Enantioselective synthesis of 1,5-anti- and 1,5-syn-diols using a highly diastereoselective one-pot double allylboration reaction sequence

Article abstract of DOI:10.1021/ja028055j

Highly diastereo- and enantioselective syntheses of 1,5-disubstituted (E)-1,5-anti-pent-2-endiols 1 and (Z)-1,5-syn-pent-2-endiols 2 have been achieved via the one-pot coupling of two different aldehydes with either (E)-γ-(1,3,2-dioxaborinanyl)-allyl]diis

Full text of DOI:10.1021/ja028055j

Published on Web 10/26/2002
Enantioselective Synthesis of 1,5-anti- and 1,5-syn-Diols Using a Highly
Diastereoselective One-Pot Double Allylboration Reaction Sequence
Eric M. Flamme and William R. Roush*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055
Received August 8, 2002
Table 1. Syntheses of (E)-1,5-anti-Diols from a Single Aldehydea
In connection with an ongoing problem in natural products
synthesis, we were interested in developing a method for the
diastereo- and enantioselective synthesis of 1,5-anti- and 1,5-syn-
diols 1 and 2 via the reactions of two different aldehydes, R1CHO
and R2CHO, with a chiral, 1,3-bifunctionalized allylmetal reagent.1-3
This represents a fundamentally interesting problem in organic
1
c
entry
R CHO
productb
%yield
%eed
synthesis, for which practical solutions do not currently exist. While
1
Ph(CH2)2CHO
Ph(CH2)2CHO
C6H11CHO
(CH3)2CHCHO
BnOCH2CHO
PhCHO
9a
ent-9a
9b
9c
9d
9e
ent-9e
9f
38
42
38
34
42
40
42
34
91
92
84
82
92
93
95
92
2e
3
4
5
6
7e
8
PhCHO
(CH3)3CCHO
a Reactions were performed by treating 1 equiv of 3 with Ipc2BH (1
equiv) in Et2O at 0 °C followed by the addition of 1.4 equiv of R1CHO at
-78 °C. The mixture was then allowed to stir at 23 °C for 24 h. The
reactions were subjected to standard oxidative workup (NaOH, H2O2) before
product isolation. b The diastereoselectivity in all cases was g20:1. c Yields
are based on 3. d Determined by the Mosher ester method. e ent-4 was used
in this experiment.
several groups have described diastereoselective syntheses of 1,5-
diols and 1,5-amino alcohols via the reactions of aldehydes with
structurally complex chiral allylstannane,4,5 allylsilane,6 and allylti-
tanium reagents,7 no examples currently exist of the type of
stereocontrolled, one-pot three-component coupling that we envis-
aged. We were intrigued by Brown’s report that (E)-γ-(1,3,2-
dioxaborinanyl)allyl]diisopinocampheylborane (4), generated by
hydroboration of 2-allenyl-(1,3,2)-dioxaborinane (3) with diisopi-
nocampheylborane [(Ipc)2BH], reacts with aldehydes at -78 °C to
give 1,2-anti-diols 6 with excellent enantioselectivity via the
intermediacy of â-alkoxyallylboronate 5.8 We recognized that if
intermediate 5, or surrogates with different diol units on boron,
could be induced to combine with a second aldehyde with control
over the equatorial or axial nature of the substituent R to boron in
the second allylboration transition state (cf., transition state 7 versus
8),9 then stereoselective access to 1 or 2 would be achieved.
reactions, performed by adding the aldehydes at -78 °C to a
solution of the in situ generated reagent 4 and then allowing the
reaction mixture to stir at ambient temperature for 24 h, provided
the 1,5-anti-diols 9a-f with g20:1 diastereoselectivity and 84-
95% ee (Table 1). The 1,5-anti stereochemistry of diols 9a-f was
assigned by hydrogenation of the double bonds, thereby producing
the optically active, C2 symmetric saturated diols. The absolute
stereochemistry of 9a-f was assigned by using the Mosher
method.10 Thus, the allylboration of 5 proceeds with excellent
selectivity by way of transition state 7. Optimization studies (see
Supporting Information) indicated that the chemical efficiency of
this process is limited by the efficiency of the hydroboration of 3
and that effective yield of the allylborating agent 4 is in the range
of 40-50% (based on 3). In addition, use of 1.4 equiv of the
aldehyde (based on 3) is required to consume the intermediate
R-substituted allylboronate 5 in the second allylboration step,
thereby avoiding production of diol 6 after oxidative reaction
workup.
