Stereoselective addition of titanium enolates to functionalized acetals: A novel approach to the γ-amino acid of bistramides and FR252921

Article abstract of DOI:10.1055/s-0028-1087351

Dialkyl acetals containing other functional groups can participate in stereoselective coupling reactions with chiral titanium enolates. Such an approach provides the protected γ-amino acid present in bistramides and FR252921 in a highly efficient manner. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087351

LETTER
2951
Stereoselective Addition of Titanium Enolates to Functionalized Acetals:
A Novel Approach to the g-Amino Acid of Bistramides and FR252921
S
ynthesis of the
r
g
-Amin
i
o
A
cid
k
of Bistramides Gálvez, Ricard Parelló, Pedro Romea,* Fèlix Urpí*
Departament de Química Orgànica, Universitat de Barcelona, Martí i Franqués 1-11, 08028 Barcelona, Catalonia, Spain
Fax +34 93 339 78 78; E-mail: felix.urpi@ub.edu; E-mail: pedro.romea@ub.edu
Received 3 June 2008
a-methyl adducts in good yields and diastereomeric ra-
tios.4 This methodology has been already applied to the
construction of the C9–C21 fragment of debromoaplysia-
toxin,5 but it remained unclear if such a procedure would
be compatible with more complex acetals to enable the
construction of structurally complex molecular architec-
tures. Herein, we document the use of dimethyl and diben-
zyl acetals containing other functional groups in the
aforementioned coupling reactions and the successful ap-
plication of this methodology to the synthesis of a highly
functionalized four-carbon fragment present in bistra-
mides and a novel immunosuppressive agent, FR252921
(Scheme 1).6,7
Abstract: Dialkyl acetals containing other functional groups can
participate in stereoselective coupling reactions with chiral titanium
enolates. Such an approach provides the protected g-amino acid
present in bistramides and FR252921 in a highly efficient manner.
Key words: stereoselective reactions, crossed aldol-like condensa-
tion, titanium enolates, acetals, bistramide, FR252921
The widespread presence of b-alkoxy oxygenated rela-
tionships in natural products has stimulated the develop-
ment of a plethora of synthetic approaches to the
corresponding b-alkoxy carbonyl compounds,1 most of
them being based on a two-step sequence: (i) stereoselec-
tive aldol reaction2 and (ii) alkylation of the aldol adduct.3
Considering that the second step is often troublesome, and
the integration of a multistep sequence in a single trans-
formation increases the efficiency of a process, we envis-
aged that the stereoselective addition of chiral enolates to
dialkyl acetals might render such b-alkoxy carbonyl com-
pounds in a straightforward manner. In accordance with
this approach, we have reported that the Lewis acid medi-
ated addition of titanium enolates of (S)-4-isopropyl-N-
propanoyl-1,3-thiazolidine-2-thione (1, Scheme 1) to
dimethyl and dibenzyl acetals affords the anti-b-alkoxy-
Initially, we examined the reaction of 1 with the dimethyl
acetals shown in Table 1,8 which encompass acetals with
a heteroatom positioned at C2 or other functional groups
that can affect the formation or the reactivity of the puta-
tive oxonium intermediate. Preliminary studies with the
commercially available bromoacetaldehyde dimethyl ace-
tal (a) proved that the experimental conditions established
for alkyl acetals provided a synthetically useless yield (see
entry 1 in Table 1). After an exhaustive optimization,9 it
was found that the stoichiometry was crucial to improve
the yield (compare entries 1–4 in Table 1). Thus, keeping
S
S
O
O
OR
O
OBn
1) TiCl4, i-Pr2NEt
2) SnCl4,
RO
FG
FG
S
N
S
N
MeO
our approach
OR
FG
FG = N3, NPhth
i-Pr
i-Pr
R1 R2
1
2
3
R = Me
R = Bn
O
OH
O
O
O
NHFmoc
Kozmin,6a Crimmins,6c
HO
C14–C18 fragment
OH
O
OTBS
H
18
Wipf,6b Panek,6d Yadav,6e
N
O
N3
N
RO
14
H
O
O
R1 = OH, R2 = H bistramide A
R1, R2 = O
bistramide C
O
O
OTBS
O
NBoc
NPhth
from FR25291
HO
HO
Cossy7a
Falck7b
Scheme 1
SYNLETT 2008, No. 19, pp 2951–2954
x
x
.x
x
.2
0
0
8
Advanced online publication: 12.11.2008
DOI: 10.1055/s-0028-1087351; Art ID: D20208ST
© Georg Thieme Verlag Stuttgart · New York

