Rhodium-Catalyzed Regio- and Enantioselective Addition of N-Hydroxyphthalimide to Allenes: A Strategy to Synthesize Chiral Allylic Alcohols

Article abstract of DOI:10.1021/acs.orglett.7b03709

We achieved the first Rh-catalyzed regio- and enantioselective additions of N-hydroxyphthalimide to allenes. This transformation is accomplished via mild reaction conditions, leveraging on Josiphos SL-J003-2 as a chiral ligand to furnish branched O-allyl compounds in good yields with moderate to excellent enantioselectivities. The substrate scope is broad, and various functional groups are tolerated. The utility of this methodology is elaborated by transformation to allylic alcohols with different functional groups as well as to chiral O-allyl hydroxylamines.

Full text of DOI:10.1021/acs.orglett.7b03709

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhodium-Catalyzed Regio- and Enantioselective Addition of
N‑Hydroxyphthalimide to Allenes: A Strategy To Synthesize Chiral
Allylic Alcohols
Zi Liu and Bernhard Breit*
Institut fur Organische Chemie, Albert-Ludwigs-Universitat-Freiburg, Albertstrasse 21, 79104 Freiburg im Breisgau, Germany
̈
̈
S
* Supporting Information
ABSTRACT: We achieved the first Rh-catalyzed regio- and enantioselective additions of N-hydroxyphthalimide to allenes.
This transformation is accomplished via mild reaction conditions, leveraging on Josiphos SL-J003-2 as a chiral ligand to furnish
branched O-allyl compounds in good yields with moderate to excellent enantioselectivities. The substrate scope is broad, and
various functional groups are tolerated. The utility of this methodology is elaborated by transformation to allylic alcohols with
different functional groups as well as to chiral O-allyl hydroxylamines.
ince enantioenriched allylic alcohols are highly valuable and
scope, the methodology has some limitations regarding
Sversatile building blocks as well as structural elements of functional group compatibility; for example, an ester function
usually cannot tolerate the allylic ester saponification step. In
this context, we envisioned that N-hydroxyphthalimide
(NHPI)13 could serve as a cheap and nontoxic oxygen
pronucleophile to couple with allenes. The resulting O-allylated
addition products may undergo reductive O−N bond cleavage
to furnish the corresponding allylic alcohols. Additionally,
phthalimide deprotection would give access to O-allyl hydroxyl-
amines.
In the past few years, transition-metal-catalyzed regioselective
and enantioselective coupling of allenes10,12,14−17 and al-
kynes11,12,18 with various nucleophiles has been widely explored
as an atom-economic variant of the Tsuji−Trost allylation. In
order to extend the utility of this new tool box for catalytic
organic synthesis, we were interested in developing an
asymmetric addition of NHPI to allenes to provide a new
strategy to synthesize branched chiral allylic alcohols.
We began by investigating the reaction of hexa-4,5-dien-1-
ylbenzene (1a) with NHPI (2a). Initial experiments were done
using 4 mol % of Rh[(COD)Cl]2 and 8 mol % of 1,4-
bis(dicyclohexylphosphino)butane (DCPB) in 1,2-dichloro-
ethane (DCE)/EtOH (4/1),19 affording the branched allylic
product 3aa in 74% yield (Table 1, entry 1) at 70 °C for 18 h.
After further screening of chiral diphosphine ligands, we were
delighted to identify that Josiphos SL-J003-2 was the most
natural products and bioactive molecules, efforts have been
made to explore new asymmetric catalytic methods for their
synthesis.1 In addition, allylic alcohol can readily undergo
subsequent diastereoselective transformations,1 including hy-
drogenation, dihydroxylation, hydroboration, cyclopropanation,
and epoxidation, etc., to install further functionalities in a regio-
and stereoselective manner. Over the past decades, significant
progress has been made for the preparation of chiral allylic
alcohols, such as 1,2-reduction of α,β-unsaturated ketones,2
addition of vinylmetal reagents to aldehydes and ketones,3 and
kinetic as well as dynamic kinetic resolution of racemic allylic
alcohols.4 In addition, enantiomerically enriched allylic alcohols
could also be obtained on the basis of transition-metal-catalyzed
asymmetric C−O bond formation.5−9 In our group, we have
developed Rh-catalyzed enantioselective addition of carboxylic
acids10,11 or 4-methoxybenzyl alcohol12 (PMBOH) to allenes as
well as alkynes (Scheme 1). Their deprotection furnishes
branched chiral allylic alcohols. Despite the broad reaction
Scheme 1. Previously Developed Asymmetric Catalytic
Additions of Carboxylic Acids and Alcohols to Alkynes and
Allenes for the Synthesis of Branched Allylic Alcohols
Received: November 29, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03709
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Optimization of the Reaction Conditions
Table 2. Exploration of Pronucleophiles
a
b
Yield of isolated product. The ee values were determined by chiral
HPLC.
