1,5-Asymmetric induction in boron-mediated aldol reactions of β-alkoxy methylketones

Article abstract of DOI:10.1021/jo8009165

(Chemical Equation Presented) Good levels of substrate-controlled, 1,5-syn-stereoinduction are obtained in boron-mediated aldol reactions of β-trichloromethyl-β-alkoxy and β-trifluoromethyl-β-alkoxy methylketones with achiral aldehydes, independent of the nature of the β-alkoxy protecting group (TBS or PMB). In the case of boron aldol reactions of β-aryl-β-alkoxy methylketones, the 1,5-anti-adducts were obtained with high levels of diastereoselectivity only with a β-OPMB group.

Full text of DOI:10.1021/jo8009165

1,5-Asymmetric Induction in Boron-Mediated Aldol Reactions of
ꢀ-Alkoxy Methylketones
Luiz C. Dias,* Anderson A. de Marchi, Marco A. B. Ferreira, and Andrea M. Aguilar†
Instituto de Qu´ımica, UniVersidade Estadual de Campinas, UNICAMP, C.P. 6154,
13084-971 Campinas, SP, Brazil
ldias@iqm.unicamp.br
ReceiVed April 29, 2008
Good levels of substrate-controlled, 1,5-syn-stereoinduction are obtained in boron-mediated aldol reactions
of ꢀ-trichloromethyl-ꢀ-alkoxy and ꢀ-trifluoromethyl-ꢀ-alkoxy methylketones with achiral aldehydes,
independent of the nature of the ꢀ-alkoxy protecting group (TBS or PMB). In the case of boron aldol
reactions of ꢀ-aryl-ꢀ-alkoxy methylketones, the 1,5-anti-adducts were obtained with high levels of
diastereoselectivity only with a ꢀ-OPMB group.
Introduction
of bryostatin 1. In the past few years, the research groups of
Paterson3 and of Evans4 made outstanding contributions and
were responsible for the development of this area of remote
1,5-asymmetric induction.5–7
In these reactions, the less substituted boron enolate 2 is
generated after treatment of the methylketone 1 with boron
triflates or dialkyl chloroboranes, followed by addition of a
tertiary amine in solvents such as CH2Cl2, Et2O, or pentane
(Scheme 1).1 Usually, high levels of 1,5-anti selectivities are
The aldol reaction between boron enolates generated from
methylketones and aldehydes provides a very attractive method
for carbon-carbon bond formation and has been applied for
the synthesis of a wide variety of natural products with
biological and pharmacological significance.1 The presence of
a ꢀ-heteroatom substituent in the boron enolates of methylke-
tones influences the stereochemical outcome of the correspond-
ing aldol reactions and controls the overall diastereoselectivity
of the process leading to moderate to high levels of 1,5-anti
stereoinduction.
(2) Blanchette, M. A.; Malamas, M. S.; Nantz, M. H.; Roberts, J. C.; Somfai,
P.; Whritenour, D. C.; Masamune, S.; Kageyama, M.; Tamura, T. J. Org. Chem.
1989, 54, 2817.
The first evidence for 1,5-anti asymmetric induction in aldol
reactions was described in 1989 by Masamune and co-workers2
in their approach to the synthesis of the AB fragment [C1-C16]
(3) Paterson, I.; Oballa, R. M.; Norcross, R. D. Tetrahedron Lett. 1996, 37,
8581.
(4) Evans, D. A.; Coˆte´, B.; Coleman, P. J.; Connell, B. T. J. Am. Chem.
Soc. 2003, 125, 10893.
(5) (a) Paterson, I.; Goodman, J. M. Tetrahedron Lett. 1989, 30, 997. (b)
Paterson, I.; Florence, G. J. Tetrahedron Lett. 2000, 41, 6935. (c) Paterson, I.;
Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996, 37, 8585. (d) Paterson, I.;
Collett, L. A. Tetrahedron Lett. 2001, 42, 1187.
* To whom correspondence should be addressed. Fax: +55-19-3521-3023.
† Present address: Universidade Federal de Sa˜o Paulo, UNIFESP, Campus
Diadema, Departamento de Cieˆncias Exatas e da Terra, R. Prof. Artur Ridel,
275, 09972-270, Diadema, SP, Brazil.
(1) (a) Dias, L. C.; Aguilar, A. M. Chem. Soc. ReV. 2008, 37, 451. (b) Dias,
L. C.; Aguilar, A. M. Quim. NoVa 2007, 30, 2007. (c) Cowden, C. J.; Paterson,
I. Org. React. 1997, 51, 1. (d) Franklin, A. S.; Paterson, I. Contemp. Org. Synth.
1994, 1, 317. (e) Heathcock, C. H. In ComprehensiVe Organic Synthesis;
Heathcock, C. H., Ed.; Pergamon Press; New York, 1991; Vol. 2, p 181. (f)
Kim, B. M.; Williams, S. F.; Masamune, S. In ComprehensiVe Organic Synthesis;
Heathcock, C. H., Ed.; Pergamon Press; New York, 1991; Vol. 2, p 239. (g)
Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1.
(6) (a) Evans, D. A.; Coleman, P. J.; Coˆte´, B. J. Org. Chem. 1997, 62, 788.
(b) Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Coˆte´, B.; Dias, L. C.; Rajapakse,
H. A.; Tyler, A. N. Tetrahedron 1999, 29, 8671. (c) Tanimoto, N.; Gerritz, S. W.;
Sawabe, A.; Noda, T.; Filla, S. A.; Masamune, S. Angew. Chem., Int. Ed. Engl.
1994, 33, 673. (d) Roush, W. R.; Bannister, T. D.; Wendt, M. D.; Jablonowski,
J. A.; Scheidt, K. A. J. Org. Chem. 2002, 67, 4275.
(7) (a) Denmark, S. E.; Fujimori, S.; Pham, S. M. J. Org. Chem. 2005, 70,
10823. (b) Denmark, S. E.; Fujimori, S. Synlett 2001, 1024. (c) Denmark, S. E.;
Fujimori, S. J. Am. Chem. Soc. 2005, 127, 8971.
10.1021/jo8009165 CCC: $40.75
Published on Web 07/11/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6299–6311 6299

Dias et al.
SCHEME 1. General Scheme for Aldol Reactions of
ꢀ-Alkoxy Boron Enolates
°C. Aldol reactions with aldehydes 10a-f, at -78 °C, provided
the corresponding 1,5-anti (11a-f) and 1,5-syn (12a-f) aldol
adducts (Scheme 3, Table 1).13
The boron-mediated aldol reactions of methylketone 5 (R )
PMB) were found to proceed with good yields and high degrees
of remote 1,5-anti stereoinduction. In all the cases studied with
methylketone 5 (R ) PMB), 1,5-anti isomers 11a-f were
isolated as the major products.14
In the case of methylketone 6 (R ) TBS), the corresponding
boron enolate addition to aldehydes 10a-f gave a mixture of
aldol adducts 13a-f and 14a-f favoring the 1,5-syn aldol
adducts 14a-f (Scheme 3, Table 1).8 The best selectivity was
observed with benzaldehyde (entry 6, anti:syn ) 29:71). It is
clear from these examples that the presence of a TBS protecting
group at the ꢀ-oxygen of the boron enolate weakly favored the
formation of the 1,5-syn product, indicating a low level of
influence on the selectivity by the resident ꢀ-OTBS group.
The relative stereochemistry for aldol adducts 11a-f (R )
PMB) was confirmed after conversion of 11a to the correspond-
ing benzylidene acetal 16 and isopropylidene acetal 17 (Scheme
4). Selective 1,3-anti reduction of 11a provided diol 15 in 54%
yield and >95:05 diastereoselectivity (via transition state A).15
Diol 15 was treated with DDQ in CH2Cl2 in the presence of
molecular sieves to give benzylidene acetal 16 in 83% yield
obtained in aldol reactions of ꢀ-alkoxy methylketones when the
ꢀ-alkoxy substituent is an alkyloxy group, a benzyloxy group
(OBn, OPMB), or a part of benzylidene acetal. With a ꢀ-silicon
protecting group, the aldol reaction gives little or no selectivity.1–4
In order to understand the principles that control the 1,5-
diastereoselectivity in aldol reactions of boron enolates generated
from ꢀ-alkoxy methylketones, we decided to study the influence
of the substituents at the ꢀ-position of the boron enolate by
using ꢀ-p-nitrophenyl and ꢀ-p-methoxyphenyl groups as well
as ꢀ-trichloromethyl and ꢀ-trifluoromethyl groups.8 In addition,
trichloromethyl and trifluoromethyl compounds are precursors
for the synthesis of various useful products such as R-substituted
carboxylic acids and terminal alkynes.9
(Scheme 4).16 Analysis of the H NMR coupling constants,
1
specifically JHa-Hc ) 11.2 Hz, JHa-Hd ) 2.7 Hz, JHb-Hc ) 11.2
Hz, and JHb-Hd ) 2.5 Hz, together with the illustrated NOE data,
proved that Ha, Hb, and Hc are all axial in 16. Treatment of
diol 15 with Me2C(OMe)2 and catalytic amounts of CSA
provided the isopropylidene acetal 17 in 77% yield (Scheme
4).17 Analysis of the 13C NMR spectra showed resonances at
24.3, 25.0, and 100.2 for 17, characteristic of a 1,3-anti-
acetonide.17
We wish to report here our results in aldol reactions using
the less substituted boron enolates of ꢀ-alkoxy-ꢀ-aryl, ꢀ-alkoxy-
ꢀ-trichloromethyl, and ꢀ-alkoxy-ꢀ-trifluoromethyl methylke-
tones with achiral aldehydes.7 Methylketones with tert-
butyldimethylsilyl (TBS), benzyl (Bn), p-methoxybenzyl (PMB),
and tert-butyl protecting groups at the ꢀ-position were employed
to evaluate the potential steric and electronic impact of the
ꢀ-alkoxy substituents.8
The next step involved the assignment of the relative
stereochemistry for aldol adducts obtained from methylketone
6 (R ) TBS). Treatment of aldol adduct 11a with DDQ, gave
diol 1,5-anti-18 in 36% nonoptimized yield (Scheme 5).16 As
we were able to separate the 34:66 mixture of anti and syn aldol
adducts 13a and 14a (R ) TBS) by flash column chromatog-
raphy, both aldols were independently treated with HF in
CH3CN/H2O (4/1) to give diols 18 and 19, respectively, in
Results and Discussion
Aldol Reactions of ꢀ-Aryl-ꢀ-alkoxy Methylketones. The
preparation of ꢀ-alkoxy-ꢀ-aryl methylketones 5 (R ) PMB), 6
(R ) TBS), 8 (R ) PMB), and 9 (R ) TBS) is described in
Scheme 2. The racemic methylketones 4 and 7 were prepared
in good yields by aldol reactions between acetone and p-
nitrobenzaldehyde or p-methoxybenzaldehyde, respectively
(Scheme 2).10 Treatment of methylketone 4 with PMB-acetimi-
date in the presence of catalytic amounts of TfOH gave
methylketone 5 in 64% yield.11 Protection of the ꢀ-oxygen in
4 as its TBS ether was achieved by using TBSCl and AgNO3
in DMF at room tempertaure for 16 h, providing 6 in 92% yield
(Scheme 2).12
1
excellent yields. At this point, by comparison of their H and
13C NMR spectra, we observed that the diol 18, prepared from
the minor aldol adduct 13a, was identical in all respects with
the 1,5-anti-diol prepared from PMB removal of 11a. This
proved that the 1,5-syn-isomer is the major product in the aldol
reactions with a TBS protecting group (Scheme 5).
Methylketone 7 was treated under similar reaction conditions
to provide the protected ꢀ-alkoxy methylketones 8 (R ) PMB)
and 9 (R ) TBS) in good yields (Scheme 2).
The enolization of methylketone 5 (R ) PMB) was performed
with (c-Hex)2BCl and Et3N in Et2O or CH2Cl2 as solvent at 0
(13) (a) Dias, L. C.; Bau´, R. Z.; de Sousa, M. A.; Zuckerman-Schpector, J.
Org. Lett. 2002, 4, 4325. (b) Dias, L. C.; Aguilar, A. M.; SallesJr, A. G.; Steil,
L. J.; Roush, W. R J. Org. Chem. 2005, 70, 10461. (c) Dias, L. C.; Aguilar,
A. M. Org. Lett. 2006, 8, 4629.
(14) (a) The ratios were determined by 1H and 13C NMR spectroscopic
analysis of the unpurified product mixture. (b) All of the percentage values
represent data obtained from at least three individual trials.
(15) (a) Evans, D. A; Chapman, K. T. Tetrahedron Lett. 1986, 27, 5939. (b)
Evans, D. A; Chapman, K. T.; Carreira, E. M J. Am. Chem. Soc. 1988, 110,
3560. (c) Dias, L. C.; de Oliveira, L. G.; Vilcachagua, J. D.; Nigsch, F. J. Org.
Chem. 2005, 70, 2225. (d) Dias, L. C.; de Oliveira, L. G. Org. Lett. 2004, 6,
2587. (e) Dias, L. C.; de Oliveira, L. G.; de Sousa, M. A. Org. Lett. 2003, 5,
265.
(8) Dias, L. C.; Marchi, A. A.; Ferreira, M. A. B.; Aguilar, A. M. Org. Lett.
2007, 9, 4869.
(9) (a) Gouverneur, V.; Purser, S.; Moore, P. R.; Swallow, S. Chem. Soc.
ReV. 2008, 37, 320. (b) Bonnet-Delpon, D.; Be´gue´, J. P. J. Fluorine Chem. 2006,
127, 992.
(10) (a) Chimni, S. S.; Mahajan, D. Tetrahedron 2005, 61, 5019. (b) Zhang,
F.; Su, N.; Gong, Y. Synlett 2006, 1703.
(16) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23,
889.
(11) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am.
Chem. Soc. 2001, 123, 9535.
(17) (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945.
(b) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990, 31, 7099.
(c) Tormena, C. F.; Dias, L. C.; Rittner, R. J. Phys. Chem. A 2005, 109, 6077.
(d) Dias, L. C.; Giacomini, R. Tetrahedron Lett. 1998, 39, 5343. (e) Dias, L. C.;
Diaz, G.; Ferreira, A. A.; Meira, P. R. R.; Ferreira, E. Synthesis 2003, 603.
(12) (a) Hakimelahi, G. H.; Proba, Z. A.; Ogilvie, K. K. Tetrahedron Lett.
1981, 22, 4775. (b) Cossy, J.; Bauer, D.; Bellosta, V. Tetrahedron 2002, 58,
5909.
6300 J. Org. Chem. Vol. 73, No. 16, 2008

