Stereoselective synthesis of highly functionalized structures from lactate-derived halo ketones

Article abstract of DOI:10.1021/jo9010798

(Chemical Equation Presented) Highly diastereoselective (i-PrO) ₂TiCl₂-mediated aldol reactions from lactate-derived α′-halo α-silyloxy ketones and subsequent treatment of the resultant aldols with a wide range of nucleophiles furnis

Full text of DOI:10.1021/jo9010798

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obtained from isothiocyanateacetyl oxazolidinones7 and,
Stereoselective Synthesis of Highly Functionalized
Structures from Lactate-Derived Halo Ketones†
more recently, an azidoacetyl thiazolidinethione.8 In turn,
similar halo carboxylic systems have been also engaged in
such kinds of reactions,5a,9 but few methodologies have
taken advantage of the synthetic potentiality of chiral halo
ketones.10,11 Thus, considering the ability of halides as
leaving groups in SN2-like processes and the high diastereos-
electivity achieved by the aldol reactions of chiral R-hydroxy
ketones,12 we envisaged that parallel substrate-controlled
additions from R0-halo R-silyloxy ketones would afford the
syn-syn halo aldols, which might be subsequently trans-
formed into highly functionalized molecular architectures
(see Scheme 1). Herein we disclose the success of such a
strategy based on the titanium-mediated aldol reactions of
lactate-derived R0-chloro- and R0-bromo-R-tert-butyldi-
methylsilyloxy ketones (R1: Me; R3Si: TBS; X: Cl, Br in
Scheme 1).13
ꢀ
Joaquim Nebot, Pedro Romea,* and Felix Urpı*
´
Departament de Quımica Organica, Universitat de Barcelona,
Martı i Franques 1-11, 08028 Barcelona, Catalonia, Spain
ꢀ
´
ꢁ
felix.urpi@ub.edu; pedro.romea@ub.edu
Received June 3, 2009
The required chloro and bromo ketones (1 and 2, respec-
tively, see Table 1) were prepared from commercially avail-
able ethyl lactate following procedures reported in the
literature.14 With a straightforward and reliable supply of
ketones 1 and 2 in hand, we began to study their titanium-
mediated aldol reactions. Preliminary studies with TiCl4 and
isobutyraldehyde (a) were disappointing. The experimental
Highly diastereoselective (i-PrO)2TiCl2-mediated aldol
reactions from lactate-derived R0-halo R-silyloxy ketones
and subsequent treatment of the resultant aldols with a
wide range of nucleophiles furnishes highly functiona-
lized arrangements useful in natural product syntheses.
(7) For representative examples, see: (a) Evans, D. A.; Weber, A. E.
J. Am. Chem. Soc. 1986, 108, 6757. (b) Boger, D. L.; Colletti, S. L.; Honda,
T.; Menezes, R. F. J. Am. Chem. Soc. 1994, 116, 5607. (c) Herbert, B.; Kim,
I. H.; Kirk, K. L. J. Org. Chem. 2001, 66, 4892. (d) Willis, M. C.; Cutting,
G. A.; Piccio, V. J.-D.; Durbin, M. J.; John, M. P. Angew. Chem., Int. Ed.
2005, 44, 1543.
The stereoselective aldol reaction based on substrates
containing a heteroatom at the enolizable position constitu-
tes a powerful tool for the construction of complex arrange-
ments of functionality and stereochemistry in natural
product syntheses.1 Indeed, the glycolate aldol reactions of
hydroxy ketones,2,3 esters,4 thioesters,5 and imides6 have
been widely used for the synthesis of polyoxygenated struc-
tures, whereas related aminooxygenated arrays have been
ꢁ
(8) Patel, J.; Clave, G.; Renard, P.-Y.; Franck, X. Angew. Chem., Int. Ed.
2008, 47, 4224.
(9) (a) Abdel-Magid, A.; Pridgen, L. N.; Eggleston, D. S.; Lantos, I.
