Catalytic enantioselective reductive cyclization of acetylenic aldehydes via hydrogenation

Article abstract of DOI:10.1055/s-2007-983829

The reductive cyclization of acetylenic aldehydes is accomplished via rhodium-catalyzed asymmetric hydrogenation. This process provides access to a wide variety of cyclic allylic alcohols in good yields and with high levels of asymmetric induction. Georg

Full text of DOI:10.1055/s-2007-983829

PRACTICAL SYNTHETIC PROCEDURES
3427
Catalytic Enantioselective Reductive Cyclization of Acetylenic Aldehydes via
Hydrogenation
Catalytic
Asymmetric
Reductive
C
y
g
clization via Hydr
U
ogenation k Rhee, Regan A. Jones, Michael J. Krische*
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA
Fax +1(512)4718696; E-mail: mkrische@mail.utexas.edu
PSP
Received 20 April 2007
No101
Abstract: The reductive cyclization of acetylenic aldehydes is accomplished via rhodium-catalyzed asymmetric hydrogenation. This pro-
cess provides access to a wide variety of cyclic allylic alcohols in good yields and with high levels of asymmetric induction.
Key words: acetylenic aldehyde, allylic alcohol, hydrogenation, rhodium, reductive cyclization
R1
X
X
Rh(COD)2OTf (5 mol%)
R1
2-Naphthoic acid (5 mol%)
Y
Y
H2 (1 atm), DCE, 45 °C
OH
R2 R2
O
R2 R2
(R)-Cl,MeO-BIPHEP (5 mol%)
Cl
MeO OMe Cl
X = O, CH2, CMe2
Y = N(p-BrBn), NTs, Bn, O
R
R
63–99% yield
91–99% ee
1 = Ph, Me, cyclopropyl, H, (CH2)5Me
2 = H, Me, -(CH2)4-, or -(CH2)5-
Ph2P PPh2
Scheme 1
Introduction
of Brønsted acid was found to enhance both the rate and
yield. This effect of Brønsted acid cocatalysts has been
Considerable effort has been invested in the development observed in related hydrogenative C–C coupling reac-
of new catalytic methods for the reductive cyclization of tions.10 Cyclic allylic alcohols are generated in good yield
acetylenic aldehydes.1,2 This is not surprising as this meth- and excellent enantiomeric excess. Furthermore, chiral
od provides direct access to allylic alcohols, which are acetylenic aldehydes undergo highly diastereoselective
valuable synthetic building blocks. The reductive cycliza- reductive cyclization.
tion of acetylenic aldehydes was first described in 1994 by
Ojima.3 Shortly thereafter, Crowe4 reported a titanocene-
catalyzed variant, and Montgomery5 reported an analo- Scope and Limitations
gous nickel-catalyzed reaction. Subsequently, the inter-
molecular reductive couplings of alkynes and aldehydes The hydrogen-mediated reductive cyclization was opti-
were reported by Montgomery6 and Jamison.7 Notably, mized using the acetylenic aldehyde 1a as substrate
Jamison has developed an asymmetric variant of the inter- (Scheme 2). After extensive optimization, it was found
molecular transformation.8 Surprisingly, despite impres- that exposure of 1a in 1,2-dichloroethane solution (0.1 M)
sive advances in this field, catalytic asymmetric at 45 °C to hydrogen (1 atm), 2-naphthoic acid (5 mol%),
intramolecular reductive cyclization of alkynes and alde- Rh(COD)2OTf (5 mol%), and (R)-Cl,MeO-BIPHEP (5
hydes had not been reported prior to the studies described mol%) resulted in the formation of 1b in 67% yield and
in this account.9
98% enantiomeric excess. Notably, when 2-naphthoic
acid was excluded, 1b was obtained in 24% yield and 95%
enantiomeric excess.
Here, the first catalytic enantioselective reductive cycliza-
tion of acetylenic aldehydes is reviewed. The reaction is
mediated by a chirally modified cationic rhodium catalyst A variety of acetylenic aldehydes were subjected to the
and utilizes molecular hydrogen as the terminal reductant optimized reaction conditions (Scheme 3, Figure 1). Elec-
(Scheme 1). The addition of substoichiometric amounts tron-deficient a,b-acetylenic amides were first examined.
Substrates 2a–4a underwent cyclization smoothly to fur-
nish the desired products 2b–4b in good yield and excel-
lent enantiomeric excess. These examples reveal that the
alkyne terminus can be substituted with aryl (2b), alkyl
SYNTHESIS 2007, No. 21, pp 3427–3430
Advanced online publication: 30.07.2007
DOI: 10.1055/s-2007-983829; Art ID: Z10307SS
x
x.
x
x
.
2
0
0
7
© Georg Thieme Verlag Stuttgart · New York