1,5-Asymmetric Induction in Boron-Mediated Aldol Reactions
SCHEME 2. Preparation of ꢀ-Alkoxy Methylketones 5-9
SCHEME 3. Aldol Reactions of ꢀ-Alkoxy Methylketones 5 and 6
TABLE 1. Aldol Reactions of 5 and 6 with R′CHO
corresponding benzylidene acetal 25 (Scheme 7). Selective
reduction of 20a to the 1,3-anti-diol 24 (52% yield) followed
by treatment of 24 with DDQ in CH2Cl2 gave benzylidene acetal
entry R (ketone)
aldehyde (R′)
dsa(1,5-anti:1,5-syn) yield (%)b
1c
2
3
PMB (5)
PMB (5)
TBS (6)
PMB (5)
PMB (5)
TBS (6)
PMB (5)
TBS (6)
PMB (5)
TBS (6)
PMB (5)
TBS (6)
PMB (5)
TBS (6)
10a, -Pr
96:04 (11a:12a)
96:04 (11a:12a)
34:66 (13a:14a)
>95:05 (11b:12b)
87:13 (11b:12b)
29:71 (13b:14b)
92:08 (11c:12c)
41:59 (13c:14c)
70
78
91
65
74
81
51
65
54
70
63
67
56
69
i
25 in 25% nonoptimized yield.15,16 Analysis of the H NMR
1
coupling constants, specifically JHa-He ) 11.1 Hz, JHa-Hd ) 2.4
Hz, JHb-He ) 11.1 Hz, and JHb-Hd ) 2.7 Hz, together with the
illustrated NOE interactions between Ha, Hb, and Hc, proved
that Ha, Hb, and Hc are all axial in 25.
In order to assign the stereochemistry for aldol adducts
obtained from methylketone 9 (R ) TBS), we first treated aldol
20a (R ) PMB), of known stereochemistry, with DDQ, H2O
in CH2Cl2, to give diol 1,5-anti-26 in 38% nonoptimized yield
(Scheme 8).
4
10b, Ph
5d
6
7
8
9
10
11
12
13
14
10c, Et
10d, C(Me)dCH2 93:07 (11d:12d)
41:59 (13d:14d)
10e, p-C6H4OMe >95:05 (11e:12e)
37:63 (13e:14e)
>95:05 (11f:12f)
43:57 (13f:14f)
10f, p-C6H4NO2
The 32:68 mixture of anti- and syn-aldol adducts 22a and
23a (entry 10, Table 2) was separated by flash column
chromatography, and the aldol products were independently
treated with TBAF and AcOH in THF to give diols 26 and 27,
respectively, in good yields (Scheme 8).18 After comparison of
a Ratio was determined by 1H NMR analysis of the diastereoisomeric
mixture of adducts. b Isolated yields of both syn and anti isomers after
SiO2 flash chromatography. c Et2O as solvent. d Aldehyde addition was
performed at 0 °C.
1
their H and 13C NMR spectra, we observed that the diol 26,
We next moved to investigate the aldol reactions of meth-
ylketones 8 (R ) PMB) and 9 (R ) TBS). The aldol reactions
of the methylketones 8 and 9 with aldehydes 10a-f were
investigated using (c-Hex)2BCl and Et3N in CH2Cl2 as solvent
for enolization to give the 1,5-anti- and 1,5-syn-aldol adducts
(Scheme 6, Table 2).8,13 The enolizations were performed at 0
°C, and the addition of the aldehyde was at -78 °C. As observed
before, these boron-mediated aldol reactions were found to
proceed with good yields and high degrees of remote 1,5-anti-
stereoinduction for methylketone 8 (R ) PMB).
Following the same trend observed for methylketone 6 (R )
TBS), the reaction of the boron enolate generated from
methylketone 9 (R ) TBS) with aldehydes 10a-f led to a
mixture of aldol adducts 22a-f and 23a-f favoring the 1,5-
syn-aldol adducts 23a-f (Scheme 6, Table 2).8 The best
selectivity was observed with propionaldehyde (entry 6, anti:
syn ) 29:71). The presence of a TBS protecting group at the
ꢀ-oxygen of the methylketone 9 again favored the formation
of the 1,5-syn-aldol adduct.
prepared from the minor aldol adduct 22a, was identical in all
respects with the 1,5-anti-diol prepared from PMB removal of
20a. Again, this proved that the 1,5-syn-isomer is the major
product in the aldol reactions of methylketone 9, with a TBS
protecting group (Scheme 5).
At this point, we decided to prepare methylketone 28 (R )
t-Bu) in order to evaluate the stereoelectronic impact of the tert-
butyl group at the ꢀ-oxygen (Scheme 9). Our intention was to
compare the aldol addition of the boron enolate of this
methylketone with that of methylketone 6 (R ) TBS). To the
best of our knowledge, there are no examples of aldol reactions
of ꢀ-Ot-Bu methylketones described in the literature. Treatment
of methylketone 4 with t-Bu-acetimidate in the presence of
catalytic amounts of CSA gave methylketone 28 in 23% yield
(nonoptimized), together with R,ꢀ-unsaturated ketone 29.19,20
Addition of aldehydes 10a, 10b, and 10e to the boron enolate
generated from methylketone 28 led to a mixture of the
corresponding 1,5-anti- and 1,5-syn-aldol adducts in good yields
with low levels of diastereoselectivity favoring the 1,5-syn-aldol
products (Scheme 10).
The 1,5-anti-relative stereochemistry for aldol adducts 20a-f
was unambiguously established after conversion of 20a to the
J. Org. Chem. Vol. 73, No. 16, 2008 6301