2952
E. Gálvez et al.
LETTER
Table 1 Lewis Acid Mediated Addition of the Titanium Enolate from 1 to Dimethyl Acetals
Cln
OMe
Ti
S
S
S
S
O
OMe
O
OMe
O
O
R
TiCl4, i-Pr2NEt
CH2Cl2
, SnCl4
MeO
R
R
+
S
N
S
N
S
N
S
N
–20 °C, time
i-Pr
i-Pr
i-Pr
i-Pr
1
2
4
Entry
Acetal
R
SnCl4 (equiv)
Acetal (equiv)
Time (h)
dr (2:4)a
90:10
93:7
Yield of 2 (%)b
1
2
a
a
a
a
b
c
d
e
f
Br
Br
Br
Br
1
1
2
2
24
1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
27
3
0.55
0.55
0.55
0.55
0.55
0.55
0.55
1
2
92:8
46
4
17
17
2
92:8
65
5
CO2Me
OBn
92:8
(82)
54 (83)
82
6
65:35
95:5
7
CH2OBn
(CH2)2OBn
NPhth
2
8
2
97:3
73
9
17
2
>97:3
>97:3
54
10
f
NPhth
80
a Determined by the HPLC analysis of the reaction mixture.
b Isolated yield of 2. Overall yield is given in parentheses.
at –20 °C a mixture of the titanium enolate from 1 and 0.5 proves the complete control exerted by the chiral auxiliary
equivalents of SnCl4 and the acetal a permitted to isolate on the configuration of the a-stereocenter. The 2,3-anti re-
the anti adduct 2a in good yield and diastereomeric ratio lationships on major diastereomers 2 and 3 were assigned
(dr = 92:8, 65% yield, see entry 4 in Table 1). Parallel re- through analysis of the 3J2,3 coupling constants (3J2,3 > 7.0
sults (see entry 5 in Table 1) were obtained with the me- Hz).11 Furthermore, it was secured for 3i by a thorough
thyl 3-oxopropanoate dimethyl acetal (b). In turn, the spectroscopic analysis of the isopropylidene acetal 7 rep-
diastereoselectivity observed for acetals c–e containing resented in Scheme 2.
benzyl ethers was highly dependent on the position of the
The abovementioned synthetic sequence makes clear that
benzyloxy group. The poorer stereocontrol was obtained
the adducts from dibenzyl acetals can be considered as
for acetal c with the OBn group at C2, but it became ex-
protected anti-aldol units. Given that their stereoselective
cellent if such group is placed at C3 or C4 (acetals d and
e, respectively). In all these cases, the reaction proceeded
faster and the yield did not increase significantly after two
hours (see entries 6–8 in Table 1). Conversely, the acetal
f possessing a phthalimido group at C2 was much less re-
active and required the addition of one equivalent of
SnCl4 to attain a high yield of a single diastereomer (com-
pare entries 9 and 10 in Table 1).
construction is still challenging12 and the thiazolidineth-
ione chiral auxiliary can be easily removed,4,5,13 this meth-
O
OBn
S
O
NaBH4
60%
N
S
N
O
3i
i-Pr
O
Next, we focused our attention on dibenzyl acetals shown
in Table 2.10 As well as their dimethyl counterparts, ace-
tals g–i emerged as suitable substrates for such coupling
reactions and afforded the 2,3-anti adducts 3 in high
yields. Interestingly, the addition of one equivalent of
SnCl4 improved the diastereoselectivity of these reac-
tions, and provided the corresponding adduct as a single
diastereomer with the exception of the azidoacetaldehyde
dibenzyl acetal h (dr = 75:25, see entry 5 in Table 2). The
reasons for such low diastereoselectivity are still elusive.
