Facile protocol for the highly regioselective and stereodivergent synthesis of substituted bishomoallylic alcohols from esters

Article abstract of DOI:10.1039/b315758j

Regio- and diastereoselective preparation of bishomoallylic alcohols was realized by a facile four-step protocol including α,α′- selective zinc-mediated bispropargylation of unactivated esters and stereoselective reduction of the resulting bishomopropargy

Full text of DOI:10.1039/b315758j

Facile protocol for the highly regioselective and stereodivergent synthesis
of substituted bishomoallylic alcohols from esters
Martin Oestreich* and Fernando Sempere-Culler
Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität, Albertstrasse 21, D-79104
Freiburg im Breisgau, Germany. E-mail: martin.oestreich@orgmail.chemie.uni-freiburg.de;
Fax: +49(0)761/203-6100
Received (in Cambridge, UK) 3rd December 2003, Accepted 26th January 2004
First published as an Advance Article on the web 13th February 2004
Regio- and diastereoselective preparation of bishomoallylic
alcohols was realized by a facile four-step protocol including
a,aA-selective zinc-mediated bispropargylation of unactivated
esters and stereoselective reduction of the resulting bishomopro-
pargylic alcohols.
mediated monopropargylation.11 Analogously, the mechanism of
the zinc-mediated bispropargylation might also involve coordina-
tion of the silyl group by bromide which in turn is coordinated by
zinc (A, Scheme 2). Transfer of the propargylic moiety onto the
carbonyl carbon atom of the ester might proceed through the six-
membered transition state B providing the a-adduct C (Scheme 2).
After collapse of the tetrahedral intermediate C, this process is
reiterated once.
Preparation of propargylic zinc reagent 5a is accomplished on a
large scale (50 mmol) by insertion of activated zinc dust12 into the
carbon–bromine bond of the corresponding 3-bromo-
1-trimethylsilyl-1-propyne.13 We were pleased to find that 5a
smoothly reacts with esters 1 without any further activation under
very mild conditions (Scheme 3).† The desired bishomopropargylic
alcohols 6 were isolated in excellent a,aA-regioselectivities and
excellent yields except for 1c (Table 1, Entries 1–5). Even easily
enolizable substrate 1d (Table 1, Entry 4) and ethyl nicotinate (1e)
(Table 1, Entry 5) performed well.
The a-regioselective formation of homoallylic alcohols from
carbonyl compounds and g-monosubstituted allyl metals has
remained a major challenge in organic synthesis.1 In addition,
controlling the double bond geometry within such a transformation
is oftentimes as intricate as the problematic a/g-selectivity. The
sole method of some generality is the use of stereogenic allylic
barium reagents which transfer the allyl group onto carbonyl
compounds with excellent regioselectivity as well as diaster-
eospecificity.2 Additionally, high regioselectivities are also
achieved using acylsilanes yet being intrinsically restricted to
monoallylations.3
Within the scope of a total synthesis project,4 we required a
reliable methodology for the selective preparation of several
bishomoallylic alcohols starting from simple esters (1 ? 2, Scheme
1). Unfortunately, it appeared extremely delicate to control both
regio- and diastereoselectivity in the direct bisallylation of esters 1
using allylic metal (zinc) reagents.
Interestingly, allylic zinc reagents5 exhibit a markedly anom-
alous behaviour since their monoaddition to carbonyl compounds is
a reversible process.6
Minor quantities of the undesired regioisomer 7 were removed
by flash chromatography on silica providing regioisomerically pure
6 (Scheme 3, Table 1).
In our hands, initial bisallylation7 of 1 with 4 gave a mixture of
a- and g-isomers which were thermally isomerized providing the
a,aA-adducts 2 exclusively. However, 2 was invariably formed in
E,Z ratios which precluded further synthetic transformations.8
These investigations led us to consider an alternative approach to
the selective preparation of alcohols 2. We envisaged a strategy in
which the issues of regio- (1 ? 3) and diastereoselectivity (3 ? 2)
are divided into two separate synthetic steps.
Scheme 2 Plausible mechanistic rationale for the a-directing effect of the
trimethylsilyl group: first step of the bispropargylation of esters.
In principle, propargylation of carbonyl compounds is generally
afflicted with the same regiochemical problems (alkyne vs. allene
formation) as allylation.1 However, if the g-substituent RA of the
propargylic zinc reagent 5 is a trimethylsilyl group (5a), proparg-
ylation exhibits surprisingly high a-selectivity.9,10
Recently, this ‘directing’ effect of the trimethylsilyl group has
been rediscovered and mechanistically rationalized for the indium-
Scheme 3 Bispropargylation of versatile esters 1.
Table 1 Yields and regioselectivities for bishomopropargylic alcohols 6
Regioselectivitya
a,gA/
Yield for
Entry Ester
R
Product a,aA (6) aA,g (7) g,gA (8) 6 (%)b
1
2
3
4
5
1a
1b
1c
1d
1e
Me
Pent
Ph
6a
6b
6c
6d
> 98
> 98
> 98
> 97
> 98
1
1
1
2
1
< 1
< 1
< 1
< 1
< 1
94
96
56
72
85
Bn
3-Pyridyl 6e
a Determined from the 1H NMR spectra of the crude products. b Isolated
yield of analytically pure product 6 after flash chromatography.
Scheme 1 Strategies for the regio- and diastereoselective synthesis of
bishomoallylic alcohols employing allylic or propargylic zinc reagents.
692
C h e m . C o m m u n . , 2 0 0 4 , 6 9 2 – 6 9 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

