Diastereoselective synthesis of 2-methoxyimidoyloxiranes via dimethyl phosphite-mediated coupling of α-keto N-sulfinyl imidates with aldehydes

Article abstract of DOI:10.1039/c6cc07723d

Dimethyl phosphite-initiated coupling of α-keto N-tert-butylsulfinyl imidates with aldehydes is reported. The epoxide formation involves a cascade transformation initiated by base-promoted addition of phosphite to α-ketoimidates, followed by [1,2]-phospha-Brook rearrangement. This generates α-phosphonyloxy enolates that are subsequently intercepted by aldehydes, leading to [1,4] O→O dialkoxyphosphinyl migration and finally to intramolecular ring closure. This protocol was used to synthesize a range of enantioenriched trans-α,β-epoxy imidates in moderate to high yields with excellent diastereoselectivities.

Full text of DOI:10.1039/c6cc07723d

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Reactivity differences of Sc
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3
N@C2n (2n
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DOI: 10.1039/C6CC07723D
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Diastereoselective synthesis of 2‐methoxyimidoyloxiranes via
dimethyl phosphite‐mediated coupling of α‐keto N‐sulfinyl
imidates with aldehydes
Received 00th January 20xx,
Accepted 00th January 20xx
ab
a
a
a
Wei Huang, Hui Liu, Chong‐Dao Lu* and Yan‐Jun Xu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
O
X'
X
Dimethyl phosphate‐initiated coupling of α‐keto N‐tert‐
butylsulfinyl imidates with aldehydes is reported. The epoxide
formation involves a cascade transformation initiated by base‐
promoted addition of phosphite to α‐ketoimidates, followed by
O
O
P
OP OR''
R
X
R
2
OR''
OR''
OR''
H
addition/
X'
phospha-Brook
rearrangement
1
I-1
base
[
1,2]‐phospha‐Brook rearrangement. This generates α‐
phosphonyloxy enolates that are subsequently intercepted by
aldehydes, leading to [1,4] OO dialkoxyphosphinyl migration
and finally to intramolecular ring closure. This protocol was used
to synthesize a range of enantioenriched trans‐α,β-epoxy imidates
in moderate to high yields with excellent diastereoselectivities.
P(O)Ph2
N
P(O)Ph2
R'
P(O)Ph2
N
R'
EtO C
N
H
2
EtO C
2
3
(a)
ref 6
X = O
X' = OEt
R'' O PO
R
I-2
R'
2
3
R
4
Epoxides are important structural units in biologically interesting
O
O
OPO R''
3
2
O
OPO R''2
3
natural products and serve as a key functional group in ring‐opening
H+
1
Ar'
reactions for the synthesis of 1,2‐bifunctional compounds.
5
X'
Ar'
X'
Ar'
(b)
O
I-3
X = O
X' = OEt, OMe
or NR2
R
Epoxidation of alkenes can yield direct access to these small‐ring
R
OH
compounds, and asymmetric catalytic protocols for such
6
ref 8
tBu
2
epoxidation have been extensively developed. Epoxides can also
O
O
O
Ar
O
3
S
Ar'
H (c)
be formed from carbonyl compounds using ylides, Darzens
tBu
S
N
OPO R''
4
5
Ar'
5
3
2
N
reagents, or carbenes.
X = NS(O)tBu
X' = OMe
R = Ar
7
MeO
Ar'
OMe
Our success in synthesizing aziridines using phosphite‐mediated
Ar
O
I-4
coupling of α‐ketoesters with aldimines in the presence of alkali
this work
6
metal amides (Scheme 1a) led us to speculate that a similar Scheme 1 Formation of epoxides by trapping α‐phosphonyloxy enolates with
aldehydes
strategy might work for constructing epoxides. The protocol in
Scheme 1a takes advantage of the good leaving ability of the
phosphonyloxy group in enolate intermediate I‐1 (X = O, X’ = OEt),
formed in situ from phosphite addition to an α‐ketoester and
presence of catalytic amounts of base, aldehydes trap intermediate
I‐1, affording mono‐protected diol 6 through aldolization, followed
by [1,4] OO dialkoxyphosphinyl migration (Scheme 1b). Using
subsequent
phospha‐Brook
rearrangement
([1,2]
CO
8
7
chiral bases allows the asymmetric version of this reaction. These
phosphonate–phosphate rearrangement). The combination of
deprotonated phosphite and α‐ketoester functions as a Darzens
reagent in the subsequent addition‐cyclization transformation (aza‐
Darzens reaction). Interception of intermediate I‐1 by aldehydes
should provide a Darzens condensation product (Scheme 1c).