Dias et al.
SCHEME 4. Proof of Stereochemistry for Aldol Adduct 11a
SCHEME 5. Proof of Stereochemistry for Aldol Adducts 13a and 14a
SCHEME 6. Aldol Reactions of ꢀ-Alkoxy Methylketones 8 and 9
TABLE 2. Aldol Reactions of 8 and 9 with R′CHO
The relative stereochemistry for the major product from the
aldol reactions of methylketone 28 was confirmed after treatment
of the 37:63 mixture of anti- and syn-aldol adducts 30a and
31a with TiCl4 in CH2Cl2 to remove the t-Bu protecting group,
leading to diols 18 and 19 in 63% combined yield (Scheme
entry R (ketone)
aldehyde (R′)
dsa (1,5-anti:1,5-syn) yield (%)b
i
1
2
2
3
5
6
7
8
PMB (8)
TBS (9)
PMB (8)
TBS (9)
PMB (8)
TBS (9)
PMB (8)
TBS (9)
PMB (8)
TBS (9)
PMB (8)
TBS (9)
10a, -Pr
>95:05 (20a:21a)
32:68 (22a:23a)
>95:05 (20b:21b)
33:67 (22b:23b)
94:06 (20c:21c)
29:71 (22c:23c)
84
88
89
74
60
65
75
81
79
50
85
78
10b, Ph
10c, Et
11).19,21 After comparison of their H and 13C NMR spectra,
1
we have observed that the 1,5-anti-diol 18, prepared from PMB
removal of 11a (Scheme 5), was identical in all respects with
the minor isomer prepared from the mixture of aldol adducts
30a and 31a. This proved that the 1,5-syn-isomer is the major
product in the aldol reactions of methylketone 28 with a t-Bu
protecting group.
10d, C(Me)dCH2 >95:05 (20d:21d)
32:68 (22d:23d)
9
10e, p-C6H4OMe >95:05 (20e:21e)
33:67 (22e:23e)
10f, p-C6H4NO2
10
11
12
>95:05 (20f:21f)
35:65 (22f:23f)
a Ratio was determined by 1H NMR analysis of the diastereoisomeric
mixture of adducts. b Isolated yields of both syn and anti isomers after
(18) Smith, A. B., III.; Ott, G. R. J. Am. Chem. Soc. 1996, 118, 13095.
(19) (a) Wuts, P. G. M.; Greene, T. W. ProtectiVe Groups in Organic
Synthesis, 4th ed.; Wiley-Interscience: New York, 2007. (b) Dias, L. C.; Meira,
P. R. R. J. Org. Chem. 2005, 70, 4762.
SiO2 flash chromatography.
(20) Armstrong, A.; Brackenridge, I.; Jackson, R. F. W.; Kirk, J. M.
Tetrahedron Lett. 1988, 29, 2483.
The observed results for methylketone 28 show that a steric
effect is responsible for the formation of the 1,5-syn-isomer with
(21) Schlessinger, R. H.; Nugent, R. A. J. Am. Chem. Soc. 1982, 104, 1116.
6302 J. Org. Chem. Vol. 73, No. 16, 2008

1,5-Asymmetric Induction in Boron-Mediated Aldol Reactions
SCHEME 7. Proof of Stereochemistry for Aldol Adduct 20a
SCHEME 8. Proof of Stereochemistry for Aldol Adducts 22a and 23a
SCHEME 9. Preparation of ꢀ-Alkoxy Methylketone 28
a ꢀ-OTBS and a ꢀ-Ot-Bu protecting groups. The lower basicity
of the oxygen attached to the silicon may not be the only effect
responsible for the observed lower selectivities as steric effects
may play a very important role in controlling the observed sense
of stereoinduction.22,23
Aldol Reactions of ꢀ-Methyl, ꢀ-Trichloromethyl, and
ꢀ-Trifluoromethyl-ꢀ-alkoxy Methylketones. We then moved
to investigate the stereochemical impact of ꢀ-methyl, ꢀ-trichlo-
romethyl, and ꢀ-trifluoromethyl substituents on the ꢀ-alkoxy
methylketones.9
at room temperature (60% yield), as shown in Scheme 12.12,24
Treatment of ketone 36 with BnBr, KI, and K2CO3 in acetone
as solvent gave ꢀ-OBn methylketone 37 in 55% yield.25
Attempts to protect the ꢀ-hydroxyl function of aldol adduct 36
as its TBS ether proved problematic under a variety of
conditions. The usual procedures resulted in decomposition and
low yields of the desired silyl ether 38. The best conditions
involved treatment of 36 with TBSCl, AgNO3, and pyridine in
DMF providing ꢀ-OTBS methylketone 38 in 89% yield (Scheme
12).12 This supports the notion that the basic nature of the
ꢀ-oxygen atom is significantly attenuated due to the strong
electron-withdrawing capability of the trichloromethyl group.
We began with the preparation of ꢀ-trichloromethyl meth-
ylketone 36, employing the directed aldol reaction of acetone
with chloral hydrate in the presence of ammonium hydroxyde
The ꢀ-alkoxy methylketones 40 and 41 were prepared under
similar conditions (Scheme 12). Aldol reaction of acetone with
trifluoroacetaldehyde ethyl hemiacetal in the presence of pyr-
rolidine at room temperature provided hydroxyketone 39 in 88%
(22) (a) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462. (b) Chen, X. N.;
Hortellano, E. R.; Eliel, E. L.; Frye, S. V. J. Am. Chem. Soc. 1990, 112, 6130.
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Chem. Soc. 1995, 117, 5055. (d) Schreiber, S. L.; Shambayati, S.; Blake, J. F.;
Wierschke, S. G.; Jorgensen, W. L. J. Am. Chem. Soc. 1990, 112, 697. (e)
Beckmann, J.; Grabowsky, S. J. Phys. Chem. A 2007, 111, 2011.
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112, 232.
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Tetrahedron Lett. 2005, 46, 8685.
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J. Org. Chem. Vol. 73, No. 16, 2008 6303

Dias et al.
SCHEME 10. Aldol Reactions of ꢀ-Alkoxy Methylketone 28
SCHEME 11. Proof of Stereochemistry for Aldols 30a and
31a
°C as well as at -78 °C. We were delighted to find that these
reactions led to the formation of 1,5-syn-products 47a-g (R )
Bn) and 49a-f (R ) TBS) as the major isomers (1,5-syn:1,5-
anti-selectivities ranging from 78:22 to 92:08) in moderate to
high yields (Scheme 14, Table 3). Usually, higher yields were
obtained with aldol reactions at 0 °C, although higher levels of
diastereoselectivities were observed at lower temperatures.
These studies showed a remarkable influence of the resident
ꢀ-trichloromethyl group on the stereochemical course of these
aldol reactions to give the 1,5-syn-isomer, independent of the
nature of the ꢀ-alkoxy protecting group.
With methylketones 40 (R ) Bn) and 41 (R ) TBS), we
observed the same trend, and the overall diastereoselection of
the process was again controlled by the facial bias of the
ꢀ-trifluoromethyl group of the boron enolate to give the 1,5-
syn-products 51a-e (R ) Bn) and 53a-e (R ) TBS) as the
major isomers (Scheme 15, Table 4).11
It is interesting that higher levels of 1,5-syn-diastereoselection
were observed with ꢀ-CCl3 methylketones 37 (R ) Bn) and 38
(R ) TBS), when compared with ꢀ-CF3 methylketones 40 (R
) Bn) and 41 (R ) TBS). This may well be related to the larger
size of the ꢀ-CCl3 group.
The relative stereochemistries of the major aldol adducts 49a
and 53a were determined by 1H NMR and NOESY analysis of
the bicyclic derivatives 59 and 60 (Scheme 16). Diastereose-
lective 1,3-anti-reduction15 of 49a and 53a with Me4NBH(OAc)3
gave the corresponding diols 55 and 56, respectively, in good
yields, which, after removal of the TBS protecting group with
HF in CH3CN/CH2Cl2, provided triol derivatives 57 (92%) and
58 (72%) (Scheme 16).
Treatment of triols 57 (X ) Cl) and 58 (X ) F) with
trimethylorthoacetate and catalytic amounts of CSA gave the
bicyclic derivatives 59 and 60, respectively, in good yields.
Analysis of the 1H NMR coupling constants for 59, specifically
yield (Scheme 12).26 Treatment of ketone 39 with BnBr, Ag2O,
and TBAI in CH2Cl2 as solvent gave ꢀ-OBn methylketone 40
in 45% yield. The best conditions for the preparation of
methylketone 41 (R ) TBS) involved treatment of 39 with
TBSCl, AgNO3, and pyridine in DMF (70% yield).12
At this point, we decided to prepare methylketones 44 and
46, containing a ꢀ-methyl group in order to compare the
corresponding aldol reactions with those using methylketones
37/38 and 40/41. The methyl group is smaller in size compared
to strongly electron-withdrawing CF3 and CCl3 groups. Monoben-
zylation of commercially available 1,3-diol 42 provided alcohol
43, which was treated with PCC in CH2Cl2 to give ꢀ-OBn
methylketone 44 in 64% yield for the two-step sequence
(Scheme 13).27,28
Methylketone 46 was easily prepared by a sequence which
involved treatment of diol 42 with TBSOTf and 2,6-lutidine in
CH2Cl2 at -78 °C to provide alcohol 45, followed by oxidation
with PCC in the presence of anhydrous NaOAc (44%, two
steps).28
Enolization of methylketones 37 (R ) Bn) and 38 (R ) TBS)
with (c-Hex)2BCl and Et3N in CH2Cl2 at room temperature
proceeded smoothly, providing the corresponding kinetic enol
borinate, which was used in the aldol reactions with aldehydes
10a-g (Scheme 14, Table 3). The reactions were studied at 0
JHa-Hc ) 6.5 Hz, JHa-Hb ) 10.0 Hz, JHd-He ) 4.0 Hz, JHd-Hf
)
11.0 Hz, and JHg-Hb ) JHg-Hf ) 6.5 Hz, proved that Ha and Hd
were both axial. This was also supported by the illustrated NOE
interaction between Ha and Hd. Analysis of the 1H NMR
coupling constants for 60, together with the illustrated NOE
interaction between Ha and Hd, proved that Ha and Hd were
both axial in 60. These results confirmed the 1,5-syn-relation-
ships for aldol adducts 49a (X ) Cl) and 53a (X ) F).
(26) Zhang, F.; Peng, Y.; Liao, S.; Gong, Y. Tetrahedron 2007, 63, 4636.
(27) Danishefsky, S.; Askin, D.; Angst, C. J. Org. Chem. 1987, 52, 622.
(28) Paquete, L. A. Encyclopedia of Reagents for Organic Synthesis; John
Wiley & Sons Ltd.: Chichester, 1995; p 4356.
(29) (a) Debenham, J. S.; Rodebaugh, R.; Frader-Reis, B. J. Org. Chem.
1997, 62, 4591. (b) Park, M. H.; Takeda, R.; Nakanishi, K. Tetrahedron Lett.
1987, 28, 3823.
6304 J. Org. Chem. Vol. 73, No. 16, 2008