OBn
1) H2, Pd/C
N
HO
2) Me2C(OMe)2, TsOH
77%
O
6
NOE
H
H
O
O
O
O
N
O
7
R
R = CH2NPhth
H
O
3Jaa = 11.1 Hz
As expected,4 only two of four possible diastereomers
were observed across all the reaction mixtures, which
Scheme 2
Synlett 2008, No. 19, 2951–2954 © Thieme Stuttgart · New York

LETTER
Synthesis of the g-Amino Acid of Bistramides
2953
Table 2 Lewis Acid Mediated Addition of the Titanium Enolate from 1 to Dibenzyl Acetals
Cln
OBn
Ti
S
S
S
S
O
O
OBn
O
OBn
O
R
TiCl4, i-Pr2NEt
CH2Cl2
, SnCl4
–20 °C, time
BnO
R
R
+
S
N
S
N
S
N
S
N
i-Pr
i-Pr
i-Pr
i-Pr
3
5
1
Entry
Acetal
R
SnCl4 (equiv)
Acetal (equiv)
Time (h)
dr (3:5)a
91:9
Yield of 3 (%)b
1
2
3
4
5
6
7
g
g
g
h
h
i
Br
Br
Br
0.55
0.5
0.5
0.5
0.5
0.5
0.5
0.5
17
2
69
1
95:5
34
1
17
17
17
2
95:5
75
N3
0.55
50:50
75:25
>97:3
>97:3
(83)
(87)
79
N3
1
1
1
NPhth
NPhth
i
17
84
a Determined by the HPLC analysis of the reaction mixture.
b Isolated yield of 3. Overall yield is given in parentheses.
odology represents an appealing entry to highly advantage of the better results achieved with the bromo
functionalized fragments containing those arrays. To con- acetal g (compare entries 3 and 5 in Table 2). Thus, the re-
firm the efficiency of this approach, we undertook the moval of the chiral auxiliary from the adduct ent-3g led to
synthesis of the protected g-amino acid embedded in bis- the corresponding alcohol and methyl ester, which, in
tramides and FR252921, as represented in Scheme 1.
turn, were subsequently treated with NaN3 to deliver the
desired azido derivatives 10 and 11 in good overall yields
(Scheme 4).16,17 This strategy failed in the case of the bu-
tyl amide, presumably as a consequence of the cyclization
of the bromoamide intermediate.
Hence, simple stirring of adduct ent-3i14 in methanol in
the presence of a catalytic amount of DMAP at room tem-
perature for 3.5 hours provided the desired methyl ester 8
in 90% (Scheme 3). This transformation can be carried
out with the crude mixture obtained from the coupling re-
action. Therefore, the two-step sequence only requires a
single chromatographic purification to provide the ester 8
in 77% overall yield.15
OBn
1) NaBH4
N3
HO
2) NaN3
S
69%
O
OBn
10
11
Since the C18 carbon is attached to the spiro fragment of
bistramides through an amido link, we speculated about
the opportunity of converting ent-3i into a model amide.
Gratifyingly, the treatment of ent-3i with one equivalent
of BuNH2 led to the butyl amide 9 in 88% yield
(Scheme 3).
Br
S
N
O
OBn
1) MeOH
i-Pr
N3
ent-3g
MeO
2) NaN3
77%
Scheme 4
The preparation of the related azido derivatives proved to
be troublesome. Since the acetal h containing the azido
group provided a poorly stereoselective reaction, we took
In summary, dimethyl and dibenzyl acetals containing dif-
ferent functional groups can participate in highly stereose-
lective Lewis acid mediated coupling reactions with the
titanium enolates from (S)-4-isopropyl-N-propanoyl-1,3-
thiazolidine-2-thione. The resultant anti-3-alkoxy-2-methyl
adducts can be easily manipulated to deliver densely func-
tionalized synthons. The efficiency of such approach has
been proved in the straightforward synthesis of several
protected precursors of the g-amino acid present in
bistramides and a novel immunosuppressive agent,
FR252921.
O
OBn
MeOH
90%
NPhth
NPhth
MeO
S
O
OBn
8
NHPhth
S
N
O
OBn
BuNH2
88%
i-Pr
ent-3i
BuHN
9
Scheme 3
Synlett 2008, No. 19, 2951–2954 © Thieme Stuttgart · New York

2954
E. Gálvez et al.
LETTER
2586. (e) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey,
C. W. J. Am. Chem. Soc. 2002, 124, 392. (f) Evans, D. A.;
Downey, C. W.; Shaw, J. T.; Tedrow, J. S. Org. Lett. 2002,
4, 1127. (g) Fanjul, S.; Hulme, A. N.; White, J. W. Org. Lett.
2006, 8, 4219.
Acknowledgment
Financial support from the Spanish Ministerio de Ciencia y Tecno-
logía and Fondos FEDER (Grant CTQ2006-13249/BQU), and the
Generalitat de Catalunya (2005SGR00584), as well as doctorate
studentship to E.G. (Universitat de Barcelona) are acknowledged.