b
c
entry
ligand
yield (%)
ee (%)
1
DCPB
(R,R)-Diop
(S,S)-BDPP
(R)-Binap
74
13
29
12
86
27
22
85
79
91
78
78
69
71
88
rac
20
−11
5
56
−16
54
−49
69
88
89
89
Next, substrate generality with respect to the allene coupling
2
3
4
5
6
7
8
9
partner was evaluated. As depicted in Table 3, a diverse set of
allenes underwent regio- and enantioselective rhodium-
catalyzed addition reaction with NHPI to furnish the
corresponding coupling products 3aa−ta in moderate to high
yields and enantioselectivities ranging from 82% to 99% ee.
Primary and secondary alkyl-substituted allenes behaved well
(1a−f). Even substrates with primary alkyl cloride and alkyl
iodide functions were tolerated (1g,h). Allenes containing
differently protected hydroxyl groups (1i−l) were introduced in
the asymmetric addition with acceptable to high yields and good
enantioselectivities. A series of allenes bearing nitrile (1m), ester
(1n,o), amide (1p), phthalimide (1q), ether (1r), thioether
(1s), and sulfone (1t) functions furnished the corresponding
addition products effectively as well. Unfortunately, aryl-
substituted allene, tertiary alkyl-substituted allene, and 1,1-
disubstituted allene were not compatible in this coupling
reaction. In addition, the O-allyl product 3aa was synthesized
under standard conditions on a 1.0 mmol scale with 85% yield
and 87% ee.
Josiphos SL-J003-2
Josiphos SL-J004-2
Josiphos SL-J009-1
i
(S,S)- Pr-Fe
d
Josiphos SL-J003-2
Josiphos SL-J003-2
Josiphos SL-J003-2
Josiphos SL-J003-2
Josiphos SL-J003-2
Josiphos SL-J003-2
Josiphos SL-J003-2
e
10
11
12
13
14
15
ef
,
eg
,
eh
,
90
91
90
ehi
,
,
ehij
,
, ,
a
All reactions were carried out in a scale of 0.2 mmol of 2a, 1.5 equiv
of 1a, 4 mol % of [Rh(COD)Cl]2, 8 mol % of ligand in DCE/EtOH
(4/1, 0.4 M) at 70 °C for 18 h. Isolated yield. Determined by chiral
HPLC. 0.2 M. 0.025 M. 8 mol % of L-tartaric acid. 8 mol % D-
b
c
d
e
f
g
h
i
j
tartaric acid. 16 mol % L-tartaric acid. 60 °C. 2.0 equiv of 1a.
The observed allylic adducts 3 could be readily transformed to
the corresponding allylic alcohols or O-allyl hydroxylamine
species (Scheme 2), thereby certifying the synthetic utility of the
allylic products 3. Compound 3aa was converted to the
corresponding hydroxylamine compound 4aa in 65% isolated
yield with 90% ee. In addition, to study the practicality of this
protocol to obtain allylic alcohol, 5aa, 5ba, 5ja, and 5qa were
prepared in the presence of molybdenum hexacarbonyl and
triethylamine with preservation of enantiopurity in 71−75%
yields, respectively. At this stage, the absolute configuration of
5ba was assigned as S by comparison with known literature
data.9
As allylic alcohols are significant structural motifs for organic
synthesis, subsequent assorted functionalizations of allylic
alcohol were elucidated (Scheme 3). The Simmons−Smith
cyclopropanation led to cyclopropane 6aa with 88% yield and
89% ee. Epoxidation by treatment with VO(acac)2 and TBHP
generated the corresponding epoxide 7aa in 90% yield with 89%
ee. The relative configuration of 7aa was determined by
inspecting diagnostic NOE correlations of its derivative (for
details, see the Supporting Information). Hydroboration of 3aa
with BH3·THF followed by oxidative workup provided 1,3-diol
8aa.
