Asymmetric synthesis of all-carbon quaternary stereocenters via desymmetrization of 2,2-disubstituted 1,3-propanediols

Article abstract of DOI:10.1021/ja1103102

A novel enantioselective desymmetrization of 2,2-disubstituted 1,3-propanediols has been established to generate all-carbon quaternary stereocenters, which has been implemented with BzCl and Et₃N in the presence of Pybox(6)-CuCl₂ complex in CH₂Cl₂ or PhMe at 78°C. While all the cyanide-comprising diols were desymmetrized with superb enantioselectivity (higher than 98% ee), the stereoinduction of the other substrates greatly depends on the size difference between the two substituents at the 2-position. When the size difference becomes larger, the corresponding substrates tend to engender enhanced enantioselectivity (up to 99% ee).

Full text of DOI:10.1021/ja1103102

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pubs.acs.org/JACS
Asymmetric Synthesis of All-Carbon Quaternary Stereocenters
via Desymmetrization of 2,2-Disubstituted 1,3-Propanediols
Ji Young Lee, Young Suk You, and Sung Ho Kang*
Molecular-Level Interface Research Center, Department of Chemistry, KAIST, Daejeon 305-701, Korea
S Supporting Information
b
nantioselective desymmetrization of symmetric molecules is
Table 1. Desymmetrization of 9 Using Pybox (L*)-CuCl2
Complexes
E
an economical way to generate chirality. The process is effec-
ted by differentiation of two enantiotopic groups and is advanta-
geous due to the relatively facile preparation of the starting subs-
trates. Among the stereogenic carbon centers, the formation of
quaternary centers directly bonded to heteroatoms or all-carbons
is particularly challenging.1 In trying to construct all-carbon qua-
ternary stereocenters, one is fighting innate steric congestion. Ca-
talytic desymmetrization has been applied rarely to forming such
carbon stereocenters.2 Most of the known approaches to them
suffer from the narrow substrate scope and/or low enantioselec-
tivity.3 They have been implemented through aldol cyclization,4
Pd-catalyzed coupling reactions,5 Diels-Alder cycloaddition,6
Rh-activated C-H bond insertion and cyclization,7 and Cu-
induced tosylation.8 It is of great significance and synthetic utility to
develop a desymmetrization method producing the quaternary
sterocenters with the enhanced substrate scope and enantio-
selectivity. Herein, we describe a catalytic asymmetric desymme-
trization of 2,2-disubstituted 1,3-propanediols to build the corre-
sponding all-carbon quaternary stereocenters.
Previously, we reported the enantioselective desymmetriza-
tion of glycerols and serinols to synthesize tert-alcohols9 and tert-
alkylamines,10 the stereochemical outcomes of which might be
rationalized by analyzing the chelated intermediates between the
Cu-catalysts and the substrates through the two heteroatoms at
1,2- rather than 1,3-positions. In the present desymmetrization of
2,2-(all-carbon)disubstituted 1,3-propanediols, the substrates
can coordinate with the catalyst through only the two hydroxyl
groups at 1,3-positions. Since their pro-stereogenic centers are
located at 2-positions and farther from the chiral ligand in the 1,3-
chelated complexes, their desymmetrization is destined to re-
main a substantial synthetic challenge. With the inherent diffi-
culty associated with the 1,3-diols in mind, the desymmetrization
of the model substrate 9 was extensively assayed under benzoyla-
tion conditions by changing or adjusting the chiral ligand, base,
temperature, etc. Eventually, the pyridinebisoxazoline 111 was
identified to reach the relatively superior enantioselectivity, pro-
posing this skeleton as the main structural frame for the pros-
pective chiral ligand (entry 1, Table 1).
entry
L*
% yield (% sm)a
% ee
1
2
3
4
5
6
7
8
9b
1
2
3
4
5
6
7
8
6
64 (32)
60 (36)
62 (36)
45 (53)
66 (30)
80 (17)
47 (50)
54 (40)
98
65
61
50
2
61
76
14
73
89
a Recovered sm in parentheses. b CH2Cl2 was used as solvent instead
of THF.
with a moderate but somewhat inferior stereoselectivity to that
for 1 (entry 2). The next examination with the tetrasubstituted
Pybox 3 and 4 revealed that both are less effective than 1, and
intriguingly they have distinctively different capability in ligand
function (entries 3 and 4). At this point, we surmised that the
Pybox-Cu(II) catalyst makes an octahedral complex with the 1,3-
diol and benzoyl chloride to transfer the benzoyl cation to the
proximate hydroxyl group, in which the tridentate Pybox is
A wide array of functionalized pyridinebisoxazolines (Pybox)
was primed and scouted in search of the optimal ligand in the
desymmetrization of 9.12 Some informational outcomes are sum-
marized in Table 1. In the beginning, the two phenyl substituents
of 1 were replaced by alkyl, benzyl, and 2-naphthyl. While a race-
mic mixture of monobenzoates was obtained with the (alkyl)2-
Pybox and (Bn)2Pybox, (2-naphthyl)2Pybox 2 afforded them
Received: November 17, 2010
Published: January 25, 2011
r
2011 American Chemical Society
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Table 2. Desymmetrization of 11-29 Using Pybox
(6)-CuCl2 complex
(Table 1). A survey of several substituents led us to elaborate
the most effective chiral ligand 6 comprising n-butyl groups
(entry 6). Furthermore, changing the solvents from THF to
CH2Cl2 enhanced both the stereoinduction and chemical conver-
sion (entry 9). On the other hand, methyl groups seem to be rather
small for the intended phenyl conformation, whereas isopropyl
groups themselves are too bulky (entries 5 and 7). In addition, the
chloride anion worked best among the catalyst anions. When 5, 15,
