Synthesis of O-benzyl protected anti aldols through the cross-coupling reaction of dibenzyl acetals with a chiral titanium enolate

Article abstract of DOI:10.1055/s-2003-39891

Addition of the chiral titanium enolate arising from 1 to dibenzyl acetals gives access to anti-β-benzyloxy-α-methyl carboxylic adducts in good yields and with diastereomeric ratios up to 99:1. These adducts can be easily converted into a plethora of enantiopure protected derivatives.

Full text of DOI:10.1055/s-2003-39891

LETTER
1109
Synthesis of O-Benzyl Protected anti Aldols through the Cross-Coupling
Reaction of Dibenzyl Acetals with a Chiral Titanium Enolate
Synthesis of
O-Be
n
nzyl
P
rotecte
a
d
anti
A
ldo
b
ls el Cosp, Igor Larrosa, Irina Vilasís, Pedro Romea,* Fèlix Urpí,* Jaume Vilarrasa
Departament de Química Orgànica, Universitat de Barcelona, Martí i Franqués 1-11, 08028 Barcelona, Catalonia, Spain
Fax +34(93)3397878; E-mail: promea@qo.ub.es; E-mail: furpi@qo.ub.es
Received 7 April 2003
versely, the use of SnCl4 allowed us to obtain the anti ad-
ducts 2 more satisfactorily (see entries 1–3 in Table 1).
Abstract: Addition of the chiral titanium enolate arising from 1 to
dibenzyl acetals gives access to anti-b-benzyloxy-a-methyl carbox-
ylic adducts in good yields and with diastereomeric ratios up to
99:1. These adducts can be easily converted into a plethora of enan-
tiopure protected derivatives.
The more reluctant isobutyraldehyde derived acetals d–f
were next evaluated. After a comprehensive analysis of
the experimental conditions, it was found that high yields
and diastereoselectivities can be achieved using SnCl4 as
the Lewis acid if two equivalents of the enolate are em-
ployed (see entries 4–6 in Table 1).
Key words: acetals, aldol reactions, chiral auxiliaries, stereoselec-
tive reactions, titanium enolates
Unfortunately, the diastereoselectivity was slightly erod-
ed and the yield was occasionally unsatisfactory when di-
allyl acetals rather than dimethyl or dibenzyl acetals were
used (see entries 3 and 5 in Table 1), probably due to the
poor stability of the corresponding oxocarbenium inter-
mediate. Therefore, and with the aim of expanding the
scope of such process, we focused our attention on the
study of other dibenzyl acetals.8
Aldol reaction nowadays constitutes one of the most pow-
erful tools for the carbon-carbon bond formation,1 giving
easy access to a-alkyl-b-hydroxy oxygenated moieties
present in the molecular architecture of a vast array of nat-
ural products.2 Taking into account that (i) in spite of re-
cent advances, the stereoselective construction of anti
aldol units is still one of the remaining challenges,3 and
that (ii) the protection of the hydroxyl group of the result-
ing aldol adducts is usually required, any methodology
able to provide stereoselectively protected anti aldol ad-
ducts in a single step would be highly desirable. In this
context, we have recently reported that the Lewis acid me-
diated cross-coupling reaction of a wide range of dimethyl
acetals with the titanium enolate arising from (S)-4-iso-
propyl-N-propanoyl-1,3-thiazolidine-2-thione (1) fur-
nishes efficiently enantiopure anti-b-methoxy-a-methyl
adducts.4 On the basis of these results, we envisaged that
the use of appropriate acetals might lead to a broader va-
riety of b-alkoxy-a-methyl carboxylic derivatives, which,
in turn, could be considered as protected aldol synthons.
Herein, we wish to report that the reaction of the titanium
enolate of 1 and dibenzyl acetals affords stereoselectively
anti-b-benzyloxy-a-methyl adducts that can be trans-
formed into a large number of enantiopure derivatives.
The results summarized in Table 2 clearly show that anti
adducts 2 can be obtained stereoselectively in good yields
irrespective of the sort of acetal.9,10 As expected, aliphatic
acetals f–i were less reactive than the aromatic or the a,b-
unsaturated counterparts, but, although they required
higher temperatures and longer reaction times to ensure an
efficient conversion, the results are significantly good
even for the non sterically demanding acetaldehyde de-
rived acetal i. It also deserves to be mentioned that the
a,b-unsaturated acetal j reacted smoothly in the presence
of a milder Lewis acid as BF3·OEt2, affording the corre-
sponding anti adduct in 70% yield and a diastereomeric
ratio up to 96:4.