3428
J. U. Rhee et al.
PRACTICAL SYNTHETIC PROCEDURES
Ph
Me
O
O
O
O
O
Rh(COD)2OTf (5 mol%)
(R)-Cl,MeO-BIPHEP (5 mol%)
BnN
p-BrBnN
BnN
BnN
BnN
OH
H2 (1 atm), DCE, 45 °C
OH
OH
OH
2b, 85% yield
97% ee
3b, 83% yield
99% ee
4b, 67% yield
95% ee
O
1a
1b
In the absence of additive: 24% yield, 95%ee
With 2-naphthoic acid (5 mol%): 67% yield, 98%ee
Ph
Me
TsN
TsN
Scheme 2
TsN
Me Me
OH
OH
OH
R1
X
Y
X
Rh(COD)2OTf (5 mol%)
5b, 99% yield
6b, 83% yield
7b, 77% yield
91% ee
R1
2-Naphthoic acid (5 mol%)
91% ee
90% ee
Y
H
2 (1 atm), DCE, 45 °C
OH
R2 R3
2a–13a
O
R2 R3
Me
Me
Me
(R)-Cl,MeO-BIPHEP (5 mol%)
Me
TsN
Cl
MeO OMe Cl
2b–13b
TsN
Me Me
TsN
Me Me
OH
OH
OH
8b, 85% yield
96% ee
9b, 76% yield
96% ee
10b, 63% yield
Ph2P PPh2
98% ee
Scheme 3 Asymmetric hydrogen-mediated reductive cyclization of
acetylenic aldehydes
Ph
Me
Me
O
O
O
(3b), or cyclopropyl (4b) moieties. Next, the reductive cy-
clization of unactivated alkynes was investigated. An as-
sortment of sulfonamide-tethered alkynes 5a–10b proved
to be efficient substrates. Notably, in the case of 9b, it was
found that unsubstituted alkynes participate in the reac-
tion. Additionally, geminal substitution adjacent to the al-
dehyde (5b) or alkyne (10b) is also tolerated. After testing
the sulfonamide-tethered substrates, ether-tethered acety-
lenic aldehydes were examined. Gratifyingly, the ether-
tethered acetylenic aldehydes 11b–13b participate in effi-
cient reductive cyclization to furnish the corresponding
alkylidene furans. Unfortunately, attempts to form six-
membered rings via hydrogen-mediated reductive cy-
clization were unsuccessful and provided mainly the
product of conventional alkyne reduction.
OH
OH
OH
Me Me
Me Me
11b, 71% yield
12b, 86% yield
13b, 73% yield
93% ee
99% ee
99% ee
Figure 1 Products obtained in the asymmetric hydrogen-mediated
reductive cyclization of acetylenic aldehydes
stereoselective reductive cyclization to provide the syn-
stereoisomers.
A plausible catalytic mechanism is proposed for the cy-
clization of acetylenic aldehyde 8a (Scheme 4). This in-
volves oxidative coupling of 8a to produce the oxa-
metallacyclic intermediate 17. Protonolytic cleavage of
the metal–oxygen bond produces 18, which hydro-
genolytically cleaves to generate 19. Reductive elimina-
tion delivers 8b with regeneration of the cationic rhodium
catalyst. This mechanism is consistent with the results of
deuterium labeling.9 Protonolytic cleavage of 17 by the
Brønsted acid cocatalyst circumvents a highly energetic
four-centered transition structure for hydrogenolysis of
the rhodium–oxygen bond embodied by 17. This allows
hydrogenolysis to occur at the stage of the rhodium car-
boxylate 18 through a lower energy six-centered transi-
tion structure.11
After examining the scope of the enantioselective process,
diastereoselective variants of the reductive cyclization
were explored. Accordingly, chiral acetylenic aldehydes
were subjected to standard conditions for hydrogen-medi-
ated reductive cyclization using the achiral ligand
BIPHEP (Figure 2). Gratifyingly, the chiral acetylenic al-
dehydes 14b–16b were found to engage in highly dia-
Ph
Ph
Me
OH
O
O
In summary, the catalytic asymmetric reductive cycliza-
tion of acetylenic aldehydes has been accomplished via
rhodium-catalyzed hydrogenation. This process furnishes
cyclic allylic alcohols in good yields with excellent enan-
tiomeric excesses. Related hydrogen-mediated fragment
couplings are currently under investigation in our labora-
tory.
TsN
Me
TsN
Me
OH
OH
Ph
16b, 54% yield
14b, 95% yield
15b, 83% yield
>20:1 dr
8.3:1 dr
>20:1 dr
Figure 2 Products obtained in the diastereoselective hydrogen-me-
diated reductive cyclization of acetylenic aldehydes
Synthesis 2007, No. 21, 3427–3430 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Asymmetric Reductive Cyclization via Hydrogenation
3429
1H NMR (CDCl3, 300 MHz): d = 7.96 (dd, J = 8.0, 0.8 Hz, 2 H),
7.40 (d, J = 8.4 Hz, 2 H), 7.29–7.37 (m, 3 H), 7.05 (d, J = 8.0 Hz,
