Enantioselective Aza-Sakurai Cyclizations: Dual Role of Thiourea as H-Bond Donor and Lewis Base

Article abstract of DOI:10.1021/jacs.6b09736

An enantioselective, catalytic aza-Sakurai cyclization of chlorolactams has been developed as an efficient entry into indolizidine and quinolizidine frameworks. Structure-enantioselectivity relationship studies and mechanistic analysis point to a dual role of the catalyst wherein the thiourea moiety of the catalyst is engaged in both anion binding and Lewis base activation of a substrate.

Full text of DOI:10.1021/jacs.6b09736

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Communication
Enantioselective Aza-Sakurai Cyclizations: Dual
Role of Thiourea as H-bond Donor and Lewis Base
Yongho Park, Corinna S. Schindler, and Eric N. Jacobsen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b09736 • Publication Date (Web): 27 Oct 2016
Downloaded from http://pubs.acs.org on October 27, 2016
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Enantioselective Aza-Sakurai Cyclizations: Dual Role of Thiourea as
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Yongho Park, Corinna S. Schindler,† Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
Supporting Information Placeholder
Scheme 1. Initial Reaction Design
ABSTRACT: An enantioselective, catalytic aza-Sakurai cyclization of
chlorolactams has been developed as an efficient entry into indolizidine
and quinolizidine frameworks. Structure-enantioselectivity relationship
studies and mechanistic analysis point to a dual role of the catalyst
wherein the thiourea moiety of the catalyst is engaged in both anion-
binding and Lewis base activation of a substrate.
Indolizidines and quinolizidines are common
N-heterocyclic motifs
present in biologically active molecules, and the development of effi-
cient methods for their synthesis has accordingly attracted considera-
ble attention from synthetic chemists.1,2 The aza-Sakurai cyclization,
which involves the intramolecular reaction of an iminium ion with an
allylsilane, represents a powerful method for constructing these hetero-
cycles,3 and diastereoselective variants of this transformation have
enabled the efficient synthesis of naturally occurring alkaloids in this
and related classes (Figure 1).4,5 Recently, asymmetric anion-binding
catalysis has been utilized successfully to effect enantioselective addi-
Table 1. Catalyst Optimizationa
tions to N
-acyliminium ions6 with a variety of nucleophiles, such as silyl
ketene acetals, indoles, and polyenes.7,8 Drawing from the precedents,
we envisioned that the thiourea-assisted ionization of chlorolactam 1-
Cl would generate a chiral ion pair that might undergo an enantioselec-
tive aza-Sakurai cyclization, thereby providing an efficient route to
bicyclic lactam 2 (Scheme 1).9,10 We report here the successful devel-
opment of this reactivity principle, together with the unexpected reve-
lation of a new mode of substrate activation involving a dual role for the
thiourea catalysts as H-bond donors and Lewis bases.
Figure 1. Examples of natural products synthesized previously us-
ing the aza-Sakurai cyclization.4b,c,e
Our initial studies focused on model substrate 1-OH, which contains a
hydroxylactam as a latent N-acyliminium precursor and a pendant
allyltrimethylsilane as a potential nucleophile (Table 1).11 With genera-
tion of chlorolactam 1-Cl accomplished in situ with TMSCl, a promis-
ing lead result was obtained with phenylpyrrolidinoamido thiourea
catalyst 3b (Table 1, entry 2). As has been observed in a wide variety of
other transformations involving anion-abstraction catalysis, the ar-
ylpyrrolidino unit proved to be an important handle for catalyst optimi-
zation, and the dibenzothiophene derivative 3c was identified to
a. Reactions run on a 0.05 mmol scale. Enantiomeric excess determined by GC
or HPLC analysis on commercial chiral columns. Yields determined by GC
analysis relative to dodecane as an internal standard.
possess the optimal arene component (3c, Table 1, entry 3).12 A signif-
icant improvement in enantioselectivity was obtained with phenylthio-
urea 3e, which is a significantly weaker H-bond donor than the
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bis(trifluoromethyl) analog 3c.13 This observation was highly unex-
Table 2. Substrate Scopea
1
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8
pected, as bis(trifluoromethyl) anilide-derived thioureas are generally
observed to display superior reactivity and enantioselectivity in anion-
binding reactions.14 The excellent performance of valine-derived cata-
lysts 3d and 3f relative to tert-leucine-derived analogs 3c and 3e is also
highly atypical in asymmetric catalysis with this family of catalysts.