authors also found that warming a mixture of an α‐benzyl‐α‐
hydroxy trialkyl phosphonoacetate and 4‐chlorobenzaldehyde to
room temperature in the presence of 120 mol% base (KOtBu)
generated epoxide in low yield (23%) with poor diastereoselectivity
8
c
(
2:1 trans/cis). In contrast, carrying out the same reaction at 78
Pioneering works from Johnson and Ooi show that, in the
o
C gave product 6 in excellent yield (97%) with comparable
8
c
diastereoselectivity (2:1 anti/syn). These results led those
researchers to propose that the epoxide product is generated via
intramolecular displacement of the vicinal phosphate in
intermediate I‐3. This reaction differs from a traditional Darzens‐
type reaction in which the oxygen atom in the oxirane ring
originates from aldehydes, since oxirane ring formation occurs after
a.
Key Laboratory of Plant Resources and Chemistry of Arid Zones, Xinjiang Technical
Institute of Physics & Chemistry, Chinese Academy of Sciences, Urumqi 830011,
China. E‐mail: clu@ms.xjb.ac.cn; xuyj@ms.xjb.ac.cn
b.
University of Chinese Academy of Sciences, Beijing 100049, China
Experimental details and spectral data. CCDC 1505786
†
(7a). See
DOI: 10.1039/x0xx00000x
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the easier and faster migration of the [1,4] OO Table 1 Dimethyl phosphite‐mediated coupling of α‐keto N‐sulfinViyelwimAirdticalteeOs nwliinthe
a
DOI: 10.1039/C6CC07723D
dialkoxyphosphinyl group.
aldehydes
These previous findings led us to predict that trapping
phosphonyloxy enolate I‐1 with aldehydes in the presence of alkali
metal amides could deliver epoxides (Scheme 1c) in a process
similar to the one described in Scheme 1b. This process should
involve an I‐3‐like intermediate I‐4, rather than the I‐2‐like
intermediate in Scheme 1a. Here we describe the phosphite‐
mediated coupling reaction of α‐keto imidates with aldehydes for
the synthesis of trisubstituted oxiranes.
b
entry
Imidate 2 (Ar)
Aldehyde 5 (Ar’)
5a (Ph)
5b (4‐ClC H )
6 4
7, yield (%)
1
2
3
4
5
6
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
7a, 78
7b, 80
7c, 83 (80)
7d, 84
7e, 77
7f, 92
7g, 76
7h, 93
7i, 83
7j, 53
7k, 63
7l, 80
7m, 75
7n, 61
7o, 79
7p, 61
7q, 73
We envisioned that enantioenriched aryl α‐keto N‐tert‐
c, d
9
5c (4‐BrC H )
6
4
butylsulfinyl (tBS) imidate (Scheme 1c; X = NtBS, X’ = OMe)
5d (4‐CNC
6
H
4
)
could serve as a chiral equivalent of α‐keto ester/amide to
3 6 4
5e (4‐CF C H )
induce chirality. We were pleased to find that N‐tBS imidate
8
5f (4‐MeOC
6 4
H )
1
0
exhibited formamide‐like reaction behavior
and was
d
7
5g (4‐tBuC
5h (4‐MeC
6
H
H
4
)
efficiently lithiated in the presence of lithium diisopropylamide
LDA) and subsequently trapped by aryl aldehydes. Addition of
methoxy imidoyllithium to benzaldehyde afforded the alcohol
in 72% yield, albeit with moderate dr (eq. 1, Scheme 2).
8
9
10
6
4
)
(
5i (3‐MeC
6 4
H )
e
5j (2‐MeC H )
6
4
9
11
5k (1‐naphthyl)
5l (2‐naphthyl)
d
Further oxidation of the alcohol furnished phenyl α‐keto N‐tBS
imidate 2a in high yield.
