Preparative-scale synthesis of both antipodes of B-γ,γ- dimethylallyldiisopinocampheylborane: Application for the synthesis of C 1-C6 subunit of epothilone

Article abstract of DOI:10.1016/j.tetlet.2003.11.087

A preparative-scale synthesis of B-γ,γ- dimethylallyldiisopinocampheylborane starting from prenyl alcohol has been described. This reagent, upon reaction with various aldehydes, provides the corresponding α,α-dimethylhomoallylic alcohols in high enantiose

Full text of DOI:10.1016/j.tetlet.2003.11.087

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1011–1013
Preparative-scale synthesis of both antipodes of B-c,c-
dimethylallyldiisopinocampheylborane: application for the synthesis
of C1–C6 subunit of epothilone
P. Veeraraghavan Ramachandran,* Bodhuri Prabhudas, J. Subash Chandra,
M. Venkat Ram Reddy and Herbert C. Brown
Department of Chemistry, Herbert C. Brown Center for Borane Research, 560 Oval Drive, Purdue University,
West Lafayette, IN 47907-82084, USA
Received 29 October 2003; revised 13 November 2003; accepted 19 November 2003
Abstract—A preparative-scale synthesis of B-c,c-dimethylallyldiisopinocampheylborane starting from prenyl alcohol has been
described. This reagent, upon reaction with various aldehydes, provides the corresponding a,a-dimethylhomoallylic alcohols in high
enantioselectivities. The application of this reagent has been demonstrated for the synthesis of C1–C6 subunit of epothilone.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Allylboration is one of the extremely important carbon–
carbon bond forming reactions in organic synthesis.1
For the past two decades, we have developed several
highly functionalized ÔallylÕ boranes based on terpenes.2
While some of these reagents have been well utilized by
the synthetic organic community for the total synthesis
of a variety of complex natural products,3 others have
been sparsely used. One of the main reasons for the lack
of interest for such reagents could be due to the difficulty
in their preparation or the cost of the starting materials.
One of the rarely used allylborane reagents is B-c,c-
dimethylallyldiisopinocampheylborane4 1 for the prep-
aration of a,a-dimethylhomoallylic alcohols. Several
natural products, such as artemesia alcohol,5 bryosta-
tin,6 epothilone,7 pederin,8 and mycalamide9 contain an
a,a-dimethylhydroxy unit in them and one could
envisage the use of 1 for the preparation of the dimethyl
alcohol moiety. Since our initial report of the synthesis
of artemesia alcohol,4 only recently Schinzer described
the application of 1 for the synthesis of epothilones.10
The wide range of potential application of 1 persuaded
us to develop a simple and inexpensive method for the
preparative-scale synthesis of the reagent. Our original
preparation of B-c,c-dimethylallyldiisopinocampheyl-
borane 1 involves the hydroboration of relatively
expensive (Aldrich $53/g) 1,1-dimethylallene 2 with diiso-
pinocampheylborane 3, thus making it impractical for
large-scale applications (Scheme 1).
B-Allyldialkylboranes can be prepared by the reaction
of the corresponding allyl Grignard reagent with
B-halodialkylborane or B-methoxydialkylborane. Our
approach was to use the dimethylallyl Grignard reagent,
that can be readily prepared from the relatively inex-
pensive prenyl alcohol (Aldrich $94/500 g). Prenyl alco-
hol was converted to the corresponding bromide by
treatment with PBr3. However, the reaction of di-
methylallylbromide with magnesium turnings was not
satisfactory and resulted in the predominant formation
of the homocoupling product. Treatment of this
reagent with (+)-B-methoxydiisopinocampheylborane
(4) resulted in very low yields of the ÔallylÕ borane
reagent 1 (ꢀ10% based on 11B NMR). We sought to
change the halide from bromide to chloride 5 in an
BH
2
B
3
Keywords: Dimethylallylboration; B-Methoxydiisopinocampheyl-
borane; Prenyl alcohol; Epothilone.
2
1
* Corresponding author. Tel.: +1-765-494-5303; fax: +1-765-494-0239;
e-mail: chandran@purdue.edu
Scheme 1.
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.087