1,5-Asymmetric Induction in Boron-Mediated Aldol Reactions
SCHEME 12. Preparation of ꢀ-Alkoxy Methylketones 37-41
SCHEME 13. Preparation of ꢀ-Alkoxy Methylketones 44
and 46
case of methylketone 46 (R ) TBS), a 50:50 mixture of 1,5-
anti-65 and 1,5-syn-66 aldol products was observed. These
results are in accordance with a stereoelectronic effect of the
ꢀ-alkoxy substituent playing a very important role in these aldol
addition reactions.
The relative stereochemistry for aldol adducts 63 was
ascertained after conversion of 63f to bicyclic derivative 69.
Reduction of 63f with Me4NBH(OAc)3 gave the corresponding
1,3-anti-diol 67 in 89% yield, which after removal of the Bn
protecting group with FeCl3 in CH2Cl2 provided triol 68 in 60%
yield (Scheme 19).29 Treatment of triol 68 with trimethy-
lorthoacetate and catalytic amounts of CSA in CH2Cl2 gave the
bicyclic derivative 69 in 63% yield.
SCHEME 14. Aldol Reactions of ꢀ-Alkoxy Methylketones
37 and 38
1
Analysis of the H NMR coupling constants for 69, specif-
ically JHa-Hd ) 12.0 Hz, JHa-Hf ) 4.0 Hz, JHd-Hb ) 5.0 Hz, JHc-
Hg ) 12.0 Hz, and JHc-He ) 3.2 Hz, JHb-Hf ) 10.0 Hz, JHb-Hg
)
3.0 Hz, and JHb-He ) 1.5 Hz, together with the illustrated NOE
interactions proved that Ha, Hc, Hd, and Hg are all axial
(Scheme 19). These results confirmed the 1,5-anti-relationships
for aldol adducts 63.
In order to assign the relative stereochemistry for aldol
adducts 47a (R ) Bn) and 51a (R ) Bn) obtained from
methylketones 37 and 40 (R ) Bn), respectively, we first treated
aldol 49a with HF in CH3CN/CH2Cl2 to give syn-diol 61 in
56% yield (Scheme 17). The mixture of syn- and anti-aldol
adducts 47a and 48a (R ) Bn) was submitted to hydrogenolysis
to give diol 61 as the major isomer. This diol was identical in
all respects with the 1,5-syn-diol 61 prepared from TBS removal
of 49a. This proved that the 1,5-syn-isomer is the major product
in the aldol reactions with both TBS and Bn protecting groups
at the ꢀ-oxygen of ꢀ-trichloromethyl methylketones 37 and 38.
Exactly the same strategy was applied for aldol adducts 53a
and 51a. Removal of the TBS protecting group in 53a and the
benzyl protecting group in 51a led to the same 1,5-syn-diol 62.
Again, this shows that the 1,5-syn-isomer is formed after aldol
reactions of ꢀ-alkoxy ꢀ-trifluoromethyl methylketones 40 (R
) Bn) and 41 (R ) TBS).
Transition State for the 1,5-anti- and 1,5-syn-Aldol
Reactions. Several computational studies indicate that chair-
like and boat-like transition states in boron-mediated aldol
reactions of methylketones are very close in energy.30–32
Recently, Paton and Goodman proposed that the aldol reactions
of boron enolates generated from ꢀ-alkoxy methylketones
proceed via boat-like transition states.30 They proposed also that
a stabilizing formyl hydrogen bond favors the 1,5-anti-aldol
adduct by minimizing steric interactions between the ꢀ-alkyloxy
substituent and one of the ligands on boron, with the magnitude
of this hydrogen bonding being determined by natural bond
orbital (NBO) analysis. In our case, due to the lower intrinsic
basicity of the oxygen with electron-withdrawing groups at the
ꢀ-position, this formyl hydrogen bonding is prevented. In
addition, the low levels of diastereoselectivity observed with a
ꢀ-OTBS and a ꢀ-Ot-Bu substituents led to the conclusion that
steric effects are playing a very important role.
The stereochemical outcome of these reactions with both TBS
and Bn protecting groups at the ꢀ-position seems to be controlled
mainly by the resident ꢀ-trichloromethyl and ꢀ-trifluoromethyl
substituents of boron enolates and tends to give the 1,5-syn-
isomer.
We believe that the main factor controlling the preference
for the 1,5-syn-isomer is a combination of steric effects and
Finally, enolization of methylketones 44 (R ) Bn) and 46
(R ) TBS) with (c-Hex)2BCl and Et3N in CH2Cl2 at room
temperature, followed by addition of aldehydes 10a, 10b, and
10f, proceeded smoothly, providing the corresponding aldol
adducts (Scheme 18, Table 5).
With methylketone 44 (R ) Bn), high levels of diastereo-
selectivity favoring the 1,5-anti-aldol 63 were obtained. In the
(30) Paton, R. S.; Goodman, J. M. Org. Lett. 2006, 8, 4299.
(31) (a) Paton, R. S.; Goodman, J. M. J. Org. Chem. 2008, 73, 1253. (b)
Stocker, B. L.; Teesdale-Spittle, P.; Hoberg, J. O. Eur. J. Org. Chem. 2004,
330.
(32) Several computational studies indicate that chair-like and boat-like
transiton states in methylketone aldol reactions are close in energy: (a) Li, Y.;
Paddon-Row, M. N.; Houk, K. N. J. Org. Chem. 1990, 55, 1535. (b) Bernardi,
F.; Robb, M. A.; Suzzi-Vall, G.; Tagliavini, E.; Trombin, C.; Umani-Ronchi,
A. J. Org. Chem. 1991, 56, 6472.
J. Org. Chem. Vol. 73, No. 16, 2008 6305

Dias et al.
TABLE 3. Aldol Reactions of 37 (R ) Bn) and 38 (R ) TBS) with R′CHO
entry
R (ketone)
aldehyde (R′)
10a, i-Pr
temp (°C)
dsa (1,5-syn:1,5-anti)
yield (%)b
1
Bn (37)
0
81:19 (47a:48a)
92:08 (47a:48a)
82:18 (49a:50a)
82:18 (49a:50a)
78:22 (47b:48b)
87:13 (47b:48b)
83:17 (49b:50b)
80:20 (47c:48c)
88:12 (47c:48c)
81:19 (49c:50c)
81:19 (49c:50c)
80:20 (47d:48d)
87:13 (47d:48d)
80:20 (49d:50d)
82:18 (49d:50d)
80:20 (49e:50e)
82:18 (47f:48f)
82:18 (49f:50f)
90:10 (47g:48g)
76
80
92
91
85
65
82
85
61
60
70
87
72
87
69
53
54
57
65
2
3
4
5
6
7
8
-78 to -20
TBS (38)
Bn (37)
0
-78 to -20
0
-78 to -20
0
10b, Ph
10c, Et
TBS (38)
Bn (37)
0
9
-78 to -20
10
11
12
13
14
15
16
17
18
19
TBS (38)
Bn (1)
0
-78 to -20
0
-78 to -20
0
-78 to -20
0
-78 to -20
-78 to -20
-78 to -20
10d, H2CdC(Me)
TBS (38)
TBS (38)
Bn (37)
TBS (38)
Bn (37)
10e, p-PhOMe
10f, p-PhNO2
10g,
a Ratio was determined by 1H NMR analysis of the diastereoisomeric mixture of adducts. b Isolated yields of the mixture of syn- and anti-isomers
after SiO2 flash chromatography.
SCHEME 15. Aldol Reactions of ꢀ-Alkoxy Methylketones
40 and 41
isomer is obtained with low levels of diastereoselectivity. These
results show that steric effects play a very important role in
these aldol reactions. The nature of the substituent at the
aromatic ring does not influence the stereochemical outcome
as p-OMe and p-NO2 lead to similar results.
Notably, we have observed that good levels of substrate-based
1,5-syn-stereocontrol could be achieved in the boron-mediated
aldol reactions of ꢀ-trichloromethyl and ꢀ-trifluoromethyl
methylketones with achiral aldehydes. Independent of the nature
of the ꢀ-protecting group (TBS or Bn), the 1,5-syn-diastereoi-
somer was always isolated as the major product. This result is
opposite to the 1,5-anti-stereoinduction observed for boron aldol
reactions of simple ꢀ-alkoxy methylketones, indicating the
overriding contribution in this special case from the substituent
at the ꢀ-position, which is a very strong electron-withdrawing
group. To the best of our knowledge, this is the first report of
boron-mediated aldol reactions of methylketones leading to the
1,5-syn-isomer with useful levels of diastereoselection, even with
a ꢀ-OBn substituent.5 These stereoselective aldol reactions
should prove valuable in polyketide syntheses, and we believe
they will allow synthetic chemists to confidently pursue more
aggressive convergent approaches toward assembling complex
polyacetate arrays in the synthesis of natural products.
TABLE 4. Aldol Reactions of 40 and 41 with R′CHO
entry R (ketone)
aldehyde (R′)
10a, i-Pr
dsa 1,5-syn:1,5-anti yield (%)b
1
2
3
4
5
6
7
8
9
Bn (40)
TBS (41)
Bn (40)
TBS (41)
Bn (40)
TBS (41)
Bn (40)
TBS (41)
Bn (40)
66:34 (51a:52a)
80:20 (53a:54a)
66:34 (51b:52b)
90:10 (53b:54b)
63:37 (51c:52c)
80:20 (53c:54c)
70
73
68
75
72
64
78
61
58
10b, Ph
10c, Et
10d, H2CdC(Me) 62:38 (51d:52d)
77:23 (53d:54d)
10e, p-PhOMe
65:35 (51e:52e)
a Ratio was determined by 1H NMR analysis of the diastereoisomeric
mixture of adducts. b Isolated yields of the mixture of syn- and
anti-isomers after SiO2 flash chromatography.
minimization of dipole moments in the corresponding boat-like
transition states A and B (Scheme 20). Transition state B is
favored for bulky substituents at the ꢀ-alkoxy oxygen, as well,
because it keeps the ꢀ-CCl3 and ꢀ-CF3 groups anti to the C-O
bond of the enolate and anti to the aldehyde CdO bond. In
transition state B, the aldehyde approaches from the side
Experimental Section
Preparation of (4RS)-4-(4-Methoxybenzyloxy)-4-(4-nitrophe-
nyl)butan-2-one (5): To a solution of 4 (1.00 g, 4.78 mmol) and
2,2,2-trichloroacetonitrile (2.02 g, 7.15 mmol) in Et2O (30 mL),
under argon atmosphere at 0 °C, was carefully added dropwise a
solution of 0.14 M triflic acid in Et2O (0.5 mL, 0.0683 mmol) and
warmed to room temperature. After 10 h, the reaction was quenched
with an aqueous solution 10% NaHCO3, and the aqueous phase
was extracted with Et2O. The organic phase was dried over MgSO4,
the solvent was removed under reduced pressure, and the resulting
oil was purified by flash chromatography (silica gel 200-400 mesh,
40% EtOAc in hexane), giving methyl ketone 5 in 64% yield (1.01
t
opposite to the OR group (R ) TBS, Bu), leading to the 1,5-
syn-isomer. Approach of the aldehyde from the same side of
t
the OR group (R ) TBS, Bu) as in transition state A should
be disfavored. Theoretical studies are underway in order to
clarify these issues.
Conclusions
1
g, 3.07 mmol): Rf 0.54 (40% EtOAc in hexane); H NMR (300
The use of boron enolates generated from ꢀ-aryl-ꢀ-alkoxy
methylketones in aldol reactions with achiral aldehydes gives
the corresponding 1,5-anti-products with high levels of diaste-
reoselectivity when the ꢀ-alkoxy substituent is a ꢀ-OPMB group.
In the case of ꢀ-OTBS and ꢀ-Ot-Bu susbtituents, the 1,5-syn-
MHz, CDCl3) δ 2.15 (s, 3H), 2.63 (dd, J ) 4.6, 16.5 Hz, 1H), 3.05
(dd, 1H, J ) 8.5, 16.5 Hz, 1H), 3.80 (s, 3H), 4.27 (d, J ) 11.0 Hz,
1H), 4.34 (d, J ) 11.0 Hz, 1H), 4.99 (dd, J ) 4.6, 8.5 Hz, 1H),
6.86 (d, J ) 8.5 Hz, 2H), 7.17 (d, J ) 8.5 Hz, 2H), 7.56 (d, J )
8.8 Hz, 2H), 8.23 (d, J ) 8.8 Hz, 2H); 13C NMR (75 MHz, CDCl3)
6306 J. Org. Chem. Vol. 73, No. 16, 2008