2 H), 6.93 (s, 1 H), 4.65 (br d, J = 5.2 Hz, 1 H), 4.47 (d, J = 14.8
Hz, 1 H), 4.25 (d, J = 15.2 Hz, 1 H), 3.47 (br s, 1 H), 3.42 (dd,
J = 10.8, 6.4 Hz, 1 H), 3.07 (dd, J = 10.4, 2.8 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): d = 165.8, 138.4, 134.9, 133.8, 133.5,
131.8, 131.2, 129.8, 129.3, 128.0, 121.5, 68.3, 53.1, 46.1.
Me
RhIIILn
Me
TsN
Me
TsN
HO2CR
O
O
Me Me
17
Me
Me
8a
RhIIILn
O2CR
LnRhI
TsN
Me Me
HRMS (CI): m/z calcd for C18H1779BrNO2 [M+ + 1]: 358.0443;
found: 358.0442.
Me
OH
18
Me
OH
H
TsN
H2
RhIIILn
H
Acknowledgment
OH
TsN
Me Me
8b
HO2CR
Acknowledgment is made to the Robert A. Welch Foundation,
Johnson & Johnson, and the NIH-NIGMS (RO1-GM69445) for
partial support of this research.
Me Me
19
Scheme 4 Plausible catalytic cycle
References
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(2) Alkyne reductive coupling may be achieved indirectly via
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followed by transmetalation to afford organozinc reagents,
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All reactions were run under an atmosphere of argon, unless other-
wise indicated. Anhydrous solvents were transferred by an oven-
dried syringe, and flasks were flame-dried and cooled under a
stream of N2. DCE was purchased from Fisher Co. and freshly dis-
tilled from CaH2. Other chemicals were purchased from Aldrich
Chemcal Co. or Across Co. and used without further purification.
Analytical TLC was carried out using 0.2 mm commercial silica gel
1
plates (EM Science precoated 60 F254). H NMR spectra were re-
corded on Varian Gemini 300 (300 MHz), Varian Mercury 400 (400
MHz), and Varian Inova 500 (500 MHz) spectrometers. Chemical
shifts are reported in delta (d) units, parts per million (ppm) down
field from TMS, and Hertz (Hz) is used for the coupling constants.
13C NMR spectra were recorded with Varian Gemini 300 (75 MHz),
Varian Mercury 400 (100 MHz), and Varian Inova 500 (125 MHz)
spectrometers. Chemical shifts are reported in delta (d) units, parts
per million (ppm) relative to the central line of CDCl3 (d = 77.00
ppm) unless otherwise mentioned. 13C NMR spectra were routinely
run with broad-band decoupling. The multiplicities are expressed
like following: s = singlet, d = doublet, t = triplet, q = quartet. IR
spectra were obtained on a Perkin-Elmer 1600 infrared spectrome-
ter. The relative intensities of IR spectra are reported as follows:
br = broad, s = strong, m = medium, w = weak. HRMS data were
obtained on a Karatos MS9 and are reported as m/z (relative inten-
sity). Accurate masses are reported for the molecular ion (M + 1, M
or M – 1) or a suitable fragment ion.
Compound 2b; Typical Procedure
To a solution of 3-phenylpropynoic acid (4-bromobenzyl)(2-oxo-
ethyl)amide (2a; 0.15 mmol, 53 mg) in dichloroethane (1.5 mL, 0.1
M) at r.t., were added Rh(COD)2OTf (5 mol%, 7.5 mmol, 3.5 mg),
2-naphthoic acid (5 mol%, 7.5 mmol, 1.3 mg), and (R)-Cl,MeO-
BIPHEP (6 mol%, 9.0 mmol, 5.9 mg). The mixture was purged with
H2 and allowed to stir at 45 °C under an atmosphere of H2 until com-
plete consumption of 2a was observed. The mixture was concentrat-
ed via rotary evaporation and the desired product 2b was isolated by
column chromatography (SiO2, hexane–EtOAc, 1:1); yield: 45 mg
(85%). HPLC: Chiral OJ-H column, 15% i-PrOH–hexane, 1.0 mL/
min, 254 nm, tR (major) = 38.5 min, tR (minor) = 45.2 min;
ee = 97%.
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IR (neat): 3380 (br s), 3065 (m), 3030 (m), 2925 (m), 1910 (w),
1670 (s), 1590 (m), 1575 (m), 1490 (s), 1435 (s), 1405 (s), 1350 (m),
1260 (s), 1200 (s), 1130 (m), 1105 (m), 1070 (s), 1010 (s), 910 (s),
835 (m), 800 (s), 730 (s), 690 cm–1 (s).
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4221.
Synthesis 2007, No. 21, 3427–3430 © Thieme Stuttgart · New York

3430
J. U. Rhee et al.
PRACTICAL SYNTHETIC PROCEDURES
(8) Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem.
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Synthesis 2007, No. 21, 3427–3430 © Thieme Stuttgart · New York