituents
(6d−h) were synthesized from the corresponding alkyne and
salicylaldehyde precursors (Figure 1). The bromide intermedi-
ate 4h was also used to introduce other substituents (aryl,
alkyne, azide, aldehyde, ester, imide) in 4i−n to examine the
functional group tolerance of the spirocyclization reactions
(Figure S2, Supporting Information).16 The exo-glycals 4i−n
were then converted to the corresponding epoxide substrates
6i−n (Figure S2, Supporting Information).16
In the spirocyclization reactions, both diastereomers of the
larger 6- and 7-membered ring spiroketals (7b,c and 8b,c)
could be obtained with complete diastereoselectivity based on
solvent selection (Figure 2). For 8b, equilibration with
Sc(OTf)3 in CH2Cl2 required elevated temperature (60 °C).
The 7-membered ring spiroketal 7c was obtained in somewhat
lower yield due to an unexpected anti-Markovnikov 6-exo
epoxide opening side reaction leading to a benzofuran
product.16
Next, we investigated the electronic effects of various aryl
substituents. A wide range of electron-withdrawing and
-donating groups were tolerated (7d−n, 8d−n), and high
diastereoselectivities were maintained. Notably, the nitro-
substituted substrate 6d was less reactive and required more
forcing conditions (7d: rt; 8d: 6 h). Conversely, the methoxy-
substituted substrate 6e was highly reactive, providing slightly
decreased diastereoselectivity in the THF reaction (7e: 93:7 dr)
and rapid equilibration in the CH2Cl2 reaction (8e: 1 h). These
results are consistent with the expected electronic influence of
these para substituents upon the reactive anomeric spiro-
epoxide center.18
We next explored spirocyclization reactions of benzannulated
exo-glycal epoxide 6a (Table 1). Notably, 6a proved unreactive
Table 1. Spirocyclization Reactions of exo-Glycal Epoxide
a
6a
entry
reagent (equiv)
solvent, temp (°C)
7a:8a
1
MeOH (excess)
Ti(OiPr)4 (2.0)
MeOH, rt
NR
2
CH2Cl2, rt
NR
3
toluene, 120
CH2Cl2, −78 → 0
THF, −78 → 0
THF, −78 → 0
THF, −78 → 0
THF, −20
NR
4
Sc(OTf)3 (2.0)
75:25
>98:2
>98:2
93:7
5
Sc(OTf)3 (2.0)
6
Sc(OTf)3 (1.0)
7
Sc(OTf)3 (0.1)
8
Sc(OTf)3 (1.0)
>98:2
90:10
<2:98
<2:98
>98:2
>98:2
30:70
75:25
<2:98
51:49
9
Sc(OTf)3 (1.0)
THF, rt
10
11
12
13
14
15
16
17
Sc(OTf)3 (1.0)
CH2Cl2, 0 → rt
CH2Cl2, 0 → rt
THF, −20
Sc(OTf)3 (0.5)
Sc(OTf)3 + DTBMP (1.0 + 1.0)
ScCl3 (1.0)
THF, rt
TfOH (1.0)
THF, −20
Sc(OTf)3 + DTBMP (0.5 + 0.5)
TfOH (0.5)
CH2Cl2, 0 → rt
CH2Cl2, 0 → rt
CH2Cl2, 0 → rt
TfOH + DTBMP (0.5 + 0.5)
a
1
Product ratios determined by H NMR analysis of crude reaction
products. NR = no reaction; DTBMP = 2,6-di-tert-butyl-4-methylpyr-
idine. See the Supporting Information for the complete table.
under our previously reported MeOH and Ti(O-i-Pr)4
spirocyclization conditions, as well as upon heating to 120 °C
in toluene (entries 1−3). After investigating a wide range of
Lewis acids,16 we were encouraged to find that Sc(OTf)3
favored the inversion product 7a (entry 4), which could be
formed exclusively by changing the reaction solvent from
CH2Cl2 to THF (entry 5). The diastereoselectivity decreased
slightly with substoichiometric Sc(OTf)3 (entries 6 and 7).
Other Lewis acids gave lower or even reversed diastereose-
lectivity.16
In low-temperature 1H NMR experiments, we found that the
Sc(OTf)3-mediated spirocyclization begins to occur at
−35 °C.16 Complete selectivity for spirocyclization with
inversion of configuration was maintained when the reaction
was run at −20 °C (entry 8), but selectivity decreased at higher
temperatures (entry 9), suggesting that the reaction proceeds
under kinetic control between −35 and −20 °C.
