Highly diastereoselective addition of cinnamylzinc derivatives to α-chiral carbonyl compounds

Article abstract of DOI:10.1021/ol702607t

Cinnamylzinc reagents react with cyclic and acyclic α-chiral ketones under very mild conditions (-78°C, 1 h), yielding the corresponding homoallylic alcohols bearing three adjacent Stereocenters with high diastereoselectivity. An extension of this reactio

Full text of DOI:10.1021/ol702607t

ORGANIC
LETTERS
2008
Vol. 10, No. 1
117-120
Highly Diastereoselective Addition of
Cinnamylzinc Derivatives to
Carbonyl Compounds
r-Chiral
Guillaume Dunet, Peter Mayer, and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t,
Butenandtstrasse 5-13, 81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received October 26, 2007
ABSTRACT
Cinnamylzinc reagents react with cyclic and acyclic
r
-chiral ketones under very mild conditions (
−78
°
C, 1 h), yielding the corresponding
homoallylic alcohols bearing three adjacent stereocenters with high diastereoselectivity. An extension of this reaction to enantioenriched
-chiral ketones is also described.
r
The stereoselective formation of a carbon-carbon bond is
of greatest importance in asymmetric synthesis. Especially
challenging is the stereoselective generation of quaternary
centers.1 This can nonetheless be achieved by the addition
of allyl metals to carbonyl derivatives.2 Although allylic
lithium and magnesium reagents display a high reactivity,
they are unstable and their synthesis can be difficult.3
Recently, we have shown that allylic zinc reagents offered
a good alternative.4 They can be readily prepared from the
corresponding allylic chlorides or phosphates via a LiCl-
mediated direct zinc insertion in high yields, and they react
diastereoselectively with carbonyl derivatives under very
mild conditions (-78 °C, 1 h). Herein, we wish to report
that allylic zinc reagents add also to R-chiral ketones, leading
to the corresponding homoallylic alcohols bearing three
adjacent stereocenters in a highly diastereoselective manner
(Table 1 and Scheme 1). Thus, when cinnamylzinc phosphate
(1a) was reacted with 2-methylcyclohexanone (2a) at -78
°C, the reaction was complete after 1 h and the homoallylic
alcohol 3a was isolated in 90% yield as a single diastereo-
isomer (dr ) 99:1; Scheme 1).5
(1) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388. (b) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40,
4591. (c) d’Augustin, M.; Palais, L.; Alexakis, A. Angew. Chem., Int. Ed.
2005, 44, 1376. (d) Sklute, G.; Amsallem, D.; Shabli, A.; Varghese, J. P.;
Marek, I. J. Am. Soc. Chem. 2003, 125, 11776. (e) Sklute, G.; Marek, I. J.
Am. Soc. Chem. 2006, 128, 4642. (f) Breit, B.; Demel, P.; Studte, C. Angew.
Chem., Int. Ed. 2004, 43, 3785. (g) Li, H.; Walsh, P. J. J. Am. Soc. Chem.
2004, 126, 6538. (h) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc.
2002, 124, 898. (i) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123,
9488. (j) Denmark, S. E.; Fu, J. Org. Lett. 2002, 4, 1951. (k) Heo, J.-N.;
Micalizio, G. C.; Roush, W. R. Org. Lett. 2003, 5, 1693.
(2) For allylmetal additions, see: (a) Chemler, S. R.; Roush, W. R. In
Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim,
Germany, 2000; Chapter 10. (b) Denmark, S. E.; Almstead, N. G. In Modern
Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, Germany,
2000; Chapter 11. (c) StereoselectiVe Synthesis, Methods of Organic
Chemistry (Houben-Weyl), E21 ed.; Helmchen, G., Hoffmann, R., Mulzer,
J., Schaumann, E., Eds.; Thieme: Stuttgart, 1996; Vol. 3. (d) Yasuda, M.;
Hirata, K.; Nishino, M.; Yamamoto, A.; Baba, A. J. Am. Chem. Soc. 2002,
124, 13442. (e) Thadani, A. N.; Batey, R. A. Org. Lett. 2002, 4, 3827. (f)
Li, S. W.; Batey, R. A. Chem. Commun. 2004, 1382. (g) Buse, C. T.;
Heathcock, C. H. Tetrahedron Lett. 1978, 1865. (h) Yamamoto, Y.; Yatagai,
H.; Naruta, Y.; Maruyama, K. J. Am. Chem. Soc. 1980, 102, 7107.
(3) (a) Czernecki, S.; Georgoulis, C. Bull. Soc. Chim. Fr. 1968, 3713.
(b) Courtois, G.; Miginiac, L. J. Organomet. Chem. 1974, 69, 1.
(c) Yamamoto, Y. Acc. Chem. ReV. 1987, 20, 243. (d) Yamamoto, Y.;
Asao, N. Chem. ReV. 1993, 93, 2207. (e) Schlosser, M.; Desponds, O.;
Lehmann, R.; Moret, E.; Rauchschwalbe, G. Tetrahedron 1993, 49,
10175. (f) Marshall, J. A. Chem. ReV. 2000, 100, 3163. (g) Denmark,
S. E.; Fu, J. Chem. ReV. 2003, 103, 2763. (h) Chabaud, L.; James, P.;
Landais, Y. Eur. J. Org. Chem. 2004, 3173. (i) Lipshutz, B. H.; Hackmann,
C. J. Org. Chem. 1994, 59, 7437. (j) Fu¨stner, A.; Voigtla¨nder, D. Synthesis
2000, 975. (k) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon: Oxford, 1991; Vol.
2, pp 1-53. (l) Kim, J. G.; Camp, E. H.; Walsh, P. J. Org. Lett. 2006, 8,
4413.
(4) Ren, H.; Dunet, G.; Mayer, P.; Knochel, P. J. Am. Chem. Soc. 2007,
129, 5376.
10.1021/ol702607t CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/08/2007

