Rearrangement of N- tert-Butanesulfinyl Enamines for Synthesis of Enantioenriched α-Hydroxy Ketone Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b03159

Treating chiral N-tert-butanesulfinyl ketimines with potassium hexamethyldisilazide (or potassium tert-butoxide) and methyl triflate gives N-methylated N-tert-butanesulfinyl enamine intermediates that undergo stereoselective [2,3]-rearrangement to afford α-sulfenyloxy ketones with excellent enantiopurities. This cascade of enamination-N-methylation-rearrangement was even used to generate acyclic tertiary α-hydroxy ketones bearing two α-substituents showing negligible differences in bulkiness, such as methyl and ethyl groups.

Full text of DOI:10.1021/acs.orglett.9b03159

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Rearrangement of N-tert-Butanesulfinyl Enamines for Synthesis of
Enantioenriched α‑Hydroxy Ketone Derivatives
‡
‡
†
,†
Chun-Tian Li, Hui Liu, Yun Yao, and Chong-Dao Lu*
†
School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
‡
Xinjiang Technical Institute of Physics & Chemistry, Chinese Academy of Sciences, Urumqi 830011, China
*
S Supporting Information
ABSTRACT: Treating chiral N-tert-butanesulfinyl ketimines
with potassium hexamethyldisilazide (or potassium tert-
butoxide) and methyl triflate gives N-methylated N-tert-
butanesulfinyl enamine intermediates that undergo stereo-
selective [2,3]-rearrangement to afford α-sulfenyloxy ketones
with excellent enantiopurities. This cascade of enamination−
N-methylation−rearrangement was even used to generate
acyclic tertiary α-hydroxy ketones bearing two α-substituents
showing negligible differences in bulkiness, such as methyl and
ethyl groups.
hiral α-hydroxy ketones are important building blocks in
Scheme 1. Rearrangement of N-tert-Butanesulfinyl
Enamines for Asymmetric Synthesis of α-Hydroxy Ketone
Derivatives
1
C
some bioactive compounds, and they serve as chiral
2
auxiliaries as well as useful intermediates for constructing fine
3
chemicals such as 1,2-diols and 1,2-amino alcohols. Several
methods have been explored for asymmetric synthesis of α-
4
hydroxy carbonyls, usually involving formation of C−C bonds
5
or C−O bonds. C−O bonds can be formed enantioselectively
using chiral auxiliaries and asymmetric catalytic methods
6
7
−10
ranging from organocatalysis
sis.
to metal-complex cataly-
However, these methods of enantioselective α-oxygen
11,12
functionalization usually work well only with carbonyl
substrates that easily form stereodefined enols or enolates,
such as α-monosubstituted carbonyls, cyclic α-branched
carbonyls, or acyclic α,α-disubstituted carbonyls bearing two
α-substituents differing greatly in bulkiness, such as an aryl
8
group and an alkyl group. These methods do not work well
with α,α-disubstituted carbonyls containing two α-substituents
1
3,14
of similar bulkiness, such as two linear alkyl groups.
A range of reagents can be used to functionalize α-oxygens
from sources such as N-sulfonyloxaziridines, peroxy reagents,
hypervalent iodines, metal oxides, molecular oxygen, and
5
nitrosoarenes. Recently, we found that amides can be α-
oxygenated from the sulfinyl group of acyl tert-butanesulfiny-
1
5
lamide via an aza-variant of the Mislow-Evans rearrangement
1
6
the α-position of ketones via simple transformation of N-tert-
butanesulfinyl (N-tBS) ketimines to the corresponding
enamines (Scheme 1b). While α-monosubstituted alkyl aryl
ketimines (R or R′ = H) can generate the required
stereodefined CC double bond in the rearrangement
precursors, the same is not true of acylic α,α-disubstituted
ketimines (R and R′ ≠ H; R ≠ R′), especially those in which R
(Scheme 1a). In this [2,3]-shift transformation, the chiral
sulfinyl group in an O-silyl N-tert-butanesulfinyl N,O-ketene
aminal migrates, and the chirality on the sulfur atom is
transferred to the α-carbon of the resulting α-sulfenyloxy
amide. This approach is attractive because it relies on Ellman’s
chiral ammonia equivalent (tert-butanesulfinylamide), which
has a low molecular weight and both of its enantiomers can be
17
purchased in bulk at low cost.
