Highly stereoselective aldol reaction based on titanium enolates from (S)-1-benzyloxy-2-methyl-3-pentanone

Article abstract of DOI:10.1021/jo050792l

Alternative titanium-mediated aldol procedures based on several protected β-hydroxy ethyl ketones have been surveyed. Eventually, enolization of (S)-1-benzyloxy-2-methyl-3-pentanone (1) with (i-PrO)TiCl₃/i-Pr ₂NEt provided a very rea

Full text of DOI:10.1021/jo050792l

SCHEME 1
Highly Stereoselective Aldol Reaction
Based on Titanium Enolates from
(S)-1-Benzyloxy-2-methyl-3-pentanone
Joan G. Solsona, Joaquim Nebot, Pedro Romea,* and
Fe`lix Urp´ı*
Departament de Quı´mica Orga`nica, Universitat de
Barcelona, Martı´ i Franque´s 1-11, 08028 Barcelona,
Catalonia, Spain
pedro.romea@ub.edu; felix.urpi@ub.edu
Received April 19, 2005
Alternative titanium-mediated aldol procedures based on
several protected â-hydroxy ethyl ketones have been sur-
veyed. Eventually, enolization of (S)-1-benzyloxy-2-methyl-
3-pentanone (1) with (i-PrO)TiCl3/i-Pr2NEt provided a very
reactive enolate that afforded the corresponding 2,4-syn-4,5-
syn aldol adducts in high yields and diastereomeric ratios
with a broad range of aldehydes
ture.4,5 In this context, enantiomerically pure 1-benzyl-
oxy-2-methyl-3-pentanone, easily prepared from Roche
ester, is arguably the most outstanding representative
of such systems. This chiral ethyl ketone, introduced and
mastered by Paterson,4,6 gives access to several stereo-
chemical arrays and has been successfully used in the
synthesis of many natural products.7 Thus, boron enolate
shown in Scheme 1 provides 2,4-anti-4,5-anti aldols
through a transition state that avoids lone pair repulsions
between the enolate oxygen and that of the benzyl
ether.6b Alternatively, tin(II) enolate takes advantage of
the coordinating ability of benzyloxy group and affords
stereoselectively the corresponding 2,4-syn-4,5-syn coun-
terparts through a chelated transition state.6c
Despite the tremendous accomplishments achieved
during the last two decades in the asymmetric aldol
arena, there is still an ongoing pursuit of more efficient
procedures to prepare optically active â-hydroxy carbonyl
compounds.1 Indeed, new catalytic methodologies are
currently challenging classical approaches based on
chiral auxiliaries.1,2 However, traditional substrate-
controlled aldol reactions, which rely upon the stereo-
chemical bias imparted by chiral ketones or aldehydes,
still hold a prominent position and are widely considered
as one of the most powerful strategies to the stereo-
selective construction of polypropionate-like natural prod-
ucts.3,4
Particularly, much attention has been paid to chiral
â-hydroxy ketones because the resulting aldol adducts
can be easily incorporated into the molecular architec-
Regardless of the high levels of diastereocontrol achieved
in the above-mentioned tin-based aldol reactions, the
involvement of tin(II) triflate means a serious drawback
(1) (a) Palomo, C.; Oiarbide, M.; Garc´ıa, J. M. Chem. Soc. Rev. 2004,
33, 65-75. (b) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-
VCH: Weinheim, Germany, 2004.
(2) (a) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-389. (b)
Carreira, E. M. Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer: Heidelberg, Germany, 1999;
Vol. 3, pp 997-1065. (c) Machajewski, T. D.; Wong, C.-H. Angew.
Chem., Int. Ed. 2000, 39, 1352-1374. (d) Johnson, J. S.; Evans, D. A.
Acc. Chem. Res. 2000, 33, 325-335. (e) Denmark, S. E.; Stavenger, R.
A. Acc. Chem. Res. 2000, 33, 432-440.
(3) Actually, substrate-controlled aldol reactions are unparalleled
for the coupling of structurally complex fragments in advanced steps
of total syntheses. (a) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.;
Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 44-122. (b) Nicolaou,
K. C.; Snyder, S. A. Classics in Total Synthesis II; Wiley-VCH:
Weinheim, Germany, 2003.
(4) (a) Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994, 1,
317-338. (b) Paterson, I.; Cowden, C. J. Organic Reactions; Wiley &
Sons: New York, 1997; Vol. 51, pp 1-200.
(5) (a) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urp´ı, F. J. Am.
