Diastereoselective Intramolecular Hydride Transfer under Br?nsted Acid Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b00590

A diastereoselective hydride transfer process has been developed under Br?nsted acid-catalyzed reaction conditions using methyl ethers or acetals as hydride donors and tertiary alcohols or alkenes as precursors of carbocation. The method enables construction of complex molecules having multiple stereogenic centers from rather simple and readily available starting materials with predictable diastereoselective control.

Full text of DOI:10.1021/acs.orglett.9b00590

This is an open access article published under an ACS AuthorChoice License, which permits
copying and redistribution of the article or any adaptations for non-commercial purposes.
Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Diastereoselective Intramolecular Hydride Transfer under Brønsted
Acid Catalysis
Bin Wang,†,§ Dhika Aditya Gandamana,†,§ Fabien Gagosz,*,‡ and Shunsuke Chiba*,†
†Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
‡Department of Chemistry and Biomolecular Sciences, University of Ottawa, K1N 6N5 Ottawa, Canada
S
* Supporting Information
ABSTRACT: A diastereoselective hydride transfer process has been
developed under Brønsted acid-catalyzed reaction conditions using methyl
ethers or acetals as hydride donors and tertiary alcohols or alkenes as
precursors of carbocation. The method enables construction of complex
molecules having multiple stereogenic centers from rather simple and readily
available starting materials with predictable diastereoselective control.
Scheme 1. 1,5-Hydride Transfer Processes
he stereocontrolled construction of stereogenic carbon
Tcenters is one of the most important areas of
investigation in synthetic organic chemistry.1,2 Despite the
recent development of various strategies, it still remains a
formidable challenge to perform predictable stereocontrol
especially in the construction of acyclic aliphatic systems. One
way to achieve high-level of stereocontrol in the creation of a
stereogenic center is to leverage the geometric, steric, and
electronic interplay in the transition state of the process. In this
context, transformations based on intramolecular 1,5-hydride
transfer3 are particularly suitable to induce stereoinduction
(Scheme 1A). From a general mechanistic point of view, such a
process is initiated by the activation of a pro-electrophilic site
(A) on the substrate (I → II), which triggers the intra-
molecular 1,5-hydride shift from a relatively electron-rich C−H
bond onto the activated electrophilic site (A+). This transfer
results in the formation of a new carbocation III, thus
rendering the overall transformation redox neutral in nature.
This 1,5-hydride transfer step commonly proceeds via a well-
ordered 6-membered ring chairlike transition state.4 The
Evans−Tishchenko reaction is one of the most beautiful
examples of stereoinduction that takes advantage of 1,5-
hydride transfer for the diastereoselective reduction of β-
hydroxy ketones in the presence of SmI2 and an aldehyde
(Scheme 1B).5 We reasoned that the 1,5-hydride transfer
proceeding on carbocation IV derived from 5-alkoxypentan-1-
ol or 6-alkoxyhex-1-ene derivatives6 enables the predictable
construction of a stereogenic center at position C1 (Scheme
1C).
stereocontrolled synthesis of aldehyde acetal, ketone, or ester
derivatives from simple and readily available starting materials.
At the outset of the project, we examined the reactivity of
methyl ether 1a having a tertiary hydroxyl group at position
The selectivity could be controlled by the presence of a
remote substituent R′′ through a 6-membered ring chairlike
transition state V.7 The resulting oxocarbenium ion VI could
be further transformed into useful oxygen functional groups
depending on the substitution pattern at position C5 (Scheme
1C). Herein, we report the execution of this concept for the
Received: February 16, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00590
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
C18 and a methyl group at position C2 (Scheme 2A). We
observed that the treatment of 1a with 5 mol % of p-
Scheme 3. 1,2-Diastereoinduction
Scheme 2. Diastereoselective 1,5-Hydride Transfer with 1a
a
Reaction conditions: 1a (0.5 mmol), acids (5 mol %), CF3CH2OH
(5 mL, 0.1 M), 50 °C 10 min, then ethylene glycol (5 equiv).
b
c
Isolated yields. Diastereomeric ratio was determined on the basis of
1H NMR analysis.
toluenesulfonic acid (TsOH) in trifluoroethanol at 50 °C
rapidly produced bis(trifluoroethyl) acetal 2a and aldehyde 2a′
(within 10 min).9,10 Because of the instability of 2a and 2a′,
the mixture was subsequently treated with ethylene glycol (5
equiv) to convert them into more stable 1,3-dioxolane 3a,
which was isolated in 80% yield with high 1,2-syn
diastereoselectivity (>98:2). We found that the use of a
stronger Brønsted acid, triflimide (Tf2NH)11 instead of TsOH,
could accelerate the acetal formation (8 h instead of 18 h). The
origin of the 1,2-syn diastereoselectivity could be rationalized
by invoking a transient 6-membered ring transition state, in
which larger substituents (Ph at C1 and Me at C2)12 would be
more favorably placed in pseudoequatorial positions (Scheme
2B).