We wondered whether this rearrangement could stereo-
selectively set up a secondary, even tertiary, hydroxy group at
Received: September 5, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03159
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and R′ are similarly bulky. Inspired by the pioneering efforts of
enamine 2a was generated using KHMDS in toluene, and then
the trimethyl phosphite was introduced after no more
unreacted 2a was detectable (entry 8). We also succeeded in
conducting the cascade of enamination/N-methylation/rear-
rangement in one pot with excellent enantioselectivity (99:1
er) albeit lower yield (53%), without the need for quenching or
workup at the stage of N-methylation (entry 9). In these
reactions (entries 8−9), a substantial amount (∼20%) of
1
3b,c
13d,e
Myers
and Zakarian
to stereoselectively enolize
challenging acyclic α,α-disubstituted chiral acid derivatives
via asymmetric deprotonation, we envisaged that the chiral N-
tBS group in N-tBS imines derived from enantioenriched α,α-
disubstituted ketones would lead to stereoselective deproto-
nation, producing stereodefined 3,3-disubstituted enamines.
Here we report a cascade involving enamination and N-
methylation-initiated aza-Mislow−Evans rearrangement for
synthesis of enantioenriched α-hydroxy ketone derivatives.
We began our study by treating N-tBS imine 1a with lithium
hexamethyldisilazide (LiHMDS) in THF at −78 °C, then
adding methyl triflate (MeOTf), which led exclusively to the
hydroxy ketone 3a was detected before addition of P(OMe) ,
3
reflecting the presence of thiophilic amines derived from metal
amides. To our delight, adding silica gel to the reaction
dramatically reduced the amount of 3a, presumably because
the gel absorbed amines and thereby reduced S−O bond
cleavage, providing α-sulfenyloxy ketone 4a in 64% yield with
18
enamination/N-methylation product. After quenching and
20
workup, the crude product was dissolved in methanol in the
excellent enantioselectivity (99.5:0.5, entry 10).
presence of thiophile P(OMe) , and the N-methylated N-tBS
Next, the substrate scope of the rearrangement reaction was
examined under optimized conditions using a range of N-tBS
ketimines (Table 2). Aryl alkyl ketimines containing electron-
deficient aromatic groups (entries 2−5), electron-rich aromatic
groups (entries 6−12), or hetereoaromatic groups (entries 11
and 12) smoothly underwent 2,3-migration of the sulfinyl
group, usually giving the desired products with enantioselec-
tivity of at least 99:1. The reaction was easily scaled up to one
gram (entry 4). Notably, the sterically hindered o-tolylpropio-
phenone-derived N-tBS imine was not a suitable substrate
(data not shown): the major product was a 1,2-diketone, which
probably formed through auto-oxidation of an α-hydroxy imine
3
enamine intermediate was allowed to undergo rearrangement
19
slowly at room temperature. The thiophile-supported S−O
bond cleavage after rearrangement. After about 40 h, the
enamine had been completely consumed and the desired
product 3a was obtained in 43% yield with 92:8 er (Table 1,
entry 1). The reaction was carried out by screening bases
(
entries 2−4) and solvents (entries 5−7). Using KHMDS or
tBuOK as a base led to high enantioselectivities (entries 3−4,
6:4−97:3 er), which were further increased by switching the
solvent from THF to toluene (entry 7, 98:2 er). The best er
99:1) and yield (74%) were obtained when the crude
9
(
21
