Novel isomerically pure tetrasubstituted allylboronates: Stereocontrolled synthesis of α-exomethylene γ-lactones as aldol-like adducts with a stereogenic quaternary carbon center

Article abstract of DOI:10.1021/ja016391e

In spite of their inherent isomerization tendency and low reactivity, 1-alkoxycarbonyl vinylcopper(I) intermediates from the conjugate addition of organocuprates onto acetylenic esters were trapped with very high cis-addition selectivity with iodomethylboronic esters in the presence of HMPA. The resulting isomerically pure 3,3-disubstituted allylboronates react with aldehydes in a highly diastereo- and enantioselective manner, providing α-exomethylene γ-lactones with a stereogenic quaternary β-carbon center. Copyright

Full text of DOI:10.1021/ja016391e

Published on Web 01/15/2002
Novel Isomerically Pure Tetrasubstituted Allylboronates: Stereocontrolled
Synthesis of r-Exomethylene γ-Lactones as Aldol-Like Adducts with a
Stereogenic Quaternary Carbon Center
Jason W. J. Kennedy and Dennis G. Hall*
Department of Chemistry, UniVersity of Alberta, Edmonton, Alberta, T6G 2G2, Canada
Received June 12, 2001
The stereoselective construction of chiral quaternary carbon
centers is one of the most difficult transformations in organic
synthesis.1 There are very few general methods available for
realizing this task in a highly diastereo- and enantiocontrolled
fashion.2 Aldol-based methodologies are generally not applicable
due to the lack of E/Z selectivity in the enolization of R,R-
disubstituted carbonyl compounds.3 Similarly, with respect to
stereogenic quaternary carbons (eq 1), a significant limitation of
allylboration methodology4 resides in the preparation of the required
3,3-disubstituted allylboronates (R1, R2 ) alkyl or aryl) with high
E/Z isomeric purity.
Figure 1. Formation of 2-alkoxycarbonyl allylboronates by tandem
carbocupration of alkynoate esters/electrophilic trapping with 8.
Table 1. Preparation of Isomerically Pure Tetrasubstituted
Allylboronates 9 from cis-Addition between 1 and 2 in THFa
1
2
c
entry
R
R
R′
additive
product yieldb (%) ratio 9:10
These reagents cannot be synthesized readily from reactive
allylmetal species and borate esters.5 One alternate route features
the reaction of configurationally stable alkenylmetal reagents with
halomethylboronates.6 A caveat to this approach, however, is the
need for a very reactive metal (e.g., Li, Mg) and the consequent
lack of functional group compatibility. For instance, although
alkenylcopper reagents are easily accessed from alkynes, they need
to be transmetalated to lithium, via the corresponding iodide, for
efficient trapping with a chloromethylboronic ester to provide 3,3-
disubstituted allylboronates.7 Herein, we report a direct entry into
a new class of tetrasubstituted 2-alkoxycarbonyl allylboronates,8
generated as pure isomers in a single operation by the carbo-
cupration of readily available alkynoate esters. Subsequent addition
to aldehydes affords R-methylene-γ-lactones as aldol-like adducts
with a stereogenic, quaternary â-carbon center in very high
diastereo- and enantioselectivity. These lactones are part of a family
of biologically important compounds with significant interest in
organic synthesis.9
The conjugate addition of organocopper reagents to acetylenic
esters is a prime method to access isomerically pure, trisubstituted
R,â-unsaturated esters.10 Unfortunately, extensions toward synthe-
sizing tetrasubstituted alkenes11 have been hampered by the low
reactivity of 1-alkoxycarbonyl vinylcopper(I) intermediate 3 and
its tendency to isomerize via a copper allenoate (4) at temperatures
above -30 °C (Figure 1).12 Yet we anticipated that halomethyl-
boronates (6-8) could be sufficiently reactive, under optimal
conditions, to trap 3 with no loss of stereochemical integrity and
afford tetrasubstituted allylboronates 9 with overall cis-addition.
Our first investigations focused on optimizing conditions for the
preparation of allylboronate 9a using ethyl 2-butynoate and
Me2CuLi (Table 1). Initially, it was clear that electrophiles 6 and
7 lacked the requisite reactivity to trap the sluggish intermediate
3. Satisfactorily, the more potent iodo analogue (8)13 was found to
be effective, although poor yield and selectivity were observed in
1
2
3
4
5
6
7
8
9
Et
Et
Et
Et
Bu
Me
Me
H
Me
Me
Me
Me
Me
Bu
Me
Me
sBu Et
iBu Et
Et
Et
Et
Et
none
9a (Z)
43
>95
>95
>95
85
1.4:1
4:1
12:1
>20:1
>20:1
>20:1
-
>20:1
13:1
>20:1
19:1