(13) For examples on the easy removal of thiazolidinethione
auxiliaries, see: (a) Crimmins, M. T.; Chaudhary, K. Org.
Lett. 2000, 2, 775. (b) Zhang, Y.; Phillips, A. J.; Sammakia,
T. Org. Lett. 2004, 6, 23. (c) Wu, Y.; Sun, Y.-P.; Yang,
Y.-Q.; Hu, Q.; Zhang, Q. J. Org. Chem. 2004, 69, 6141.
(d) Osorio-Lozada, A.; Olivo, H. F. Org. Lett. 2008, 10, 617.
(14) Enantiomeric adducts ent-3 are obtained from ent-1, which
in turn is prepared from the commercially available (R)-
valinol.
References and Notes
(1) Misra, M.; Luthra, R.; Singh, K. L.; Sushil, K. In
Comprehensive Natural Products, Vol. 4; Barton, D. H. R.;
Nakanishi, K.; Meth-Cohn, O., Eds.; Pergamon: Oxford,
1999, 25.
(2) For recent reviews on aldol reactions, see: (a) Alcaide, B.;
Almendros, P. Eur. J. Org. Chem. 2002, 1595. (b) Modern
Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, 2004. (c) Schetter, B.; Mahrwald, R. Angew.
Chem. Int. Ed. 2006, 45, 7506.
(3) For an overview on the alkylation of alcohols, see: Wuts,
P. G. M.; Greene, T. W. In Protective Groups in Organic
Synthesis, 4th ed.; John Wiley and Sons: Hoboken, 2007.
(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. (c) Cosp, A.; Larrosa, I.; Vilasís, I.;
Romea, P.; Urpí, F.; Vilarrasa, J. Synlett 2003, 1109.
(d) Baiget, J.; Cosp, A.; Gálvez, E.; Gómez-Pinal, L.;
Romea, P.; Urpí, F. Tetrahedron 2008, 64, 5637.
(5) Cosp, A.; Llàcer, E.; Romea, P.; Urpí, F. Tetrahedron Lett.
2006, 47, 5819.
(6) For the synthesis of bistramides, see: (a) Statsuk, A. V.; Liu,
D.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 9546.
(b) Wipf, P.; Hopkins, T. D. Chem. Commun. 2005, 3421.
(c) Crimmins, M. T.; DeBaille, A. C. J. Am. Chem. Soc.
2006, 128, 4936. (d) Lowe, J. T.; Wrona, I. E.; Panek, J. S.
Org. Lett. 2007, 9, 327. (e) Yadav, J. S.; Chetia, L. Org.
Lett. 2007, 9, 4587.
(7) For the synthesis of FR252921, see: (a) Amans, D.;
Bellosta, V.; Cossy, J. Org. Lett. 2007, 9, 4761. (b) Falck,
J. R.; He, A.; Fukui, H.; Tsutsui, H.; Radha, A. Angew.
Chem. Int. Ed. 2007, 46, 4527.
(8) Dimethyl acetals a and b are commercially available. The
other acetals (c–f) have been prepared following standard
procedures reported in the literature. See: (a)Greene, T. W.;
Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd
ed.; John Wiley and Sons: New York, 1999. (b) Kocienski,
P. J. Protecting Groups; Thieme: Stuttgart, 1994.
(9) The stoichiometry, the reaction temperature, and time were
carefully evaluated.
(10) Dibenzyl acetals g–i have been prepared from the
corresponding dimethyl acetal, see: Vidal-Pascual, M.;
Martínez-Lamarca, C.; Hoffmann, H. M. R. Org. Synth.
2005, 83, 61.
(11) This pattern has been established in preceding reports
mentioned in ref. 4 and was supported by structural studies,
see: Cosp, A.; Larrosa, I.; Anglada, J. M.; Bofill, J. M.;
Romea, P.; Urpí, F. Org. Lett. 2003, 5, 2809.
(15) Preparation of Methyl Ester 8
Neat TiCl4 (0.12 mL, 1.1 mmol) was added dropwise to a
solution of ent-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-Pr2NEt (0.19
mL, 1.1 mmol) in CH2Cl2 (1 mL) was added. The dark red
enolate solution was stirred for 2 h at –50 °C. Then, 1 M
SnCl4 in CH2Cl2 (1.1 mL, 1.1 mmol), followed by acetal i
(314 mg, 1.1 mmol) in CH2Cl2 (1 mL), was successively
added dropwise at –78 °C. The resulting mixture was stirred
at –78 °C for 30 min and kept at –20 °C for 2 h. The reaction
was cooled at –78 °C and quenched by the addition of sat.