intermediate. N-tBS imines derived from dialkyl ketones,
such as 1m (R = cyclohexyl) and 1n (R = iPr), participated in
the reaction but gave slightly lower enantioselectivities (entries
Table 1. Enamination−Methylation−Rearrangement of
Propiophenone-Derived N-tert-Butanesulfinyl Ketimine
a
13 and 14). The bulky tert-butyl analogue was transformed to
the corresponding N-methylated enamine in 70% isolated
yield, which then failed to undergo rearrangement. Most
rearrangements of functionalized acetophenone-based keti-
mines bearing a range of α-substitutions such as linear alkyl
(
1o), benzyl (1p), allyl (1q), azide-functionalized alkyl (1r),
branched alkyl (1s), or phenyl (1t) groups proceeded with
excellent enantioselectivities (entries 15−19). The exception
22
b
c
was α-phenyl imine 1t (entry 20), which also suffered from
low yield (46%) due to competing formation of benzil
byproduct. Using the enantiomer of ketimine 1f (ent-1f) as
starting material generated the enantiomer of 4f (ent-4f) with
0.5:99.5 enantioselectivity (entry 21). The absolute config-
uration of ent-4f was determined as 2S based on comparison of
the optical rotation of its S−O bond cleavage product with the
entry
base
solvent
product
er (yield, %)
d
1
LiHMDS
NaHMDS
KHMDS
tBuOK
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
THF
THF
THF
THF
CH Cl
3a
3a
3a
3a
3a
3a
3a
3a
3a
4a
92:8 (43%)
89:11
96:4 (47%)
97:3 (40%)
91:9
97:3
98:2
99:1 (74%)
99:1 (53%)
99.5:0.5 (64%)
d
2
d
3
d
4
d
5
2
2
d
6
Et O
2
23
d
literature.
7
toluene
toluene
toluene
toluene
e
After these studies of rearrangements involving α-mono-
substituted alkyl aryl ketimines, we explored the suitability of
this transformation for α,α-disubstituted imines. First, phenyl
isopropyl N-tBS ketimine 5 was subjected to the reaction
conditions of enamination/N-methylation/rearrangement, and
α-sulfenyloxy ketone 6 was obtained in high yield (Scheme 2).
We then applied the protocol to synthesis of enantioen-
riched acyclic tertiary α-hydroxy ketones (Table 3). Luckily,
with few modifications to the reaction conditions, we were able
8
e
,
f
9
1
g
0
a
Reaction conditions: 1a (0.20 mmol) and base (0.24 mmol) were
stirred in anhydrous solvent (2.0 mL) at −78 °C for 30 min, after
which methyl triflate (0.26 mmol) was added. The mixture was
maintained at −78 °C until complete consumption of starting
material and then quenched with water. After common workup, the
crude product was dissolved in methanol and maintained at rt after or
before introduction of trimethyl phosphite. For production of 4a,
crude product 2a and silica gel (1 g) were stirred at rt in EtOAc.
Enantiomeric ratios were determined using HPLC with a chiral
stationary phase. Isolated yield after silica gel chromatography. The
mixture of crude 2a and P(OMe) in MeOH was stirred for 43 h at rt.
After crude 2a was stirred in MeOH for 43 h at rt, P(OMe) was
to convert (R ,2S)-imine 7a to (2R)-hydroxy ketone 8a in 75%
S
yield with 98:2 er (entry 1). This excellent enantioselectivity is
impressive given the similar bulkiness of the methyl and ethyl
b
c
d
substituents at the α-position of the imine. Imine (S ,2S)-7b,
S
that is an epimer of 7a, underwent rearrangement to give the
same enantiomer of the hydroxyl ketone 8a with excellent
enantioselectivity (entry 2), even though 7b and 7a possess the
opposite configuration at the sulfur atom. Apparently, the
3
e
3
f
g
added. Rearrangement without workup. 5.0 equiv of HMPA were
used.
