Effective 1,5-stereocontrol in Pd(0)/InI promoted reactions of chiral N-Ts-4-vinylazetidin-2-ones with aldehydes. An efficient entry into nonracemic semi-protected (3Z)-2,6-anti-enediols

Article abstract of DOI:10.1039/c5cc01485a

ε-Amido-allylindiums generated in situ from N-Ts-4-vinylazetidin-2-ones in the presence of 2 eq. of InI and catalytic amounts of Pd(PPh₃)₄ react with a number of aromatic and aliphatic aldehydes with effective remote 1,5-stereocontrol to afford (3Z)-2,6-anti-enediols as major products in good yields and with excellent diastereoselectivity. This journal is

Full text of DOI:10.1039/c5cc01485a

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Effective 1,5-stereocontrol in Pd(0)/InI promoted
reactions of chiral N-Ts-4-vinylazetidin-2-ones
with aldehydes. An efficient entry into nonracemic
semi-protected (3Z)-2,6-anti-enediols†
Cite this: Chem. Commun., 2015,
51, 6796
Received 17th February 2015,
Accepted 11th March 2015
Urszula K. Klimczak and Bartosz K. Zambron*
´
DOI: 10.1039/c5cc01485a
www.rsc.org/chemcomm
e-Amido-allylindiums generated in situ from N-Ts-4-vinylazetidin- these compounds as chiral building blocks.4 Although the trans-
2-ones in the presence of 2 eq. of InI and catalytic amounts of formation of 4-vinyl-azetidin-2-ones by C–N bond cleavage using
Pd(PPh3)4 react with a number of aromatic and aliphatic aldehydes Pd(0) catalysts and subsequent reactions of electrophilic Pd(II)
with effective remote 1,5-stereocontrol to afford (3Z)-2,6-anti-enediols complexes generated in this manner with nucleophiles have been
as major products in good yields and with excellent diastereoselectivity. seldom reported,5 umpolung of these species by transmetalation
and subsequent reactions with electrophiles including carbonyl
The synthesis of homoallylic alcohols via the reaction of allylmetal compounds have not been described yet.
reagents with carbonyl compounds is one of the most effective
In this communication, we wish to report the highly stereo-
C–C bond formation methods in organic synthesis.1 Among many selective synthesis of (3Z)-2,6-anti-enediols by umpolung of
reagents the nontoxic, water tolerant allylindiums generated in situ b-lactams and their addition to aldehydes in the presence of InI
by reductive transmetalation of p-allylpalladium(II) complexes, and a catalytic amount of Pd(PPh3)4 for the first time (Scheme 1).
providing high yields and often excellent selectivity under mild The 2,6-anti-enediols obtained in this manner can be easily
reaction conditions, constitute very interesting alternatives.2 transformed into a variety of linear and heterocyclic derivatives,
Since the pioneering work by Marshal on the reactions of chiral which is exemplified in the following article.
nonracemic allenylindiums generated from enantioenriched
As a model compound, racemic N-Ts-4-vinylazetidin-2-one (Æ)-2,
secondary propargylic mesylates in the presence of InI and readily available in two steps from known b-lactam (Æ)-1, was
5 mol% Pd(0) catalyst and their additions to aldehydes,2d several chosen.6 A bulky OTIPS substituent on C-3 of the b-lactam ring
interesting articles using this methodology have appeared during was expected to provide good stereoselectivity of the addition step,
the last decade.2e–o However, the utility of 4-vinylazetidin-2-ones as while a strongly electron withdrawing Ts group attached to the
precursors of chiral e-amido-allylindiums and regio- and stereo- nitrogen atom, facilitating Pd(0)-promoted C–N bond cleavage.
selectivity of their additions to electrophiles have not been
reported so far.
