Tert-butyldimethylsilyl-directed highly enantioselective approach to axially chiral α-allenols

Article abstract of DOI:10.1002/chem.201201948

A highly efficient and enantioselective synthesis of axially chiral α-allenols was realized in practical yields with 96-99 % ee or de from TBS-protected propargylic alcohols, aldehydes, and a commercially available, inexpensive, chiral, secondary amine (S)-α,α-diphenylprolinol or its enantiomer followed by desilylation. The easily removable TBS group not only acts as a protecting group, but also as a possible sterically directing group for the excellent enantioselectivity and in situ prevention of possible allene racemization. Copyright

Full text of DOI:10.1002/chem.201201948

DOI: 10.1002/chem.201201948
tert-Butyldimethylsilyl-Directed Highly Enantioselective Approach to
Axially Chiral a-Allenols
Juntao Ye,[a] Wu Fan,[b] and Shengming Ma*[a, b]
Abstract: A highly efficient and enantioselective synthesis of axially chiral a-alle-
nols was realized in practical yields with 96–99% ee or de from TBS-protected
propargylic alcohols, aldehydes, and a commercially available, inexpensive, chiral,
secondary amine (S)-a,a-diphenylprolinol or its enantiomer followed by desilyla-
tion. The easily removable TBS group not only acts as a protecting group, but also
as a possible sterically directing group for the excellent enantioselectivity and in
situ prevention of possible allene racemization.
Keywords: allenes · amines · chiral-
ity · enantioselectivity · steric hin-
drance
Introduction
tivity. In this approach, the axial chirality is generated highly
stereoselectively without racemization, whereas the central
chirality, if one is present, remains untouched (Scheme 1).
Allenes have become a very important class of basic chemi-
cals in organic synthesis, medicinal chemistry, and materials
science;[1] thus, methods for the efficient synthesis of allenes
with an axial chirality are currently of high interest.[2] Of
particular interest are axially chiral primary a-allenols,
which are not only versatile building blocks for the synthesis
of different types of heterocycles[3,4] but are also the most
basic starting materials for the synthetically attractive axially
chiral allenyl amines,[5,6] malonates,[7,8] thiols,[9] aldehydes or
ketones,[10] and carboxylic acids.[11] So far, enantioselective
synthesis of a-allenols is still challenging due to the fact that
such axial chirality spreads over three carbon atoms and
there is a free hydroxyl group. Traditionally, a tedious low-
yielding route to axially chiral primary a-allenols from opti-
cally active propargylic alcohols by using inconvenient and
dangerous chemicals such as nBuLi and LiAlH4 has been
used (Scheme 1).[12] Thus, a highly efficient approach to such
primary a-allenols is in great demand. In this paper, we wish
to report a straightforward solution to this issue by using
TBS, not only as the protecting group, but also as a possible
sterically directing group to achieve excellent enantioselec-
Scheme 1. Approaches to a-allenols; TBAF=tetrabutylammonium fluo-
ride.
Results and Discussion
Recently, a ZnI2-mediated one-pot reaction of p-nitrobenzyl
propargyl ether and nBuCHO with (S)-a,a-diphenylprolinol
[(S)-4] affording p-nitrobenzyl (R)-2,3-octadienyl ether in a
low yield (46%) with 98% ee was realized.[13] However, a
number of drawbacks were found for this one-pot reaction:
1) In most cases, the enantioselectivity and yield are not sat-
isfactory or practical with either ZnI2 or ZnBr2. 2) The re-
sults, especially the ee values are sometimes time-dependent,
thus, not easily reproducible, indicating in situ racemiza-
tion.[14] 3) Most notably, the reaction of propynol 1a with
CyCHO 2a afforded only trace amounts of allenol (R)-3aa,
although the starting materials are completely consumed
(Table 1, entry 1).[13] After careful analysis of all the failed
experimental data for this one-pot transformation, we rea-
soned that the nature of the substituent on the terminal
alkyne should be crucial for obtaining a much more match-
ed reactivity towards aldehydes in the presence of chiral
amine 4 as well as improving the enantioselectivity. The
[a] J. Ye, Prof. Dr. S. Ma
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences 345 Lingling Lu
Shanghai 200032 (P.R. China)
Fax : (+86)21-6416-7510
E-mail: masm@sioc.ac.cn
[b] W. Fan, Prof. Dr. S. Ma
Shanghai Key Laboratory of Green Chemistry
and Chemical Processes
Department of Chemistry
East China Normal University
3663 North Zhongshan Road
Shanghai 200062 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201948.
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FULL PAPER
Table 1. Reaction of propynol 1a and silyl-protected propynols 1b–e.[a]
entry 10): ZnBr2 (0.75 equiv), (S)-4 (1 equiv), alkyne
(1.1 equiv), and aldehyde (1.5 equiv), in toluene at 1308C
(10 h), for further study.