Table 1. Reaction of Cinnamylzinc Reagentsa with Cyclic
R-Chiral Ketones
Scheme 1. Diastereoselective Addition of Cinnamylzinc
Reagents to R-Chiral Ketones
lectivities (entries 2 and 3). Similarly, other heteroatom-
substituted cyclohexanones reacted smoothly with reagents
1a and 1b. Thus, the chloro- and thiophenyl-substituted
homoallylic alcohols (3e and 3f) were both isolated with dr
> 98:2 (entries 4 and 5). Under the same conditions, 3-(2-
oxocyclohexyl)propionitrile (2g) reacted with allylzinc re-
agent 1a, affording within 1 h at -78 °C compound 3g,
whose structure was confirmed by X-ray analysis (92%; dr
) 99:1; entry 6).6 Interestingly, when 2-phenylcyclohexanone
(2h) was reacted with cinnamylzinc phosphate (1a) under
the same conditions, the corresponding homoallylic alcohol
(3h) was isolated in 26% yield (dr ) 98:2; entry 7). This
may be explained by the competitive deprotonation of the
benzylic proton R to the keto function.7 Similarly, 2-meth-
ylcyclopentanone (2i) led to the alcohol 3i in 75% as a single
diastereoisomer when reacted with 1a (dr ) 99:1; entry 8).
The substitution pattern on the allylic system is important,
and a decreased diastereoselectivity was observed when the
substituted allylic reagent 1c was reacted with 2-methoxy-
cyclohexanone (2b), leading to the alcohol 3j in 90% yield
with dr ) 86:14 (entry 9).
The selectivity observed in this reaction can be rationalized
by considering a cyclic chair-like transition state (TS1),
where the allylic zinc reagent approaches from the sterically
less crowded side (opposite side of the methyl group, as
depicted in Scheme 1).
This addition proved to be a valuable tool to build
polycyclic systems. Thus, when 2-allylcyclohexanone was
added to cinnamylzinc phosphate (1a), the alcohol 3k was
obtained in 83% yield as a single diastereoisomer (dr )
99:1). Subsequent metathesis8 with Grubbs II catalyst9 (5
mol %) led to the bicyclic alcohol 4 in 93% yield, whose
structure was confirmed by X-ray analysis (Scheme 2).
Likewise, we have prepared spiro-tetrahydrofurans in a
two-step procedure starting from the homoallylic alcohols
3b and 3d (Scheme 3). After a hydroboration-oxidation
a Unless stated otherwise, all reactions were carried out with 1 mmol of
ketone and 1.2 mmol of allylic zinc reagent at -78 °C for 1 h. b The dr
was determined by NMR. c Isolated yield of analytically pure product.
d Structure determined by X-ray analysis.
This reaction could then be extended to various R-chiral
cyclohexanones, regardless of the substitution pattern in the
R-position of the keto function. Thus, R-methoxycyclohex-
anone (2b) reacted smoothly with 1a, leading to the
corresponding homoallylic alcohol (3b) in 87% yield and
dr ) 99:1 (entry 1 of Table 1) within 1 h at -78 °C.
Likewise, larger substituents such as an R-acetoxy or an
R-benzyloxy group led to the corresponding homoallylic
alcohols 3c and 3d in 83-90% yield and high diastereose-
(6) Crystallographic data for compounds 3c (CCDC 664517), 3g (CCDC
664518), 4 (CCDC 664519), 6b (CCDC 664520), and 8 (CCDC 664521)
are available free of charge via www.ccdc.cam.ac.uk/data-request/cif.
(7) Most of the ketone remained unreacted (GC analysis).
(8) For a review on ring-closing metathesis, see: Grubbs, R. H.; Miller,
S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446.
(5) When cinnamylzinc chloride (1b) was reacted with 2a, the alcohol
3a was isolated in 97% yield and dr ) 99:1.
(9) (a) Trnka, T. M; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (b)
Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751.
118
Org. Lett., Vol. 10, No. 1, 2008