Strikingly, when the room-temperature reaction was carried
out in CH2Cl2 instead of THF, thermodynamic equilibration of
an initially formed diastereomeric mixture afforded the
retention product 8a with complete stereoselectivity (entries
10, 11).19 A structural rationale for the observed thermody-
namic preference is nonobvious, due to the conformational
flexibility of 5-membered rings,20 and remains a subject for
further investigation. However, on the basis of these results, it is
apparent that Sc(OTf)3 plays divergent roles in the
The reactions also tolerated other reactive functionalities
including alkyne (7j, 8j), azide (7k, 8k), aldehyde (7l, 8l), ester
(7m, 8m), and phthalimide (7n, 8n) groups. In the case of
2475
dx.doi.org/10.1021/ol500853q | Org. Lett. 2014, 16, 2474−2477

Organic Letters
Letter
Figure 2. Scope of Sc(OTf)3-mediated spirocyclization reactions. (a) THF: 1.0 equiv Sc(OTf)3, THF, −20 °C, 2−3 h; CH2Cl2: 0.5 equiv Sc(OTf)3,
1
CH2Cl2, 0 °C to rt, 1−12 h; diastereomeric ratios determined by H NMR analysis of crude reaction mixtures; stereochemistry assigned based on
NOESY analysis except 8b, which was determined by X-ray crystallography;16 isolated yields after column chromatography shown in parentheses.
(b) 60 °C. (c) 30% anti-Markovnikov 6-exo-cyclization side product also recovered.16 (d) rt.
azide 8k, Sc(OTf)3 equilibration in CH2Cl2 required elevated
temperature (60 °C).
ACKNOWLEDGMENTS
■
We thank Dr. George Sukenick, Rong Wang, Dr. Hui Liu, Hui
Fang, and Dr. Sylvi Rusli (MSKCC) for expert NMR and mass
spectral support, Emil Lobkovsky (Cornell University) for
X‑ray crystallographic analysis, and the NIH (P41 GM076267)
and Lucille Castori Center for Microbes, Inflammation, and
Cancer (postdoctoral fellowship to I.S.) for generous financial
support.
In conclusion, we have developed novel, solvent-dependent
Sc(OTf)3-mediated spirocyclizations of exo-glycal epoxides for
the stereocontrolled synthesis of benzannulated spiroketals.
This exo-glycal-based approach overcomes a key limitation of
our previous endo-glycal-based approach and tolerates a wide
range of functionalities. Applications to the diversity-oriented
synthesis of stereochemically diverse spiroketal libraries are
ongoing and will be reported in due course.
REFERENCES
■
(1) Reviewed in: (a) Sperry, J.; Wilson, Z. E.; Rathwell, D. C. K.;
Brimble, M. A. Nat. Prod. Rep. 2010, 27, 1117−1137. For general
reviews on spiroketals, see: (b) Aho, J. E.; Pihko, P. M.; Rissa, T. K.
Chem. Rev. 2005, 105, 4406−4440. (c) Perron, F.; Albizati, K. F. Chem.
Rev. 1989, 89, 1617−1661.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures and analytical data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(2) (a) Stierle, A. A.; Stierle, D. B.; Kelly, K. J. Org. Chem. 2006, 71,
5357−5360. (b) Buchgraber, P.; Snaddon, T. N.; Wirtz, C.; Mynott,
R.; Goddard, R.; Furstner, A. Angew. Chem., Int. Ed. 2008, 47, 8450−
̈
AUTHOR INFORMATION
8454.
■
(3) (a) Traxler, P.; Fritz, H.; Fuhrer, H.; Richter, W. J. J. Antibiot.
Corresponding Author
1980, 33, 967−978. (b) Barrett, A. G. M.; Pena, M.; Willardsen, J. A. J.
̃
Org. Chem. 1996, 61, 1082−1100. (c) Varona, R.; Perez, P.; Duran, A.
FEMS Microbiol. Lett. 1983, 20, 243−247.
*E-mail: tand@mskcc.org.
Notes
(4) Qi, J.; Lu, J.-J.; Liu, J.-H.; Yu, B.-Y. Chem. Pharm. Bull. 2009, 57,
134−137.
The authors declare no competing financial interest.
2476
dx.doi.org/10.1021/ol500853q | Org. Lett. 2014, 16, 2474−2477

Organic Letters
Letter
(5) Reviewed in: Brasholz, M.; Soergel, S.; Azap, C.; Reissig, H.-U.
Eur. J. Org. Chem. 2007, 3801−3814.
(6) (a) Bardone, M. R.; Martinelli, E.; Zerilli, L. F.; Coronelli, C.