Dimethyl phosphate (1a) was deprotonated using lithium
bis(trimethylsilyl)amide (LHMDS) and then exposed to ketone
12
1
3
2b (4‐MeC
2c (3‐MeC
2d (4‐FC
2e (4‐ClC
2f (4‐MeOC
6
H
H )
6 4
4
)
5c (4‐BrC
5c (4‐BrC
5c (4‐BrC
5c (4‐BrC
5c (4‐BrC
6
H
6
H
6
H
6
H
6
H
4
)
4
)
4
)
4
)
4
)
d
1
1
1
4
5
6
d
d
d
6
H
4
)
6 4
H )
H )
6 4
2
a, affording addition/rearrangement product 10a in good
11

13
17
yield with excellent diastereoselectivity (eq. 2).
a
1
(0.26 mmol), 2 (0.26 mmol) and 5 (0.20 mmol) in anhydrous THF under
Introducing benzaldehyde (5a) to the reaction mixture of 1a argon unless otherwise noted. Diastereomeric ratios were determined by
1
b
c
H NMR analysis of crude reaction mixtures. Yield of isolated product. 1 g
and
2 to trap the addition/rearrangement intermediate
d
o
synthesis ofe 7c
.
Reaction mixture was stirred at 10 C for 3h before
quenching. Reaction mixture was warmed to 0 C for 1h before quenching.
afforded epoxide product 7a with 20:1:0:0 dr (eq. 3).
o
Slight excess of 2a and 1a (1.3 equiv) was used to guarantee
1
4
good isolated yield (78%). The structure and absolute
stereochemistry of epoxide 7a were assigned based on X‐ray
crystallographic analysis, which indicated a trans‐configuration
1
5, 16
for the epoxide and (E)‐configuration for the C=N bond.
Raising the reaction temperature to room temperature gave
1
8
lower yield of 7a. Performing the reaction with O‐labeled
benzaldehyde (eq. 4) provided product 7a without effective
1
8
incorporation of O label into the epoxide, clearly indicating
that the epoxide oxygen atom is not derived from the
aldehyde.
Next we examined the scope and limitations of phosphite‐
mediated coupling of α‐keto imidates with aldehydes. Aryl
aldehydes that were electron‐deficient (entries 2
rich (entry 6), or electron‐neutral (entries 11
products in moderate to good yields. Scaling the reaction up to
g led to comparable yield and dr (entry 3). Meta‐ or ortho‐

5), electron‐

12) afforded
1
substituted aryl aldehydes performed well in the reaction,
providing ready access to the corresponding epoxyimidates
(
entries 9
10). In contrast, heteroaryl aldehydes such as furan‐
2
‐carbaldehyde, thiophene‐2‐carbaldehyde, and pyridine‐2‐
carbaldehyde yielded complex mixtures of unidentified
products. Enolizable and non‐enolizable aliphatic aldehydes
such as nBuCHO, iPrCHO, and tBuCHO proved to be unsuitable
coupling partners: no desired product was observed in any of
these cases. Several substituted aryl α‐ketoimidates
successfully participated in the cascade transformations,
Scheme
2 Synthesis of α‐keto N‐tert‐butylsulfinylimidate 2a and initial
investigation of its application in epoxide formation.
2
| J. Name., 2012, 00, 1‐3
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O
PhNH , Sc(OTf) , PhMe
HO
View Article Online
DOI: 10.1039/C6CC07723D
2
3
Ar
0 oC, 14 h
S Ph
Ar
Li
OPO Me
6
H
3
2
O
S
N
H O
70%
NHPh
2
O
N
S
OMe
N
OMe
Ar
1
1 (anti-)
O
MeO
Ph
O
O
(Z)-enolate
Ar
H
S
H
OPO3Me2
MeMgBr, THF, 40 oC, 4 h
5%
Ph
O
S
Ar
H
N
(2R, R )-10
S
Ar'CHO
7
N
OMe
c (Ar= 4-BrC6H4)
O
7
Me 12
Ar
2R
Ar'
H
S
Ar'
3S
O
RS
S
OPO3Me2
N
Ph
O
O
Ar
O
Ar
NaBH4, THF, rt, 2h
6%
Ar
H
S
O
N
O
Li
H
OMe
9
HN
Ar
Li
O
13
C(=Nt-BS)OMe
(2R, 3S, RS)
O
PO H
MeO
1
M H SO , rt, 15 h
Ph
Not observed
2
4
Ar
H
S
[
1,4] O O
TS-1
91%
HN
phosphinyl migration
O
14
Li
Ar'
Scheme 3 Further transformations of α,β‐epoxy imidates.
O
Ar
Me O PO
3
-exo-tet
ring closure
H
2
3
generating a range of trisubstituted trans‐
α
,
β
-epoxy imidates
17). Excellent diastereoselectivity (>20:1:0:0 dr)
was observed in all reactions listed in Table 1.
Further transformations of -epoxy imidates were
(2S, 3R, RS)-7
C(=Nt-BS)OMe
17
(
entries 13
I-4 (in Scheme 1)
Scheme 4 Plausible stereochemical model.