We then investigated the substituent effect on the 1,2-
diastereoinduction using various methyl ethers 1 (Scheme 3A).
The process was not affected by the electronic nature of the
aryl group at position C1: both electron-rich and -deficient
arenes could be installed with high 1,2-syn diastereoselectivity
(for 3b and 3c). As for the nature of C2 substituent, the
sterically more demanding benzyl, isopropyl, and phenyl
groups were tolerated (for 3d−f) and no noticeable erosion
of the diastereoselectivity was observed.13 It is noteworthy that
the current protocol allows for the use of non benzylic alcohols
that are relatively less prone to electrophilic activation. Thus,
alcohols 1g and 1h having isobutyl and 1-adamantyl groups,
respectively, provided the corresponding 1,3-dioxolanes 3g and
3h in good yields despite the moderate diastereoselectivity
observed in 3g (d.r. = 85:15). The reactions of cyclic alcohols
1i and 1j proceeded smoothly to yield 3i and 3j, respectively.
In both cases, a high 1,2-trans diastereoselectivity (>99:1) was
obtained probably due to the involvement of a cis-decalin-like
transition state (Scheme 3B). We also found that the method
was applicable to the use of secondary alkyl ether 4 and 1,3-
a
Reaction conditions: 1 (0.5 mmol), Tf2NH (5 mol %), CF3CH2OH
(5 mL, 0.1 M), 50 °C, 10 min, then ethylene glycol (5 equiv). Isolated
b
c
d
yields and diastereomeric ratio of 3 are given. 80 °C. 24 °C. With
Tf2NH (10 mol %). Reaction conditions: 4 or 6 (0.5 mmol), TsOH
(5 mol %), CF3CH2OH (5 mL, 0.1 M), 50 °C. Isolated yields and
diastereomeric ratio of 5 and 7 are given.
e
B
DOI: 10.1021/acs.orglett.9b00590
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
dioxolanes 6 as hydride donors for the efficient and highly
diastereoselective construction of ketone 5 and glycol esters 7,
respectively (Scheme 3C).
Alkenes 8 and 9 were also proven to be viable sources of
carbocations for the 1,5-hydride transfer process since the
corresponding acetal 3a and ketone 5 could be obtained in
good yields and with high diastereoselectivity (Scheme 4).
diastereomeric ratios for the formation of products 11a−d
(67:33−72:28) were not as high as those obtained in the case
of 1,2-stereoinduction (97:3−99:1). On the other hand,
cyclohexanol derivative 10e could be transformed into the
diastereomerically pure 1,3-trans cyclohexane 11e presumably
through a rigid bicyclic chair/chair-like transition state
(Scheme 5B). In addition, we observed a higher diaster-
eoselectivity of 93:7 in the conversion of alcohol 10f,14 which
possesses methyl and phenyl substituents at positions C2 and
C3, respectively. The corresponding acetal 11f was isolated in
64% yield (Scheme 5C).15 Notably, this 1,2,3-diastereoselec-
tive induction could be attained in almost a 8 mmol scale, thus
demonstrating the scalability of the present protocol.
Scheme 4. Diastereoselective 1,5-Hydride Transfer with
Alkenes 8 and 9
Finally, we examined the possibility to perform 1,4-diastereo
induction with substrates possessing a substituent at position
C4. The reaction with acyclic substrate 12a proceeded
smoothly to give acetal 13a in 75% yield, but unfortunately
with no diastereoinduction (Scheme 6A). In sharp contrast,
Scheme 6. 1,4-Diastereoinduction
We also found that the presence of a substituent at position
C3 could induce a 1,3-syn diastereoselectivity during the 1,5-
hydride transfer process (Scheme 5A). While the reactions of
acyclic alcohols 10a−d were efficient (65−81%) and various
groups (alkyl, aryl, or vinyl) could be tolerated, the observed
Scheme 5. 1,3- and 1,2,3-Diastereoinduction
a
Reaction conditions: 12 (0.5 mmol), Tf2NH (5 mol %),
CF3CH2OH (5 mL, 0.1 M), 50 °C, 10 min, then ethylene glycol
b
(5 equiv). Isolated yields and diastereomeric ratio of 13 are given. 80
°C, 1 h.