1,5-Asymmetric Induction in Boron-Mediated Aldol Reactions
SCHEME 16. Proof of Stereochemistry for Aldols 49a and 53a
SCHEME 17. Proof of Stereochemistry for Aldols 47a and 51a
SCHEME 18. Aldol Reactions of ꢀ-Alkoxy Methylketones 44 and 46
TABLE 5. Aldol Reactions of 44 and 46 with R′CHO
entry R (ketone) aldehyde (R′) dsa (1,5-anti:1,5-syn) Yield (%)b
The solution was filtered and the precipitated was washed with Et2O.
The solution was diluted with water, and the aqueous phase was
extracted with Et2O. The organic phase was dried over MgSO4,
the solvent was removed under reduced pressure, and the resulting
oil was purified by flash chromatography (silica gel 200-400 mesh,
30% EtOAc in hexanes), providing methylketone 6 in 92% yield
1
Bn (44)
Bn (44)
TBS (46)
Bn (44)
Bn (44)
10a, i-Pr
>95:05 (63a:64a)
75:25 (63a:64a)
50:50 (65a:66a)
94:06 (63b:64b)
78
66
73
64
67
2c
c d
,
3
4
5
10b, Ph
1
(1.43 g, 4,42 mmol): Rf 0.56 (30% EtOAc in hexane); H NMR
10f, p-PhNO2 >95:05 (63f:64f)
(300 MHz, CDCl3) δ -0.14 (s, 3H), 0.04 (s, 3H), 0.86 (s, 9H),
2.16 (s, 3H), 2.58 (dd, J ) 4.4, 15.8 Hz, 1H), 2.95 (dd, J ) 8.1,
15.8 Hz, 1H), 5.28 (dd, J ) 4.4, 8.1 Hz, 1H), 7.52 (d, J ) 8.8 Hz,
2H), 8.19 (d, J ) 8.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ -5.2,
-4.7, 18.1, 25.7, 31.8, 53.9, 70.7, 123.6, 126.5, 147.2, 151.9, 205.9;
IR νmax (film) 3060, 2931, 1718, 1608, 1523, 1348, 1263, 1089,
838; HRMS (ESI TOF-MS) calcd for C16H26NO4Si 324.1631; found
324.1627.
a Ratio was determined by 1H NMR analysis of the diastereoisomeric
mixture of adducts. b Isolated yields of the mixture of syn- and
anti-isomers after SiO2 flash chromatography. c Aldehyde addition was
performed at 0 °C. d Aldehyde addition at -78 °C led to the same
result.
δ 31.0, 51.6, 55.3, 71.2, 76.2, 113.8, 123.9, 127.4, 129.3, 129.5,
147.5, 149.0, 159.3, 205.2; IR νmax (film) 3485, 3392, 3055, 2958,
2842, 1720, 1612, 1515, 1418, 1348, 1265, 1175, 1093, 1034, 856,
73; HRMS (ESI TOF-MS) calcd for C18H19NO5Na 352.1161; found
352.1196.
Preparation of (4RS)-4-(tert-Butyldimethylsilyloxy)-4-(4-ni-
trophenyl)butan-2-one (6): To a solution of 4 (1.00 g, 4.78 mmol)
in DMF (15.4 mL), under argon atmosphere at room temperature,
was added 3.85 mL of pyridine (47.8 mmol) followed by AgNO3
(3.25 g, 19.1 mmol), waiting for the complete dissolution. Then,
TBSCl (2.88 g, 19.1 mmol) was added, leading to the precipitation
of a white solid (AgCl). The resulting mixture was stirred for 18 h.
(4RS)-4-(4-Methoxybenzyloxy)-4-(4-methoxyphenyl)butan-2-
one (8): To a solution of 7 (1.60 g, 8.24 mmol) and 4-methoxy-
benzyl 2,2,2-trichloroacetimidate (4.66 g, 16.5 mmol) in CH2Cl2
(25 mL), under argon atmosphere at 25 °C, was added CSA
(catalytic). After 7 h, the reaction was quenched by the addition of
10% aqueous NaHCO3, and the aqueous phase was extracted with
Et2O. The organic phase was dried over MgSO4, the solvent was
removed under reduced pressure, and the resulting oil was purified
by flash chromatography (silica gel 200-400 mesh, 40% EtOAc
in hexane), giving methylketone 8 in 57% yield (1.48 g, 4.70 mmol):
1
Rf 0.55 (40% EtOAc in hexane); H NMR (250 MHz, C6D6) δ
J. Org. Chem. Vol. 73, No. 16, 2008 6307

Dias et al.
SCHEME 19. Proof of Stereochemistry for Aldol 63f
SCHEME 20. Possible Transition States
dropwise (c-Hex)2BCl (2.0 equiv, 0.592 mmol). After this, Et3N
(2.5 equiv, 0.740 mmol) was added dropwise. The resulting mixture
was stirred for 30 min at 0 °C. The aldehyde (4.0 equiv, 1.18 mmol)
was added dropwise to the enolate solution at -78 °C, and the
resulting mixture was stirred for 3 h at -78 °C. The reaction was
quenched by addition of 3.0 mL of MeOH and warmed to room
temperature. The solvent was removed under reduced pressure, and
the resulting oil was purified by flash chromatography (silica gel
200-400 mesh), providing the aldol adducts.
(1SR,5SR)-1-(tert-Butyldimethylsilyloxy)-5-hydroxy-6-methyl-
1-(4-nitrophenyl)heptan-3-one (13a): Rf 0.50 (hexane:EtOAc:
1
CH2Cl2, 40:10:50); H NMR (250 MHz, C6D6) δ -0.19 (s, 3H),
0.07 (s, 6H), 0.83 (d, J ) 6.8 Hz, 3H), 0.89 (d, J ) 6.8 Hz, 3H),
0.90 (s, 9H), 1.42-1.62 (m, 1H), 1.99 (dd, J ) 3.5, 16.0 Hz, 1H),
2.17-2.25 (m, 2H), 2.51 (dd, J ) 9.0, 16.0 Hz, 1H), 2.61 (d, J )
3.3 Hz, 1H), 3.75-3.87 (m, 1H), 5.11 (dd, J ) 3.5, 9.0 Hz, 1H),
6.93 (d, J ) 8.9 Hz, 2H), 7.85 (d, J ) 8.9 Hz, 2H); 13C NMR
(62.5 MHz, C6D6) δ -5.1, -4.7, 17.7, 18.2, 18.5, 25.9, 33.4, 48.3,
53.7, 70.8, 71.9, 123.7, 126.4, 147.6, 151.5, 208.4; IR νmax (film)
3446, 3082, 2956, 1714, 1608, 1523, 1348, 1261, 1081, 838, 700;
HRMS (ESI TOF-MS) calcd for C20H34NO5Si 396.2206; found
396.2310.
1.72 (s, 3H), 2.31 (dd, J ) 4.6, 15.6 Hz, 1H), 2.83 (dd, 1H, J )
8.7, 15.6 Hz, 1H), 3.29 (s, 3H), 3.33 (s, 3H), 4.21 (d, J ) 11.1 Hz,
1H), 4.37 (d, J ) 11.1 Hz, 1H), 4.90 (dd, J ) 4.6, 8.7 Hz, 1H),
6.85-6.75 (m, 4H), 7.26-7.14 (m, 4H); 13C NMR (63 MHz, C6D6)
δ 30.6, 52.1, 54.8, 70.4, 77.3, 114.0, 114.3, 128.3, 129.6, 131.0,
134.0, 159.7, 159.9, 204.5; IR νmax (film) 3001, 2957, 2935, 2908,
2837, 1715, 1612, 1585, 1514, 1463, 1357, 1302, 1248, 1173, 1070,
1034, 835; HRMS (ESI TOF-MS) calcd for C19H22O4Na 337.1416;
found 337.1228.
(1SR,5RS)-1-(tert-Butyldimethylsilyloxy)-5-hydroxy-6-methyl-
1-(4-nitrophenyl)heptan-3-one (14a): Rf 0.63 (hexane:EtOAc:
(4RS)-4-(tert-Butyldimethylsilyloxy)-4-(4-methoxyphenyl)bu-
tan-2-one (9): To a solution of 7 (1.16 g, 5.97 mmol) in CH2Cl2
(15 mL), under argon atmosphere at 25 °C, was added TBSCl (1.08
g, 7.16 mmol) followed by imidazole (0.569 g, 8.36 mmol), waiting
for the complete dissolution. The resulting mixture was stirred for
24 h. The solution was diluted with water, and the aqueous phase
was extracted with Et2O. The organic phase was dried over MgSO4,
the solvent was removed under reduced pressure, and the resulting
oil was purified by flash chromatography (silica gel 200-400 mesh,
20% EtOAc in hexanes), providing methylketone 9 in 92% yield
1
CH2Cl2, 40:10:50); H NMR (250 MHz, C6D6) δ -0.19 (s, 3H),
0.07 (s, 6H), 0.83 (d, J ) 6.7 Hz, 3H), 0.88 (d, J ) 6.7 Hz, 3H),
0.91 (s, 9H), 1.40-1.60 (m, 1H), 2.02 (dd, J ) 3.6, 16.0 Hz, 1H),
2.06 (dd, J ) 2.5, 17.1 Hz, 1H), 2.28 (dd, J ) 9.6, 17.1 Hz, 1H),
2.54 (dd, J ) 8.8, 16.0 Hz, 1H), 2.72 (d, J ) 3.5 Hz, 1H),
3.66-3.77 (m, 1H), 5.12 (dd, J ) 3.6, 8.8 Hz, 1H), 6.96 (d, J )
8.5 Hz, 2H), 7.86 (d, J ) 8.9 Hz, 2H); 13C NMR (62.5 MHz, C6D6)
δ -5.1, -4.7, 17.6, 18.2, 18.6, 25.9, 33.4, 48.4, 53.5, 70.8, 72.1,
123.7, 126.5, 147.6, 151.6, 208.6; IR νmax (film) 3465, 3077, 2958,
2858, 1708, 1608, 1523, 1348, 1253, 1081, 838; HRMS (ESI TOF-
MS) calcd for C20H34NO5Si 396.2206; found 396.2310.
1
(1.69 g, 5.49 mmol): Rf 0.58 (20% EtOAc in hexane); H NMR
(250 MHz, C6D6) δ -0.06 (s, 3H), 0.14 (s, 3H), 0.96 (s, 9H), 1.72
(s, 3H), 2.24 (dd, J ) 4.1, 15.4 Hz, 1H), 2.73 (dd, J ) 8.7, 15.4
Hz, 1H), 3.29 (s, 3H), 5.24 (dd, J ) 4.1, 8.7 Hz, 1H), 6.80 (d, J )
8.7 Hz, 2H), 7.19 (d, J ) 8.7 Hz, 2H); 13C NMR (63 MHz, C6D6)
δ -4.93, -4.48, 18.4, 26.0, 31.2, 54.3, 54.7, 71.8, 114.0, 127.3,
128.3, 137.1, 159.5, 204.9; IR νmax (film) 3001, 2957, 2932, 2897,
2856, 1719, 1612, 1514, 1472, 1362, 1304, 1250, 1173, 1084, 1038,
1005, 868, 837, 779; HRMS (ESI TOF-MS) calcd for C17H28O3SiNa
331.1705; found 331.1543.
(1SR,3SR,5SR)-1-(4-Methoxybenzyloxy)-6-methyl-1-(4-nitro-
phenyl)heptan-3,5-diol (15): Acetic acid (1 mL) was added to a
stirring suspension of Me4NHB(OAc)3 (0.758 g, 2.88 mmol) in
acetonitrile (1 mL) at room temperature. The resulting mixture was
stirred for 30 min and after was cooled to -40 °C. The aldol adduct
11a (0.145 g, 0.360 mmol) in acetonitrile (1 mL) was added
dropwise. After 1 min, a solution of CSA (0.041 g, 0.18 mmol),
acetic acid (1 mL), and acetonitrile (1 mL) was added and the
mixture was stirred for 18 h at -22 °C. The reaction was quenched
by addition of a sodium bicarbonate aqueous solution (25 mL)
followed by addition of potassium tartarate aqueous solution (25
Representative Procedure for Methylketone Aldol Reactions.
To a solution of the corresponding methylketone (0.296 mmol) in
CH2Cl2 (3.7 mL), under argon atmosphere at -10 °C, was added
6308 J. Org. Chem. Vol. 73, No. 16, 2008