Chem. Soc. 1991, 113, 1047-1049. (b) Evans, D. A.; Dart, M. J.; Duffy,
J. L.; Rieger, D. L. J. Am. Chem. Soc. 1995, 117, 9073-9074. (c) Evans,
D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996,
118, 4322-4343.
(6) (a) Paterson, I.; Lister, M. A. Tetrahedron Lett. 1988, 29, 585-
588. (b) Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989,
30, 7121-7124. (c) Paterson, I.; Tillyer, R. D. Tetrahedron Lett. 1992,
33, 4233-4236. (d) Paterson, I.; Tillyer, R. D. J. Org. Chem. 1993, 58,
4182-4184.
(7) (a) Paterson, I.; Perkins, M. V. J. Am. Chem. Soc. 1993, 115,
1608-1610. (b) Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.;
Lister, M. A. J. Am. Chem. Soc. 1994, 116, 11287-11314. (c) Paterson,
I.; Yeung, K.-S.; Ward, R. A.; Smith, J. D.; Cumming, J. G.; Lamboley,
S. Tetrahedron 1995, 51, 9467-9486. (d) Paterson, I.; Doughty, V. A.;
McLeod, M. D.; Trieselmann, T. Angew. Chem., Int. Ed. 2000, 39,
1308-1312. (e) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.;
Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9535-9544.
10.1021/jo050792l CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/09/2005
J. Org. Chem. 2005, 70, 6533-6536
6533

TABLE 1. Titanium-Mediated Aldol Reactions Based on
for this methodology because of the expense and opera-
tional complexity associated to this Lewis acid. Surpris-
ingly, parallel titanium chemistry5a,b has been scarcely
explored, and just a few examples, mainly concerned with
matched cases in the double stereodifferentiating pro-
cesses, have been reported.8,9 Given our experience in
titanium-mediated aldol reactions based on chiral R-hy-
droxy ketones,10 we envisaged that the appropriate choice
of titanium Lewis acid and hydroxyl-protecting group
might trigger a stereoselective aldol process. Therefore,
we surveyed alternative enolization conditions of â-hy-
droxy ketones 1-3 with different protecting groups such
as Bn, PMB, or TBDPS.11
Ketones 1-3 with Isobutyraldehyde
entry
ketone (PG)
Lewis acid
dr (SS:AS)
yielda (%)
1
2
3
4
5
6
7
1 (Bn)
TiCl4
77:23b
95
88
93
88
95
90
65d
1 (Bn)
TiCl4 (2 eq)
(i-PrO)TiCl3
(i-PrO)TiCl3
TiCl4
95:5b
Preliminary experiments with isobutyraldehyde showed
that the TiCl4-mediated aldol reaction based on ketone
1 afforded the corresponding 2,4-syn-4,5-syn adduct (SS)
in good yield but nonsynthetic useful diastereomeric ratio
(see entry 1 in Table 1). Otherwise, we were pleased to
observe that diastereoselectivity is dramatically improved
by addition of a second equivalent of TiCl4 to the reacting
mixture, or even better, when a softer Lewis acid as
(i-PrO)TiCl3 is employed (see entries 2 and 3 in Table
1). Most importantly, the yield and the diastereomeric
ratio are both remarkably high and match those obtained
with tin chemistry. In the case of â-OPMB ketone 2, the
less robust protecting group precluded the use of a
powerful titanium Lewis acid as TiCl4,12 but it was
possible to carry out the enolization with (i-PrO)TiCl3,
which provided similar yield and stereocontrol than
ketone 1 (compare entries 3 and 4 in Table 1). Eventually,
the less satisfactory results obtained in the case of
â-OTBDPS ketone 3 (see entries 5-7 in Table 1) clearly
prove that a â-chelating protecting group is required to
control the stereochemical outcome of the process.
Following a short evaluation of the reaction times, the
(i-PrO)TiCl3 procedure based on ketone 1 was applied to
a representative range of aldehydes. In all cases, high
4,5-syn aldol selectivity was observed (4,5-anti aldol
1 (Bn)
97:3b
2 (PMB)
3 (TBDPS)
3 (TBDPS)
3 (TBDPS)
95:5b
70:30c
80:20c
80:20c
TiCl4 (2 eq)
(i-PrO)TiCl3
a Overall isolated yield. b Determined by HPLC. c Determined
by 1H NMR (400 MHz). d 30% of ketone 3 was recovered.