Taken together, these results suggested that the Lewis basicity of the
thiourea moiety was critical to catalyst performance in the model aza-
Sakurai reaction. The marked difference in reactivity and enantioselec-
tivity between thiourea 3e and urea 4 (Table 1, entry 6) also supported
this hypothesis.
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The scope of the cyclization reaction was investigated with optimal
catalyst 3e (Table 2). Carbamate-derivative 5 underwent cyclization
with similar enantioselectivity to the structurally analogous lactam 2
(Table 2, entry 2). From hydantoin-derived 7, the cyclization was
achieved at a sterically hindered carbon adjacent to a quaternary center
in good yield and enantioselectivity (Table 2, entry 3). The reaction
scope was extended to access 6,6-fused bicyclic systems (Table 2, en-
tries 4–6). Substrates derived from glutarimide 9 and dihydrouracils
bearing different
N-substituents (11, 13) afforded the corresponding
bicycles (10, 12, 14) in excellent yield and enantioselectivity. Use of the
trisubstituted allylsilane 15 allowed enantioselective construction of a
quaternary stereocenter (Table 2, entry 7). In this instance, thiourea
3g afforded improved enantioselectivity relative to 3e (88 vs 75% ee).
The absolute stereochemistry of the products was assigned through the
synthesis of two alkaloid natural products (Scheme 2). Lemieux–
Johnson oxidation15 of ent-2,16 followed by a global reduction gave (–)-
tashiromine in 90% yield over two steps.17 The same two-step sequence
from 10 afforded (+)-epi-lupinine in 72% yield.18
As noted above, the catalyst structure-enantioselectivity relationships
observed during the catalyst optimization studies point to a critical role
for the nucleophilicity of the thiourea sulfur in enantioinduction. Fol-
lowing Denmark’s report that sulfur-based Lewis bases such as tetra-
methylthiourea can serve as efficient halocyclization catalysts,19 various
thiourea derivatives have been developed as chiral Lewis-base catalysts
to achieve enantioselective reactions such as halofunctionalizations.20,21
We considered whether the combination of thiourea Lewis basicity
with its well-established H-bond donor properties might underlie a
dual mechanistic function of the catalyst in the aza-Sakurai cyclizaton.
Combining the inherent Lewis basicity of chiral thioureas with their
anion-binding ability could enable the use of relatively weak nucleo-
philes species in the reactions with chiral electrophilic ion pairs.
a. Reactions run on a 0.2 mmol scale. b. Isolated yields. c. Enantiomeric excess
determined by GC or HPLC analysis on commercial chiral columns. d. Reac-
tion run using 20 mol% thiourea catalyst. e. Reaction run for 3 days. f. Reaction
run for 1 day. g. Reactions run at -30 °C. h. Catalyst 3g used instead of 3e.
The importance of the putative Lewis acid-base interaction was evalu-
ated by studying the aza-Sakurai reaction of a series of substrates con-
taining differently substituted silyl groups (Table 3). In experiments
with thiourea 3e, substrates containing more electron rich allylsilane
were consumed more slowly despite being more inherently nucleo-
philic (krel: 18 > 1 > 17).22 With urea 4, however, faster rates were ob-
served with intrinsically more nucleophilic substrates (krel: 17 > 1 > 18).