Initially, the formation of the corresponding allylindium
from (Æ)-2 and its subsequent addition to benzaldehyde under
Due to well-known antibiotic activity of b-lactams (azetidin- the conditions developed in Takemoto’s group was attempted.2e, f
2-ones) a great number of methods of asymmetric syntheses of As shown in Table 1 (entry 1), the reaction gave exclusively 2,6-anti-
these types of compounds have been developed. Thus a variety of enediols (Æ)-3a and (Æ)-3b, in 88% total yield, with moderate
them are readily available in both enantiomeric forms in excellent (Z)-selectivity and significant remote 1,5-asymmetric induction.
optical purity.3 The high reactivity of b-lactams, resulting from the
strained 4-membered ring, the high chirality content that can be
easily transferred to a variety of products and the rigidity of their
structure often make the reactions involving them very stereo-
selective, which has engendered many synthesis methods of a
number of derivatives not containing a b-lactam fragment using
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52,
01-224 Warsaw, Poland. E-mail: bartosz.zambron@icho.edu.pl
† Electronic Supplementary Information (ESI) available: Experimental details,
full characterization data and copies of NMR spectra for all new compounds.
CCDC 1048357. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c5cc01485a
Scheme 1 Reactions of p-allylpalladium(II) complexes generated from
b-lactams.
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Table 1 Solvent effect on the Pd(PPh3)4/InI-mediated addition of N-Ts-
4-vinylazetidin-2-one (Æ)-2 to benzaldehyde
Table 2 Pd(PPh3)4/InI-mediated addition of N-Ts-4-vinylazetidin-2-one
(Æ)-2 to aromatic and aliphatic aldehydes
(Æ)-3a yielda
(Æ)-3b yielda
(3Z)-2,6-Enediol;
(3E)-2,6-Enediol;
yielda [%] (d.r.)b
yielda [%] (d.r.)b
Entry Solvent
Time
[%]; (d.r.)b
[%]; (d.r.)b
Entry
R
1
2
3
4
5
6
Ph
(Æ)-3a 80 (95 : 5)
(Æ)-4a 81 (95 : 5)
(Æ)-5a 74 (93 : 7)
(Æ)-6a 65 (92 : 8)
(Æ)-7a 70 (94 : 6)
(Æ)-8a 79c (97 : 3)
(Æ)-3b 15 (92 : 8)
(Æ)-4b 17 (94 : 6)
(Æ)-5b 17 (88 : 12)
(Æ)-6b 33 (79 : 21)
(Æ)-7b 27 (85 : 15)
(Æ)-8b 17c (92 : 8)
1
2
3
4
5
6
7
8
9
10
THF
Dioxane
DME
DMF
NMP
30 min 59 (91 : 9)
29 (69 : 31)
28 (71 : 29)
14 (63 : 37)
67 (80 : 20)
69 (78 : 22)
p-CN-Ph
p-OMe-Ph
Et
i-Pr
t-Bu
3 h
1 h
57 (86 : 14)
68 (87 : 13)
12 h
12 h
3 days
22 (89 : 11)
26 (86 : 14)
Complex mixture
MeOH
THF/HMPA (4 : 1) 30 min 71 (95 : 5)
THF/HMPA (3 : 1) 30 min 80 (95 : 5)
THF/HMPA (2 : 1) 30 min 81 (96 : 4)
THF/DMPU (3 : 1) 30 min 29 (90 : 10)
14 (91 : 9)
15 (92 : 8)
16 (92 : 8)
68 (77 : 23)
7
(Æ)-9a 65 (94 : 6)
(Æ)-9b 20 (82 : 18)
8
9
a
(Æ)-10a 70 (95 : 5)
(Æ)-11a 35 (83 : 17)
(Æ)-10b 18 (94 : 6)
(Æ)-11b 60 (76 : 24)
a
b
Isolated yields. Assayed by 1H NMR integration.
Isolated yields. Assayed by 1H NMR integration. Assayed by 1H NMR
b
c
Is it worth noting that the presented reaction constitutes an
example of a usually unfavourable a-allylation process where
the addition of an allylmetal to a carbonyl group takes place on
integration of an inseparable mixture of (Æ)-8a and (Æ)-8b.