the use of cyclohexanol derivative 12b having a methoxymethyl
tether at position C4 resulted in the formation of cyclohexane
13b with high 1,4-trans diastereoselectivity (95:5). Similarly,
diastereoselective 1,5-hydride transfer took place in the
conversion of 1,3-dioxolane 12c into ester 13c. In these
cases, the 1,5-hydride transfer step most likely proceeds via a
boat-like transition state that would account for the observed
1,4-trans diastereoselectivity.16,17
In summary, this work demonstrates diastereoselective
construction of tertiary stereogenic centers by taking advantage
of 1,5-hydride transfer processes under Brønsted acid catalysis.
This redox neutral process allows for enhancement of the
molecular complexity from rather simple and readily available
starting materials. Further application of the present method to
the synthesis of complex molecules is currently ongoing in our
laboratory.
a
Reaction conditions: 10 (0.5 mmol), Tf2NH (5 mol %),
CF3CH2OH (5 mL, 0.1 M), 50 °C, 10 min, then ethylene glycol
(5 equiv). Isolated yields and diastereomeric ratio of 11 are given. 80
°C. Reaction was conducted using 7.93 mmol (2.37 g) of 10f with
Tf2NH (5 mol %) in CF3CH2OH (79 mL, 0.1 M) at 24 °C for 15
min, then ethylene glycol (5 equiv) at 50 °C.
b
c
C
DOI: 10.1021/acs.orglett.9b00590
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Gagosz, F. Adv. Synth. Catal. 2017, 359, 3108. (g) Stefan, E.; Taylor,
R. E. Tetrahedron Lett. 2015, 56, 3416. (h) Jiao, Z.; Zhang, S.; He, C.;
Tu, Y.; Wang, S.; Zhang, F.; Zhang, Y.; Li, H. Angew. Chem., Int. Ed.
2012, 51, 8811. (i) Cambeiro, F.; Lopez, S.; Varela, J. A.; Saa, C.
Angew. Chem., Int. Ed. 2012, 51, 723. (j) Bolte, B.; Gagosz, F. J. Am.
Chem. Soc. 2011, 133, 7696. (k) Jurberg, I. D.; Odabachian, Y.;
Gagosz, F. J. Am. Chem. Soc. 2010, 132, 3543. (l) Mori, K.; Kawasaki,
T.; Sueoka, S.; Akiyama, T. Org. Lett. 2010, 12, 1732. (m) McQuaid,
K. M.; Sames, D. J. Am. Chem. Soc. 2009, 131, 402. (n) Vadola, P. A.;
Sames, D. J. Am. Chem. Soc. 2009, 131, 16525. (o) McQuaid, K. M.;
Long, J. Z.; Sames, D. Org. Lett. 2009, 11, 2972. (p) Shikanai, D.;
Murase, H.; Hata, T.; Urabe, H. J. Am. Chem. Soc. 2009, 131, 3166.
(q) Bhunia, S.; Liu, R. J. Am. Chem. Soc. 2008, 130, 16488.
(r) Bajracharya, G. B.; Pahadi, N. K.; Gridnev, I. D.; Yamamoto, Y. J.
Org. Chem. 2006, 71, 6204. (s) Pastine, S. J.; McQuaid, K. M.; Sames,
D. J. Am. Chem. Soc. 2005, 127, 12180. (t) Yoshimatsu, M.; Hatae, N.;
Shimizu, H.; Kataoka, T. Chem. Lett. 1993, 22, 1491.
(8) The stereochemistry of position C1 for the alcohol substrates
was not determined except for compound 10f. The diastereomeric
ratio of the alcohol starting materials varies with the nature of the
substituents. See the Supporting Information for more details.
(9) Acetal 2a and aldehyde 2a′ were formed in 54% and 14% yields,
respectively, according to 1H NMR spectroscopy analysis of the crude
residue.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00590.
■
S
Experimental procedures, spectral data (PDF)
Accession Codes
CCDC 1894803, 1894805, and 1894807−1894808 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by e-mailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: shunsuke@ntu.edu.sg.