α,β
examined using compound 7c as a model (Scheme 4). Ring 21372255), the Recruitment Program of Global Experts
opening promoted by scandium triflate in the presence of (Xinjiang Program) and the Director Foundation of XTIPC
aniline gave anti‐α‐hydroxy‐β‐amino imidate 11. N‐tert‐ (2015RC014) is gratefully acknowledged.
butylsulfinyl imidate was easily converted to ketoimine 12 via
addition with Grignard reagent, to amine 13 via reduction with
Notes and references
NaBH , and to amide 14 via acid treatment.
4
The observed stereochemistry of the reaction can be
1
For selected reviews on epoxides and their synthetic
applications, see (a) P. Crotti and M. Pineschi, Epoxides in
Complex Molecule Synthesis, in Aziridines and Epoxides in
Organic Synthesis, ed. A. K. Yudin, Wiley‐VCH, Weinheim,
1
8
rationalized as reflecting the formation of (E)‐enolate derived
from phosphite addition to aryl α‐keto N‐sulfinyl imidate and
subsequent phospha‐Brook rearrangement. Quenching the
reactive intermediate with aqueous solution gave (2R, RS)‐10
because the bulky tert‐butylsulfinyl group blocks the re‐face of
the enolate, forcing the proton to approach from the si‐face.
Trapping the enolate with aldehydes via a chair‐like 6/4
2
3
006, Chapter 8, p 271; (b) C. Schneider, Synthesis, 2006,
919; (c) B. Das and K. Damodar, Epoxides and Oxetanes, in
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Majumdar and S. K. Chattopadhyay, Wiley‐VCH, Weinheim,
2
011, Chapter 3, p 63; (d) S. Meninno and A. Lattanzi,
1
9
Chem.–Eur. J., 2016, 22, 3632.
bicyclic transition state TS‐1 forces the si‐face of the enolate
to bond with the re‐face of the aldehyde, thereby preventing
2
For selected reviews on epoxidation of alkenes, see: (a) Y.
Zhu, Q. Wang, R. G. Cornwall and Y. Shi, Chem. Rev., 2014,
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1
,3‐diaxial interaction of the aryl group on the aldehyde with
the methoxy group on the imidate. After [1,4] O
O
phosphinyl migration, 3‐exo‐tet ring closure proceeds with
stereochemical inversion at the aldehyde carbon, providing
the epoxide (2S, 3R, RS)‐7.
In summary, we have developed a synthetic protocol
providing highly distereoselective access to enantioenriched
1
071; (c) G. De Faveri, G. Ilyashenko and M. Watkinson,
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via dimethyl phosphite‐triggered coupling of aryl α‐keto
imidates with aryl aldehydes. The epoxide ring is constructed
from the carbon of the aldehyde and the carbonyl group of the
α‐keto imidate. This constitutes a rare case in which aldehydes
function like Darzens reagents or carbenes that react with
carbonyl groups to form epoxides. The epoxide and N‐tBS
imidate functional groups in the resulting chiral oxiranes
provide useful handles for further manipulations toward the
synthesis of oxygen‐ and nitrogen‐containing compounds.
Financial support of this work by the National Natural
Science Foundation of China (U1403301, 21572262, and
(
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5
5
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Brook, Acc. Chem. Res., 1974, 7, 77; (h) G. R. Boyce, S. N. 14 When the reaction was carried out using 1 equiv 2a, the
Greszler, J. S. Johnson, X. Linghu, J. T. Malinowski, D. A.
Nicewicz, A. D. Satterfield, D. C. Schmitt and K. M. Steward,
J. Org. Chem., 2012, 77, 4503; (i) G. Eppe, D. Didier and I.
Marek, Chem. Rev., 2015, 115, 9175.
product was obtained in 55% yield. Besides LHMDS,
NaHMDS also proved to be a suitable base, giving 7a in
comparable yield. KHMDS, in contrast, gave low yield of
desired product.
8
9
(a) M. A. Horwitz, B. P. Zavesky, J. I. Martinez‐Alvarado and J. 15 Single crystals of compound 7a were grown by slow
S. Johnson, Org. Lett., 2016, 18, 36; (b) M. A. Horwitz, N.
evaporation of an ethyl acetate solution of the compound.
Tanaka, T. Yokosaka, D. Uraguchi, J. S. Johnson, and Ooi, T.