1,5-Asymmetric Induction in Boron-Mediated Aldol Reactions
mL) and Et2O (50 mL), stirring vigorously at room temperature
for 8 h. The organic phase was separated, and the aqueous phase
was extracted four times with Et2O. The organic phase was
combinated and dried over MgSO4. The solvent was removed under
reduced pressure, and the resulting oil was purified by flash column
chromatography (silica gel 200-400 mesh, hexane:EtOAc:CH2Cl2,
20:5:75) giving 15 (54%, 0.0787 g, 0.195 mmol) as a yellow oil in
>95:5 diastereoseletivity: Rf 0.41 (hexane:EtOAc:CH2Cl2, 5:20:
hexane) gave 18 as a yellow oil (36%, 9.2 mg, 3.3 mmol): Rf 0.23
(hexane:EtOAc:CH2Cl2, 5:20:75); H NMR (250 MHz, CDCl3) δ
1
0.77 (d, J ) 6.8 Hz, 3H), 0.83 (d, J ) 6.8 Hz, 3H), 1.32-1.52 (m,
1H), 1.95 (dd, J ) 2.5, 16.4 Hz, 1H), 2.07 (dd, J ) 3.0, 17.2 Hz,
1H), 2.16 (dd, J ) 8.1, 16.4 Hz, 1H), 2.26 (dd, J ) 9.5, 17.2 Hz,
1H), 2.45 (d, J ) 2.5 Hz, 1H), 3.24 (d, J ) 3.0 Hz, 1H), 3.62-3.73
(m, 1H), 4.82-4.92 (m, 1H), 6.97 (d, J ) 8.4 Hz, 2H), 7.90 (d, J
) 8.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 17.5, 18.4, 33.6,
47.2, 51.7, 68.8, 72.2, 123.6, 126.3, 147.6, 150.3, 210.5; IR νmax
(film) 3425, 2962, 1704, 1606, 1519, 1348, 1064, 856, 750, 702;
HRMS (ESI TOF-MS) calcd for C14H19NO5Na 304.1161; found
304.1218.
Method 2: 13a (24.1 mg, 0.0609 mmol) was dissolved in 1.5
mL of 4:1 CH3CN:CH2Cl2 at room temperature, and four drops of
48% aqueous HF were added. After 20 h, 5 mL of saturated aqueous
NaHCO3 was added to quench and the mixture was extracted with
four 10 mL portions of CH2Cl2. The combined organic extracts
were dried over anhydrous Na2SO4 and concentrated in vacuo.
Purification by flash chromatography (silica gel 200-400 mesh,
50% EtOAc in hexane) gave 15 as a yellow oil (95%, 16.3 mg,
0.0579 mmol).
(1SR,5SR)-1,5-Dihydroxy-6-methyl-1-(4-nitrophenyl)heptan-
3-one (18) and (1SR,5RS)-1,5-Dihydroxy-6-methyl-1-(4-nitro-
phenyl)heptan-3-one (19): A solution of a mixture of 30a and
31a (0.0200 g, 0.0590 mmol) in anhydrous CH2Cl2 (0.5 mL) at 0
°C was treated with 1.5 equiv of TiCl4 (0.01 mL, 0.09 mmol). After
2 min, 1 mL of saturated aqueous solution of NH4Cl and 5 mL of
Et2O were added. The aqueous phase was extracted, and the organic
extracts were dried over anhydrous MgSO4 and concentrated in
vacuo. Purification by flash chromatography (silica gel 200-400
mesh, hexane:EtOAc:CH2Cl2, 20:5:75) gave 18 (minor isomer) and
19 (major isomer) as colorless oils (63%, 0.0104 g, 0.0370 mmol):
Rf 0.17 (hexane:EtOAc:CH2Cl2, 20:5:75).
(1SR,5RS)-1,5-Dihydroxy-6-methyl-1-(4-nitrophenyl)heptan-
3-one (19): 14a (30.1 mg, 0.0761 mmol) was dissolved in 1.5 mL
of 4:1 CH3CN:CH2Cl2 at room temperature, and four drops of 48%
aqueous HF were added. After 20 h, 5 mL of saturated aqueous
NaHCO3 was added to quench and the mixture was extracted with
four 10 mL portions of CH2Cl2. The combined organic extracts
were dried over anhydrous Na2SO4 and concentrated in vacuo.
Purification by flash chromatography (silica gel 200-400 mesh,
50% EtOAc in hexane) gave 19 as a yellow oil (93%, 19.9 mg,
0.0708 mmol): Rf 0.15 (hexane:EtOAc:CH2Cl2, 5:20:75); 1H NMR
(300 MHz, CDCl3) δ 0.78 (d, J ) 6.8 Hz, 3H), 0.83 (d, J ) 6.8
Hz, 3H), 1.35-1.54 (m, 1H), 1.96 (dd, J ) 2.5, 16.5 Hz, 1H),
2.07 (dd, J ) 2.9, 17.2 Hz, 1H), 2.20 (dd, J ) 9.9, 16.5 Hz, 1H),
2.33 (dd, J ) 9.6, 17.2 Hz, 1H), 2.59 (s, 1H), 3.38 (s, 1H), 3.68
(ddd, J ) 2.5, 5.4, 9.7 Hz, 1H), 4.89 (dd, J ) 2.5, 9.5 Hz, 1H),
6.99 (d, J ) 8.4 Hz, 2H), 7.90 (d, J ) 8.8 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 17.5, 18.4, 33.6, 47.4, 51.9, 69.0, 72.5, 123.6, 126.3,
147.6, 150.3, 210.7; IR νmax (film) 3384, 3072, 2962, 1716, 1598,
1517, 1342, 1056, 854, 748; HRMS (ESI TOF-MS) calcd for
C14H19NO5Na 304.1161; found 304.1218.
1
75); H NMR (300 MHz, C6D6) δ 0.87 (d, J ) 6.7 Hz, 3H), 0.96
(d, J ) 6.7 Hz, 3H), 1.33-1.46 (m, 2H), 1.50-1.66 (m, 2H), 1.97
(dt, J ) 9.6, 14.4 Hz, 1H), 2.69 (brs, 1H), 3.31 (s, 3H), 3.65-3.75
(m, 1H), 3.81 (brs, 1H), 3.90 (d, J ) 11.2 Hz, 1H), 4.01-4.11 (m,
1H), 4.13 (d, J ) 11.2 Hz, 1H), 4.40 (dd, J ) 4.2, 9.6 Hz, 1H),
6.80 (d, J ) 8.5 Hz, 2H), 6.93 (d, J ) 8.8 Hz, 2H), 7.08 (d, J )
8.5 Hz, 2H), 7.90 (d, J ) 8.8 Hz, 2H).
(SR)-1-((2SR,4SR,6SR)-2-(4-Methoxyphenyl)-6-(4-nitrophenyl)-
1,3-dioxan-4-yl)-3-methylbutan-2-ol (16): Diol 15 (0.0580 g,
0.144 mmol) was dissolved in CH2Cl2 (2 mL), under argon
atmosphere, followed by addition of powdered dry 4 Å molecular
sieves (0.060 g). The solution was cooled to -10 °C, DDQ (0.0390
g, 0.173 mmol) was added, and the solution was stirred for 1.5 h
at 0 °C. The resulting mixture was diluted with Et2O and poured
onto a pad of silica gel (200-400 mesh). The pad was washed
repeatedly with CH2Cl2. The solvent was removed under reduced
pressure, and the resulting oil was purified by flash chromatography
(silica gel 200-400 mesh, hexane:EtOAc:CH2Cl2, 20:5:75), giving
acetal 16 (83%, 0.0480 g, 0.120 mmol) as yellow oil: Rf 0.44
1
(hexane:EtOAc:CH2Cl2, 15:10:75); H NMR (300 MHz, CDCl3)
δ 0.85 (d, J ) 6.7 Hz, 3H), 0.91 (d, J ) 6.7 Hz, 3H), 1.25 (dt, J
) 2.6, 13.0 Hz, 1H), 1.34-1.66 (m, 5H), 3.28 (s, 3H), 3.70 (ddd,
J ) 2.0, 5.1, 9.9 Hz, 1H), 4.03 (ddt, J ) 2.7, 8.4, 11.2 Hz, 1H),
4.40 (dd, J ) 2.5, 11.2 Hz, 1H), 5.54 (s, 1H), 6.87 (d, J ) 8.7 Hz,
2H), 7.04 (d, J ) 8.7 Hz, 2H), 7.62 (d, J ) 8.7 Hz, 2H), 7.91 (d,
J ) 8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 17.4, 18.7, 34.4,
39.1, 40.1, 54.8, 72.1, 74.4, 77.5, 101.4, 113.9, 123.6, 126.3, 127.7,
127.9, 131.6, 148.8, 160.7; IR νmax (film) 3487, 3082, 2958, 1614,
1517, 1348, 1249, 1110, 1010, 831, 698; HRMS (ESI TOF-MS)
calcd for C22H28NO6 402.1917; found 402.1845.
(4SR,6SR)-4-((SR)-2-(4-Methoxybenzyloxy)-2-(4-nitrophenyl-
)ethyl)-6-isopropyl-2,2-dimethyl-1,3-dioxane (17): The diol 15
(0.0207 g, 0.0513 mmol) was dissolved in 2,2-dimethoxypropane
(1 mL), followed by addition of CSA dissolved in 2,2-dimethox-
ypropane (1 mL) at room temperature and under argon atmosphere
and was stirred for 18 h. The resulting mixture was diluted with
Et2O. The solvent was removed under reduced pressure, and the
resulting oil was purified by flash chromatography (silica gel
200-400 mesh, hexane:EtOAc:CH2Cl2, 20:5:75) giving 17 (77%,
0.0175 g, 0.0395 mmol) as a colorless oil: Rf 0.80 (Hexane:EtOAc:
CH2Cl2, 20:5:75); 1H NMR (300 MHz, CDCl3) δ 0.79 (d, J ) 6.6
Hz, 3H), 0.87 (d, J ) 6.6 Hz, 3H), 1.23 (s, 3H), 1.31 (s, 3H),
1.40-1.57 (m, 3H), 1.74 (ddd, J ) 4.8, 8.0, 12.8 Hz, 1H), 2.20
(ddd, J ) 6.4, 8.7, 13.9 Hz, 1H), 3.37 (dt, J ) 7.2, 14.4 Hz, 1H),
3.45-3.56 (m, 1H), 3.79 (s, 3H), 4.19 (d, J ) 11.1 Hz, 1H), 4.30
(d, J ) 11.1 Hz, 1H), 4.57 (d, J ) 6.5, 7.8 Hz, 1H), 6.85 (d, J )
8.5 Hz, 2H), 7.17 (d, J ) 8.5 Hz, 2H), 7.52 (d, J ) 8.8 Hz, 2H),
8.23 (d, J ) 8.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 17.5,
18.7, 24.3, 25.0, 32.9, 36.2, 44.0, 55.3, 63.3, 70.6, 71.4, 77.1, 100.2,
113.8, 123.7, 128.0, 129.5, 129.7, 147.6, 149.7, 159.3; IR νmax (film)
3054, 2987, 1610, 1523, 1348, 1265, 1033, 740; HRMS (ESI TOF-
MS) calcd for C25H33NO6Na 466.2206; found 466.2124.
(1SR,3SR,5SR)-1-(4-Methoxybenzyloxy)-6-methyl-1-(4-meth-
oxyphenyl)heptan-3,5-diol (24): Acetic acid (1 mL) was added
to a stirring suspension of Me4NHB(OAc)3 (0.577 g, 2.19 mmol)
in acetonitrile (1 mL) at room temperature. The resulting mixture
was stirred for 30 min and was cooled to -40 °C. The aldol adduct
20a (0.106 g, 0.274 mmol) in acetonitrile (1 mL) was added
dropwise. After 1 min, a solution of CSA (0.031 g, 0.14 mmol),
acetic acid (1 mL), and acetonitrile (1 mL) was added and the
mixture was stirred for 18 h at -22 °C. The reaction was quenched
by addition of a saturated aqueous solution of sodium bicarbonate
(25 mL) followed by addition of a potassium tartarate aqueous
solution (25 mL) and Et2O (50 mL), stirring vigorously at room
temperature for 8 h. The organic phase was separated, and the
aqueous phase was extracted four times with Et2O. The organic
phase was combined and dried over MgSO4. The solvent was
removed under reduced pressure, and the resulting oil was purified
(1SR,5SR)-1,5-Dihydroxy-6-methyl-1-(4-nitrophenyl)heptan-
3-one (18): Method 1: To a stirred solution of PMB ether 11a
(36.1 mg, 0.0899 mmol) in CH2Cl2 (1 mL) and H2O (0.10 mL) at
0 °C was added DDQ (20.1 mg, 0.0910 mmol). After 2.5 h at 0
°C, the solution was warmed to room temperature and stirred for
an additional 30 min. The reaction mixture was partitioned with
saturated aqueous NaHCO3 (4 mL) and extracted with CH2Cl2 (3
× 8 mL). The combined organic extracts were dried over MgSO4.
Flash chromatography (silica gel 200-400 mesh, 50% EtOAc in
J. Org. Chem. Vol. 73, No. 16, 2008 6309