Scheme 2. Synthesis of Bicyclic Alcohol 4
Scheme 4. Reaction of Cinnamylzinc Reagents with Acyclic
R-Chiral Ketones
Interestingly, when other 3-halobutan-2-ones were reacted
with cinnamylzinc chloride (1b) under the same reaction
conditions, the corresponding homoallylic alcohols were not
isolated; instead, epoxide 10 was obtained diastereoselec-
tively. Likewise, 3-tosyloxybutan-2-one led to epoxide 10
when reacted with cinnamylzinc chloride (1b; Scheme 5).
sequence, the corresponding diols 5a and 5b were cyclized
by the action of MsCl in the presence of Et3N, leading to
the spiro-compounds 6a and 6b in 55-78% yield.
Finally, the prepared alcohols were found to undergo a
selective epoxidation directed by the free OH group.10 Thus,
the homoallylic alcohol 2a was treated with m-CPBA to yield
the corresponding epoxide 7 in 82% yield as a single
diastereoisomer. Subsequent LiAlH4-mediated opening of the
epoxide led to the diol 8, bearing four contiguous stereo-
centers with a defined configuration (the structure of 8 was
confirmed by X-ray analysis).
Scheme 5. Synthesis of Epoxide 10
The reaction of allylic zinc reagents with acyclic R-sub-
stituted ketones was also studied. Thus, cinnamylzinc
chloride (1b) was treated with 3-chlorobutan-2-one in THF
at -78 °C. After 1 h, the homoallylic alcohol 9a was iso-
lated in 83% yield as a single diastereoisomer (dr g 98:2;
Scheme 4).
When others groups, such as Ph or SPh, were used as
substituents, the addition reaction afforded the corresponding
homoallylic alcohols with lower selectivity. Thus, the alcohol
9b was isolated in 87% yield (dr ) 91:9). Under the same
conditions, the thiophenyl alcohol 9c was obtained in almost
quantitative yield as a mixture of two diastereoisomers (96%;
dr ) 81:19).
In this case, the observed selectivity can be explained by
considering the Cornforth model.11
This diastereoselective addition could then be applied to
enantioenriched R-chiral ketones, affording the corresponding
homoallylic alcohols without loss of stereochemistry. Thus,
when (2S)-2-methoxycyclohexanone12 ((2S)-2b; 94% ee) was
treated with cinnamylzinc chloride (1b) at -78 °C for 1 h,
the corresponding alcohol (2S,1R,1′S)-3b was obtained in
81% yield (dr ) 99:1; 94% ee, Scheme 6).
Scheme 3. Synthesis of Spiro-Compounds 6a,b and Diol 8
Likewise, the reaction of (3R)-3-tosyloxybutanone13 with
1b led to the enantioenriched epoxide 10, which, upon
treatment with LiAlH4, afforded the homoallylic alcohol 11
in good yield (87%; dr ) 99:1; 99% ee; Scheme 7). This
(10) See: Houk, K. N.; Liu, J.; DeMello, N. C; Condroski, K. R. J. Am.
Chem. Soc. 1997, 119, 10147.
(11) (a) Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem.
Soc. 1959, 112. (b) Evans, D. A.; Siska, S. J.; Cee, V. J. Angew. Chem.,
Int. Ed. 2003, 42, 1761. (c) Cee, V. J.; Cramer, C. J.; Evans, D. A. J. Am.
Chem. Soc. 2006, 128, 2920.
(12) Prepared by the PDC oxidation of the commercially available (2S)-
methoxycyclohexan-(1S)-ol.
(13) Prepared from the commercially available (2R,3R)-butan-2,3-diol
in a two-step sequence: monotosylation and PDC oxidation.
Org. Lett., Vol. 10, No. 1, 2008
119

