Super silyl group for a sequential diastereoselective aldol- polyhalomethyllithium addition reaction

Article abstract of DOI:10.1021/ol702825p

The super silyl group governs high diastereoselectivity and yields for a sequential aldol-polyhalomethyllithium addition reaction. This unique silyl group is necessary to obtain the diastereoselectivties associated with this sequential reaction, capable o

Full text of DOI:10.1021/ol702825p

ORGANIC
LETTERS
2008
Vol. 10, No. 3
453-455
Super Silyl Group for a Sequential
Diastereoselective
Aldol−Polyhalomethyllithium Addition
Reaction
Matthew B. Boxer and Hisashi Yamamoto*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
yamamoto@uchicago.edu
Received November 21, 2007
ABSTRACT
The super silyl group governs high diastereoselectivity and yields for a sequential aldol
silyl group is necessary to obtain the diastereoselectivities associated with this sequential reaction, capable of generating two new stereocenters.
-Polyhalomethylcarbinols are generated with the simple and inexpensive dihalomethanes and trihalomethanes.
−polyhalomethyllithium addition reaction. This unique
r
Halogens have a long-standing importance in chemistry
and have received considerable attention due to their
abundance and distinct reactivity. Polyhalomethanes (PHa-
Ms) are small, inexpensive molecules that are able to
create a variety of functional groups as electrophiles (halo-
gens as leaving group) and nucleophiles (after metal-halogen
exchange). Currently, fluoro and chloro compounds are
receiving considerable attention due to their special reactivity
in biological settings as well as crop management.1 They
have often conferred resumed anticancer and antibacterial
activity on otherwise drug-resistant strains of bacteria. While
the importance of these halogens is obvious, stereo
controlled introduction of the polyhalomethyl group is
still of importance and not widely achievable.2 One of
the most straightforward pathways to generate these
useful derivatives would be the nuceloephilic addition of
the polyhalomethyllithiums (PHaMLis) to aldehydes
(Scheme 1).
Scheme 1. Generation of PhaMLi and Addition of an
Aldehyde
The potential difficulties with this approach would be a
lack of control in the stereochemistry of the addition as well
as dealing with the instability of such species.3 We have
(2) For one example of modest diastereoselectivity, see: Mukaiyama,
T.; Yamaguchi, M.; Kato, J.-I. Chem. Lett. 1981, 10, 1505. Select examples
of nonstereocontrolled reactions: (a) Taguchi, H.; Yamamoto, H.; Nozaki,
H. J. Am. Chem. Soc. 1974, 96, 3010. (b) Villieras, J.; Perriot, P.; Normant,
J. F. Synthesis 1979, 968. (c) Benner, J. P.; Gill, G. B.; Parrott, S. J.; Wallace,
B. J. Chem. Soc. Perkin Trans. 1 1984, 331. (d) Teager, D. S.; Ward, H.
D.; Marray, Jr. R. K. J. Org. Chem. 1993, 58, 5493. (e) Hu, D.-M.; Tu,
M.-H. J. Fluorine Chem. 1994, 67, 9. (f) Concello´n, J. M.; Bernad, P. L.;
Pe´rez-Andre´s, J. A. Tetrahedron Lett. 1998, 39, 1409.
(1) (a) Naumann, K. J. Prakt. Chem. 1999, 341, 417. (b) Isanbor, C.;
O’Hagan, D. J. Fluorine Chem. 2006, 127, 303. (c) Kirk K. L. J. Fluorine
Chem. 2006, 127, 1013. (d) Le´ze´, M.-P.; Le Borgne, M.; Pinson, P.;
Palusczak, A.; Duflos, M.; Le Baut, G.; Hartmann, R. W. Bioorg. Med.
Chem. Lett. 2006, 16, 1134.
(3) (a) Ko¨brich, G. Angew. Chem., Int. Ed. Engl. 1967, 6, 41. (b) Hoeg,
D. F.; Lusk, D. I. J. Am. Chem. Soc. 1964, 86, 928. (c) Kirmse, W. Carbene
Chemistry, 2nd ed.; Academic Press: New York, 1971.
10.1021/ol702825p CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/09/2008