promising ligand, furnishing 3aa in 86% yield with 56% ee
(Table 1, entry 5). Interestingly, lowering the substrate
concentration from 0.4 M to 0.2 M to 0.025 M increased the
enantiomeric excess of 3aa up to 88% (Table 1, entries 9 and
10). When 8 mol % of either L-tartaric acid or D-tartaric acid was
used as cocatalyst,20 3aa was obtained in 78% yield with 89% ee
(Table 1, entries 11 and 12). Further increasing the loading of L-
tartaric acid to 16 mol % led to a slight increase in the ee value to
90%, although the yield decreased (Table 1, entry 13). Finally,
further optimizing the reaction parameters (reaction temper-
ature and the amount of allene) provided the product 3aa in 88%
yield and 90% ee (Table 1, entry 15).21
With the optimized reaction conditions in hand, we explored
the scope of different N-hydroxylimides upon coupling with
allene 1a as the model substrate (Table 2). N-Hydroxysuccini-
mide participated in the reaction leading to 3ab in a slightly
lower yield and enantioselectivity. Moreover, the reaction
substrates, 2,3-dimethyl-N-hydroxymaleimide, N-hydroxycyclo-
hexene-1,2-dicarboximide, and N-hydroxynaphthalimide, were
inferior to NHPI. Notably, the fused bicyclic system, N-hydroxy-
5-norbornene-2,3-dicarboxylic acid imide, afforded the corre-
sponding addition product 3ad in 79% yield and 91% ee. We
then decided to focus on 2a as a water surrogate for further
investigations.
Inspired by the above results, the new NHPI allylation was
applied to the formal total synthesis of putaminoxin E, which
B
DOI: 10.1021/acs.orglett.7b03709
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Substrate Scope of Regio- and Enantioselective
Addition of Allenes to NHPI
Scheme 3. Functionalization of Branched Allylic Alcohol 5aa
a b
,
possesses interesting cyctotoxic activity.22 As shown in Scheme
4, 1u could be regioselectively and enantioselectively allylated to
Scheme 4. Utilization of Allylic Alcohol To Access
Putaminoxin E
supply the corresponding product 3ua in 87% yield with 90% ee.
Allylic alcohol 5ua, which has been used as an important
intermediate in a total synthesis of putaminoxin E, was derived
from subsequent deprotection of N-phthalimide in 72% yield
and 88% ee.22
In conclusion, we developed a regio- and enantioselective
addition of NHPI to allenes giving access to important
functional motif O-allylic addition products which provide an
alternative access to preparing enantiomerically pure allylic
alcohols as well as O-allyl hydroxylamines. Various substituted
allenes could participate in this reaction to furnish the
corresponding branched allylic compounds with moderate to
good yields and good to high enantioselectivities. Follow-up
chemistry for such cyclopropanation, epoxidation, and hydro-
boration reactions highlights the synthetic potential of these
building blocks. Furthermore, the value and versatility of this
methodology were demonstrated through a formal total
synthesis of putaminoxin E.
a
b
Yield of isolated product. The ee values were determined by chiral
c
d
HPLC. The reaction was conducted on a 1.0 mmol scale. 1.5 equiv
of allene, without L-tartaric acid, at 70 °C. TBS = tert-
butyldimethylsilyl, Bz = benzoyl, Bn = benzyl, Phth = phthaloyl.
Scheme 2. Transformations of Branched Allylic Adducts 3
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03709.
Experimental details and analytic data (NMR, HRMS,
GC, and HPLC) (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bernhard.breit@chemie.uni-freiburg.de.
C
DOI: 10.1021/acs.orglett.7b03709
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
2004, 6, 4631−4634. (h) Petrassi, H. M.; Sharpless, K. B.; Kelly, J. W.
Org. Lett. 2001, 3, 139−142.
Bernhard Breit: 0000-0002-2514-3898
Notes
(14) For selected examples on Rh-catalyzed coupling of nucleophiles
to allenes, see: (a) Beck, T. M.; Breit, B. Angew. Chem., Int. Ed. 2017, 56,
1903−1907. (b) Thieme, N.; Breit, B. Angew. Chem., Int. Ed. 2017, 56,
1520−1524. (c) Koschker, P.; Breit, B. Acc. Chem. Res. 2016, 49, 1524−
1536. (d) Kawamoto, T.; Hirabayashi, S.; Guo, X.-X.; Nishimura, T.;
Hayashi, T. Chem. Commun. 2009, 3528−3530.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(15) For selected examples on Pd-catalyzed coupling of nucleophiles
to allenes, see: (a) Zhou, H.; Wang, Y.; Zhang, L.; Cai, M.; Luo, S. J. Am.
Chem. Soc. 2017, 139, 3631−3634. (b) Lim, W.; Kim, J.; Rhee, Y. H. J.
Am. Chem. Soc. 2014, 136, 13618−13621. (c) Trost, B. M.; Xie, J.;
Sieber, J. D. J. Am. Chem. Soc. 2011, 133, 20611−20622. (d) Trost, B.
This work was supported by the DFG and the Fond of the
Chemical Industry Germany. We thank Umicore, BASF, and
Wacker for generous gifts of chemicals. Z.L. thanks the Chinese
Scholarship Council for a Ph.D. fellowship.
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2000, 100, 3067−3126. (f) AlMasum, M.; Yamamoto, Y. J. Am. Chem.
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DOI: 10.1021/acs.orglett.7b03709
Org. Lett. XXXX, XXX, XXX−XXX