Although the procedure is initially limited to the trimethylsilyl
group as the terminal substituent, it allows for further functional
group manipulation in this position. The terminal alkynes were
liberated by treatment of 6 with substoichiometric amounts of
TBAF (0.15 equivalents per alkyne). Subsequent arylation was
accomplished by Sonogashira coupling14 without protection of the
tertiary alcohol (6 ? 9, Scheme 4).15 The modified bishomopro-
pargylic alcohols 9 were isolated regioisomerically pure in good
overall yields (Table 2, Entries 1/2 and 3/4).
In the second step of our strategy, we intended to control the
configuration of both double bonds in the bishomoallylic alcohols
(3 ? 2, Scheme 1). Simple reduction of diynes 9b and 9d with Red-
Al® (7.0 equiv.) at elevated temperature gave the corresponding
(E,EA)-dienes 10 in good yields and diastereoselectivities (Scheme
4). The reasonable overall diastereoselectivity of E/Z = 96 : 4 is
slightly diminished due to the presence of two reducible branches
(Table 2, Entries 1 and 3). In order to demonstrate the potential
stereodivergency of our approach, we also performed Z-selective
reductions and subjected 9b and 9d to Lindlar conditions (Scheme
4). Overreduction was fairly problematic but, after some optimiza-
tion, (Z,ZA)-10 were isolated in good yields and excellent overall
diastereoselectivities of E/Z = 1 : 99 (Table 2, Entries 2 and 4).
In summary, we have elaborated a preparatively straightforward
and scalable four-step protocol for the regio- and diastereoselective
synthesis of bishomoallylic alcohols 10. Within this reaction
sequence, the a,aA-selective bispropargylation of esters using zinc
reagent 5a plays the decisive role.
Breisgau. M. O. is indebted to the Deutsche Forschungsge-
meinschaft for an Emmy Noether fellowship (2001–2005). The
authors thank Ilona Hauser and Engelbert Redel for skilful
technical assistance, Sebastian Rendler for orientating experiments,
and Professor Reinhard Brückner for his continuous support.
Notes and references
† Representative experimental procedure: A flask equipped with an argon
inlet and a reflux condenser was charged with zinc dust (2.27 g, 34.7 mmol,
6.00 equiv.) and flame-dried until sublimation of zinc occurred. The
thermally activated zinc was suspended in dry THF (45 mL) and
subsequently treated with 1,2-dibromoethane (693 mg, 3.69 mmol, three
cycles) followed by refluxing and Me3SiCl (149 mg, 1.37 mmol, three
cycles) without external heating. After cooling to ambient temperature,
3-bromo-1-trimethylsilyl-1-propyne13 (3.31 g, 17.3 mmol, 3.00 equiv.) was
carefully added dropwise via syringe in order to maintain a gentle reflux.
Upon complete addition, the reaction mixture was maintained at room
temperature for 12 h providing the propargylic zinc reagent 5a in almost
quantitative yield. A solution of ester 1a (R = Me) (509 mg, 5.78 mmol)
and dry THF (5 mL) was added via syringe in one portion. After 12 h at
room temperature, saturated aqueous NH4Cl (50 mL) was added, the
organic phase was separated and the aqueous phase was extracted with t-
butyl methyl ether (TBME) (3 3 25 mL). The combined organic phases
were washed with brine (25 mL), dried over MgSO4 and concentrated under
reduced pressure. The yellow residue was purified by flash chromatography
on silica gel (cyclohexane : TBME = 30 : 1) furnishing 6a (1.05 g, 94%)
as a white solid. Rf = 0.27 (CH : TBME = 10 : 1). Mp 54–55 °C (CH). IR