Next, the reaction of 1 and ent-1 with dibenzyl acetal 411
was tested in order to gain insight into the influence of the
chirality of the acetals (see Scheme 1). The Felkin adduct
512 was favored to the point that only one diastereomer (dr
99:1) was obtained (71% yield) in the case of 1 (matched
pair13), whereas a mixture 66:34 of two diastereomers, 6
and 7, was isolated (86% yield) in the case of ent-1 (mis-
matched pair13). In accordance to our previous studies,4
the stereochemical outcome of these reactions supports a
SN1-like mechanism based on the addition of the enolate
to an oxocarbenium intermediate through an open transi-
tion state.
Initially, we examined the reaction of 1 with diallyl and
dibenzyl acetals derived from benzaldehyde and isobu-
tyraldehyde,5,6 which could afford aldol adducts with eas-
ily removable protecting groups (see Table 1).6
In the case of benzaldehyde derived acetals b and c the ex-
perimental conditions previously optimized for dimethyl
acetal a (BF3·OEt2, –78 °C, 2.5 h) proved to be unsuitable
because longer reaction times and/or higher temperatures
were required to attain synthetically useful yields.7 Con-
The chiral auxiliary was eventually removed under very
mild conditions, which permits the adduct 5 to be trans-
formed into a large number of protected derivatives, as
alcohol 8, aldehyde 9, ester 10, and amide 11 (see
Scheme 2).
Synlett 2003, No. 8, Print: 24 06 2003.
Art Id.1437-2096,E;2003,0,08,1109,1112,ftx,en;D08503ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1110
A. Cosp et al.
LETTER
Table 1 Lewis Acid Mediated Addition of the Titanium Enolate from 1 to Dialkyl Acetals
Entry
Acetal
R
R¢
Lewis acid
BF3·OEt2
SnCl4
Temp, time
dr 2:3a
88:12
85:15
87:13
95:5
Yield of 2 (%)
1
a
b
c
d
e
f
Ph
Me
–78 °C, 2.5 h
–78 °C, 20 min
–78 °C, 20 min
–20 °C, 2 h
75
64
92b
75
40
73
2
Ph
CH2CH = CH2
3
Ph
Bn
SnCl4
4c
5c
6c
i-Pr
i-Pr
i-Pr
Me
SnCl4
CH2CH=CH2
Bn
SnCl4
–20 °C, 2 h
89:11
90:10
SnCl4
–20 °C, 2 h
a Determined by HPLC analysis of the crude reaction mixture.
b Overall isolated yield of 2 and 3.
c Two equivalents of 1 are used.
Table 2 Lewis Acid Mediated Addition of the Titanium Enolate from 1 to Dibenzyl Acetals
Entry
Acetal
R
Lewis acid
SnCl4
Temp, time
–78 °C, 20 min
–20 °C, 2 h
–20 °C, 2 h
–20 °C, 2 h
–20 °C, 2 h
–78 °C, 1 h
dr 2:3a
Yield of 2 (%)
1
2c
3
4
5
6
c
f
Ph
87:13
90:10
92:8
92b
73
i-Pr
SnCl4
g
h
i
i-Bu
SnCl4
71
Pr
SnCl4
90:10
82:18
96:4
60
Me
SnCl4
86b
70
j
(E)-PhCH=CH(Me)
BF3·OEt2
a Determined by HPLC analysis of the crude reaction mixture.
b Overall isolated yield of 2 and 3.
c Two equivalents of 1 are used.
Scheme 1
Synlett 2003, No. 8, 1109–1112 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Synthesis of O-Benzyl Protected anti Aldols
1111
Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002, 124,
392. (j) Yamashita, Y.; Ishitani, H.; Shimizu, H.; Kobayashi,
S. J. Am. Chem. Soc. 2002, 124, 3292.
(4) (a) Cosp, A.; Romea, P.; Talavera, P.; Urpí, F.; Vilarrasa, J.;
Font-Bardia, M.; Solans, X. Org. Lett. 2001, 3, 615.
(b) Cosp, A.; Romea, P.; Urpí, F.; Vilarrasa, J. Tetrahedron
Lett. 2001, 42, 4629.
(5) Diallyl and dibenzyl acetals have been prepared according to
reported procedures: (a) Tsunoda, T.; Suzuki, M.; Noyori,
R. Tetrahedron Lett. 1980, 21, 1357. (b) Brogan, J. B.;
Richard, J. E.; Zercher, C. K. Synth. Commun. 1995, 25, 587.