recently reported a one-pot stereoselective cascade and
sequential aldol reactions (SA reactions) based on a super
silyl/super Brønsted acid system.4 Since the requisite acid
catalyst is present at only 0.05 mol % and the reaction
proceeds in a non-protic solvent, we envisioned being able
to couple the reaction with sequential C-C bond formation
using PhaMLis (Scheme 2). One-pot, sequential, and mul-
Table 1. Solvent/Temperature Screening for Sequential
Aldol-PhaMLi Addition Reaction
entrya diluting solvent base solvent T (°C) % yieldb
drc
Scheme 2. In Situ Generation of PhaMLi
1
2
3
4
5
6
7
8
none
THF
THF
Et2O
toluene
toluene
THF
THF
THF
THF
Et2O
THF
Et2O
THF
-30
-30
-78
-78
-78
-78
-100
trace nd
<10 60/30/5/5
68 80/10/5/5
65 70/20/5/5
50 70/20/5/5
35 66/24/5/5
72 85/5/5/5
70 73/17/5/5
ticomponent reactions are garnering significant attention due
to their many economic advantages.5 To this end, this
reaction sequence is amenable to these conditions. We now
wish to report the acetaldehyde super silyl enol ether’s use
in conjunction with PhaMLis generated in situ by deproto-
nation of polyhalomethyls with the bulky lithium amide
LiTMP (TMP ) 2,2,6,6-tetramethylpiperidine). The entire
process proceeds smoothly with high stereoselectivities due
to the efficient stereocontrol exhibited by the super silyl
group.
It should be noted that PHaMLi species are rather unstable
even at low temperature.2,3 However, if a solution of aldehyde
in the presence of excess PHaMs is treated with the lithium
amide, the kinetically generated lithium carbenoid specie
reacts with the aldehyde before side reactions and decom-
position occur.3a
2-Me-THF
2-Me-THF -100
a General reaction protocol: 1 mmol of silyl enol ether and 1 mmol of
aldehyde in the indicated solvent were cooled to the indicated temperature,
and a solution HNTf2 was added dropwise. After 15 min, the polyhalom-
ethane and THF were added, and the solution was cooled to -100 °C.
Lithium amide was then added dropwise and the solution stirred for 1 h at
-100 °C. b Isolated yield. c Determined by H NMR.
1
which all generated the syn-diols.7 Dichloromethyllithium
gave the lowest diastereoselectivities, producing 2 and 3 with
moderate selectivity. It is particularly noteworthy that the
initial aldol reaction in entry 2 (Table 2) highly discriminates
an ethyl group from a methyl group,8 showcasing the power
Using our standard aldol reaction of the super silyl enol
ether and 2-phenylpropionaldehyde,4b we screened a variety
of solvents and temperatures for the diastereoselective
sequential addition of the dibromomethyllithium to generate
the R-dibromomethylcarbinol 1 (Table 1). Dichloromethane
could not be used due to competitive deprotonation of the
dichloromethane molecule, so dichloroethane was used (high
Felkin selectivity still observed for initial aldol).6 After
completion of the aldol reaction (15 min at -30 °C), the
solution was diluted with another solvent and cooled to the
indicated temperature. It was found that temperatures at or
below -78 °C were necessary for good selectivities and
yields likely due to high reactivity and stability issues of
the carbenoid species (entries 1-3). Diethyl ether and toluene
gave similar results, while THF gave slightly better results
at -78 °C (compare entry 3 to entries 4-6). Cooling to
-100 °C and comparing THF and 2-Me-THF showed a
somewhat surprisingly large difference in selectivity between
the solvents. Clearly, THF was the superior choice, and these
conditions were taken forward.
Table 2. Sequential One-Pot Aldol-PhaMLi Addition
Reaction
Naturally, the scope of the reaction was next investigated
using a variety of aldehydes as well as different PhaMLi’s,
(4) (a) Boxer, M. B.; Yamamoto, H. Org. Lett. 2005, 7, 3127. (b) Boxer,
M. B.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 48. (c) Boxer, M. B.;
Yamamoto, H. Nat. Protocols 2006, 1, 2434-2438. (d) Boxer, M. B.;
Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 2762.
(5) (a) Hall, N. Science 1994, 266, 32. (b) Tietze, L. F.; Beifuss, U.
Angew. Chem., Int. Ed. Engl. 1993, 32, 131.
a General reaction protocol: 1 mmol of silyl enol ether and 1 mmol of
aldehyde in the indicated solvent were cooled to the indicated temperature,
and a solution HNTf2 was added dropwise. After 15 min, the polyhalom-
ethane and THF were added, and the solution was cooled to -100 °C.
Lithium amide was then added dropwise and the solution stirred for 1 h at
1
-100 °C. b Isolated yield. c Determined by H NMR.
(6) Felkin selectivity is 90/10, which is similar to when dichloromethane
is used (see ref 4b).
454
Org. Lett., Vol. 10, No. 3, 2008