Under the optimized reaction conditions, the scope of the
aldehydes is quite general (Table 3); s-alkyl (Table 3, en-
tries 1–3, 6, and 9), or sec-alkylmethyl (Table 3, entry 4), n-
alkyl (Table 3, entries 5 and 7), and phenylethyl (Table 3,
entry 8) carbinals may all be used, affording the correspond-
ing axially chiral primary a-allenols in decent yields with
96–99% ee upon desilylation. When (R)-4 was used as the
chiral amine, the enantiomer (S)-3aa was also conveniently
prepared with 99% ee (Table 3, entry 3). To demonstrate
the practicality of this methodology, the reaction of 1c, 2a,
or 2b, and (S)-4 was conducted on a scale of 10 or 3 mmol
(Table 3, entries 2 and 3), respectively.
Entry
R
Yield [%][b]
ee [%]
[c]
1
2
3
4
5
H (1a)
trace [(R)-3aa]
58 [(R)-5ba]
61 [(R)-5ca]
33 [(R)-5da]
34 [(R)-5ea]
–
TMS (1b)
TBS (1c)
TIPS (1d)
TBDPS (1e)
95[d]
95[d]
[c]
–
[c]
–
[a] The reactions were carried out on a 1.0 mmol scale of 1 in toluene
(5 mL). [b] Determined by H NMR spectroscopic analysis. [c] Not deter-
mined. [d] Determined after desilylation to (R)-3aa. Cy=cyclohexyl,
TMS=trimethylsilyl, TBS=tert-butyldimethylsilyl, TIPS=triisopropylsil-
yl, TBDPS=tert-butyldiphenylsilyl.
1
Table 3. Synthesis of axially chiral primary a-allenols.[a]
soluACHTUNGTRENNUNGtion would be to identify a sterically bulky, yet easily re-
movable, protecting group (OPG) for propynol. For such a
purpose, after many unsuccessful attempts with propargyl
carboxylates, a relatively straightforward approach was en-
ACHTUNGTRENNUNGvisioned that involved steric and shielding effects of silyl
Entry
R1
(R)-3
groups for the protection of the alcoholic oxygen atom.
Gratifyingly, TMS- and TBS-protected propargyl alcohols
1b and 1c afforded the axially chiral protected allenols not
only in respectable yields (Table 1, entry 1 vs. entries 2 and
3) but also with 95% ee. TIPS and TBDPS gave rather
lower yields, probably due to their steric bulk (Table 1, en-
tries 4 and 5).
Encouraged by these results and considering the stability,
TBS-protected propargyl alcohol 1c was then chosen for fur-
ther optimization (Table 2). The enantiomeric purity of (R)-
5ca was improved to 99% when ZnBr2 was used instead of
ZnI2 (Table 2, entry 2);[13] ZnCl2 was less efficient for the re-
action (Table 2, entry 3). A preliminary screening on other
experimental parameters (Table 2, entries 4–10) led us to
define the following optimized conditions (Table 2,
Yield [%][b]
ee [%][c]
1
Cy (2a)
Cy (2a)
Cy (2a)
iBu (2b)
nC5H11 (2c)
cC5H9 (2d)
nC7H15 (2e)
68 [(R)-3aa]
70 [(R)-3aa]
66 [(S)-3aa]
45 [(R)-3cb]
59 [(R)-3cc]
59 [(R)-3cd]
65 [(R)-3ce]
60 [(R)-3cf]
63 [(R)-3cg]
99
99
99
98
98
98
97
96
98
2[d]
3[e]
4[f]
5
6
7
8
9
Ph
ACHTUGNERTN(NUNG CH2)2 (2 f)
Et2CH (2g)
[a] The reactions were carried out on a 1.0 mmol scale of (S)-4 in toluene
(3 mL) unless otherwise noted. [b] Isolated yields of (R)-3 over two steps.
[c] Determined by chiral HPLC analysis. [d] The reaction was conducted
on a 10 mmol scale. [e] (R)-4 was used. [f] The reaction was conducted
on a 3.0 mmol scale.
It should be noted that racemization of the a-allenol
products was not observed, since control experiments
showed that (R)-3aa was consistently obtained with 99% ee
even when the reaction time was prolonged to 12, 14, or
16 h (Scheme 2).
Table 2. Optimization of reaction conditions.[a]
Entry
X ([equiv])
2a [equiv]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
I (0.8)
1.5
1.5
1.5
1.5
1.3
1.7
1.5
1.5
1.5
1.5
62
66
49
52
41
65
74
74
68
74
95
99
Br (0.8)
Cl (0.8)
Br (1.0)
Br (0.8)
Br (0.8)
Br (0.8)
Br (0.75)
Br (0.7)
Br (0.75)
[d]
–
–
–
[d]
[d]
99
99
99
99
99
7[e]
8[e]
9[e]
10[e,f]
Scheme 2. Synthesis of (R)-3aa within 12, 14, and 16 h.