(6) (a) Greene, T. W.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley & Sons: New York,
1999. (b) Kocienski, P. J. In Protecting Groups; Thieme:
Stuttgart, 1994.
(7) Yields lower than 50% were usually obtained under the
reported conditions.
(8) Di-(p-methoxybenzyloxy) acetal derived from isobutyr-
aldehyde, i-PrCH(OPMB)2, was also tested. In this case,
complex reaction mixtures were obtained because of the
unstability of the corresponding oxocarbenium intermediate.
(9) Typical Experimental Procedure. Neat TiCl4 (0.12 mL,
1.1 mmol) was added dropwise to a solution of 1 (217 mg,
1.0 mmol) in CH2Cl2 (8 mL), at 0 °C under N2. The yellow
suspension was stirred for 5 min at 0 °C, cooled at –78 °C,
and a solution of i-Pr2EtN (0.19 mL, 1.1 mmol) in CH2Cl2 (1
mL) was added. The dark red enolate solution was stirred for
2 h at –40 °C, and 1 M SnCl4 in CH2Cl2 (1.1 mL, 1.1 mmol)
followed by acetal g (314 mg, 1.1 mmol) in CH2Cl2 (1 mL)
were successively added dropwise at –78 °C. The resulting
mixture was stirred at –78 °C for 15 min and kept at –20 °C
for 2 h. The reaction was cooled at –78 °C and quenched by
the addition of saturated NH4Cl (8 mL) with vigorous
stirring. The layers were separated. The aqueous layer was
re-extracted with CH2Cl2, and the combined organic extracts
were dried (Na2SO4), filtered, concentrated, and analyzed by
HPLC. Purification by flash column chromatography on
deactivated (2.5% Et3N) silica gel (from hexanes to hexanes/
CH2Cl2 1:1), afforded 278 mg (71%) of the major
Scheme 2 (a) LiBH4, THF, r.t., 12 h. (b) DIBALH, CH2Cl2, –78 °C,
2 h. (c) EtOH, DMAP cat., r.t., 16 h. (d) Morpholine, THF, 0 °C, 5 h.
In summary, it has been described a simple and efficient
procedure to prepare anti-b-benzyloxy-a-methyl adducts
based on the stereoselective addition of a chiral titanium
enolate to a wide range of dibenzyl acetals. In turn, the ad-
ducts can be smoothly converted into a large number of
chiral building blocks of high scope in the total synthesis
of natural products. It is worth pointing out that the afore-
mentioned transformation does not require the protection
step in the reaction sequence, which certainly enhances
the synthetic potentiality of such a methodology.
Acknowledgment
diastereomer 2g: Yellow oil. Rf = 0.6 (CH2Cl2). HPLC
(hexanes/EtOAc 98:2) tR = 17.2 min. [a]D = +106.5 (c =
0.75, CHCl3). IR (film) 2957, 2861, 1699, 1684, 1653, 1559,
1456, 1364, 1256, 1157, 1094 cm–1. 1H NMR (500 MHz,
CDCl3) d 7.40–7.20 (5 H, m, ArH), 5.25 (1 H, ddd, J = 8.5
Hz, J = 5.3 Hz, J = 1.4 Hz, NCH), 5.13–5.07 (1 H, m,
COCHCH3), 4.61 (1 H, d, J = 11.4 Hz, OCHxHyPh), 4.55 (1
H, d, J = 11.4 Hz, OCHxHyPh), 4.06 (1 H, ddd, J = 9.4 Hz,
J = 6.5 Hz, J = 2.7 Hz, CHOBn), 3.43 (1 H, dd, J = 11.5 Hz,
J = 8.5 Hz, SCHxHy), 2.94 (1 H, dd, J = 11.5 Hz, J = 1.4 Hz,
SCHxHy), 2.19 [1 H, hepd, J = 6.9 Hz, J = 5.3 Hz,
Financial support from the Ministerio de Ciencia y Tecnología and
Fondos FEDER (Grant BQU2002-01514), and the Generalitat de
Catalunya (2001SGR00051), as well as doctorate studentships (Ge-
neralitat de Catalunya) to A. C. and I. L. are acknowledged.
References
(1) (a) Cowden, C. J.; Paterson, I. In Organic Reactions, Vol.
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Eds.; Springer: Heidelberg, 1999, 997.