of the super silyl aldol reaction. After proceeding under high
Felkin control, the sequential PHaMLi addition is also quite
selective. The bigger chloroform derived anion shows a
significant increase in diastereoselectivitiy generating 4 in a
90/10 syn/anti ratio (entry 3). The best selectivity was
obtained with the largest tribromomethyllithium anion, giving
5 in high yield with high syn selectivity (entry 4). Di-
iodomethane is also successfully deprotonated under these
conditions and adds with high selectivity to give R-diiodom-
ethylcarbinols 6 and 7 in good yield. Use of iodoform under
a variety of conditions and temperatures did not yield any
desired R-triiodocarbinol presumably due to solubility prob-
lems of iodoform at lower temperatures.
A mixed R-polyhalomethylcarbinol was also synthesized
using the method of Kuroboshi.9 The aldol reaction was
performed under standard conditions, and after dilution with
THF/Et2O (2/1) and addition of CFBr3 the solution was
cooled to -130 °C. Br2FCLi was prepared in situ by lithium
bromine exchange with n-BuLi. The R-dibromofluoro-
carbinol 8 was produced in moderate yield with good
selectivity (Scheme 3). This product could be converted to
the (Z)-R-haloenol ester 9 by use of CrCl2 in refluxing THF.10
Scheme 4. Transformations to Vinyl Halides
for the bromo and iodo derivatives were near perfect, while
the chloro compound was less reactive and gave a lower
selectivity as well. The R-trichlorocarbinol adduct was
transformed to the vinylidene dichloride by conversion to
the mesylate and subsequent treatment with In metal in
refluxing DMF.13
In order to access the vinyl fluoride (not accessible via
aforementioned route due to the difficulty in generating
difluoromethyllithium), a survey of the literature uncovered
a report using CFCl3 and Bu3P to generate a unique species
capable of Wittig-type olefinatin to generate Z-vinyl fluo-
rides.14 This sequential reaction sequence succeeded in which
the aldol reaction was followed by addition to the in situ
prepared Bu3P-CF-PBu3Cl. After the mixture was stirred
for 12 h, 10% NaOH was added and stirring continued for
12 h. This NaOH-induced hydrolysis of the vinyl phospho-
nium moiety generated the Z-vinyl fluoride in moderate yield
with very high selectivity (Scheme 5).
Scheme 3. Synthesis of a Mixed R-Halomethylcarbinol and
Its Conversion to the (Z)-R-Haloenol Ester
Scheme 5. One-Pot Synthesis of Z-Vinyl Fluoride
We next decided to endeavor on a few useful transforma-
tions of some of the aforementioned products. The utility of
vinyl halides is widely known in synthetic chemistry,11 and
the conversion to these compounds was done with a simple
two-step one-purification sequence. The R-dihalocarbinol
adducts were converted to the acetate and treated with SmI2
in THF at room temperature for a clean conversion to the
Z-vinyl halides (Scheme 4).12 The yields and selectivities
In conclusion, we have described a sequential reaction
protocol capable of generating R-polyhalomethylcarbinols
in good yield with high selectivity. Clean and easy conver-
sion to the vinyl halides is also achieved with high diaste-
reoselectivity. The use of the super silyl group goverened
aldol reaction is a key for obtaining the high selectivities.
Further utility of this unique silyl group is being in-
vestigated.
(7) Relative stereochemistry determined by conversion to the ac-
etonides: Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993,
58, 3511.
Acknowledgment. M.B.B. thanks Novartis Pharmaceu-
(8) Aldol proceeds with 86/14 Felkin selectivity. See the Supporting
Information for conversion to known compounds.
ticals for the ACS Division of Organic Chemistry Fellowship.
(9) Kuroboshi, M.; Yamada, N.; Takebe, Y.; Hiyama, T. Synlett 1995,
987.
Supporting Information Available: Experimental pro-
cedures, compound characterization, and spectra. This mate-
rialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
(10) Bejot, R.; Tisserand, S.; Reddy, L. M.; Barma, D. K.; Baati, R.;
Falck, J. R.; Mioskowski, C. Angew. Chem., Int. Ed. 2005, 44, 2008.
(11) Trost, B. M.; Fleming, I.; Semmelhack, M. F. ComprehensiVe
Organic Synthesis; Pergamon Press: Oxford, 1991; Vol. 4, pp 851-856.
(b) Katritzky, A. R.; Meth-Cohn, O.; Rees, C. W.; Ley S. V. ComprehensiVe
Organic Functional Group Transformations; Pergamon Press: Oxford,
1995; Vol. 2, p 605. (c) Negishi, E.; de Meijere, A.; Ba¨ckvall, J. E.; Cocchi,
S.; Hayashi, T.; Ito, Y.; Kosugi, M.; Murahashi, S. I.; Oshima, K.;
Yamamoto, Y. Organopalladium Chemistry for Organic Synthesis; John
Wiley & Sons, Inc.: New York, 2002; Vols. 1 and 2. (d) Liu, F.; Loh,
T.-P. Org. Lett. 2007, 9, 2063.
OL702825P
(12) Concello´n, J. M.; Rodr´ıguez-Solla, H.; Huerta, M.; Pe´rez-Andre´s,
J. A. Eur. J. Org. Chem. 2002, 1839.
(13) Ranu, B. C.; Samanta, S.; Das, A. Tetrahedron Lett. 2002, 43, 5993.
(14) Cox, D. G.; Gurusamy, N.; Burton, D. J. J. Am. Chem. Soc. 1985,
107, 2811.
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