Crystal data: C H NO S, M = 357.45, orthorhombic, a =
2
0
23
3
3
Chem. Sci., 2015,
6, 6086; (c) M. Corbett, D. Uraguchi, T. Ooi
8.304(1), b = 10.274(2), c = 22.465(3) Å, V = 1916.7(5) Å , T
and J. S. Johnson, Angew. Chem., Int. Ed., 2012, 51, 4685.
The (RS) tert‐butanesulfinamide that was used as starting
= 296 K, space group P212121, Z = 4, 9795 reflections
int
‐
measured, 3388 unique (R = 0.0329), which were used in
material for preparing α‐keto N‐tBS imidate was purchased
from AllyChem (Dalian, China). We determined its
enantiopurity to be 99.0% ee. Several examples of alkyl N‐
all calculations. The final R was 0.0372 [I ≥ 2σ(I)] and wR2
1
was 0.0993 (all data), CCDC 1505786. See the ESI for the
single‐crystal structure of compound 7a
.
tBS imidates serving as nucleophiles exist in the literature. 16 To date, all reported X‐ray analyses of N‐tert‐butyl‐
For alkylation reactions: (a) F. Colpaert, S. Mangelinckx, G.
Verniest and N. De Kimpe, J. Org. Chem., 2009, 74, 3792; (b)
F. Colpaert, S. Mangelinckx and N. De Kimpe, J. Org. Chem.,
sulfinylimidate derivatives have indicated an E configuration
for the sulfinylimidate group (refs 9c, 9f, 9h, and 9j).
Therefore, we have depicted all related sulfinylimidates in
this report as E‐isomers.
2
011, 76, 234. For aldol reactions: (c) H. E. Bartrum, A.
Viceriat, S. Carret and J.‐F. Poisson, Org. Lett., 2014, 16
972. For Mannich reactions: (d) F. Colpaert, S. Mangelinckx,
,
17 We have so far been unable to extend this reaction to α‐
ketoimidates containing α‐alkyl substitutions, since our
efforts to prepare alkyl α‐keto N‐tert‐butylsulfinyl imidate
using the methods in Scheme 2 (eq. 1) have failed. Aliphatic
aldehydes did not undergo nucleophilic addition with
1
and N. De Kimpe, Org. Lett., 2010, 12, 1904; (e) F. Colpaert,
S. Mangelinckx, S. De Brabandere and N. De Kimpe, J. Org.
Chem., 2011, 76, 2204; (f) E. Semina, F. Colpaert, K. Van
Hecke, N. De Kimpe and S. Mangelinckx, Eur. J. Org. Chem.,
imidate 8 under the conditions we tested so far.
2
015, 4847. For 1,4‐additions: (g) J. Wang, Y. Zhou, L. Zhang, 18 Formation of (E)‐enolate from N‐sulfinylimidate in the
Z. Li, X. Chen and H. Liu, Org. Lett., 2013, 15, 1508; (h) H. presence of base was proposed in references 9c d.
Wang, P. Tang, Q. Zhou, D. Zhang, Z. Chen, H. Huang and Y. 19 The chair‐like 6/4‐membered bicyclic transition state has

Qin, J. Org. Chem., 2015, 80, 2494; (i) X. Wang, D. Xia, L. Tan,
H. Chen, H. Huang, H. Song and Y. Qin, Chem.–Eur. J., 2015,
been proposed on several occasions to rationalize observed
stereochemical outcomes of reactions involving tBS‐imines.
For examples, see: (a) T. P. Tang and J. A. Ellman, J. Org.
Chem., 1999, 64, 12; (b) T. P. Tang and J. A. Ellman, J. Org.
Chem., 2002, 67, 7819.
2
1
, 14602; (j) H.‐X. Huang, H.‐J.; Tan, L. Wang, S.‐Q. Wang, P.
Tang, H. Song, X.‐Y. Liu, D. Zhang and Y. Qin, J. Org. Chem.
016, DOI: 10.1021/acs.joc.6b01237. For examples of N‐tBS
2
amidines serving as nucleophiles, see: (k) T. Kochi and J. A.
Ellman, J. Am. Chem. Soc., 2004, 126, 15652.
0 For recent examples of nucleophilic addition of carbamoyl
anions, see: (a) J. T. Reeves, Z. Tan, M. A. Herbage, Z. S. Han,
M. A. Marsini, Z. Li, G. Li, Y. Xu, K. R. Fandrick, N. C. Gonnella,
S. C. Campbell, S. Ma, N. Grinberg, H. Lee, B. Z. Lu and
Senanayake, C. H. J. Am. Chem. Soc., 2013, 135, 5565; (b) J. T.
1
4
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