The reversal of the relative reactivity due to S vs. O substitution in the
catalyst lends definitive support to the proposal of nucleophilic activa-
tion of allylsilane by the thiourea moiety in 3e.23
Scheme 2. Total synthesis of (–)-tashiromine and (+)-epi-lupinine
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Table 3. Effect of silicon Lewis acidity on reaction ratea
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Supporting Information
Complete experimental procedures and characterization data for prod-
ucts and all isolated intermediates. This material is available free of
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
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jacobsen@chemistry.harvard.edu
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Current Addresses
† Department of Chemistry, University of Michigan, 930 North Uni-
versity Avenue, Ann Arbor, Michigan 48109, United States
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support for this research from the NIH-NIGMS R01-
GM43214, the NSF (predoctoral fellowship to Y.P.), and the Alexan-
der von Humboldt Foundation (Feodor Lynen postdoctoral fellowship
to C.S.S.) are gratefully acknowledged.
a. Relative rates were assigned by comparing the initial rates of each system. See
the Supporting Information for details.
REFERENCES
(1) For a review, see: Michael, J. P. Nat. Prod. Rep. 2008, 25, 139.
(2) For examples of recent efforts directed toward the synthesis of In-
dolizidines and quinolizidine motifs, see: (a) Miaskiewicz, S.; Gaillard, B.; Kern,
Scheme 3. Proposed Catalytic Cycle
N.; Weibel, J.-M.; Pale, P.; Blanc, A. Angew
Day, J.; Mckeever-Abbas, B.; Dowden, J. Angew
(c) Kalaitzakis, D.; Triantafyllakis, M.; Sofiadis, M.; Noutsias, D.; Vassilikogi-
annakis, G. Angew Chem Int Ed. 2016, 55, 4605. (d) Yang, Z.-P.; Wu, Q.-F.;
Shao, W.; You, S.-L. Am Chem Soc. 2015, 137, 15899. (e) Donets, P. A.;
Cramer, N. Angew Chem Int Ed. 2015, 54, 633. (f) Koley, D.; Krishna, Y.;
Srinivas, K.; Khan, A. A.; Kant, R. Angew Chem Int Ed. 2014, 53, 13196. (g)
Ortega, N.; Tang, D.-T. D.; Urban, S.; Zhao, D.; Glorius, F. Angew Chem Int
Ed. 2013, 52, 9500. (h) Xu, X.; Zavalij, P. Y.; Doyle, M. P. Am Chem Soc
2013, 135, 12439. (i) Brimioulle, R.; Bach, T. Science, 2013, 342, 840. (j) Pro-
nin, S. V.; Tabor, M. G.; Jansen, D. J.; Shenvi, R. A. Am Chem Soc. 2012,
134, 2012. (k) Wong, H.; Garnier-Amblard, E. C.; Liebeskind, L. S. Am
Chem Soc. 2011, 133, 7517. (l) Seki, H.; Georg, G. I. Am Chem Soc. 2010,
132, 15512. (m) Yang, D.; Micalizio, G. C. Am Chem Soc. 2009, 131, 17548.
(n) Dalton, D. M.; Oberg, K. M.; Yu, R. T.; Lee, E. E.; Perreault, S.; Oinen, M.
E.; Pease, M. L.; Malik, G.; Rovis, T. Am Chem Soc. 2009, 131, 15717.
(3) For pioneering work, see (a) Overman, L. E.; Malone, T. C.; Meier, G.
Am Chem Soc. 1983, 105, 6993. (b) Overman, L. E.; Bell, K. L.; Ito, F.
Chem Soc. 1984, 106, 4192. (c) Overman, L. E.; Goldstein, S. W. Am
Chem Soc. 1984, 106, 5360. (d) Overman, L. E.; Robichaud, A. J. Am Chem
Soc. 1989, 111, 300.
(4) Selected total syntheses using the aza-Sakurai cyclization: (a)
.
Chem
.
Int
.
.
Ed. 2016, 55, 9088. (b)
Int. Ed. 2016, 55, 5809.
.
Chem
.
.
.
J.
.