J. Am. Chem. Soc. 1986, 108, 4595. (b) Evans, D. A.; Sjogren, E. B.; Weber,
A. E.; Conn, R. E. Tetrahedron Lett. 1987, 28, 39. (c) Evans, D. A.; Weber,
A. E. J. Am. Chem. Soc. 1987, 109, 7151. (d) Jones, T. K.; Reamer, R. A.;
Desmond, R.; Mills, S. G. J. Am. Chem. Soc. 1990, 112, 2998. (e) Wang,
Y.-C.; Su, D.-W.; Lin, C.-W.; Tseng, H.-L.; Li, C.-L.; Yan, T.-H. J. Org.
Chem. 1999, 64, 6495. (f) Ghosh, A. K.; Kim, J.-H. Org. Lett. 2004, 6, 2725.
(g) Hoover, T. R.; Groeper, J. A.; Parrott, R. W.; Chandrashekar, S. P.;
Finefield, J. M.; Dominguez, A.; Hitchcock, S. R. Tetrahedron: Asymmetry
2006, 17, 1831. (h) Son, J. B.; Hwang, M.-h.; Lee, W.; Lee, D.-H. Org. Lett.
2007, 9, 3897. (i) Yu, D.-S.; Xu, W.-X.; Liu, L.-X.; Huang, P.-Q. Synlett
2008, 1189.
† This paper is dedicated to Prof. Santiago Olivella on the occasion of his 65th
birthday.
(1) For an overview on aldol methodologies for the synthesis of polyke-
tides, see: Schetter, B.; Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506.
(2) (a) Paterson, I.; Tillyer, R. D. J. Org. Chem. 1993, 58, 4182.
(b) Hayward, C. M.; Yohannes, D.; Danishefsky, S. J. J. Am. Chem. Soc.
1993, 115, 9345. (c) Paterson, I.; Doughty, V. A.; McLeod, M. D.; Triesel-
mann, T. Angew. Chem., Int. Ed. 2000, 39, 1308. (d) Trost, B. M.; Ito, H.;
Silcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367. (e) Murga, J.; Ruiz, P.;
Falomir, E.; Carda, M.; Peris, G.; Marco, J. A. J. Org. Chem. 2004, 69, 1987.
(f) Evans, D. A.; Glorius, F.; Burch, J. D. Org. Lett. 2005, 7, 3331.
(3) For a review on aldol additions of dihydroxyacetone, see: Markert,
M.; Mahrwald, R. Chem. Eur. J. 2008, 14, 40.
(4) (a) Andrus, M. B.; Soma Sekhar, B. B. V.; Meredith, E. L.; Dalley,
N. K. Org. Lett. 2000, 2, 3035. (b) Dixon, D. J.; Ley, S. V.; Polara, A.;
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V.; Turner, T. M.; Meredith, E. L. Tetrahedron Lett. 2001, 42, 7197.
(d) Denmark, S. E.; Chung, W.-j. J. Org. Chem. 2008, 73, 4582.
(10) (a) Enders, D.; Hett, R. Synlett 1998, 961. (b) Palomo, C.; Oiarbide,
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M.; Sharma, A. K.; Gonzalez-Rego, M. C.; Linden, A.; Garcıa, J. M.;
Gonzalez, A. J. Org. Chem. 2000, 65, 9007.
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(11) For organocatalyzed reactions from chloroacetone, see: (a) He, L.;
Tang, Z.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Tetrahedron 2006,
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62, 346. (b) Guillena, G.; Hita, M. C.; Najera, C. Tetrahedron: Asymmetry
2007, 18, 1272.
(12) For seminal contributions on stereoselective aldol reactions based on
chiral R-hydroxy ketones, see: (a) Masamune, S.; Choy, W.; Kerdesky, F. A.
J.; Imperiali, B. J. Am. Chem. Soc. 1981, 103, 1566. (b) Van Draanen, N. A.;
Arseniyadis, S.; Crimmins, M. T.; Heathcock, C. H. J. Org. Chem. 1991, 56,
2499. (c) Paterson, I.; Wallace, D. J.; Velazquez, S. M. Tetrahedron Lett.
1994, 33, 9083.
(13) For titanium-mediated aldol reactions from lactate-derived ethyl
and methyl ketones, see: (a) Solsona, J. G.; Romea, P.; Urpı, F.; Vilarrasa, J.