the corresponding homoallylic alcohols bearing three con-
tiguous stereocenters with high diastereoselectivity.14,15 These
alcohols proved to be a valuable tool to achieve the synthesis
of complex polycyclic compounds in a stereocontrolled man-
ner. This allyl metal addition was then applied to enantio-
enriched ketones, leading to the corresponding homoallylic
alcohols with retention of stereochemistry. Extensions of this
method are currently underway in our laboratories.
Scheme 6. Synthesis of Enantioenriched Homoallylic Alcohol
3a
Acknowledgment. We thank the DFG (SFB 749) and
the Fonds der Chemischen Industrie for generous financial
support. We thank Chemetall GmbH (Frankfurt), Degussa
AG (Hanau), and BASF AG for the generous gift of
chemicals.
result contrasts with the direct reaction of butanone with
cinnamylzinc chloride (1b) that displays a poor diastereo-
selectivity (dr ) 61:39), showing the advantage of our
approach.
In summary, we have shown that cinnamylzinc derivatives
add to various cyclic and acyclic R-chiral ketones, affording
Note Added after ASAP Publication. Products 3b-k in
Table 1 and Scheme 2 contained an extra carbon in the
version published ASAP December 8, 2007; the corrected
version was published ASAP December 12, 2007.
Supporting Information Available: Experimental pro-
cedures and full characterization of all compounds. This
material is available free of charge via Internet at http://
pubs.acs.org.
Scheme 7. Synthesis of Enantioenriched Homoallylic Alcohol
11
OL702607T
(14) Preparation of cinnamylzinc chloride (1a): LiCl (1 g, 25 mmol)
was placed in a nitrogen-flushed Schlenk flask and dried 3 min at 450 °C
under high vacuum (0.1 mbar). The operation was repeated before zinc
dust (2 g, 30 mmol) was added. The mixture was heated to 450 °C for
another 3 min under high vacuum. THF (5 mL) was subsequently added,
and the zinc was activated with DBE (0.1 mL) and TMSCl (0.05 mL). A
solution of cinnamyl chloride in THF (15 mL) was subsequently added at
25 °C, and the suspension was further stirred at this temperature for 1 h.
After centrifugation, the zinc species was titrated via iodolysis.
(15) Typical Procedure: Preparation of 2-methyl-1-(1-phenylallyl)-
cyclohexanol (3a): A solution of the 2-methylcyclohexanone (450 mg, 4
mmol) in THF (4 mL) was added dropwise to a solution of cinnamylzinc
phosphate (1a, 4.8 mmol, 1.2 equiv) at -78 °C. The resulting solution was
further stirred at this temperature for 1 h. The reaction was subsequently
quenched with water (1 mL) and extracted several times with diethyl ether.
The organic phases were combined, dried over MgSO4, and concentrated
to afford a crude product. Purification by flash chromatography (eluent:
pentane/ether ) 8:2 + 1% Et3N) provided the pure compound 3a (824 mg,
90%) as a colorless oil (dr ) 99:1).
120
Org. Lett., Vol. 10, No. 1, 2008