NCHCH(CH3)2], 1.87–1.79 [1 H, m, CHxHyCH(CH3)2], 1.57
[1 H, ddd, J = 10.2 Hz, J = 9.4 Hz, J = 4.1 Hz,
CHxHyCH(CH3)2], 1.30–1.23 [1 H, m, CH2CH(CH3)2], 1.16
(3 H, d, J = 6.8 Hz, COCHCH3), 0.93 (3 H, d, J = 6.9 Hz,
CH3), 0.92 (3 H, d, J = 6.7 Hz, CH3), 0.89 (3 H, d, J = 6.9 Hz,
CH3), 0.87 (3 H, d, J = 6.6 Hz, CH3). 13C NMR (75.4 MHz,
CDCl3) d 202.5 (C), 176.1 (C), 138.8 (C), 128.1 (CH), 127.6
(CH), 127.3 (CH), 78.0 (CH), 71.8 (CH), 71.7 (CH2), 42.1
(CH), 39.5 (CH2), 30.8 (CH), 29.1 (CH2), 24.5 (CH), 24.1
(CH3), 21.9 (CH3), 19.0 (CH3), 16.9 (CH3), 12.5 (CH3).
HRMS(+FAB): calcd for [M + H]+ C21H32NO2S2 394.1874,
found 394.1891.
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(10) The stereochemistry of the adducts has been assigned by
analogy. The absolute stereochemistry of 2i has been
confirmed by chemical correlation.
Synlett 2003, No. 8, 1109–1112 ISSN 1234-567-89 © Thieme Stuttgart · New York

1112
A. Cosp et al.
LETTER
(11) Acetal 4 was prepared from commercially available methyl
(S)-3-hydroxy-2-methyl propionate following reported
procedures: (a) Ley, S. V.; Anthony, N. J.; Armstrong, A.;
Brasca, M. G.; Clarke, T.; Culshaw, D.; Greck, C.; Grice, P.;
Jones, A. B.; Lygo, B.; Madin, A.; Sheppard, R. N.; Slawin,
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CHxHyOSi), 3.35 (1 H, dd, J = 11.4 Hz, J = 8.5 Hz, SCHxHy),
2.88 (1 H, dd, J = 11.4 Hz, J = 1.2 Hz, SCHxHy), 2.10–2.03
[1 H, m, CH(CH3)2], 1.98–1.85 (1 H, m, CHCH2OSi), 1.08
[9 H, s, SiC(CH3)3], 1.07 (3 H, d, J = 6.9 Hz, COCHCH3),
0.82 (6 H, d, J = 6.9 Hz, 2 × CH3), 0.81 (3 H, J = 6.9 Hz,
CH3). 13C NMR (75.4 MHz, CDCl3) d 202.6 (C), 177.0 (C),
139.4 (C), 135.6 (CH), 135.5 (CH), 133.8 (C), 133.7 (C),
129.7 (CH), 129.6 (CH), 128.0 (CH), 127.6 (CH), 126.9
(CH), 126.8 (CH), 80.3 (CH), 74.3 (CH2), 71.8 (CH), 64.1
(CH2), 41.4 (CH), 37.3 (CH), 30.9 (CH), 28.7 (CH2), 26.9
(CH3), 19.2 (C), 19.0 (CH3), 16.8 (CH3), 15.1 (CH3), 9.8
(CH3). HRMS(+FAB): calcd for [M + H]+ C36H48NO3SiS2
634.2845, found 634.2823.
(12) Selected data for 5. [a]D = +75.5 (c = 0.75, CHCl3). 1H NMR
(300 MHz, CDCl3) d 7.70–7.60 (4 H, m, ArH), 7.46–7.14
(11 H, m, ArH), 5.31 (1 H, ddd, J = 8.5 Hz, J = 5.5 Hz, J =
1.2 Hz, NCH), 5.07 (1 H, dq, J = 9.9 Hz, J = 6.9 Hz,
COCHCH3), 4.67 (1 H, d, J = 11.7 Hz, OCHxHyPh), 4.61 (1
H, d, J = 11.7 Hz, OCHxHyPh), 4.30 (1 H, dd, J = 9.9 Hz,
J = 1.7 Hz, CHOBn), 3.67 (1 H, dd, J = 10.1 Hz, J = 9.3 Hz,
CHxHyOSi), 3.56 (1 H, dd, J = 10.1 Hz, J = 6.2 Hz,
(13) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.
Synlett 2003, No. 8, 1109–1112 ISSN 1234-567-89 © Thieme Stuttgart · New York