Org. Lett. 2003, 5, 519. (b) Solsona, J. G.; Romea, P.; Urpı, F. Tetrahedron
Lett. 2004, 45, 5379. (c) Nebot, J.; Figueras, S.; Romea, P.; Urpı, F.; Ji, Y.
Tetrahedron 2006, 62, 11090. (d) Rodrıguez-Cisterna, V.; Villar, C.; Romea,
P.; Urpı, F. J. Org. Chem. 2007, 72, 6631. (e) Pellicena, M.; Solsona, J. G.;
Romea, P.; Urpı, F. Tetrahedron Lett. 2008, 49, 5265.
(5) (a) Gennari, C.; Vulpetti, A.; Pain, G. Tetrahedron 1997, 53, 5909.
(b) Kobayashi, S.; Horibe, M. Chem. Eur. J. 1997, 3, 1472. (c) Fanjul, S.;
Hulme, A. N. J. Org. Chem. 2008, 73, 9788.
(6) For representative examples, see: (a) Evans, D. A.; Gage, J. R.;
Leighton, J. L; Kim, A. S. J. Org. Chem. 1992, 57, 1961. (b) Evans, D. A.;
Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990,
112, 7001. (c) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121,
5653. (d) Li, Z.; Wu, R.; Michalczyk, R.; Dunlap, R. B.; Odom, J. D.; Silks,
L. A. J. Am. Chem. Soc. 2000, 122, 386. (e) Crimmins, M. T.; McDougall, P.
J. Org. Lett. 2003, 5, 591. (f) Zhang, W.; Carter, R. G.; Yokochi, A. F. T. J.
Org. Chem. 2004, 69, 2569. (g) Owen, R. M.; Roush, W. R. Org. Lett. 2005, 7,
3941. (h) Vincent, G.; Mansfield, D. J.; Vors, J.-P.; Ciufolini, M. A. Org. Lett.
2006, 8, 2791. (i) Crimmins, M. T.; Ellis, J. M. J. Org. Chem. 2008, 73, 1649.
~
ꢁ
(14) (a) Barluenga, J.; Baragana, B.; Alonso, A.; Concellon, J. M.
J. Chem. Soc., Chem. Commun. 1994, 969. (b) Kaluza, Z.; Kazimierski, A.;
Lewandowski, K.; Suwinska, K.; Szczesna, B.; Chmielewski, M. Tetrahedron
2003, 59, 5893.
7518 J. Org. Chem. 2009, 74, 7518–7521
Published on Web 09/04/2009
DOI: 10.1021/jo9010798
r
2009 American Chemical Society

Nebot et al.
JOCNote
SCHEME 1
TABLE 1. Titanium-Mediated Aldol Reactions of Lactate-Derived
Ketones 1 and 2 with Isobutyraldehyde (a)
entry
ketone
TiL4
TiCl4
TiCl4
(i-PrO)TiCl3
(i-PrO)TiCl3
(i-PrO)2TiCl2
(i-PrO)2TiCl2
(i-PrO)2TiCl2
(i-PrO)2TiCl2
aldol
dr (ss/as)a
yieldb (%)
conditions early used for the structurally related ethyl ketone
(method A: (i) TiLn, i-Pr2NEt, CH2Cl2, -78 °C, 30 min;
(ii) i-PrCHO, -78 °C, 30 min) afforded the 2,4-syn-4,5-syn
halo aldols 4a (X: Cl) and 6a (X: Br) in high yields but in
lower diastereomeric ratios than expected (see entries 1 and 2
in Table 1).15,16 Therefore, other titanium(IV) Lewis acids
were surveyed. We were pleased to observe that the diaster-
eoselectivity could be improved using weaker Lewis acids as
(i-PrO)TiCl3 or (i-PrO)2TiCl2 (compare entries 1-6 in
Table 1). Such improvement was particularly remarkable
with (i-PrO)2TiCl2, although 4a and 6a were isolated in low
yields (see entries 5 and 6 in Table 1). Given that these
discouraging results could be due to an incomplete enoliza-
tion or to the lack of reactivity of the resultant titanium
enolate, we carried out an exhaustive optimization of the
temperature and the reaction time both on the enolization
and the aldol addition steps. Finally, we found a new set of
conditions (method B: (i) (i-PrO)2TiCl2, i-Pr2NEt, CH2Cl2,
-78 to -20 °C, 1.5 h; (ii) i-PrCHO, -78 °C for 2 h, -20 °C
for 1 h) that provide 4a and 6a in good yields and excellent
diastereomeric ratios (see entries 7 and 8 in Table 1).