1012
P. V. Ramachandran et al. / Tetrahedron Letters 45 (2004) 1011–1013
S
N
(i) Mg
(ii)
O
10
BOMe
Cl
B
OH
2
15
5
Epothilone B
6
1
4
O
1
Scheme 2.
O
OH
O
O
6
1
PMBO
attempt to minimize the homocoupling. The chloride
was prepared by the reaction of prenyl alcohol with
thionyl chloride and subsequent addition of magnesium
resulted in the successful formation of Grignard reagent.
This, upon reaction with (+)-4 at 0 ꢁC, provided the
required ÔallylÕ borane 1 in essentially quantitative
yield. Methoxymagnesium chloride was filtered using a
Kramer filter under nitrogen and the solvent was evap-
orated under vacuum to provide 90% yield of B-c,c-
C1-C6 Subunit
TBSO
Figure 1.
Similarly, b-chiral aldehyde 6g (entry 7) also provided
the homoallylic alcohol 7g in 93% yield and 95% de
(Table 1).
dimethylallyldiisopinocampheylborane
1
(11B NMR
peak at d 79) (Scheme 2). Similarly starting from ())-B-
methoxydiisopinocampheylborane, the antipode of the
reagent 1 was prepared. To demonstrate the potential
for large-scale applications, we carried out the reaction
on a 0.5 mol scale and obtained highly reproducible
results.11
To demonstrate the application of the above reagent for
organic synthesis, we synthesized the C1–C6 subunit 8 of
the potent anti-cancer molecule epothilone B7 (Fig. 1).
Monoprotection of 1,3-propanediol 9 as the p-meth-
oxybenzyl ether followed by Swern oxidation provided
3-(p-methoxybenzyloxy)propionaldehyde 10. Dimethyl-
allylboration of 10 with 1 at )100 ꢁC furnished the
homoallylic alcohol 11 in 95% ee. Protection of 11 as the
silyl ether 12, followed by ozonolysis afforded the alde-
hyde 13. Reaction of 13 with ethylmagnesium bromide
yielded the alcohol 14. Dess–Martin periodinane oxi-
dation of 14 resulted in the formation of the required
C1–C6 subunit 8 of epothilone (Scheme 3).
We then studied the allylboration of various aldehydes
with 1. The reaction of aliphatic aldehydes, such as
propionaldehyde 6a, isobutyraldehyde 6b, pivalaldehyde
6c (entries 1–3), took place smoothly, and the product
homoallylic alcohols 7a–c were obtained in very good
yields (81%–88%) and in excellent ee (95%–97%) (Table
1). The ee was determined by derivatizing the homo-
allylic alcohols as their p-nitrobenzoate esters, and ana-
lyzed on an HPLC using a Chiralcel OD-HTM column.
Similarly benzaldehyde 6d and cinnamaldehyde 6e
(entries 4–5) also provided alcohols 7d and 7e in excellent
yield and ee. The reaction of an a-chiral aldehyde 6f
(entry 6) took place in a reagent-controlled manner and
the homoallylic alcohol 7f was obtained in 92% de.
In conclusion, we have developed a simple and inex-
pensive procedure for the preparative-scale synthesis
of both antipodes of B-c,c-dimethylallyldiisopinocam-
pheylborane and have examined the reactivity of the
reagent with a wide variety of aldehydes providing
Table 1
OH
(i) 1
O
Ether/pentane, -1000C
(ii) NaOH/H2O2
R
R
6 a-g
H
7a-g
Entry
Aldehyde
Homoallylic alcohol
Yield (%)
#
R
#
ee/de (%)
1
2
3
4
5
6a
6b
6c
6d
6e
CH3CH2–
(CH3)2CH–
(CH3)3C–
C6H5–
7a
7b
7c
7d
7e
81
85
88
92
90
97
95
95
95
87
C6H5CH@CH–
6
6f
7f
90
92
PMBO
OMe
MeO
7
6g
7g
93
95