Dias et al.
by flash column chromatography (silica gel 200-400 mesh, hexane:
EtOAc:CH2Cl2, 20:5:5) giving 24 (52%, 0.0556 g, 0.143 mmol) as
a yellow oil in >95:5 diastereoseletivity: Rf 0.45 (hexane:EtOAc:
(1SR,5RS)-1,5-Dihydroxy-6-methyl-1-(4-methoxyphenyl)hep-
tan-3-one (27): A solution of 23a (0.0626 g, 0.165 mmol) in
anydrous THF (8.5 mL) at room temperature was treated with a
solution of TBAF/AcOH (1:1, 1 M in THF, 1.65 mL, 1.65 mmol).
After 7 days, 20 mL of saturated aqueous solution of NaHCO3, 20
mL of saturated aqueous solution of potassium/sodium tartarate,
and 100 mL of Et2O were added. This solution was vigorously
stirred for 8 h. The organic extracts were dried over anhydrous
MgSO4 and concentrated in vacuo. Purification by flash chroma-
tography (silica gel 200-400 mesh, 50% EtOAc in hexane) gave
27 as a yellow oil (45%, 0.0198 g, 0.0743 mmol): Rf 0.22 (hexane:
1
CH2Cl2, 5:20:75); H NMR (250 MHz, C6D6) δ 0.90 (d, J ) 6.8
Hz, 3H), 1.01 (d, J ) 6.8 Hz, 3H), 1.73-1.38 (m, 4H), 2.21 (dt, J
) 10.0, 14.6 Hz, 1H), 3.11 (brs, 1H), 3.29 (s, 3H), 3.35 (s, 3H),
3.83-3.74 (m, 1H), 4.06 (d, J ) 11.3 Hz, 1H), 4.30-4.15 (m,
2H), 4.32 (d, J ) 11.3 Hz, 1H), 4.44 (dd, J ) 3.2, 10.0 Hz, 1H),
6.77 (d, J ) 8.8 Hz, 2H), 6.84 (d, J ) 8.7 Hz, 2H), 7.19-7.10 (m,
4H); 13C NMR (63 MHz, C6D6) δ 18.1, 18.9, 34.4, 40.4, 45.5, 54.75,
54.84, 70.0, 70.2, 73.3, 81.9, 114.3, 114.4, 128.3, 129.8, 130.2,
134.0, 159.9, 160.0; IR νmax (film) 3449, 2955, 2872, 2837, 1614,
1585, 1514, 1464, 1302, 1248, 1173, 1072, 1034, 833, 737; HRMS
(ESI TOF-MS) calcd for C23H32O5Na 411.2148; found 411.2113.
1
EtOAc:CH2Cl2, 5:20:75); H NMR (250 MHz, C6D6) δ 0.82 (d, J
) 6.8 Hz, 3H), 0.88 (d, J ) 6.8 Hz, 3H), 1.61-1.43 (m, 1H),
2.10-1.98 (m, 1H), 2.42-2.27 (m, 2H), 2.81-2.66 (m, 1H), 3.33
(s, 3H), 4.12-3.09 (br, 2H), 3.84-3.73 (m, 1H), 5.19-5.10 (m,
1H), 6.83 (d, J ) 8.8 Hz, 2H), 7.27 (d, J ) 8.8 Hz, 2H); 13C NMR
(63 MHz, C6D6) δ 17.7, 18.6, 33.6, 47.7, 52.9, 54.8, 69.9, 72.4,
114.1, 127.3, 136.2, 159.6, 211.5; IR νmax (film) 3414, 2961, 2916,
1707, 1612, 1514, 1466, 1387, 1304, 1248, 1177, 1034, 833; HRMS
(ESI TOF-MS) calcd for C15H22O4Na 289.1416; found 289.1276.
(4RS)-4-tert-Butoxy-4-(4-nitrophenyl)butan-2-one (28): To a
solution of 4 (3.30 g, 15.8 mmol) and 4-tert-butoxy-2,2,2-
trichloroacetimidate (6.90 g, 31.6 mmol) in CH2Cl2 (35 mL), under
argon atmosphere at 25 °C, was added CSA (catalytic). After 15 h,
the reaction was quenched with 10% NH4Cl aqueous solution and
the aqueous phase was extracted with Et2O. The organic phase was
dried over MgSO4, the solvent was removed under reduced pressure,
and the resulting oil was purified by flash chromatography (silica
gel 200-400 mesh, 40% EtOAc in hexane), giving methyl ketone
28 in 23% yield (0.964 g, 3.63 mmol): Rf 0.70 (40% EtOAc in
(SR)-1-((2SR,4SR,6SR)-2-(4-Methoxyphenyl)-6-(4-methox-
yphenyl)-1,3-dioxan-4-yl)-3-methylbutan-2-ol (25): Diol 24 (0.0427
g, 0.109 mmol) was dissolved in CH2Cl2 (1.5 mL), under argon
atmosphere, followed by addition of powdered dry 4 Å molecular
sieves (0.046 g). The solution was cooled to -10 °C, DDQ (0.0290
g, 0.130 mmol) was added, and the solution was stirred for 1.5 h
at 0 °C. The resulting mixture was diluted with Et2O and poured
onto a pad of silica gel (200-400 mesh). The pad was washed
repeatedly with CH2Cl2. The solvent was removed under reduced
pressure, and the resulting oil was purified by flash chromatography
(silica gel 200-400 mesh, hexane:EtOAc:CH2Cl2, 20:5:75) giving
acetal 25 (25%, 0.0106 g, 0.0274 mmol) as yellow oil: Rf 0.32
1
(Hexane:EtOAc:CH2Cl2, 15:10:75); H NMR (500 MHz, CDCl3)
δ 0.86 (d, J ) 6.7 Hz, 3H), 0.93 (d, J ) 6.7 Hz, 3H), 1.43 (dt, J
) 2.2, 13.1 Hz, 1H), 1.58-1.48 (m, 2H), 1.62 (ddd, J ) 2.2, 8.2,
14.5 Hz, 1H), 1.82-1.73 (m, 2H) 3.26 (s, 3H), 3.33 (s, 3H),
3.77-3.72 (m, 1H), 4.07 (ddt, J ) 2.7, 8.4, 11.1 Hz, 1H), 4.62
(dd, J ) 2.5, 11.3 Hz, 1H), 5.64 (s, 1H), 6.83 (d, J ) 8.6 Hz, 2H),
6.87 (d, J ) 8.6 Hz, 2H), 7.34 (d, J ) 8.8 Hz, 2H), 7.67 (d, J )
8.8 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 17.6, 18.8, 34.4, 39.5,
40.1, 54.7, 54.8, 72.2, 74.7, 78.6, 101.5, 113.8, 114.0, 127.5, 128.3,
132.2, 159.7, 160.4; IR νmax (film) 3530, 2959, 2874, 2837, 1614,
1516, 1466, 1302, 1250, 1173, 1101, 1034, 829; HRMS (ESI TOF-
MS) calcd for C23H30O5Na 409.1991; found 409.1892.
(1SR,5SR)-1,5-Dihydroxy-6-methyl-1-(4-methoxyphenyl)hep-
tan-3-one (26): Method 1: To a stirred solution of PMB ether 20a
(0.128 g, 0.331 mmol) in CH2Cl2 (3.7 mL) and H2O (0.5 mL) at 0
°C was added DDQ (0.0788 mg, 0.347 mmol). After 2.5 h at 0 °C,
the solution was warmed to room temperature. The reaction mixture
was partitioned with saturated aqueous NaHCO3 (4 mL) and
extracted with CH2Cl2. The combined organic extracts were dried
over MgSO4. Flash chromatography (silica gel 200-400 mesh, 50%
EtOAc in hexane) gave 26 as a yellow oil (38%, 0.0335 g, 0.126
mmol).
1
hexane); H NMR (250 MHz, C6D6) δ 0.95 (s, 9H), 1.68 (s, 3H),
1.90 (dd, J ) 4.1, 15.7 Hz, 1H), 2.45 (dd, J ) 8.7, 15.7 Hz, 1H),
4.89 (dd, J ) 4.1, 8.5 Hz, 1H), 6.96 (d, J ) 8.7 Hz, 2H), 7.83 (d,
J ) 8.7 Hz, 2H); 13C NMR (63 MHz, C6D6) δ 28.5, 31.2, 52.3,
70.2, 74.9, 123.6, 126.7, 147.3, 153.2, 204.1; IR νmax (film) 2974,
2931, 1705, 1599, 1518, 1346, 1190, 1163, 1065, 1011, 845, 750,
698.
(4RS)-4-(Benzyloxy)pentan-2-one (44): NaH, 60% in mineral
oil (1.628 g, 40.7 mmol) was suspended in dry THF (50 mL) under
argon atmosphere at room temperature. Diol 42 (2.0 mL, 18.5
mmol) was added dropwise, and the suspension was stirred for 30
min. After, BnBr (2.2 mL, 18.5 mmol) and a catalytic amount of
TBAI (50 mg) were added, and the reaction was refluxed over 18 h.
The mixture was poured into water (20 mL), the layers were
separated, and the aqueous layer was extracted with EtOAc (3 ×
30 mL). The combined organic extracts were washed with brine
(30 mL), dried (MgSO4), and the solvent removed in vacuo.
Purification by flash column chromatography (30% EtOAc in
hexane) afforded compound 43 (2.41 g) as a colorless oil. 43 (2.41
g, 12.4 mmol) was dissolved in CH2Cl2 (40 mL) under argon
atmosphere, PCC (5.36 g, 24.9 mmol) was added, and the
suspension was stirred at room temperature overnight. The solid
was removed by filtration in silica, and the solution was concen-
trated in vacuo. Purification by flash chromatography (20% EtOAc
in hexane) afforded the compound 44 (2.26 g) as colorless oil in
Method 2: A solution of 22a (0.0286 g, 0.165 mmol) in
anhydrous THF (4.0 mL) at room temperature was treated with a
solution of TBAF/AcOH (1:1, 1 M in THF, 0.75 mL, 0.752 mmol).
After 7 days, 20 mL of saturated aqueous solution of NaHCO3, 20
mL of saturated aqueous solution of potassium/sodium tartarate,
and 100 mL of Et2O were added. This solution was strongly stirred
for 8 h. The organic extracts were dried over anhydrous MgSO4
and concentrated in vacuo. Purification by flash chromatography
(silica gel 200-400 mesh, 50% EtOAc in hexane) gave 26 as a
yellow oil (65%, 0.0492 g, 0.0492 mmol): Rf 0.28 (hexane:EtOAc:
1
63% to two steps: H NMR (250 MHz, C6D6) δ 7.33-7.20 (m,
5H), 4.51 (d, J ) 11.5 Hz, 1H), 4.39 (d, J ) 11.5 Hz, 1H), 4.04
(m, 1H), 2.74 (dd, J ) 16.0, 7.3 Hz, 1H), 2.42 (dd, J ) 16.0, 5.5
Hz, 1H), 2.10 (s, 3H), 1.18 (d, J ) 6.3 Hz, 3H); 13C NMR (62.5
MHz, C6D6) δ 207.4, 138.4, 128.3, 127.7, 127.5, 71.5, 70.8, 50.7,
31.0, 19.8; IR νmax (film) 3066, 3031, 2972, 2930, 1714, 1450, 1373,
1171, 1135, 1092, 949.
1
CH2Cl2, 5:20:75); H NMR (250 MHz, C6D6) δ 0.80 (d, J ) 6.8
Hz, 3H), 0.87 (d, J ) 6.8 Hz, 3H), 1.48 (octet, J ) 6.7 Hz, 1H),
2.05 (ddd, J ) 1.3, 2.7, 16.7 Hz, 1H), 2.21 (ddd, J ) 1.6, 9.8, 16.7
Hz, 1H), 2.32 (ddd, J ) 1.3, 3.0, 16.7 Hz, 1H), 2.60 (ddd, J ) 1.9,
9.5, 16.7 Hz, 1H), 3.41-2.81 (brs, 2H), 3.33 (s, 3H), 3.74 (dddd,
J ) 1.2, 2.5, 5.4, 8.1 Hz, 1H), 5.09 (dd, J ) 2.7, 9.5 Hz, 1H), 6.82
(d, J ) 8.8 Hz, 2H), 7.23 (d, J ) 8.8 Hz, 2H); 13C NMR (63 MHz,
C6D6) δ 17.7, 18.6, 33.5, 47.5, 52.5, 54.8, 69.8, 72.1, 114.1, 127.2,
136.0, 159.6, 211.4; IR νmax (film) 3329, 2961, 2916, 2849, 1705,
1612, 1514, 1464, 1385, 1302, 1248, 1177, 1034, 833.
(4RS)-4-(tert-Butyldimethylsilyloxy)pentan-2-one (46): A mix-
ture of TBSOTf (2.71 mL, 11.75 mmol) and 2,6-lutidine (2.81 mL,
24.1 mmol) in CH2Cl2 was added dropwise to a cooled at -78 °C
solution of diol 42 (1.2 g, 11.5 mmol) in CH2Cl2 (85 mL) under
argon atmosphere. The reaction was stirred at -78 °C for 1 h. After
this time, MeOH (0.5 mL) was added and the mixture was allowed
to warm to room temperature. The mixture was washed with water
6310 J. Org. Chem. Vol. 73, No. 16, 2008