1c
2c
3c
4c
5c
6c
7d
8d
1
2
1
2
1
2
1
2
4a
6a
4a
6a
4a
6a
4a
6a
82:18
90:10
91:9
94:6
97:3
>97:3
97:3
>97:3
79
81
77
79
40
35
74
69
aDetermined by 1H NMR analysis of the reaction mixture. bOverall
isolated yield. cMethod A: (i) TiL4, i-Pr2NEt, CH2Cl2, -78 °C, 30 min;
(ii) i-PrCHO, -78 °C, 30 min. dMethod B: (i) TiL4,i-Pr2NEt, CH2Cl2,-78 °C,
15 min, -20 °C, 1.5 h; (ii) i-PrCHO, -78 °C, 2 h, -20 °C, 1 h.
SCHEME 2. Mechanistic Model for Aldol Reactions from 1 and 2
Having established the best experimental conditions for
isobutyraldehyde, we next surveyed a wide range of alde-
hydes to determine the scope of the reaction. The results are
summarized in Table 2. As shown, both ketones delivered the
corresponding 2,4-syn-4,5-syn halo aldols in good yields
(67-78%) and high diastereomeric ratios (dr >92:8). Parti-
cularly outstanding were the results of bromo ketone 2 with
aliphatic and R,β-unsaturated aldehydes (see entries 4-6, 8,
and 9 in Table 2) since a single aldol 6 was identified in the
reaction mixtures irrespective of the steric hindrance.
Although a thorough understanding of the stereochemical
outcome of these reactions is hampered by the lack of
knowledge on the structure of the titanium enolates,17 it is
likely that they involve a Z-enolate that evolves through a
cyclic six-membered chairlike transition state. Then, the
antiperiplanar distribution of TBSO-C and C-OTi bonds
shapes the configuration of the major aldol 4 or 6 since the
less sterically demanding CR substituent (H vs Me) is placed
pointing toward the inside of the ring (Scheme 2).12
We are aware that this model does not easily account for
the influence of the halide and the substituents of the
titanium on the diastereoselectivity. Regarding the impact
of the halides, it might be tentatively traced to steric effects.
Indeed, a bare inspection of the results represented in
Figure 1 for the titanium-mediated aldol reactions of several
lactate-derived silyloxy ketones with isobutyraldehyde shows
that the smaller the X group the worse the diastereoselecti-
vity. However, the diastereoselectivity of the ethyl (X: Me)13c
and methyl ketones (X: H)18 is rather insensitive to the
titanium Lewis acid, which suggests that not steric but other
electronic effects may be the reasons for the changes in the
diastereoselectivity observed across the whole series.19
The remarkable stereocontrol on the aldol reactions from
bromo ketone 2 and the apparent ease of displacement of
bromine in SN2-like processes made aldols 6 highly appeal-
ing substrates to undertake their conversion into highly
functionalized structures. Initially, we assessed the intermo-
lecular substitution of the bromine with a large set of
oxygenated nucleophiles including carboxylates, alcohols,
and water. To our displeasure and in spite of many efforts,
we were unable to obtain the fully oxygenated system.
(15) For the proof of the stereochemsitry of 4a and 6a, see the Supporting
Information.
ꢀ
(18) Unpublished results from Lorente, A. Master Experimental, Universitat
de Barcelona, 2009.
(19) The influence of Ti-Lewis acids on the aldol reactions of tert-butyl
hydroxyacetate has been reported; see: Gawas, D.; Kazmaier, U. J. Org.
Chem. 2009, 74, 1788.
(16) The halo aldols 2,4-syn-4,5-syn (4a or 6a) and 2,4-anti-4,5-syn (5a or
7a) were the only diastereomers observed in the reaction mixtures.