TABLE 2. (i-PrO)TiCl3-Mediated Aldol Reactions of
Ketone 1 with Achiral Aldehydes
entry
R
aldehyde
dra (4:5)
yield (%)
1
2
3
4
5
6
i-Pr
i-Bu
Et
a
b
c
d
e
f
97:3
94:6
93:7
94:6
97:3
96:4
95b
95b
88b
87c
91b
93b
(8) To the best of our knowledge, there is just a single mention of a
TiCl4-mediated aldol reaction of ketone 1 with an achiral aldehyde. In
the case of methacrolein, Paterson reported a 62:38 mixture of the
corresponding 2,4-syn-4,5-syn and 2,4-anti-4,5-syn aldols (see footnote
11 in ref 6c). Similarly, Morris described that TiCl4-mediated aldol
reaction of (S)-1-hydroxy-2-methyl-3-pentanone with isobutyraldehyde
produces 2,4-syn-4,5-syn aldol in 92% yield and 88:12 diastereoselec-
tivity. See: Luke, G. P.; Morris, J. J. Org. Chem. 1995, 60, 3013-
3019.
Ph
H2CdC(CH3)
(E) CH3CHdCH
a Determined by HPLC. b Overall isolated yield. c Isolated yield
of 4.
(9) (a) Perkins, M. V.; Sampson, R. A. Org. Lett. 2001, 3, 123-126.
(b) Paterson, I.; Temal-La¨ıb, T. Org. Lett. 2002, 4, 2473-2476. (c)
Enders, D.; Vicario, J. L.; Job, A.; Wolberg, M.; Mu¨ller, M. Chem.-
Eur. J. 2002, 8, 4272-4284.
(10) (a) Figueras, S.; Mart´ın, R.; Romea, P.; Urp´ı, F.; Vilarrasa, J.
Tetrahedron Lett. 1997, 38, 1637-1640. (b) Esteve, C.; Ferrero´, M.;
Romea, P.; Urp´ı, F.; Vilarrasa, J. Tetrahedron Lett. 1999, 40, 5079-
5082. (c) Solsona, J. G.; Romea, P.; Urp´ı, F.; Vilarrasa, J. Org. Lett.
2003, 5, 519-522. (d) Solsona, J. G.; Romea, P.; Urp´ı, F. Org. Lett.
2003, 5, 4681-4684. (e) Solsona, J. G.; Romea, P.; Urp´ı, F. Tetrahedron
Lett. 2004, 45, 5379-5382. (f) Solsona, J. G.; Nebot, J.; Romea, P.; Urp´ı,
F. Synlett 2004, 2127-2130.
adducts accounted for e2% of the product). Moreover, the
2,4-syn-4,5-syn diastereomer 4 was formed preferentially
irrespective of the aldehyde with a dr higher than 93:7.
Finally, purification of the reaction mixture through
column chromatography permitted us to isolate syn aldols
in 87-95% yields. The results are summarized in Table
2.
(11) Ketones 1-3 were prepared following reported procedures. See
refs 7b and 7e.
(12) Greene, T. W.; Wuts, R. G. M. In Protective Groups in Organic
Synthesis; Wiley & Sons: New York, 1999.
At this point, the stereochemistry of aldols 4c, 4e, and
4f was secured by comparison with the physical and
6534 J. Org. Chem., Vol. 70, No. 16, 2005

TABLE 3. (i-PrO)TiCl3-Mediated Aldol Reactions of Ketone 1 with Chiral Aldehydes
entry
aldehyde
dra
major diastereomer
yield (%)b
1
6
>97:3
94:6
72:28
>97:3
>97:3
8
9
10
11
11
88
92
90
95
87
2
ent-6
7
3
4
ent-7
ent-7
5c
a Determined by HPLC. b Overall isolated yield. c 1.1 equiv of aldehyde was used; reaction time was 1 h.
spectroscopic data already reported in the literature.
Furthermore, catalytic hydrogenation of aldols 4a and
4e yielded quantitatively the same ketodiol, which
guarantees the 2,4-syn-4,5-syn configuration of aldol 4a
(see Supporting Information).
aldehyde with similar results (compare entries 4 and 5
in Table 3).
Although the mechanistic details of this reaction are
still poorly understood, the reported results closely
resemble those arising from R-hydroxy ketones.10 The
stereochemical outcome of the process is consistent with
a selective formation of a Z-enolate and addition to the
aldehyde through a chelating chair transition state.
Furthermore, the impact of the titanium Lewis acid used
in the enolization step on the stereochemical outcome of
the aldol reaction is once more noteworthy, which clearly
proves that choice of ligands must be carefully evaluated.