B
DOI: 10.1021/acs.orglett.9b03159
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Substrate Scope
b
c
entry
ketimine (R, R′)
1a (Ph, Me)
1b (4-BrC H , Me)
product
er (yield, %)
1
2
3
4a; 3a
4b
4c
4d; 3d
4e
4f
4g
4h
4i
99.5:0.5 (64%); 99:1 (74%)
99:1 (72%)
99:1 (66%)
99:1 (62%) ; 99:1 (77%)
97:3 (70%)
99:1 (66%)
99:1 (56%)
99:1 (66%)
99:1 (73%)
6
4
d
1c (4-ClC H , Me)
6
4
e
e
4
5
6
7
8
9
1d (4-FC H , Me)
6
4
1e (4-CF C H , Me)
3
6
4
1f (4-MeOC H , Me)
6
4
1g (4-MeSC H , Me)
6
4
1h (4-MeC H , Me)
6
4
1i (3-MeC H , Me)
6
4
10
11
12
13
14
15
16
17
18
19
20
21
1j [2-(6-MeO-naphthyl), Me]
1k (2-furyl, Me)
1l (2-thienyl, Me)
1m (cyclohexyl, Me)
1n (iPr, Me)
3j
4k
4l
4m
4n
3o
4p; 3p
4q
3r
3s
97.5:2.5 (54%)
98:2 (57%)
99.5:0.5 (80%)
f
95:5 (56%)
97:3 (56%)
99:1 (78%)
99.5:0.5 (55%); 99:1 (68%)
99:1 (55%)
99:1 (68%)
98:2 (74%)
93.5:6.5 (46%)
0.5:99.5 (67%)
1o (4-BrC H , nC H )
6
4
5
11
1p (Ph, Bn)
1q (Ph, allyl)
g
1r (Ph,CH CH N )
2
2
3
1s (Ph, iPr)
1t (Ph, Ph)
ent-1f (PMP, Me)
3t
ent-4f
h
a
b
d
Reaction conditions: 1 (0.20 mmol), KHMDS (0.24 mmol), MeOTf (0.26 mmol) and HMPA (1.0 mmol) in anhydrous toluene (2.0 mL).
c
Enantiomeric ratios were determined using HPLC with a chiral stationary phase. Isolated yield after silica gel chromatography.
e
f
Dichloromethane was used instead of ethyl acetate. 1.0-g scale reaction of 1d. Pyridine p-toluenesulfonate (PPTS) was used instead of silica
g
h
gel. Higher yield required purification of the N-methylated enamine intermediate using silica gel chromatography. The (S)-enantiomer of N-tert-
butanesulfinamide was used.
2
5
Scheme 2. Rearrangement of Phenyl Isopropyl N-tBS-
ketimine
N-tBS-imine via a well-documented chelated chairlike 6/4
26
bicyclic transition state TS-1, followed by N-methylation,
affords the fully substituted (R ,E)-enamine, in which the C
S
C double bond adopts the E-configuration. In TS-1, the proton
lies on the same face as the oxygen atom of the chiral sulfinyl
group, which facilitates deprotonation; in addition, the tBu of
the tBS group occupies the equatorial position in the chair−
chairlike conformation of the eight-membered ring, which
prevents 1,3-diaxial-like steric clashes with the Ar group in the
axial-like position. The bulky group at the 2-position of the
absolute configuration of the rearrangement product was
determined by the configuration at the α-stereocenter, which
was the same in the two substrates, rather than by the
configuration of the sulfinyl group. Indeed, using a mixture of
diastereomers 7a and 7b as substrates gave product 8a with
excellent er (entry 3 vs entries 1 and 2). This implies that
(
R , E)-enamine intermediate leads to [2,3]-migration of the
S
27
sulfinyl group via an exo-transition state (TS-2), yielding the
aza-Mislow−Evans rearrangement product α-sulfenyloxy N-Me
imine in a (2R)-configuration. Cleavage of the S−O bond and
hydrolysis of the azomethine furnish (2R)-acyclic tertiary
hydroxyl ketone. Deprotonation of (S ,2S)-N-tBS-imine
imines prepared by condensation of racemic tBSNH with
S
2
proceeds with the opposite facial selectivity as deprotonation
enantioenriched ketone can be used directly, regardless of the
dr value of the diastereomer mixture. The enantiomer of 8a
of the (R ,2S)-imine, forming (S ,Z)-enamine via TS-1′.