>20:1
HMPA (1 equiv) 9a
HMPA (3 equiv) 9a
HMPA (9 equiv) 9a
Me DMPU (1:1)
Et
Et
9b (Z)
HMPA (9 equiv) 9c (E)
HMPA (9 equiv) 9d
>95
>95
>95
Me HMPA (9 equiv) 9e (E)
Me
HMPA (9 equiv) 9f (E)
HMPA (9 equiv) 9g (E)
70d
10e Me
11e Me
45d
60d
60d
allyl Me HMPA (9 equiv) 9h (E)
Me HMPA (9 equiv) 9i (Z)
12f POCH2 Me
a Allylboronates 9 were prepared as described in the text and Supporting
Information. b Unoptimized yields of crude products. c Ratio of cis-addition
to trans-addition products 9:10 (determined by 1H NMR). d Purified by flash
chromatography. e Made from Grignard reagents R2MgCl and CuBr. f P )
t-BuPh2Si.
THF alone as solvent (entry 1). As shown with entries 2-4, small
amounts of HMPA had a huge impact on the reaction. Not only
were the yields improved, but cis-addition products were obtained
almost exclusively with nine equiv. of HMPA.14 The use of DMPU
as cosolvent was also effective but yields were generally lower.
Cuprates formed from Grignard reagents work equally well.
Through using the crucial combination of HMPA as additiVe and
iodomethylpinacol boronate as the electrophile, several tetrasub-
stituted allylboronates 9 were generated in very high cis-addition
selectivity. As shown with 9b and 9c (entries 5-6), permutation
of respective alkyne and cuprate R1 and R2 groups allows isomeric
allylboronates to be made independently. Functionalized acetylenic
esters can also serve as effective precursors. In this respect,
allylboronate 9i bears a versatile, masked formyl group at the R1
position (entry 12).
A small excess (1.5 equiv) of the crude allylboronates 9 were
treated immediately with various aliphatic and aromatic aldehydes
(Table 2). While the reactions are rather slow, they are operationally
simple and even those with p-MeO-benzaldehyde (a notoriously
9
898 VOL. 124, NO. 6, 2002 J. AM. CHEM. SOC.
10.1021/ja016391e CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Stereocontrolled Synthesis of γ-Lactones 12
In summary, by overcoming the inherent isomerization tendency
and low reactivity of 1-alkoxycarbonyl vinylcopper(I) intermediates,
we have developed the first direct and general entry into isomeri-
cally pure 3,3-disubstituted 2-alkoxycarbonyl allylboronates. These
allylboronates add onto aldehydes, in a highly diastereo- and
enantioselective manner, to afford R-exomethylene γ-lactones with
a stereogenic quaternary â-carbon center. These adducts are not
attainable using standard aldol-based methodologies.
1
2
3
entry boronate (R ,R )
aldehyde (R )
conditionsa product yield (%)b
drc
1
2
3
4
5
6
9a (Et, Me)
9a (Et, Me)
9a (Et, Me)
9a (Et, Me)
9b (Bu, Me)
9c (Me, Bu)
C6H5
A
B
C
B
B
D
E
A
B
A
C
C
B
12a
12b
12b
12c
12d
12e
12f
12g
12h
12i
89
70
55
81
76
67
75
68
60
26
65
48
75
>20:1
19:1
20:1
>20:1
>20:1
>20:1
4-MeO-C6H4
4-MeO-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
PO(CH2)2
C9H19
C6H5
4-NO2-C6H4
4-MeO-C6H4
4-MeO-C6H4
Acknowledgment. This work was funded by the Natural
Sciences and Engineering Research Council (NSERC) of Canada
and the University of Alberta. Further support from a Boehringer
Ingelheim Young InVestigator Award for Organic Chemistry to
D.G.H. is gratefully acknowledged. J.W.J.K. thanks NSERC and
the Alberta Heritage Foundation for Medical Research (AHFMR)
for graduate scholarships. The authors thank Mr. Naheed Rajabali
for the preparation of 13-H2.
7d 9d (Me, Me)
8
9
9a (Et, Me)
9e (H, Me)
18:1
>20:1
15:1e
>20:1
f
10 9f (Me, sBu)
11 9g (Me, iBu)
12 9h (Me, allyl)
12j
12k
12l
13d 9i (POCH2, Me) 4-NO2-C6H4
>20:1
Supporting Information Available: Experimental details, char-
acterization data (IR, NMR, MS), and spectral reproductions for all
allylboronates and lactones (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
a Reaction scale: approximately 1 mmol. Methods. A: toluene, rt, >12
d; B: toluene, 80 °C, 16-120 h; C: toluene, 110 °C, 16-24 h; D: CH2Cl2,
40 °C, 48 h; E: neat, rt, >12 d. b Unoptimized yields of pure products
isolated after flash chromatography (for 12j and 12l) and Kugelrohr
distillation (12a-i,k). c Determined by 1H NMR or HPLC. d P ) t-BuPh2Si.
e 1:1 mixture of epimers at the s-butyl side chain center. f The [3,3]
rearrangement product was isolated.
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(18) Made from the trapping of 3 with ICH2B(O-i-Pr)2.
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OD, Daicel).16 The sense of induction has not yet been assigned.
JA016391E
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