We next explored the use of two different aldehydes in the double
allylboration reaction (Table 2). Optimal results were obtained when
a -78 °C solution of 4, prepared in situ by the hydroboration of
allene 3, was treated with 0.54 equiv of the first aldehyde (R1-
CHO). The mixture was stirred for 2 h at -78 °C, and then a full
equivalent of the second aldehyde (R2CHO) was added, and the
mixture was allowed to warm to ambient temperature and stir for
24 h. This provided the 1,5-anti-diols 1a-e with 20:1 diastereo-
selectivity, 89-95% ee, and in 65-87% yield based on R1CHO as
the limiting reagent. Small amounts (1-5%) of the 1,5-anti-diols
9 resulting from double allylboration of the second aldehyde (R2-
This plan was probed by allowing the boryl-substituted allylbo-
rane 4 to react with a series of achiral aldehydes (Table 1). These
* To whom correspondence should be addressed. E-mail: roush@umich.edu.
9
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J. AM. CHEM. SOC. 2002, 124, 13644-13645
10.1021/ja028055j CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Synthesis of (E)-1,5-anti-Diols from Two Aldehydesa
Table 3. Synthesis of (Z)-1,5-syn-Diols from Two Aldehydesa
1
2
c
entry
R CHO
R CHO
productb yield
1:9d
%eee
1
2
3
4
5
(CH3)2CHCHO Ph(CH2)2CHO
1a
1b
1c
1d
1e
69
83
87
74
65
50:1
100:1
20:1
100:1
50:1
92
89
91
96
95
entry
R CHO
R CHO
productb,c
yieldd
%eee
Ph(CH2)2CHO
PhCHO
C6H11CHO
PhCHO
PhCHO
Ph(CH2)2CHO
PhCHO
1
2
1f
2
3
4
5
6
Ph(CH2)2CHO
(CH3)2CHCHO
PhCHO
Ph(CH2)2CHO
(CH3)2CHCHO
Ph(CH2)2CHO
Ph(CH2)2CHO
PhCHO
Ph(CH2)2CHO
(CH3)2CHCHO
Ph(CH2)2CHO
C6H11CHO
2a
2b
2c
2d
2e
2f
72
88
95
92
95
91
91
92
95
94
95
94
(CH3)3CCHO
a Reagent 4 was prepared as described in Table 1. After the addition of
R1CHO (0.54 equiv) at -78 °C (2 h), 1 equiv of R2CHO was added, and
the mixture was then allowed to stir for 24 h at 23 °C. Reaction workup
was performed as described in Table 1. b Diastereoselectivity in all cases
was g20:1. c Yields are based on R1CHO as the limiting reagent. d Product
ratios determined by 1H NMR analysis. e Determined by the Mosher ester
method.
a Reagent 11 was prepared in situ by hydroboration of 10 (1 equiv) with
1.0 equiv of Ipc2BH in CH2Cl2 at 0 °C. R1CHO (0.82 equiv) was added at
-78 °C (2 h), followed by 1.7 equiv of R2CHO. The mixture was then
allowed to stir at 23 °C for 24 h. All reactions were then worked up as
described in Table 1. b Diastereoselectivity in all cases was g14:1, and the
CHO) were also obtained. If smaller quantities of R1CHO were
used at the outset, greater amounts of 1,5-anti-diols 9 were obtained.