the less substituted carbon of the allyl system.1,2 For instance, the with high (Z)-(84 : 16) and excellent 2,6-anti-(96 : 4) selectivity
observed regioselectivity stays in sharp contrast to the results of (Table 1, entry 9). The use of the 3 : 1 THF : HMPA mixture gave
analogous reactions of 2-vinylaziridines, which under the same comparable results and it was used in the further investigation, as
conditions afforded mainly 1,3-aminoalcohols, typical g-allylation reducing the amount of HMPA is advantageous due to its high
products.2e, f
toxicity (Table 1, entry 8). Further reduction in the amount of HMPA
Although the obtained result was quite encouraging, product led to a significant decrease of yield and (Z)/(E)-selectivity (Table 1,
distribution was not fully satisfactory. Therefore in the next step, entry 7). Surprisingly, attempts to replace HMPA with less toxic
the solvent effect on the reaction outcome was explored. At first, DMPU resulted in the reversal of (Z)/(E)-selectivity and in this case
other common relatively polar ethers were tested. The use of (3E)-2,6-anti-enediol (Æ)-3b was isolated as the major product in 68%
anhydrous dioxane led to a similar yield and (Z)-selectivity but yield, with moderate (77 : 23) 2,6-anti-selectivity (Table 1, entry 10).
d.r. of predominant (3Z)-2,6-anti-enediol (Æ)-3a dropped signifi-
To further explore our methodology, a variety of aromatic and
cantly (Table 1, entry 2). Carrying out the reaction in anhydrous aliphatic aldehydes were subjected to optimized reaction condi-
DME gave higher yield and better (Z)-selectivity but again the tions (Table 2). All of the reactions involving aromatic aldehydes,
2,6-syn :2,6-anti ratio of both (3Z)- and (3E)-enediols suffered electron rich or deficient, including furfural, afforded (3Z)-2,6-
(Table 1, entry 3). When less polar solvents were applied (Et2O, anti-enediols as major products in 70–81% yield and with high
MTBE, toluene and DCM) only partial conversion (o50%) of the 2,6-anti-selectivity (Table 2, entries 1–3 and 8). Reactions of
starting material was observed within several days, most likely due aliphatic aldehydes usually proceeded with somewhat lower
to poor solubility of the reagents. Surprisingly, the use of more (Z)- but the same high 2,6-anti-selectivity (Table 2, entries 4–7).
polar, aprotic solvents (DMF and NMP) caused (Z)/(E)-selectivity An exception is the reaction involving 3-methylbut-2-enal, resulting
reversal and in these cases (3E)-2,6-anti-enediol (Æ)-3b was isolated in the formation of (3Z)-2,6-anti-isomer (Æ)-11a as a minor product
as the major product in good yield and with moderate (80 : 20) in 35% yield and moderate (83 : 17) 2,6-anti-selectivity (Table 2,
2,6-anti-selectivity (Table 1, entries 4 and 5). Performing the entry 9). Interestingly, the use of highly sterically hindered pival-
reaction in MeOH resulted in the formation of a complex mixture aldehyde had no effect on the reaction rate and selectivity (Table 2,
of products, indicating that protic solvents are not suitable for the entry 6). Also the application of 4-hydroxybutyric aldehyde contain-
transformation (Table 1, entry 6). Since it has been reported that ing an unprotected hydroxyl group (existing mainly in hemiacetal
HMPA is often employed as a beneficial additive in Pd(0)/InI form) proved to be very successful, giving (Æ)-9a in 65% yield and
chemistry,2c,g–i several experiments using THF : HMPA mixtures excellent 2,6-anti-selectivity (Table 2, entry 7).
in different proportions were carried out (Table 1, entries 7–10).
Next, a series of experiments were conducted using modified
As a result of this study it was established that a mixture of THF azetidin-2-ones to determine the effect of the b-lactam structure
and HMPA in a 2 : 1 ratio gave the optimal result. Under these on the reaction outcome. Attempts of replacing the Ts group
conditions, (3Z)-2,6-anti-enediol (Æ)-3a was obtained in 81% yield, with common Boc and PMP protecting groups failed, as within
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Scheme 2 Pd(PPh3)4/InI-mediated addition of N-Ts-3-iPr-azetidin-2-
one (Æ)-12 to benzaldehyde.
Scheme 4 Synthesis and Pd(PPh3)4/InI-mediated addition of enantio-
enriched b-lactam (À)-2 to aldehydes.
3 days no conversion was observed. These substrates appeared to
be inert under optimized reaction conditions, indicating that a
strongly electron withdrawing group attached to the nitrogen atom
of b-lactam is necessary. Also the replacement of vinyl substituent
with (E)-propenyl caused a dramatic drop in the reaction rate and
only slight conversion (o5%) was observed within several days.