As a matter of fact, the incorporation of different ligands
in the titanium(IV) not only tunes its acidity but also
affects the structure of the enolate complex and has a
dramatic influence on the aldol transition state (Scheme
2).
In summary, we have demonstrated that enolization
of (S)-1-benzyloxy-2-methyl-3-pentanone, the Paterson
well-known dipropionate equivalent, with (i-PrO)TiCl3/
i-Pr2NEt permits highly stereoselective aldol reactions
in excellent yields with a broad range of achiral and
chiral aldehydes. The reported methodology is simple and
practical and might be applied to other â-chelating
O-protecting groups. Investigations along this line are
currently underway in our laboratory.
The high diastereoselectivity achieved with achiral
aldehydes prompted us to challenge the synthetic poten-
tiality of the above-mentioned methodology in double
stereodifferentiating processes13 involving chiral alde-
hydes 6 (and ent-6)14 and 7 (and ent-7)15 represented
below. The results summarized in Table 3 show that most
reactions are highly stereoselective, which confirms the
remarkable stereocontrol exerted by (i-PrO)TiCl3 enolate
from ketone 1. As expected, the less selective pair
concerns the more demanding (R) lactate-derived alde-
hyde 7, which gives the mismatched antiFelkin adduct
10 in a rather disappointing diastereomeric ratio
(72:28).16,17 With the exception of this case, these double
stereodifferentiating aldol reactions give access to a wide
array of enantiopure intermediates useful for stereo-
selective syntheses.18 Finally, it is worth mentioning that
this aldol reaction can be carried out using 1.1 equiv of
(13) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1-30.
(14) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc.
1990, 112, 6348-6359.
(15) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org. Chem. 1983,
48, 5180-5182.
(18) Actually, stereochemistry of aldol 11 has been secured through
conversion into an advanced intermediate reported for the synthesis
of erythronolides: (a) Mulzer, J.; Kirstein, H. M.; Buschmann, J.;
Lehmann, C.; Luger, P. J. Am. Chem. Soc. 1991, 113, 910-923. (b)
Gerber-Lemaire, S.; Ainge, S. W.; Glanzmann, C.; Vogel, P. Helv. Chim.
Acta 2002, 85, 417-430. For experimental details, see Supporting
Information.
(16) Roush, W. R. J. Org. Chem. 1991, 56, 4151-4157.
(17) For recent aldol reactions involving R-hydroxy aldehydes, see:
(a) Reference 10b. (b) Evans, D. A.; Siska, S. J.; Cee, V. J. Angew.
Chem., Int. Ed. 2003, 42, 1761-1765. (c) Marco, J. A.; Carda, M.; Dı´az-
Oltra, S.; Murga, J.; Falomir, E.; Roeper, H. J. Org. Chem. 2003, 68,
8577-8582.
J. Org. Chem, Vol. 70, No. 16, 2005 6535

2.22, CHCl3) [lit.6c ent-4a [R]D -26.1 (c 3.2, CHCl3)]; IR (film):
υ 3511, 3032, 2964, 2936, 1706, 1456, 1373, 1095 cm-1; 1H NMR
(400 MHz, CDCl3): δ 7.35-7.26 (5H, m), 4.47 (1H, AB system,
J ) 11.9), 4.44 (1H, AB system, J ) 11.9), 3.64 (1H, t, J ) 8.8),
3.61 (1H, dd, J ) 9.0, J ) 2.3), 3.46 (1H, dd, J ) 8.8, J ) 4.9),
3.21-3.12 (1H, m), 2.85 (1H, qd, J ) 7.0, J ) 2.3), 1.70-1.61
(1H, m), 1.07 (3H, d, J ) 7.0), 1.02 (3H, d, J ) 7.0), 0.99 (3H, d,
J ) 6.4), 0.81 (3H, d, J ) 6.4); 13C NMR (100.6 MHz, CDCl3): δ
218.2 (C), 137.5 (C), 128.4 (CH), 127.8 (CH), 127.7 (CH), 75.4
(CH), 73.5 (CH2), 73.3 (CH2), 48.4 (CH), 44.4 (CH), 30.3 (CH),
19.6 (CH3), 18.8 (CH3), 13.7 (CH3), 7.9 (CH3); HRMS (+FAB):
m/z calcd for C17H27O3 [M + H]+: 279.1960. Found: 279.1960.