Tetrahedron 1974, 30, 2747−2751. (b) Kirillov, S.; Vitali, L. A.;
Goldstein, B. P.; Monti, F.; Semenkov, Y.; Makhno, V.; Ripa, S.; Pon,
C. L.; Gualerzi, C. O. RNA 1997, 3, 905−913.
(7) Ueno, T.; Takahashi, H.; Oda, M.; Mizunuma, M.; Yokoyama, A.;
Goto, Y.; Mizushina, Y.; Sakaguchi, K.; Hayashi, H. Biochemistry 2000,
39, 5995−6002.
endo-glycal spirocyclization: Sun, Z.; Winschel, G. A.; Borovika, A.;
Nagorny, P. J. Am. Chem. Soc. 2012, 134, 8074−8077.
(10) (a) Potuzak, J. S.; Moilanen, S. B.; Tan, D. S. J. Am. Chem. Soc.
2005, 127, 13796−13797. (b) Moilanen, S. B.; Potuzak, J. S.; Tan, D.
S. J. Am. Chem. Soc. 2006, 128, 1792−1793.
(11) Liu, G.; Wurst, J. M.; Tan, D. S. Org. Lett. 2009, 11, 3670−3673.
(12) (a) Fittig, R.; Strom, K. T. Justus Liebigs Ann. Chem. 1892, 267,
191−203. (b) Dedek, V.; Trska, P. Collect. Czech. Chem. Commun.
1970, 35, 651−660. (c) Ley, S. V.; Lygo, B.; Organ, H. M.;
Wonnacott, A. Tetrahedron 1985, 41, 3825−3836.
(8) For examples from benzannulated spiroketal natural product total
synthesis, see the following. Berkelic acid: (a) Wu, X.; Zhou, J.; Snider,
B. B. Angew. Chem., Int. Ed. 2009, 48, 1283−1286. (b) Bender, C. F.;
Yoshimoto, F. K.; Paradise, C. L.; De Brabander, J. K. J. Am. Chem. Soc.
2009, 131, 11350−11352. (c) Snaddon, T. N.; Buchgraber, P.;
(13) (a) Ahmad, M. S.; Baddeley, G. J. Chem. Soc. 1961, 4303−4306.
(b) Ernest, I.; Fritz, H.; Rihs, G. Helv. Chim. Acta 1987, 70, 203−209.
(c) Adam, W.; Hadjiarapoglou, L.; Jaeger, V.; Seidel, B. Tetrahedron
Lett. 1989, 30, 4223−4226. (d) Adam, W.; Hadjiarapoglou, L.; Wang,
X. Tetrahedron Lett. 1989, 30, 6497−6500.
Schulthoff, S.; Wirtz, C.; Mynott, R.; Furstner, A. Chem.Eur. J. 2010,
̈
(14) (a) Brady, B. A.; Geoghegan, M.; O’Sullivan, W. I. J. Chem. Soc.,
Perkin Trans. 1 1989, 1557−1562. (b) Nicotra, F.; Panza, L.; Russo, G.
Tetrahedron Lett. 1991, 32, 4035−4038.
16, 12133−12140. (d) McLeod, M. C.; Wilson, Z. E.; Brimble, M. A.
Org. Lett. 2011, 13, 5382−5385. (e) Wenderski, T. A.; Marsini, M. A.;
́
Pettus, T. R. R. Org. Lett. 2011, 13, 118−121. (f) Fananas, F. J.;
̃
(15) Harkat, H.; Blanc, A.; Weibel, J.-M.; Pale, P. J. Org. Chem. 2008,
73, 1620−1623.
Mendoza, A.; Arto, T.; Temelli, B.; Rodriguez, F. Angew. Chem., Int.
Ed. 2012, 51, 4930−4933. Papulacandins: (g) Barrett, A. G. M.; Pena,
̃
(16) See the Supporting Information for full details.
(17) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
6661−6666.
M.; Willardsen, J. A. J. Chem. Soc., Chem. Commun. 1995, 1147−1148.
(h) Denmark, S. E.; Regens, C. S.; Kobayashi, T. J. Am. Chem. Soc.
2007, 129, 2774−2776. Heliquinomycinone: (i) Qin, D.; Ren, R. X.;
Siu, T.; Zheng, C.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40,
4709−4713. (j) Siu, T.; Qin, D.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 2001, 40, 4713−4716. Rubromycins: (k) Reviewed in refs 1 and
5. (l) Akai, S.; Kakiguchi, K.; Nakamura, Y.; Kuriwaki, I.; Dohi, T.;
Harada, S.; Kubo, O.; Morita, N.; Kita, Y. Angew. Chem., Int. Ed. 2007,
46, 7458−7461. (m) Rathwell, D. C. K.; Yang, S.-H.; Tsang, K. Y.;
Brimble, M. A. Angew. Chem., Int. Ed. 2009, 48, 7996−8000. (n) Wu,
K.-L.; Mercado, E. V.; Pettus, T. R. R. J. Am. Chem. Soc. 2011, 133,
6114−6117. (o) Wei, L.; Xue, J.; Liu, H.; Wang, W.; Li, Y. Org. Lett.