Conversely, if greater amounts of R1CHO were used, the products
of double allylboration of the first aldehyde (R1CHO) were
produced. Thus, the relative rates of the two allylboration reactions
are sufficiently different11,12 that clean heterocoupling of two
different aldehydes can be achieved, provided that the proper
amount of R1CHO relative to 4 is used.
ratio of 2 to 12 was g30:1 in all cases. c Product ratios determined by H
1
NMR analysis. d Yields are based on R1CHO as the limiting reagent.
e Determined by the Mosher ester method. f Reaction was performed by
adding 2 equiv of PhCH2CH2CHO to the reaction mixture at -78 °C, and
then allowing the mixture to stir at ambient temperature for 24 h.
in 5 (or in the analogous substituted methallylboronate deriving
from 11) is transmitted to a new C-O stereocenter via transition
states 7 and 8. Thus, keys to the success of this method are the
excellent stereocontrol in the allylboration step leading to 5,8 the
stereospecificity of the subsequent allylboration reaction of 5 and
the corresponding intermediate derived from 11, and the ability of
the diol auxiliary to induce equatorial or axial placement of the
R-boryl substituent in transition states 7 and 8.
On the basis of early studies published by Hoffmann,9 we
reasoned that if a bulky diol unit was incorporated in the starting
allenylboronic ester, the second allylboration would proceed
preferentially by way of transition state 8 with the substituent R to
boron in an axial position, thereby providing stereoselective access
to the 1,5-syn-diols 2 with an intervening (Z)-double bond. After
screening several hindered diols, we determined that the tetraphe-
nylethylene glycol ester in 10 and the derived allylborane 11 would
nicely serve our purposes. Owing to the poor solubility of 10 in
Et2O, the hydroboration of 10 was performed in CH2Cl2 using 1.0
equiv of Ipc2BH. The hydroboration of 10 is more efficient than
that of 3, as treatment of the in situ generated 11 with 2 equiv of
PhCH2CH2CHO provides the targeted (Z)-syn-1,5-diol 2a in 72%
yield, with an enantiomeric purity of 91% ee and diastereoselectivity
of 14:1 (Table 3, entry 1). In addition, optimal conditions for the
double allylboration of 11 using two different aldehydes were
achieved by using 0.82 equiv of the first aldehyde (R1CHO). Under
these conditions, the ratio of the heterocoupled product 2 to the
product 12 of homocoupling of the second aldehyde (R2CHO) was
30:1. In all cases (entries 2-6, Table 3), the targeted 1,5-syn-diols
2 were obtained in 88-95% yield and 92-95% ee.
The level of selectivity reported here for the double allylboration
reactions of reagents 4 and 11 is unprecedented. Although Hoffmann
has previously reported that methallylboronates could be induced
to react with the R-methyl substituent either in an equatorial or an
axial position in the six-centered, chairlike allylboration transition
state by changing the boronate ester, the level of selectivity achieved
was only ca. 3:1 at best.9 The exquisite control over the 1,5-diol
relationships in 1 and 2 is a consequence of the pericyclic nature
of the second allylboration step, in which the C-B stereochemistry
Applications of this method in the synthesis of natural products
will be reported in due course.
Acknowledgment. Financial support provided by the National
Institutes of Health (GM 38436) is gratefully acknowledged.
Supporting Information Available: Experimental procedures,
optimization studies, stereochemical assignments, and tabulated spec-
troscopic data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991; Vol. 2, p 1.
(2) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207.
(3) Chemler, S. R.; Roush, W. R. In Modern Carbonyl Chemistry; Otera, J.,
Ed.; Wiley-VCH: Weinheim, 2000; p 403.
(4) Taylor, N. H.; Thomas, E. J. Tetrahedron 1999, 55, 8757.
(5) Thomas, E. J. In Stereocontrolled Organic Synthesis; Trost, B. M., Ed.;
Blackwell Scientific Publications: Oxford, 1994; p 235.
(6) Panek, J. S.; Yang, M. J. Org. Chem. 1991, 56, 5755.
(7) Xin, T.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1998, 39, 6927.
(8) Brown, H. C.; Narla, G. J. Org. Chem. 1995, 60, 4686.
(9) Hoffmann, R. W.; Weidmann, U. J. Organomet. Chem. 1980, 195, 137.
(10) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092.
(11) Roush, W. R.; Banfi, L.; Park, J. C.; Hoong, L. K. Tetrahedron Lett. 1989,
30, 6457.
(12) Brown, H. C.; Racherla, U. S.; Pellechia, P. J. J. Org. Chem. 1990, 55,
1868.
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