or 20 mol % of 6 was loaded, 10 was procured in a little lower yield
(95%) with a slightly lower ee value (88%).
Diverse 1,3-diols 11-29 were desymmetrized under the
asymmetric monobenzoylation conditions as detailed by entry
9 of Table 1. Outstanding desymmetrization was attained
especially with most of the 2-methyl 1,3-diols as depicted in
Table 2. Remarkably, the small ethyl group in 11 was distin-
guished from the methyl group with higher than 10:1 er (entry
2). In contrast, why the bulkier substituent-containing diols 15
and 20 were monobenzoylated with somewhat lower enantio-
selectivity than estimated from other substrates is not readily
explained (entries 6 and 11). While the chirality generation
from the vinyl diol 17 proceeded with a moderate stereoselec-
tion probably due to the smaller size difference between the
two pendants, replacement of the vinyl group by the bulkier
β,β-dibromovinyl (18) and R-methylvinyl (19) resulted in
respectably higher % ee values (entries 8-10). As for 20 and
21, attachment of a methyl substituent to the conjugated ester
branch of 20 augmented the % ee value significantly from 85 to
98 (entries 11 and 12). This similar proclivity was observed to a
lesser extent with a β-bromo substituent in the allyl diols 9 and
22 (entries 1 and 13). Scrutiny of the experimental data reveals
that the stereoselectivity was enhanced with the 2-methyl diols
having the second substituent with R- or β-branches (entries 3,
5, 9, 10, 12, and 13). The 2-cyano diols 16, 27 and 28 were
desymmetrized more stereoselectively by 20-25% ee in to-
luene than in CH2Cl2 (entries 7, 18, and 19). In practice a 20:1
mixture of toluene and CH2Cl2 was used to enhance solubility.
Little difference in stereoselectivity was found between this
mixture and toluene. It is unlikely that the superb enantio-
selectivity for the cyano diols can be rationalized simply by con-
sidering the relative sizes of their substituents. Since considerable
amounts (15-25%) of the corresponding dibenzoates were
formed with Et3N in the monobenzoylation of the cyano diols,
the base was switched to i-Pr2NEt. With significant sup-
press of the side reaction, 4-7% of the dibenzoates still formed.
In order to clarify whether kinetic resolution was resp-
onsible for the observed excellent stereoselectivity, ee values
from the reaction of 28 were analyzed every 4 h and found to be
consistent, excluding this possibility. Somewhat lower material
balances for the cyano diols are partially ascribed to separation
difficulty from the Pybox ligand and their higher solubilities in
water. As expected, the desymmetrization of the diols bearing
two substituents different from the methyl group proceeded with
reduced stereoinduction (entries 15-17). Also, the enantiotopic
differentiation of 24 and 25 was found to be more effective in
toluene (entries 15 and 16). It is worth mentioning that the
monobenzoylation of the methylenylcyclopentane diol 29 was
consummated with a noteworthy 87% ee value (entry 20).
We have established an asymmetric monobenzoylation of
readily accessible symmetric 2,2-disubstituted 1,3-diols to install
all-carbon quaternary stereocenters. The most efficient chiral
ligand turned out to be the Pybox 6 having 4-phenyl and 5,5-di-n-
butyl substituents, thought to enable the two phenyl and
entry substrate/product reaction time (t h) % yield (% sm)c % eed,e
1
9/10
12
12
5
98
89
84 (R)
94 (R)
95 (R)
95 (R)
83 (R)
99 (R)
54 (R)
97 (R)
96 (R)
85 (R)
98 (R)
92
2
11/30
12/31
13/32
14/33
15/34
16/35
17/36
18/37
19/38
20/39
21/40
22/41
23/42
24/43
25/44
26/45
27/46
28/47
29/48
95 (2)
96 (2)
99
3
4
3
5
12
3
85 (10)
98
6
7a
5
73 (10)
91 (7)
99
8
20
3
9
10
11
12
13
14
15b
16b
17b
18a
19a
20
12
12
12
15
12
12
12
12
12
18
20
97
95 (3)
95 (2)
93 (3)
98
94
98
49 (R)
84
88 (5)
91 (5)
67 (15)
72 (18)
92 (5)
51
98
98
87
a The reaction was carried out with BzCl (1.5 equiv) and (i-Pr)2NEt (1.2
equiv) in a 20:1 mixture of PhMe and CH2Cl2. b PhMe was used as
solvent. c Percentage of recovered sm in parentheses. d Determined by
HPLC analysis using DAICEL chiral columns (see Supporting Infor-
mation [SI]). e Absolute configuration of the major enantiomer in
parentheses (see SI).
situated equatorially, benzoyl chloride axially, and the substrate
both equatorially and axially. In the proposed transition state, the
smaller group of the substrate is expected to occupy the space
near the 4-phenyl substituent of the oxazoline ring based on
sterics. Thus, we inferred that enough room should be secured
in the space to accommodate the smaller methyl substituent.
The inference suggested that the ineffectiveness of 4 as a chiral
ligand could be ascribed to the conformationally inflexible
planarity of the indanyl substituents. We designed the attach-
ment of two substituents at the 5-position of the oxazoline ring
in order to force the phenyl group perpendicularly to the ring
to allow for extra room as shown in the intermediate I
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COMMUNICATION
oxazolidine planes to cross vertically in securing the reserved
space for the smaller substituent of the substrate.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details. This ma-
b
terial is available free of charge via the Internet at http://pubs.acs.
org.
’ AUTHOR INFORMATION
Corresponding Author
shkang@kaist.ac.kr.
’ ACKNOWLEDGMENT
This work was supported by Midcareer Researcher program
through an NRF grant funded by the MEST (2010-0000780) as
well as by the MEST (2010-0001957). This paper is dedicated
with respect to the memory of Prof. Chi Sun Hahn.
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