(17) For the biradical character of some titanium(IV) enolates, see:
Moreira, I.; de, P. R.; Bofill, J. M.; Anglada, J. M.; Solsona, J. G.; Nebot,
J.; Romea, P.; Urpı, F. J. Am. Chem. Soc. 2008, 130, 3242.
J. Org. Chem. Vol. 74, No. 19, 2009 7519

Nebot et al.
JOCNote
TABLE 2. (i-PrO)2TiCl2-Mediated Aldol Reactions of Lactate-Derived Ketones 1 and 2
entry
ketone
aldehyde
R
aldol
dr (ss/as)a
yieldb (%)
1
2
3
4
5
6
7
8
9
1
1
1
2
2
2
2
2
2
a
d
e
a
b
c
d
e
f
i-Pr
Ph
4a
4d
4e
6a
6b
6c
6d
6e
6f
97:3
94:6
97:3
>97:3
>97:3
>97:3
92:8
>97:3
95:5
74
67
71
69
70
77
70
78
70
(E) CHdCHCH3
i-Pr
i-Bu
Et
Ph
(E) CHdCHCH3
C(CH3)=CH2
aDetermined by 1H NMR analysis of the reaction mixture. bOverall isolated yield.
SCHEME 3
SCHEME 4
FIGURE 1. Diastereoselectivity of titanium-mediated aldol reac-
tions from lactate-derived ketones.
Instead, we took advantage of the vicinal alcohol and
triggered the intramolecular cyclization to prepare cis-R,
β-epoxy ketones 8 and 9 in high yields by treatment of 6a
with K2CO3 or TBAF (see eqs 1 and 2 in Scheme 3).
The introduction of a nitrogenated nucleophile became a
thorny transformation as well. Indeed, the intermolecular
reaction required a careful optimization to avoid undesired
epimerizations, but we finally found that the reaction of 6a
with NaN3 in DMSO furnished the azido derivative 10 in
84% yield (see eq 3 in Scheme 4). Once the intermolecular
process had been completed, we next examined the intramo-
lecular counterpart. Thus, we were pleased to observe that
treatment of 6a with N-tosylisocyanate produced a carba-
mate, which afforded the oxazolidinone 11 upon addition of
K2CO3 (see eq 4 in Scheme 4).
SCHEME 5
the weak Lewis acid (i-PrO)2TiCl2 must be employed to
achieve diastereomeric ratios up to 97:3 of the corresponding
2,4-syn-4,5-syn halo aldols. Furthermore, the resultant bro-
mo aldols have been converted into complex arrangements
of functionality and stereochemistry through SN2-like inter-
and intramolecular transformations.
Eventually, we took advantage of the reactivity of sulfur
nucleophiles. Therefore, a thiophenol group was introduced
on TES-protected bromo aldol 12 in the presence of K2CO3
(see eq 5 in Scheme 5), whereas the thioacetate did not require
any protection and enabled the ready transformation of 6e
into 14 in excellent yield (see eq 6 in Scheme 5).
Experimental Section
In summary, we have developed a new substrate-con-
trolled aldol reaction from lactate-derived R0-halo R-silyloxy
ketones. It is noteworthy, the titanium Lewis acid used for
the enolization of these ketones plays a crucial role on the
diastereoselectivity of the reaction, having established that
General Procedure for the Titanium-Mediated Aldol Reactions
from 1 and 2. Recently distilled (i-PrO)4Ti (163 μL, 0.55 mmol)
was added to a solution of TiCl4 (60 μL, 0.55 mmol) in CH2Cl2
(1 mL) at 0 °C under N2. The resultant mixture was stirred for
7520 J. Org. Chem. Vol. 74, No. 19, 2009

Nebot et al.
JOCNote
10 min at 0 °C, diluted with CH2Cl2 (1 mL), and further stirred
for 10 min at room temperature, which afforded an almost
colorless solution. This (i-PrO)2TiCl2 (1.1 mmol) solution in
CH2Cl2 (2 mL) was carefully added via cannula (þ1 mL of
CH2Cl2) to a solution of 1 or 2 (1 mmol) in CH2Cl2 (2 mL) at
-78 °C under N2, which developed a yellow-orange color. It was
stirred for 3-4 min at -78 °C, and i-Pr2NEt (190 μL, 1.1 mmol)
was dropwise added. The resultant mixture was stirred for
15 min at -78 °C and 1.5 h at -20 °C. Eventually, the color
of the reaction mixture became dark red. Then, it was cooled
at -78 °C, and a recently distilled aldehyde (1.5 mmol) was added.