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. A solution of
the residue and a crystal of DMAP in MeOH (8 mL) was
stirred for 3.5 h at r.t. under N2, diluted in Et2O, and washed
with 2 M NaOH, 2 M HCl, sat. NaHCO3, and brine. The
organic layer was dried (Na2SO4), filtered, and concentrated.
Purification of the resultant oil through a pad of SiO2
(CH2Cl2) afforded 141 mg (0.38 mmol, 77% yield) of methyl
ester 8. Colorless oil. Rf = 0.2 (CH2Cl2). [a]D +16.1 (c 0.95,
CHCl3). IR (film): n = 2948, 1773, 1715, 1395, 1196, 1071
cm–1. 1H NMR (400 MHz, CDCl3): d = 7.79–7.76 (2 H, m,
ArH), 7.71–7.67 (2 H, m, ArH), 7.31–7.04 (5 H, m, ArH),
4.57 (1 H, d, J = 11.3 Hz, PhCHxHy), 4.52 (1 H, d, J = 11.3
Hz, PhCHxHy), 4.01 (1 H, ddd, J = 7.3, 5.8, 4.5 Hz,
CHOBn), 3.91–3.82 (2 H, m, CH2N), 3.65 (3 H, s, OCH3),
2.85–2.76 (1 H, m, COCHCH3), 1.33 (3 H, d, J = 7.0 Hz,
COCHCH3). 13C NMR (100.6 MHz, CDCl3): d = 174.6 (C),
168.2 (C), 137.7 (C), 133.8 (CH), 132.0 (C), 128.1 (2 × CH),
127.5 (CH), 123.2 (CH), 78.3 (CH), 72.7 (CH2), 51.8 (CH3),
42.7 (CH), 38.3 (CH2), 12.6 (CH3). ESI-HRMS: m/z calcd
for C21H22NO5 [M + H]+: 368.1492; found: 368.1488.
(16) Ok, T.; Jeon, A.; Lee, J.; Lim, J.-H.; Hong, C.-S.; Lee, H.-S.
J. Org. Chem. 2007, 72, 7390.
(17) Selected Data for Methyl Ester 11
[a]D +34.6 (c 1.3, CHCl3). IR (film): n = 2950, 2101, 1737,
1455, 1285, 1262, 1197, 1172, 1098, 1065 cm–1. 1H NMR
(400 MHz, CDCl3): d = 7.38–7.25 (5 H, m, ArH), 4.65 (1 H,
d, J = 11.3 Hz, PhCHxHy), 4.57 (1 H, d, J = 11.3 Hz,
PhCHxHy), 3.83 (1 H, ddd, J = 7.5, 5.7, 3.2 Hz, CHOBn),
3.68 (3 H, s, OCH3), 3.44 (1 H, dd, J = 13.2, 3.2 Hz,
CHxHyN3), 3.30 (1 H, dd, J = 13.2, 5.7 Hz, CHxHyN3), 2.92–
2.84 (1 H, m, COCHCH3), 1.13 (3 H, d, J = 7.1 Hz,
COCHCH3). 13C NMR (100.6 MHz, CDCl3): d = 174.6 (C),
137.6 (C), 128.4 (CH), 127.9 (CH), 127.8 (CH), 79.9 (CH),
72.8 (CH2), 51.8 (CH3), 51.2 (CH2), 42.0 (CH), 12.7 (CH3).
ESI-HRMS: m/z calcd for C13H17N3NaO3 [M + Na]+:
286.1162; found: 286.1174.
(12) Asymmetric anti-aldol reactions were early recognized as
more challenging than the syn counterparts. For
stereoselective procedures based on chiral auxiliaries, see:
(a) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56,
5747. (b) Wang, Y.-C.; Hung, A.-W.; Chang, C.-S.; Yan,
T.-H. J. Org. Chem. 1996, 61, 2038. (c) Ghosh, A. K.;
Onishi, M. J. Am. Chem. Soc. 1996, 118, 2527. (d) Abiko,
A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119,
Synlett 2008, No. 19, 2951–2954 © Thieme Stuttgart · New York