However, the reaction of azetidin-2-one (Æ)-12 containing the i-Pr
substituent on C3 of the b-lactam ring proceeded smoothly to give
(Z)-homoallylic alcohol (Æ)-13a as the major product in 76% yield
and with excellent 2,6-anti-selectivity (Scheme 2).
Semi-protected 2,6-anti-enediols with internal (3Z)-substituted
double bond and N-Ts-amide function could serve in the synthesis
of a variety of linear derivatives and heterocycles of different ring
sizes and substitution patterns. As a simple example of applica-
tion of enediol (Æ)-3a in synthesis, chiral caprolactams (Æ)-15,
(Æ)-16 and caprolactone (Æ)-17 were prepared using well-established
methods (Scheme 3). Directly subjecting enediol (Æ)-3a to
Mitsunobu conditions afforded N-Ts-lactam (Æ)-15 as a single
isomer in 46% yield. In the course of this transformation unexpected
migration of a CQC double bond was observed, which was
confirmed by NMR. Chemoselective methylation of the amide
function of (Æ)-3a under PTC conditions giving (Æ)-14 and sub-
sequent cyclisation involving alkoxide generated in situ afforded
lactone (Æ)-17 in 63% yield. Lactam (Æ)-16, in turn, was prepared
from (Æ)-14 in two steps by the formation of an azide under
Mitsunobu conditions and subsequent reduction with simulta-
neous cyclisation. Caprolactams and caprolactones constitute an
important structural motif found in a range of natural products
and their synthetic analogs exhibiting interesting pharmacologi-
cal activities which make them highly desirable.7
Finally, in order to verify that the method being developed may
serve in asymmetric synthesis, enantioenriched 4-vinylazetidin-2-
one (À)-19 (499% ee according to HPLC, see ESI†) was prepared
from racemic acetyloxy-b-lactam (Æ cis)-18 via lipase-catalysed
kinetic resolution (Scheme 4).8 Reactions of this compound
with 4-methoxybenzaldehyde and isobutyric aldehyde gave the
expected (Z)-2,6-anti-enediols (+)-5a and (+)-7a in good yield
without any trace of racemisation, which was proven by the
NMR study of Mosher’s esters 20, 21 (see ESI†).
Different methods were used to determine the configuration
of the obtained (3Z)- and (3E)-2,6-anti-enediols 3a–11a, 3b–11b
and homoallylic alcohols (Æ)-13a and (Æ)-13b. Their (Z)/(E)-
configurations were easily assigned by analysis of coupling
1
constants of the olefinic protons in H NMR spectra ( J B 10 Hz
for (Z)- and J B 15 Hz for (E)-isomers). Also d.r.’s of all (3Z)- and
(3E)-products were established using 1H NMR spectroscopy. X-ray
analysis of (Æ)-5a allowed us to establish its relative configuration
as 2,6-anti (see ESI†). The configurations of other (3Z)-2,6-enediols
were assigned by analogy. The relative configuration of (3E)-
isomer (Æ)-5b was determined by the reduction of CQC double
bonds of compounds (Æ)-5a and (Æ)-5b and by 1H and 13C NMR
spectra comparison of obtained products (Æ)-22 and (Æ)-23,
which clearly showed that the predominant diastereoisomer of
(Æ)-5b has an 2,6-anti configuration (Scheme 5). The configura-
tions of other (3E)-2,6-enediols were assigned by analogy.
The mechanism of the transformations being investigated has
not been studied and details are not clear. However, a plausible
reaction pathway based on the observed regio- and stereo-
selectivity of the process is depicted in Scheme 6. The initial step
consists of C4–N b-lactam bond cleavage by Pd(PPh3)4 followed
by reductive transmetalation of the transient p-allylpalladium(II)
Scheme 3 Application of (3Z)-2,6-anti-enediol (Æ)-3a in the synthesis of
caprolactams (Æ)-15, (Æ)-16 and caprolactone (Æ)-17.
Scheme 5 Reduction of double bond of enediols (Æ)-5a and (Æ)-5b.
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Financial support for this research, provided by Foundation
for Polish Science, grant HOMING PLUS/2013-0/14, is gratefully
acknowledged.
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