S
S
Subsequent rearrangement of the (S ,Z)-enamine via TS-2′
(
ent-8a) can be accessed by using ent-7a or ent-7b as
S
24
also leads to (2R)-product. Deprotonation of the α-
monosubstituted N-tBS-imine preferentially generates (E)-
enamine since the α-position of the imine features two
removable protons, and the bulky N-methylated tert-
butanesulfinylamino group in the 3-monosubstituted enamine
causes the α-substituent (R group in Scheme 3) to lie on the
rearrangement precursors (entries 4−5). This process also
showed excellent stereoselective control with α-aryl-/α-alkyl-
disubstituted ketimines (entries 6 and 7).
We propose the mechanism in Scheme 3 to rationalize the
high enantiomeric ratios in the rearrangement of α,α-
disubstituted N-tBS ketimines. Deprotonation of the (R ,2S)-
S
C
DOI: 10.1021/acs.orglett.9b03159
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Enantioselective Synthesis of α,α-Disubstituted α-Hydroxy Ketones via Rearrangement
c
d
entry
ketimine (R, R′)
configuration of ketimine; er
,
bf
product
yield (%)
er (configuration)
1
2
3
4
5
7a (Me, Et)
7b (Me, Et)
7a + 7b (∼1:1)
ent-7a (Me, Et)
ent-7b (Me, Et)
7c (Ph, Et)
(R ,2S); (99:1)
8a
8a
8a
ent-8a
ent-8a
8b
75
76
83
80
83
88
94
98:2 (2R)
97.5:2.5 (2R)
97.5:2.5 (2R)
3:97 (2S)
3:97 (2S)
98:2 (2R)
S
,
bf
(S ,2S); (99:1)
S
,
bf
(R ,2S)/(S ,2S); (99:1)
S
S
,
bf
(S ,2R); (98:2)
S
,
bf
(R ,2R); (98:2)
S
e
f
6
e
(S ,2S); (98:2)
S
f
7
ent-7c (Ph, Et)
(R , 2R); (98:2)
ent-8b
2:98 (2S)
S
a
Reaction conditions: 7 (0.20 mmol), tBuOK (0.40 mmol), MeOTf (0.40 mmol), HMPA (1.0 mmol), and P(OMe) (1.0 mmol) were used. See
3
b
c
the SI for details. Enantiomeric ratios for the ketones used to prepare ketimines 7a and 7b. Isolated yield after silica gel chromatography.
d
e
f
Enantiomeric ratios were determined using HPLC with a chiral stationary phase. Methanol was used instead of 1,4-dioxane. Enantiomeric ratios
for the corresponding ketone generated from imino-hydrolysis of ketimines.
Scheme 3. Rationalization of Stereochemistry
opposite side of the CC bond as the bulky amino group.
intermediates. Our laboratory is now using the enamine
intermediates in nucleophilic addition reactions to construct
valuable synthetic targets.
Rearrangement of (R ,E)-enamine via exo-transition state TS-3
S
affords (2R)-product, while (S ,E)-enamine gives the (2S)-
S
product via TS-3′.
We have developed an aza-variant of Mislow−Evans
rearrangement for synthesis of enantioenriched α-hydroxy
ASSOCIATED CONTENT
■
*
S
Supporting Information
ketones. Simple enamination/N-methylation of N-tBS imine
initiates migration of its sulfinyl group with excellent
stereocontrol. For rearrangements of α,α-disubstituted N-tBS
imines, diastereomers can be used as the starting material
because the absolute configuration of the rearrangement
product is determined by the configuration at the α-
stereocenter, rather than by the configuration of the sulfinyl
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03159.
Experimental details and characterization data for all
new compounds (PDF)
Accession Codes
group (Table 3, entry 3). Thus, racemic tBSNH can be used
2
directly to condense with enantioenriched ketones for
preparation of precursors of stereoselective rearrangement.
Our experiments also provide a novel method to access
stereodefined acyclic 3,3-disubstituted chiral metalloenamine
CCDC 1949225−1949226 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
D
DOI: 10.1021/acs.orglett.9b03159
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(10) For a review of organocatalyzed α-hydroxylation of the ketones
called β-ketoesters, see: Govender, T.; Arvidsson, P. I.; Maguire, G. E.
M.; Kruger, H. G.; Naicker, T. Chem. Rev. 2016, 116, 9375.