The mixture was stirred for 2 h at -78 °C and 1 h at -20 °C. The
reaction was quenched by addition of satd NH4Cl (5 mL). The
mixture was diluted with Et2O and washed with H2O, satd
NaHCO3, and brine, and the aqueous layers were extracted with
Et2O. The organic extracts were dried and concentrated. The
residue was analyzed by 1H NMR and purified by column
chromatography to afford the desired aldols 4 or 6. Note: Aldols
6 must be handled with care. They must be concentrated at room
temperature, kept in the refrigerator (-20 °C), and used within
weeks.
(50 mg, 141 μmol) and NaN3 (9.7 mg, 149 μmol) in DMSO
(0.5 mL) was stirred at room temperature for 2 h under N2. The
reaction mixture was diluted with Et2O and washed with H2O
and brine. The aqueous layers were extracted with Et2O, and the
organic extracts were dried and concentrated. The resultant oil
was purified by column chromatography (hexanes/EtOAc
80:20) to afford 37.5 mg (84% yield) of 10 as a colorless oil: Rf
(hexanes/EtOAc 80:20)=0.50; [R]20D þ84.7 (c 1.1, CHCl3); IR
(film) ν 3503, 2960, 2860, 2103, 1725, 1471 cm-1; 1H NMR (400
MHz, CDCl3) δ4.36 (1H, q, J=6.8 Hz), 4.23 (1H, d, J=8.6 Hz),
3.78 (1H, ddd, J=8.6 Hz, J=7.4 Hz, J=3.7 Hz), 2.49 (1H, d, J=
7.4 Hz), 2.01-1.90 (1H, m), 1.38 (3H, d, J=6.8 Hz), 1.03 (3H, d,
J=6.9 Hz), 0.96 (3H, J=6.8 Hz), 0.93 (9H, s), 0.15 (3H, s), 0.13
(3H, s); 13C NMR (100.6 MHz, CDCl3) δ 210.3, 75.6, 74.4, 60.9,
30.5, 25.8, 19.9, 19.4, 18.1, 15.3, -4.8, -4.8; HRMS (þFAB) m/
z calcd for C14H30N3O3Si [M þ H]þ 316.2050, found 316.2050.
Preparation of S-[(2S,4S,5S,6E)-2-(tert-butyldimethylsilyl-
oxy)-5-hydroxy-3-oxo-6-octen-4-yl] Thioacetate (14). A mixture
of 6e (36 mg, 102 μmol) and AcSK (12.3 mg, 108 μmol) in 40:8:1
THF/DMSO/H2O (1 mL) was stirred for 20 min at room
temperature under N2. The reaction mixture was partitioned
with 1:1 CH2Cl2/pH 7 phosphate buffer, and the aqueous layer
was extracted with CH2Cl2. The organic extracts were dried and
concentrated. The resultant oil was purified through column
chromatography (hexanes/EtOAc 85:15) to afford 32 mg (90%
yield) of 14 as a colorless oil: Rf (hexanes/EtOAc 85:15)=0.25;
6a: Rf (hexanes/EtOAc 90:10) = 0.25; [R]20 þ68.7 (c 1.1,
D
CHCl3); IR (film) ν 3529, 2960, 2860, 1717, 1472 cm-1; 1H NMR
(400 MHz, CDCl3) δ5.06 (1H, d, J=3.1 Hz), 4.34 (1H, q, J=
6.8 Hz), 3.43 (1H, dt, J=7.8 Hz, J=3.1 Hz), 3.31 (1H, d, J=3.1
Hz), 1.91-1.79 (1H, m), 1.51 (3H, d, J=6.8 Hz), 1.05 (3H, d, J=
6.6 Hz), 0.93 (9H, s), 0.91 (3H, d, J=6.8 Hz), 0.12 (3H, s), 0.09
(3H, s); 13C NMR (100.6 MHz, CDCl3) δ 208.9, 75.0, 73.9, 48.6,
31.6, 25.7, 22.9, 18.8, 18.3, 18.0, -4.5, -5.0; HRMS (þESI) m/z
calcd for C14H3079BrO3Si [M þ H]þ 353.1142, found 3053.1139.