[a] The reactions were carried out on a 1.0 mmol scale of (S)-4 in toluene
(3 mL). [b] Yield determined by 1H NMR spectroscopic analysis. [c] De-
termined by chiral HPLC after desilylation. [d] Not determined. [e] The
reaction was conducted at 1308C. [f] Reaction time: 10 h.
Furthermore, this strategy may also be seamlessly applied
to the preparation of secondary a-allenols 6 fa–ha, with
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S. Ma et al.
either central or axial chiralities, with high de and ee values
from the corresponding terminal alkynes 1 f–h in practical
yields (Table 4). It should be noted that the ee and de values
of 6ha prepared by this protocol are much higher than those
obtained in our previously reported protocol.[13a]
In an effort to shed further light on the role of the TBS
group in the protected propargylic alcohols, we scaled up
the reaction of the unprotected propynol 1a with CyCHO
2a in the presence of (S)-a,a-diphenylprolinol 4. The corre-
sponding allenol (R)-3aa was obtained in 6% yield (72%
purity) with 78% ee after careful chromatography on silica
gel (Scheme 4), which clearly showed that the TBS group is
Table 4. Synthesis of axially chiral secondary a-allenols from racemic
TBS-protected secondary propargylic alcohols.[a]
R
Isolated
yield [%]
(Ra,S)-6
ACHTUNGTERN(NUNG Ra,R)-6
de/ee [%][b]
de/ee [%][b]
Scheme 4. Reaction of unprotected propynol 1a: the role of TBS.
Cy (1 f)
nC7H15 (1g)
Ph (1h)
61 (6 fa; dr=1:1.2)
70 (6ga; dr=1:1.1)
73 (6ha; dr=1.1:1)
98/99
97/98
99/99
99/98
98/97
99/99
not merely acting as a protecting group, it is also responsible
for the matched reactivity as well as the excellent enantiose-
lectivity for the formation of the optically active propargylic
amine intermediate with a central chirality, which is then
highly stereoselectively transferred to the axial chirality of
the newly generated allene functionality through intra-
[a] The reactions were carried out on a 1.0 mmol scale of (S)-4 in toluene
(3 mL). [b] The de values were calculated separately for diastereoisomers
having the same central chiralities, that is, (Ra,S) vs. (Sa,S) and (Ra,R) vs.
(Sa,R), based on the results shown in Scheme 3.
AHCTUNGTREGmNNUN olecular hydride-transfer. In addition, it should be noted
As expected, the reaction of optically active (R)-1 f af-
forded allenols (R,R)-6 fa in a decent yield and >99% de/ee
here that, under the standard conditions, all the results are
easily reproducible, thus, it also helps to prevent the racemi-
zation of this in situ generated allene moiety[14] at tempera-
tures as high as 1308C. The low yielding nature of this pri-
mary alcohol may be caused by the strong interaction be-
tween Zn2+ and the free hydroxyl group, which may cause
some side reactions because the alcohol was consumed com-
pletely after 12 h.
[Eq. (1), Scheme 3]. Notably, all of the four dia
isomers of 6ga were highly stereoselectively prepared by
simply adjusting the absolute configurations of the central
chiralities in the TBS-protected secondary propargylic alco-
ACHTUNGTRNEsNUNG tereo-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
hols 1 and a,a-diphenylprolinol 4 [Eqs. (2)–(5), Scheme 3].
The absolute configurations of allenes were assigned on
the basis of previous studies.[13] A model to predict the abso-
lute configuration of the allene moiety for the highly enan-
tioselective formation of (R)-3 from (S)-a,a-diphenylproli-
nol 4 is shown in Scheme 5.[13,15] The steric bulk of the TBS
group in the alkynylzinc specie 11 helps to make an Re-face
attack of the in situ generated iminium ion 12 more favor-
Scheme 5. Proposed mechanism and prediction of the absolute configura-
tion of the allene.
Scheme 3. Synthesis of (Ra,R)-6 fa and four diastereoisomers of 6ga.
718
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Chem. Eur. J. 2013, 19, 716 – 720

Axially Chiral a-Allenols
FULL PAPER
A
the scientific community. Further studies on the scope,
working mechanism for the effect of TBS, and synthetic ap-
plications are being pursued in our laboratory.
in iminium ion 12, furnishing propargylic amine intermedi-
ate (S)-13 highly stereoselectively, which then undergoes in-
tramolecular hydride transfer and b-elimination followed by
desilylation to afford (R)-3. In should be noted that the p-ni-
trobenzyl group in our original report[13a] may also act as a
bulky group and therefore lead to excellent enantioselectivi-
ty. However, removal of this group is more difficult than
that of the TBS group. It should also be noted that the size
of the protecting group is crucial for this transformation:
very bulky groups such as TIPS or TBDPS gave lower
yields, as shown in Table 1.