(
11) For selected examples of asymmetric metal-catalytic α-
AUTHOR INFORMATION
■
*
hydroxylation of common ketones, see: (a) Momiyama, N.;
Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 6038. (b) Kawasaki,
M.; Li, P.; Yamamoto, H. Angew. Chem., Int. Ed. 2008, 47, 3795. For
representative examples of the racemic version, see: (c) Chuang, G. J.;
Wang, W.; Lee, E.; Ritter, T. J. Am. Chem. Soc. 2011, 133, 1760.
Corresponding Author
E-mail: clu@ynu.edu.cn.
ORCID
(
d) Liang, Y.-F.; Jiao, N. Angew. Chem., Int. Ed. 2014, 53, 548.
Chong-Dao Lu: 0000-0001-8968-0134
Notes
(12) Numerous reports of metal-catalytic asymmetric α-hydrox-
ylation of β-keto acid derivatives have been published. For selected
recent examples, see: (a) Ding, W.; Lu, L.-Q.; Zhou, Q.-Q.; Wei, Y.;
Chen, J.-R.; Xiao, W.-J. J. Am. Chem. Soc. 2017, 139, 63. (b) Yang, F.;
Zhao, J.; Tang, X.; Wu, Y.; Yu, Z.; Meng, Q. Adv. Synth. Catal. 2019,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
3
61, 1673.
13) For formation of fully substituted acyclic enolates, see:
a) Manthorpe, J. M.; Gleason, J. L. J. Am. Chem. Soc. 2001, 123,
This work was supported by the National Natural Science
Foundation of China (21871292) and Yunnan University.
(
(
2091. (b) Kummer, D. A.; Chain, W. J.; Morales, M. R.; Quiroga, O.;
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Chem. Soc. 2002, 124, 12084. (c) Linghu, X.; Potnick, J. R.; Johnson,
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́
dez de la
Ro
2
1
̈
hr, C.; Liu, H.-w.; Mu
389. (e) Goodman, C. G.; Johnson, J. S. J. Am. Chem. Soc. 2014, 136,
4698 For enantioselective nucleophilic addition to diketone, see: .
, C.; Nieto, J. Org. Lett.
̈
ller, M. Angew. Chem., Int. Ed. 2010, 49,
(
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(
2
f) Infante, R.; Martin-Alvarez, J. M.; Andres
́
(
18) We also observed α-C-methylation products in some cases, with
0% yield in the reaction involving 1c and 18% yield in the reaction
involving 1f.
017, 19, 1516.
5) (a) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919.
b) Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek, E. In Organic
Reactions; Overman, L. E., Ed.; John Wiley & Sons Inc.: New York,
1
(
(
(
19) Heating of the reaction mixture resulted in reduced er.
(20) Addition of HMPA partially suppressed C-methylation and
2
003; Vol.62, pp 1−356. (c) Takemoto, Y.; Miyabe, H. Catalytic
improved the yield of rearrangement product.
Asymmetric Synthesis; Wiley: Hoboken, 2010; pp 227−267. (d) Smith,
(21) For auto-oxidation of α-hydroxy imines, see: Murakami, M.;
A. M. R.; Hii, K. K. Chem. Rev. 2011, 111, 1637.
Komoto, I.; Ito, H.; Ito, Y. Synlett 1993, 1993, 511−512. The
presence of amine in the reaction mixture means that we cannot
exclude the possibility that the 1,2-diketone formed via tBuSH
elimination from the rearrangement product α-sulfenyloxy ketone
derivative.
(
6) For aldehyde- and ketone-derived metalated chiral hydrazones,
see: Enders, D.; Bhushan, V. Tetrahedron Lett. 1988, 29, 2437.
7) For early asymmetric α-aminoxylation of ketones using chiral
amine catalysis, see: (a) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Shoji,
M. Angew. Chem., Int. Ed. 2004, 43, 1112. (b) Bøgevig, A.; Sunden
H.; Cordova, A. Angew. Chem., Int. Ed. 2004, 43, 1109. For aldehydes,
(
́
,
́
(22) N-tBS ketimines derived from 1-tetralone underwent smooth
see: (c) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247. (d) Brown,
S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc.
enamination/N-methylation but extremely slow rearrangement.