.
.
.
.
.
.
.
.
.
.
J.
.
.
.
J
.
.
.
J.
.
.
J
.
.
.
J.
.
.
J
.
.
.
Based upon these observations, the catalytic cycle outlined in Scheme 3
is proposed. Ionization of chlorolactam is induced by thiourea catalyst
P.
J.
.
.
J.
Am
.
.
J.
.
to generate an
N-acyliminium thiourea-bound chloride ion pair. The
.
J.
.
.
Lewis basicity of the thiourea should be enhanced by the anion binding,
and this charged moiety proposed to activate the allylsilane in the cy-
clization event. Elimination of the β-silyl cation from the resulting
cyclic intermediate would generate the lactam product.
Grieco, P. A.; Fobare, W. F.
Hong, C. Y.; Kado, N.; Overman, L. E.
He, F.; Bo, Y.; Altom, J. D.; Corey, E. J.
Sun, P.; Sun, C.; Weinreb, S. M. Org Lett. 2001,
Hong, R. Angew Chem Int
Am Chem Soc. 2012, 134, 15237. (g) Nocket, A. J.; Weinreb, S. M. Angew
Chem Int
Hong, R. Org
J.
Chem
.
Soc., Chem
Am Chem
Am Chem
.
Commun. 1987, 185. (b)
J
J
.
.
. Soc. 1993, 115, 11028. (c)
.
.
.
Soc. 1999, 121, 6771. (d)
In summary, we have developed a catalytic enantioselective aza-Sakurai
.
3
, 3507. (e) Wang, Y.; Zhu, L.;
cyclization with
N-acyliminium ions as a route to various indolizidine,
.
.
.
Ed. 2011, 50, 2787. (f) Yang, D.; Micalizio, G. C.
J.
quinolizidine, and related bicyclic frameworks. The catalyst structure-
enantioselectivity relationship and substrate studies point toward a
previously unrecognized mechanism for thiourea catalysis in which the
thiourea is not only involved in the generation of the reactive cationic
electrophile through anion-abstraction, but also engaged in the Lewis
base activation of the allylsilane nucleophile. We anticipate this dual
activation strategy will be valuable in other transformations involving
relatively weak nucleophiles.
.
.
.
.
.
Ed. 2014, 53, 14162. (h) Liu, H.; Yu, J.; Li, X.; Yan, R.; Xiao, J.-C.;
Lett. 2015, 17, 4444.
.
(5) For reviews on the use of allylsilanes in allylation of carbonyl com-
pounds, see: (a) Yus, M.; Gonzáles-Gómez, J. C.; Foubelo, F. Chem. Rev. 2011,
111, 7774. (b) Chabaud, L.; James, P.; Landais, Y. Eur
3173. (c) Langkopf, E.; Schinzer, D. Chem Rev. 1995, 95, 1375. (d) Masse, C.
E.; Panek, J. S. Chem Rev. 1995, 95, 1293-1316.
(6) For reviews on reactions involving
see: (a) Maryanoff, B. E.; Zhang, H. C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C.
A. Chem Rev. 2004, 104, 1431. (b) Royer, J.; Bonin, M.; Micouin, L. Chem
. J. Org. Chem. 2004,
.
.
N
-acyliminium intermediates,
.
.
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Page 4 of 5
Rev. 2004, 104, 2311. (c) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron
2000, 56, 3817.
(7) (a) Taylor, M. S.; Jacobsen, E. N.
10558. (b) Taylor, M. S.; Jacobsen, E. N. Angew
1
2
3
4
5
6
7
8
J
.
Am
.
Chem
Int. Ed. 2005, 44, 6700.
. Soc. 2004, 126,
.
Chem
.
(c) Raheem, I. T.; Thiara, P. V.; Peterson, E. A.; Jacobsen, E. N.
Soc. 2007, 129, 13404. (d) Knowles, R. R.; Lin, S.: Jacobsen, E. N.