(CDCl3): 3016, 2401, 1521, 1214, 929 cm21. 1H NMR (400 MHz, CDCl3):
d = 0.15 (s, 18H), 1.35 (s, 3H), 2.19 (s, 1H), 2.49 (d, J = 16.8 Hz, 1H), 2.52
(d, J = 16.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): d = 0.0, 25.8,
33.0, 71.0, 88.2, 102.8 ppm. LRMS (CI): m/z = 267 [(M + H)+]. Anal.
Calcd for C14H26OSi2 (266.53): C, 63.09; H, 9.83; Found: C, 63.22; H,
9.82%.
Application of this methodology in total synthesis as well as the
use of bishomoallylic alcohols in desymmetrization reactions are
currently being investigated in our laboratories.4
The research was supported by the Fonds der Chemischen
Industrie and the Wissenschaftliche Gesellschaft in Freiburg im
1 A. Yanagisawa and H. Yamamoto, in Advances in Carbanion
Chemistry, Ed. V. Snieckus, JAI Press, London, 1996, Vol. 2, pp.
87–110 and references cited therein.
2 A. Yanagisawa, S. Habaue and H. Yamamoto, J. Am. Chem. Soc., 1991,
113, 8955–8956.
3 A. Yanagisawa, S. Habaue and H. Yamamoto, J. Org. Chem., 1989, 54,
5198–5200.
4 M. Oestreich and F. Sempere-Culler, submitted for publication.
5 Z. Zha, Z. Xie, C. Zhou, M. Chang and Z. Wang, New J. Chem., 2003,
27, 1297–1300 and references cited therein.
6 C. Bouchoule and P. Miginiac, Bull. Soc. Chim. Fr., 1968, 4675–4676.
For a synthetic application of this phenomenon, see: P. Jones and P.
Knochel, J. Org. Chem., 1999, 64, 186–195.
7 For zinc-promoted bisallylation of acid chlorides, see: Y. Ishino, M.
Mihara and M. Kageyama, Tetrahedron Lett., 2002, 43, 6601–6604.
8 Thermal isomerization of 2 (RA = Ph) as a mixture of all regioisomers
(a,aA/a,gA/aA,g/g,gA) strongly favored the a,aA-adducts yet with medi-
ocre diastereoselectivity (E,EA/E,ZA/EA,Z/Z,ZA) and in deteriorated yields.
For an extensive study disregarding diastereoselectivity, see: F. Barbot,
J. Laduranty, C. H. Chan and P. Miginiac, Bull. Soc. Chim. Fr., 1989,
864–871.
Scheme 4 Terminal modification of bishomopropargylic alcohols 6 and
diastereoselective formation of bishomoallylic alcohols 10.
9 For references reporting the observation of this effect, see: (a) D.
Mesnard and P. Miginiac, J. Organomet. Chem., 1990, 397, 127–137;
(b) D. Mesnard and P. Miginiac, J. Organomet. Chem., 1990, 397,
139–146.
Table 2 Yields for desilylation/Sonogashira coupling sequence (6 ? 9) and
for reduction (9
? 10), respectively, and diastereoselectivities for
bishomoallylic alcohols 10
10 A substantial decrease of the regioselectivity was observed when RA =
Me3Si (5a) was replaced by H (5b) and Ph (5c), respectively.
11 M.-J. Ming and T.-P. Loh, J. Am. Chem. Soc., 2003, 125,
13042–13043.
Diastereoselectivitya
Yield for
9 (%)b
Yield for
Entry Alkyne
R
E,EA
E,ZA/EA,Z Z,ZA 10 (%)b
12 P. Knochel, M. J. Rozema and C. E. Tucker, in A Practical Approach –
Organocopper Reagents, Ed. R. J. K. Taylor, Oxford University Press,
Oxford, 1993, pp. 85–104.
13 R. B. Miller, Synth. Commun., 1972, 2, 267–272.
14 K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett., 1975, 16,
4467–4470.
15 Since alkylation or carboxylation of the alkyne would demand
protection of the tertiary alcohol functionality, we have exemplarily
chosen an arylation protocol which tolerates the hydroxyl group.
1
2
3
4
6b
6b
6d
6d
Pent 72
Pent (2 steps)
93
0
93
0
6
2
6
2
1
98
1
65
75
65
80
Bn
Bn
61
(2 steps)
98
a Ratio of diastereoisomers was determined from the 1H NMR spectra of the
crude products by integration. b Isolated yield of analytically pure product
9 or 10 after flash chromatography.
C h e m . C o m m u n . , 2 0 0 4 , 6 9 2 – 6 9 3
693