Rearrangement of imine derived from α-tert-butyl-substituted
acetophenone provided desired product in very low yield (∼10%).
Several known N-alkylated N-tBS enamines have been reported
without mention of [2,3]-rearrangement. For cyclic N-tBS enamines,
see: (a) Chen, D.; Xu, M.-H. Chem. Commun. 2013, 49, 1327.
(b) Healy, A. R.; Izumikawa, M.; Slawin, A. M. Z.; Shin-ya, K.;
Westwood, N. Angew. Chem., Int. Ed. 2015, 54, 4046. (c) Li, J.; Jiang,
S.; Procopiou, G.; Stockman, R. A.; Yang, G. Eur. J. Org. Chem. 2016,
2016, 3500. For acyclic N-tBS enamines, see: (d) Rainoldi, G.;
Faltracco, M.; Lo Presti, L.; Silvani, A.; Lesma, G. Chem. Commun.
2016, 52, 11575. For N-tBS enamines derived from α-unsubstituted
ketimines, see: (e) Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad,
K. R. J. Org. Chem. 2003, 68, 2410. For N-tBS enamines derived from
aldimines, see: (f) Chogii, I.; Das, P.; Fell, J. S.; Scott, K. A.;
2
003, 125, 10808. (e) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji,
M. Tetrahedron Lett. 2003, 44, 8293. (f) Cordova, A.; Sunden, H.;
Engqvist, M.; Ibrahem, I.; Casas, J. J. Am. Chem. Soc. 2004, 126, 8914.
g) For a recent report of enantioselective oxidative coupling of
́
́
(
carboxylic acids to α-branched aldehydes, see: Leth, L. A.; Næsborg,
L.; Reyes-Rodríguez, G. J.; Tobiesen, H. N.; Iversen, M. V.; Jørgensen,
K. A. J. Am. Chem. Soc. 2018, 140, 12687.
(
8) For chiral phase-transfer catalysts, see: Sim, S. B. D.; Wang, M.;
Zhao, Y. ACS Catal. 2015, 5, 3609. See also references cited therein.
9) For chiral iminium salt catalysts, see: Bulman Page, P. C.;
(
Almutairi, S. M.; Chan, Y.; Stephenson, G. R.; Gama, Y.; Goodyear, R.
L.; Douteau, A.; Allin, S. M.; Jones, G. A. J. Org. Chem. 2019, 84, 544.
See also references cited therein.
E
DOI: 10.1021/acs.orglett.9b03159
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Crawford, M. N.; Houk, K. N.; Njardarson, J. T. J. Am. Chem. Soc.
2
(
6
(
017, 139, 13141.
23) Honda, Y.; Ori, A.; Tsuchihashi, G. Bull. Chem. Soc. Jpn. 1987,
0, 1027.
24) The absolute configuration of ent-8a was determined by
comparing its chiral HPLC analysis with that of the azomethine
hydrolysis product of compound 9 whose absolute configuration was
assigned based on single-crystal X-ray diffraction analysis (CCDC
1
949226). For details, see the SI. The compound 9 is the N-tBS imine
derivative of ketone ent-8a and was synthesized via direct α-
hydroxylation of N-tBS ketimine ent-7b with molecular oxygen in
the presence of trimethyl phosphite. Studies of this reaction are
underway in our laboratory.
(
25) X-ray crystallographic analysis of the α-branched N-tBS
ketimine 7c (CCDC 1949225) revealed that, in the solid state, the
substrate adopts the rotameric form in which the N-tBS group is trans
to the α-stereogenic center. This is likely to be the case in solution as
well.
(
1
(
26) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2003,
25, 11276.
27) (a) Hoffmann, R. W.; Goldmann, S.; Gerlach, R.; Maak, N.
Chem. Ber. 1980, 113, 845. (b) Goldmann, S.; Hoffmann, R. W.;
Maak, N.; Geueke, K.-J. Chem. Ber. 1980, 113, 831.
F
DOI: 10.1021/acs.orglett.9b03159
Org. Lett. XXXX, XXX, XXX−XXX