Soc. 2010, 132, 5030.
J
J
.
.
Am
Am
.
Chem
.
.
. Chem
(8) For a review, see: Brak, K.; Jacobsen, E. N. Angew
2013, 52, 534.
(9) Hiemstra, H.; Sno, M. H. A. M.; Vijn, R. J.; Speckamp, W. N.
Chem. 1985, 50, 4014.
(10) For a review on organocatalytic cyclizations, see: Moyano, A.; Rios,
R. Chem Rev. 2011, 111, 4703.
(11) No reactions were observed with analogs of 1 bearing unactivated
alkenes.
.
Chem
.
Int.
Ed.
J.
Org
.
9
.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(12) See the Supporting Information for details. For illustrative exam-
ples of the importance of arylpyrrolidinoamido components in thiourea-based
chiral catalysts, see ref. 7d, 14b, and (a) Brown, A. R.; Uyeda, C.; Brotherton, C.
A.; Jacobsen, E. N.
Schindler, C. S.; Wallentin, C.-J.; Jacobsen, E. N.; Stephenson, C. R. J. Chem
Sci. 2014, , 112.
J. Am. Chem. Soc. 2013, 135, 6747. (b) Bergonzini, G.;
.
5
(13) Jakab, G.; Tancon, C.; Zhang, Z.; Lippert, K. M.; Schreiner, P. R.
. Lett. 2012, 14, 1724.
Org
(14) (a) Zhang, H.; Lin, S.; Jacobsen, E. N.
16485. (b) Yeung, C. S.; Ziegler, R. E.; Porco, J. A., Jr.
136, 13614. (c) Lin, S.; Jacobsen, E. N. Nature Chem. 2012,
J
.
Am
.
Chem
.
Soc. 2014, 136
Chem Soc. 2014,
, 817.
,
J.
Am
.
.
4
(15) Poppo, R.; Allen, Jr., D. S.; Lemieux, R. U.; Johnson, W. S.
Chem. 1956, 21, 478.
(16) Ent-2 was obtained using ent-3e.
(17) Cutter, A. C.; Miller, I. R.; Kelly, J. F.; Bellingham, R. K.; Light, M.
E.; Brown, R. C. D. Org Lett. 2011, 13, 3988.
J. Org.
.
(18) The absolute stereochemistry of ent-2 and 6 was assigned by com-
paring the optical rotation of synthetic tashiromine and epi-lupinine to their
values in the literature. The stereochemistry of all other products was assigned
by analogy.
(19) Denmark, S. E.; Burk, M. T. Proc
(20) For selected examples of using thiourea as a chiral Lewis base: (a)
Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung, Y.-Y. Am Chem Soc. 2010,
132, 15474. (b) Zhou, L.; Chen, J.; Tan, C. K.; Yeung, Y.-Y. Am Chem
2011, 133, 9164. (c) Jiang, X.; Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Angew Chem
Int Ed. 2012, 51, 7771. (d) Zhao, Y.; Jiang, X.; Yeung, Y.-Y. Angew Chem Int
Ed. 2013, 52, 8597.
(21) For a recent review on catalytic, asymmetric halofunctionlization,
. Natl. Acad. Sci. 2010, 107, 20655.
J.
.
.
J.
.
.
Soc
.
.
.
.
.
.
.
see: (a) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew
.
Chem
.
Int.
Ed.
2012, 51, 10938. (b) Cheng, Y. A.; Yu, W. Z.; Yeung, Y.-Y. Org
.
Biol
.
Chem
.
2014, 12, 2333.
(22) (a) Mayr, H.; Hagen, G.
J.
Chem. Soc., Chem. Commun. 1989, 91-
92. (b) Hagen, G.; Mayr, H. Am Chem.
J
.
.
Soc. 1991, 113, 4954.
(23) The sizeable inverse secondary KIE (0.83-0.85) measured in the
system shown below is consistent with rate-limiting cyclization. See the Sup-
porting Information for details.
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