*E-mail: fgagosz@uottawa.ca.
ORCID
(10) The initial optimization of the reaction conditions for the 1,5-
hydride transfer was conducted using acetal 6a and trifluoroethanol
was found the optimal solvent for the process. See the Supporting
Information for more details.
Fabien Gagosz: 0000-0002-0261-4925
Shunsuke Chiba: 0000-0003-2039-023X
Author Contributions
§These authors contributed equally.
(11) Zhao, W.; Sun, J. Chem. Rev. 2018, 118, 10349.
(12) The relative steric demands are evaluated on the basis of the A-
values for a phenyl group (2.8 kcal/mol) and a methyl group (1.74
kcal/mol). For A-values of various substituents, see: Eliel, E. L.;
Wilen, S. H.; Doyle, M. P. Basic Organic Stereochemistry; Wiley, 2001;
p 444.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(13) The stereochemistry of the major isomer of 3f was determined
by X-ray crystallography analysis. See the Supporting Information for
details.
(14) Synthesis of 10f was accomplished by a sequence of
diastereoselective α-methylation of ketone followed by addition of
MeMgBr to the carbonyl group as shown below (for details, see the
Supporting Information). The stereochemistry of 10f was confirmed
by X-ray crystallography analysis.
■
This work was supported by funding from Nanyang
Technological University (for S.C.), the Singapore Ministry
of Education (Academic Research Fund Tier 1:2015-T1-001-
040 for S.C.), and the Natural Sciences and Engineering
Research Council (for F.G.). We acknowledge Dr. Yongxin Li
(Division of Chemistry and Biological Chemistry, Nanyang
Technological University) for assistance in X-ray crystallo-
graphic analysis.
REFERENCES
■
(1) Carreira, E. M.; Kvaerno, L. Classics in Stereoselective Synthesis;
Wiley-VCH: Weinheim, 2009.
(2) For recent reviews, see: (a) Bhadra, S.; Yamamoto, H. Chem.
Rev. 2018, 118, 3391. (b) Eppe, G.; Didier, D.; Marek, I. Chem. Rev.
2015, 115, 9175.
(3) For reviews, see: (a) Haibach, M. C.; Seidel, D. Angew. Chem.,
Int. Ed. 2014, 53, 5010. (b) Wang, L.; Xiao, J. Adv. Synth. Catal. 2014,
356, 1137. (c) Peng, B.; Maulide, N. Chem. - Eur. J. 2013, 19, 13274.
(d) Wang, M. ChemCatChem 2013, 5, 1291. (e) Pan, S. C. Beilstein J.
Org. Chem. 2012, 8, 1374. (f) Tobisu, M.; Chatani, N. Angew. Chem.,
Int. Ed. 2006, 45, 1683.
(4) Hill, R. K.; Carlson, R. M. J. Am. Chem. Soc. 1965, 87, 2772.
(5) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447.
(6) For reviews on generation and use of carbocations, see:
(a) Akiyama, T.; Mori, K. Chem. Rev. 2015, 115, 9277. (b) Naredla,
R. R.; Klumpp, D. A. Chem. Rev. 2013, 113, 6905.
(7) For selected examples on the use of alkyl ethers as hydride
donors, see: (a) Li, J.; Preinfalk, A.; Maulide, N. J. Am. Chem. Soc.
2019, 141, 143. (b) Bauer, A.; Maulide, N. Org. Lett. 2018, 20, 1461.
(c) Bauer, A.; Maulide, N. Tetrahedron 2018, 74, 6883.
(d) Gandamana, D. A.; Wang, B.; Tejo, C.; Bolte, B.; Gagosz, F.;
Chiba, S. Angew. Chem., Int. Ed. 2018, 57, 6181. (e) Mori, K.;
Umehara, N.; Akiyama, T. Chem. Sci. 2018, 9, 7327. (f) Zhao, Q.;
(15) The stereochemistry of the major isomer of 11f was determined
by the X-ray crystallography analysis of its 4-bromobenzoate
derivative 11f′. See the Supporting Information for details.
(16) Partial loss of diastereoselectivity (formation of 1,4-cis isomer)
is most due to the epimerization of the oxocarbenium ion
intermediates.
(17) The stereochemistry of the major isomer of 13b was
determined by the X-ray crystallography analysis. See the Supporting
Information for details.
D
DOI: 10.1021/acs.orglett.9b00590
Org. Lett. XXXX, XXX, XXX−XXX