Experimental Section
Synthesis of (R)-4-cyclohexyl-2,3-butadien-1-ol (R-3aa); Typical proce-
dure: To a 100 mL flame-dried, three-necked flask was added ZnBr2
(1.6912 g, 7.5 mmol). The flask was dried under vacuum with a heating
gun. Compound (S)-4 (2.5857 g, 10 mmol, 98%), 1c (1.8738 g, 11 mmol)
in toluene (20 mL), and 2a (1.6831 g, 15 mmol) in toluene (10 mL) were
then added sequentially under an Ar atmosphere. The flask was then
equipped with a condenser and placed in a pre-heated oil bath at 1308C,
with stirring. After 10 h, the reaction was complete as monitored by
TLC. After cooling to RT, the crude reaction mixture was filtered
through a short pad of silica gel and eluted with ether (50 mL). After
evaporation, the residue was filtered through a short column of silica gel
(petroleum ether/ethyl ether=50:1) to collect the nonpolar TBS-pro-
These enantioenriched primary a-allenols are very useful
precursors of a variety of synthetically useful, but not readi-
ly available, optically active heterocyclic compounds with a
central chirality, or functionalized allenes with an axial chi-
ACHTUNGTRENNUNGrality (Scheme 6). For example, silver-catalyzed cycloisomer-
ization[3e,16] and iodocyclization with NIS (NIS = N-iodosuc-
cinimide)[17] afforded dihydrofuran (R)-7 and (R)-8 with
complete transfer of the axial chirality; optically active
AHCTUNGERTGtNNUN ected allenol after evaporation. The allenol was directly dissolved in
THF (30 mL) without further characterization and treated at 08C with
TBAF·3H2O (3.1563 g, 10 mmol). The resulting mixture was allowed to
warm to RT with stirring. After 1.5 h, the reaction was complete (reaction
monitored by TLC analysis), and H2O (20 mL) and ether (20 mL) were
then added. The organic layer was separated and the aqueous layer was
extracted with ether (3ꢁ20 mL). The combined organic layer was washed
with brine (20 mL) and dried over anhydrous Na2SO4. After filtration
and evaporation, the residue was purified with chromatography on silica
gel (petroleum ether/ethyl acetate=15:1!10:1) to afford (R)-3aa
(1.0624 g, 70%) as a liquid: 99% ee [HPLC conditions: Chiralcel AS-H
ACHTUNGTRENNUNG
allenyl amine (R)-9[6] or (2,3-butadienyl)malonate (R)-10[8]
may also be prepared with 99% ee by the Mitsunobu reac-
tion[18] followed by deprotection or nucleophilic substitution,
respectively.
column; hexane/iPrOH=98:2; 0.6 mLminꢀ1
;
l=214 nm; tR =11.9
(major), 12.9 min (minor)]; [a]2D2 =ꢀ100.3 (c=1.00, CHCl3); 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=5.42–5.26 (m, 2H; CH=C=CH), 4.11
(s, 2H; OCH2), 2.07–1.94 (m, 1H; CH from Cy), 1.82–1.49 (m, 6H; OH
and protons from Cy), 1.36–1.00 ppm (m, 5H; protons from Cy);
13C NMR (75 MHz, CDCl3, 258C, TMS): d=201.8, 99.7, 92.5, 60.7, 36.9,
33.0, 32.9, 26.0, 25.9 ppm; IR (neat): n˜ =3326, 2923, 2850, 1961, 1448,
1302, 1259, 1214, 1062, 1008 cmꢀ1; MS (70 eV): m/z (%): 152 (0.70) [M]+,
55 (100); HRMS: m/z calcd for C10H16O: 152.1201 [M+]; found:
152.1203.
Acknowledgements
Financial support from the National Natural Science Foundation of
China (Grant No. 21232006) and the National Basic Research Program
of China (2009CB825300) is greatly appreciated. We thank Mr. Pengbin
Li in our group for reproducing the results presented in Table 3, entry 7,
Equation (1) in Scheme 3, and the synthesis of (R)-9 in Scheme 6.
Scheme 6. Transformations of axially chiral a-allenol (R)-3aa; Ts=tosyl,
Boc=tert-butoxycarbonyl, DEAD=diethyl azodicarboxylate, TFA=tri-
fluoroacteic acid, Ms=methane sulfonyl, DMAP=4-dimethylaminopyri-
dine.
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We have developed a straightforward route to axially chiral
a-allenols from TBS-protected propargylic alcohols, alde-
hydes, and inexpensive, commercially available (R)- or (S)-
a,a-diphenylprolinol 4 in practical yields with very high effi-
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Received: June 3, 2012
Revised: September 6, 2012
Published online: November 9, 2012
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