2012, 14, 5302−5305. (p) Wang, W.; Xue, J.; Tian, T.; Zhang, J.; Wei,
L.; Shao, J.; Xie, Z.; Li, Y. Org. Lett. 2013, 15, 2402−2405.
(18) Wurst, J. M.; Liu, G.; Tan, D. S. J. Am. Chem. Soc. 2011, 133,
7916−7925.
(19) A benzylidenedihydrofuranone, presumed to arise from opening
of the benzannulated ring followed by elimination of the C2-OTIPS
group, was also recovered as a minor byproduct (Figure S1,
Supporting Information).16
(20) Tlais, S. F.; Dudley, G. B. Org. Lett. 2010, 12, 4698−4701.
(21) (a) Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Chem.Eur. J. 2004,
10, 484−493. (b) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.;
Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179−4182.
(c) Dang, T. T.; Boeck, F.; Hintermann, L. J. Org. Chem. 2011, 76,
9353−9361.
(9) For other selected approaches to benzannulated spiroketals, see
the following. (a) Acid-catalyzed endo-glycal spirocyclization: Knabe,
J.; Schaller, K. Arch. Pharm. 1968, 301, 457−464. (b) Chromone
intramolecular Michael addition and chromone epoxide spirocycliza-
tion: Cremins, P. J.; Wallace, T. W. J. Chem. Soc., Chem. Commun.
1986, 1602−1603. (c) Dihydroxy ketone bicyclization: Tanaka, T.;
Miyaguchi, M.; Mochisuki, R. K.; Tanaka, S.; Okamoto, M.; Kitajima,
Y.; Miyazaki, T. Heterocycles 1987, 25, 463−484. (d) endo-Glycal
epoxide spirocyclization: Friesen, R. W.; Sturino, C. F. J. Org. Chem.
1990, 55, 5808−5810. (e) endo-Glycal intramolecular alkoxyselena-
tion: Elsley, D. A.; MacLeod, D.; Miller, J. A.; Quayle, P.; Davies, G.
M. Tetrahedron Lett. 1992, 33, 409−412. (f) Glycoside dehydrative
spirocyclization: Barrett, A. G. M.; Pena, M.; Willardsen, J. A. J. Chem.
̃
Soc., Chem. Commun. 1995, 1147−1148. (g) Alkyne cyclotrimeriza-
tion: McDonald, F. E.; Zhu, H. Y. H.; Holmquist, C. R. J. Am. Chem.
Soc. 1995, 117, 6605−6606. (h) C-Aryl glycoside ring rearrangement:
Kumazawa, T.; Asahi; Matsuba, S.; Sato, S.; Furuhata, K.; Onodera, J.-
I. Carbohydr. Res. 1998, 308, 213−216. (i) Arylfuran Achmatowicz
reaction: Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2, 4033−
4036. (j) C-Vinyl O-arylglycoside Claisen rearrangement−spirocyc-
lization: Van Hooft, P. A. V.; Van Swieten, P. F.; Van der Marel, G. A.;
Van Boeckel, C. A. A.; Van Boom, J. H. Synlett 2001, 269−271. (k) o-
Quinone methide−exo-glycal hetero-Diels−Alder: Zhou, G.; Zheng,
D.; Da, S.; Xie, Z.; Li, Y. Tetrahedron Lett. 2006, 47, 3349−3352. (l)
β-Diketone−exo-glycal 1,3-dipolar cycloaddition: Lindsey, C. C.; Wu,
K. L.; Pettus, T. R. R. Org. Lett. 2006, 8, 2365−2367. (m) Alkyne diol
hydroalkoxylation: Messerle, B. A.; Vuong, K. Q. Organometallics
2007, 26, 3031−3040. (n) Oxidative radical spirocyclization: Liu, Y.-
C.; Sperry, J.; Rathwell, D. C. K.; Brimble, M. A. Synlett 2009, 793−
797. (o) Intramolecular Ullmann ether coupling: Yoshioka, K.;
Takaishi, I.; Shiozawa, K.; Fukushi, Y.; Tahara, S. Biosci., Biotechnol.,
Biochem. 2008, 72, 2632−2639. (p) Multicomponent cascade
reaction: Barluenga, J.; Mendoza, A.; Rodriguez, F.; Fananas, F. J.
Angew. Chem., Int. Ed. 2009, 48, 1644−1647. (q) Enantioselective
2477
dx.doi.org/10.1021/ol500853q | Org. Lett. 2014, 16, 2474−2477