P. V. Ramachandran et al. / Tetrahedron Letters 45 (2004) 1011–1013
1013
2. (a) Ramachandran, P. V. Aldrichim. Acta 2002, 35, 23; (b)
Brown, H. C.; Ramachandran, P. V. J. Organomet. Chem.
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3. (a) Smith, A. B.; Adams, C. M.; Barbosa, S. A. L.;
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Holoboski, M. A.; Keown, L. E.; Kolz, C. S. N.; Phillips,
B. W. J. Org. Chem. 2002, 67, 7750.
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1215.
5. Epstein, W. W.; Poulter, C. D. Phytochemistry 1973, 12,
737.
O
a, b
c
OH OH
OPMB
PMBO
OH
O
11
10
9
d
e
f
PMBO
OTBS
PMBO
OTBS
13
12
g
PMBO
PMBO
6. Pettit, G. R.; Herald, C. L.; Doubek, D. L.; Herald,
D. L.; Arnold, E.; Clardy, J. J. Am. Chem. Soc. 1982, 104,
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7. For reviews on epothilones see: (a) Stachel, S. J.; Biswas,
K.; Danishefsky, S. J. Curr. Pharm. Design 2001, 7, 1277;
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Nicolaou, K. C.; Roschanger, F.; Vourloumis, D. Angew.
Chem., Intl. Ed. 1998, 37, 2015.
14
8
TBSO
OH
TBSO
O
Scheme 3. Reagents and conditions: (a) NaH, p-CH3OC6H4CH2Cl,
NþBu4Iꢁ, 80%; (b) (COCl)2, DMSO, Et3N, 85%; (c) 1, 82%; (d)
TBSOTf, 2,6-lutidine, 90%; (e) O3, 78%; (f) EtMgBr; (g) DMP, 88%
(overall for the two steps).
8. Nakata, T.; Nagao, S.; Oishi, T. Tetrahedron Lett. 1985,
26, 6465.
9. Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Pannell, L. K.
J. Am. Chem. Soc. 1988, 110, 4851.
10. Schinzer, D.; Limberg, A.; Bohm, O. M. Chem. Eur. J.
1996, 2, 1477.
homoallylic alcohols in high diastereo- and enantio-
selectivities. We have also demonstrated the applicabil-
ity of this reagent for the synthesis of C1–C6 subunit of
the potent anti-cancer agent epothilone B. With an
economical procedure now available, we believe that
this reagent will find further applications in organic
synthesis.
11. Preparation of B-c,c-dimethylallyldiisopinocampheyl-
borane (1): 1-Chloro-3-methyl-2-butene (90.2 mL, 1.0 mol)
was added dropwise to a stirred suspension of Mg (120 g,
2.5 mol) in 200 mL ether cooled to 0–10 ꢁC and was stirred
for 1 h. Meanwhile, a solution of 4 (158.2 g, 0.5 mol) in
500 mL ether was cooled to 0 ꢁC. The previously made
Grignard reagent was added to 4. After the completion of
the reaction (3 h) as monitored by 11B NMR (d 79), the
reaction mixture was filtered under nitrogen and concen-
trated under vacuum. n-Pentane (200 mL) was added to it
using a canula, stirred for 5 min and allowed to settle
down. The supernatant liquid was then transferred via a
canula into another round bottom flask under nitrogen
and the solvent was evaporated off under vacuum. After
repeated washing with pentane (4 · 200 mL), the concen-
trate (90%, 159.4 g, 450 mmol) was dissolved in 450 mL
pentane to prepare a 1 M stock solution. 11B NMR
analysis of the stock solution showed a clean formation of
the product allylborane (singlet: d 79).
Acknowledgements
Financial assistance from Herbert C. Brown Center for
Borane Research12 and Aldrich Chemical Company are
gratefully acknowledged.
References and notes
1. (a) Hoffmann, R. W. Pure Appl. Chem. 1988, 60, 123; (b)
Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207; (c)
Roush, W. R. In Methods of Organic Chemistry (Houben-
Weyl); Georg Thieme: Stuttgart, 1995; Vol. E 21, p 1410.
12. Contribution # 30 from Herbert C. Brown Center for
Borane Research.