(2S,4R,5R,6S)-1-Benzyloxy-6-(tert-butyldiphenylsilyloxy)-
5-hydroxy-2,4-dimethyl-3-heptanone (11): Colorless oil. Rf
(CH2Cl2) ) 0.2; HPLC (hexanes/i-PrOH 99.5:0.5) tR ) 8.5 min;
[R]D +5.3 (c 1.04, CHCl3); IR (film): υ 3525, 3070, 2934, 2858,
SCHEME 2
1710, 1456, 1428, 1108 cm-1 1H NMR (400 MHz, CDCl3): δ
;
7.72-7.64 (4H, m), 7.46-7.22 (11H, m), 4.40 (2H, s), 3.91 (1H,
dd, J ) 7.2, J ) 3.5), 3.75 (1H, dq, J ) 7.2, J ) 6.1), 3.59 (1H,
t, J ) 8.7), 3.43 (1H, dd, J ) 8.7, J ) 5.0), 3.18-3.06 (2H, m),
1.05 (3H, d, J ) 6.1), 1.05 (9H, s), 1.02 (3H, d, J ) 6.9), 0.96
(3H, d, J ) 7.0); 13C NMR (100.6 MHz, CDCl3): δ 217.7 (C), 137.7
(C), 135.9 (CH), 135.8 (CH), 134.4 (C), 133.4 (C), 129.8 (CH),
129.6 (CH), 128.4 (CH), 127.8 (CH), 127.7 (CH), 127.6 (CH), 127.4
(CH), 74.7 (CH), 73.4 (CH2), 73.0 (CH2), 69.7 (CH), 47.3 (CH),
44.8 (CH), 27.0 (CH3), 19.8 (CH3), 19.3 (C), 13.8 (CH3), 9.3 (CH3);
HRMS (+FAB): m/z calcd for C32H43O4Si [M + H]+: 519.2931.
Found: 519.2918.
Experimental Section
General (i-PrO)TiCl3-Mediated Aldol Procedure. Freshly
distilled (i-PrO)4Ti (83 µL, 0.28 mmol) was added dropwise to a
solution of TiCl4 (92 µL, 0.84 mmol) in CH2Cl2 (1 mL) at 0 °C
under N2. The mixture was stirred for 10 min at 0 °C and 10
min at room temperature and diluted with CH2Cl2 (1 mL), and
the resulting colorless solution was added via cannula or syringe
(2 × 0.5 mL) to a solution of 1 (206 mg, 1.0 mmol) in CH2Cl2 (2
mL) at -78 °C under N2 (alternatively, a stock solution of 0.55
M (i-PrO)TiCl3 in CH2Cl2 (2 mL, 1.1 mmol) was added dropwise
to a solution of 1 (206 mg, 1.0 mmol) in CH2Cl2 (3 mL) at -78
°C under N2). The pale yellow solution was stirred for 2 min,
and i-Pr2NEt (190 µL, 1.1 mmol) was added dropwise. The
resulting orange-red solution was stirred for 30 min at -78 °C,
and 1.5 equiv of aldehyde were added. After 30-40 min at -78
°C the reaction was quenched by addition of saturated NH4Cl
(5 mL) and vigorously stirred at room temperature. The mixture
was diluted with Et2O and washed with H2O, saturated NaH-
CO3, and brine. The aqueous layers were extracted with Et2O,
and the combined extracts were dried (MgSO4) and concentrated.
The resulting oil was analyzed by HPLC and purified by flash
chromatography on silica gel (hexanes/EtOAc or CH2Cl2).
(2S,4R,5S)-1-Benzyloxy-5-hydroxy-2,4,6-trimethyl-3-hep-
tanone (4a): colorless oil. Rf (hexanes/EtOAc 85:15) ) 0.2;
HPLC (hexanes/i-PrOH 99.5:0.5) tR ) 18.1 min; [R]D +25.4 (c
Acknowledgment. Financial support from the Min-
isterio de Ciencia y Tecnolog´ıa and Fondos FEDER
(Grant BQU2002-01514), the Generalitat de Catalunya
(2001SGR00051), as well as doctorate studentships
(Universitat de Barcelona) to J.G.S. and J.N. are
acknowledged.
Supporting Information Available: Experimental pro-
cedures reported in Table 1, characterization data of aldols 4
1
and 8-10, stereochemical proof for aldols 4a and 11, and H
and 13C spectra of aldols 4 and 8-11. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO050792L
6536 J. Org. Chem., Vol. 70, No. 16, 2005