Preparation of (2S,4S,5S)-2-(tert-Butyldimethylsilyloxy)-4,
5-epoxy-6-methyl-3-heptanone (8). A mixture of 6a (87 mg,
0.25 mmol) and K2CO3 (171 mg, 1.24 mmol) in 50:10:1 THF/
DMSO/H2O (2.4 mL) was stirred for 3 h at room temperature
under N2. The reaction mixture was partitioned in 1:1 Et2O/
H2O (50 mL), and the aqueous layer was extracted with Et2O
(15 mL). The organic extracts were dried and concentrated. The
resultant oil was purified through column chromatography
(hexanes/EtOAc 90:10) to afford 58 mg (86% yield) of 8 as a
[R]20 -65.2 (c 0.5, CHCl3); IR (film) ν 3475, 2930, 2857,
D
1702 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.75 (1H, dqd, J=
15.2 Hz, J=6.5 Hz, J=1.0 Hz), 5.45 (1H, ddq, J=15.2 Hz, J=
6.9 Hz, J=1.6 Hz), 4.93 (1H, d, J=7.1 Hz), 4.36 (1H, q, J=
6.8 Hz), 4.36-4.28 (1H, m), 3.02 (1H, d, J=7.6 Hz), 2.32 (3H, s),
1.69 (3H, ddd, J=6.5 Hz, J=1.6 Hz, J=1.0 Hz), 1.33 (3H, d, J=
6.8Hz), 0.94(9H, s), 0.16 (3H, s), 0.13 (3H, s);13CNMR(75.4MHz,
CDCl3) δ 209.7, 193.8, 130.1, 129.6, 74.5, 73.3, 51.4, 30.1, 25.7,
19.7, 18.0, 17.6, -4.7, -4.9; HRMS (þESI) m/z calcd for
C16H30NaO4SSi [M þ Na]þ 369.1526, found 369.1511.
Acknowledgment. Financial support from the Spanish
Ministerio de Ciencia y Tecnologıa and Fondos FEDER
(Grant No. CTQ2006-13249/BQU) and the Generalitat de
Catalunya (2005SGR00584), as well as a doctorate stu-
dentship to J.N. (Universitat de Barcelona), are acknowl-
edged.
colorless oil: Rf (hexanes/EtOAc 90:10) = 0.35; [R]20 -55.1
D
1
(c 0.65, CHCl3); IR (film) ν 2961, 2859, 1729, 1471 cm-1; H
NMR (400 MHz, CDCl3) δ4.37 (1H, q, J=6.7 Hz), 4.09 (1H, d,
J=4.9 Hz), 2.97 (1H, dd, J=9.4 Hz, J=4.9 Hz), 1.43-1.33
(1H, m), 1.32 (3H, d, J=6.7 Hz), 1.11 (d, J=6.6 Hz), 0.93 (9H, s),
0.91 (d, J=6.8 Hz), 0.14 (3H, s), 0.13 (3H, s);13C NMR (100.6 MHz,
CDCl3) δ 207.4, 74.4, 65.1, 57.8, 26.2, 25.6, 20.0, 19.9, 18.4, 17.9,
-4.5, -5.2; HRMS (þFAB) m/z calcd for C14H29O3Si [M þ H]þ
273.1886, found 273.1898.
Supporting Information Available: Experimental proce-
dures, physical and spectroscopic data for ketones 1 and 2,
aldols 4 and 6, and derivatives 8-11, 13, and 14 and proof of
stereochemistry of 4a and 6a. This material is available free of
charge via the Internet at http://pubs.acs.org.
Preparation of (2S,4S,5S)-4-Azido-2-(tert-butyldimethylsilyl-
oxy)-5-hydroxy-6-methyl-3-heptanone (10). A mixture of 6a
J. Org. Chem. Vol. 74, No. 19, 2009 7521