1,5-Asymmetric Induction in Boron-Mediated Aldol Reactions
(30 mL) and brine (30 mL) and dried (MgSO4), and the solvent
was removed in vacuo. Purification by flash column chromatography
(30% EtOAc in hexane) afforded compound 45 (1.26 g) as a
colorless oil. 45 (1.26 g, 5.77 mmol) was dissolved in CH2Cl2 under
argon atmosphere, PCC (3.12 g, 17.3 mmol) and anhydrous NaOAc
(3.55 g, 43.25 mmol) were added, and the suspension was stirred
at room temperature overnight. The solid was removed by filtration
in silica, and the solution was concentrated in vacuo. Purification
by flash chromatography (20% EtOAc in hexane) afforded the
compound 44 (1.10 g) as colorless oil in 44% yield in two steps:
1H NMR (250 MHz, C6D6) δ 4.27 (m, 1H), 2.64 (dd, J ) 15.0, 7.3
Hz, 1H), 2.41 (dd, J ) 15.0, 5.3 Hz, 1H), 2.15 (s, 3H), 1.16 (d, J
) 6.3 Hz, 3H), 0.86 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H); 13C NMR
(62.5 MHz, C6D6) δ 208.1, 65.6, 53.1, 31.7, 25.8, 24.0, 17.9, -4.5,
-5.0; IR νmax (film) 2960, 2930, 2858, 1720, 1473, 1367, 1255,
1134, 1081, 1022, 902.
Acknowledgment. We are grateful to FAPESP and CNPq
for financial support. We also thank Prof. Carol H. Collins
(Institute of Chemistry, UNICAMP) for helpful suggestions
about English grammar and style.
Supporting Information Available: Product characterization
for the compounds prepared. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO8009165
J. Org. Chem. Vol. 73, No. 16, 2008 6311