Synthetic routes to the stereoisomers of 2,4-dimethylpentane-1,5-diol derivatives

Article abstract of DOI:10.1016/j.tetlet.2003.09.199

Five different routes to every stereoisomer of non-symmetric derivatives of 2,4-dimethylpentanedioic acid and/or of O-monoprotected 2,4-dimethylpentane- 1,5-diols, which are common building blocks for the total synthesis of many polypropionates, have been investigated. Alkylation of the lithium enolate of N-propanoylpseudoephedrine turned out to be the most appropriate method, in connection with the synthesis of fragment C1-C5 of amphidinolide K.

Full text of DOI:10.1016/j.tetlet.2003.09.199

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8805–8809
Synthetic routes to the stereoisomers of
2,4-dimethylpentane-1,5-diol derivatives
Gemma Mas, Llu¨ısa Gonza´lez and Jaume Vilarrasa*
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica, Av. Diagonal 647, Universitat de Barcelona, 08028 Barcelona,
Catalonia, Spain
Received 25 July 2003; revised 12 September 2003; accepted 24 September 2003
Abstract—Five different routes to every stereoisomer of non-symmetric derivatives of 2,4-dimethylpentanedioic acid and/or of
O-monoprotected 2,4-dimethylpentane-1,5-diols, which are common building blocks for the total synthesis of many polypropio-
nates, have been investigated. Alkylation of the lithium enolate of N-propanoylpseudoephedrine turned out to be the most
appropriate method, in connection with the synthesis of fragment C1–C5 of amphidinolide K.
© 2003 Elsevier Ltd. All rights reserved.
Access to stereoisomers of non-symmetric 2,4-dimethyl-
glutaric acid esters 1, and/or of related molecules with
different oxygen functionalities at C1 and C5 such as 2
and 3, has been a subject of continuous interest, since
these compounds are appropriate building blocks for
the synthesis of complex natural products, especially of
macrolide-like antibiotics.1 Prelog–Djerassi lactonic
acid 42 is a typical example of a substance that may be
readily synthesised from precursors such as a suitable
syn-1 or (2R,4S)-2. Representative examples of natural
product syntheses from stereoisomers of 1–3 are those
of 6-deoxyerythronolide B,3a conglobatin,3b,c mycino-
lide V,3d the side chain of zaragozic acid A,3e–g
siphonarienone,3h the antibiotic borrelidin,3i the
aliphatic chain of microcolin B,3j salinomycin,3k a,g-
dimethyl g- and d-amino acids,3l,m a scyphostatin frag-
ment,3n azaspiracid3o,p and supellapyrone.3q
mers 1–3 and both anti enantiomers, with the hope that
our results will save time for researchers who face
similar problems in the future.
Separation and resolution of the commercially available
meso/dl mixture of 2,4-dimethylglutaric acids7 was first
considered. After dehydration of 2,4-dimethylglutaric
acids by heating with acetic anhydride, meso-glutaric
anhydride (6) could be separated after several crystalli-
sations from ethyl acetate, the mother liquors contain-
ing mainly racemic anhydride. Asymmetrisation of the
meso isomer by treatment with (R)-1-phenylethylamine,
reduction of the carboxyl group with borane, separa-
tion of the diastereomeric monoamides (7 and 7%) by
crystallisation (with purification by flash column chro-
matography), and hydrolysis of the amide group (with
cyclisation) afforded the corresponding enantiomeric
lactones (8 and ent-8, respectively).8 However, we
found that the overall process was cumbersome, as it
requires several crystallisations, and did not allow one
to obtain pure anti stereoisomers.9
In this context, we focussed our attention on the struc-
ture of (−)-amphidinolide K, a cytotoxic macrolide
isolated by Kobayashi et al.,4 the ‘southern’ part of
which is 5. The absolute configurations of the stereo-
centres at C2 and C4 were not immediately estab-
lished.4 Thus, we started a project5 on the total
synthesis of amphidinolide K and congeners beginning
the preparation of samples of the four possible C1–C5
substructures.6 We explain here all the approaches that
we investigated to reach both enantiomers of syn iso-
Keywords: alkylation; asymmetric synthesis; diastereoselection; eno-
lates; macrolides; Michael reactions.
* Corresponding author. E-mail: jvilarrasa@ub.edu
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.199

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G. Mas et al. / Tetrahedron Letters 44 (2003) 8805–8809
10, the major product appeared to be that methylated
at the position a to the oxazolidinone moiety,14 with
recovery of starting material and the camphorsultam
auxiliary after the workup. In the presence of HMPA,
which is usually required to perform alkylations of
enolates of N-acyl derivatives of the camphorsultam,11a
we did not detect any dimethylated product either. In
the case of 11, our best result was a 67% yield of the
product methylated at the position a to the oxazolidi-
none moiety (by using >2 equiv. of NaHMDS and
methyl iodide) and a 25% yield of the partially
hydrolysed starting material. Treatment of 12 with
either LDA or NaHMDS (1.1 equiv.) and then with
either methyl iodide or methyl triflate did not yield the
desired dimethylated product.
A simple retrosynthetic analysis of structures 9a,b
(related to 1–3) affords a plethora of possible routes,
four of which (those indicated in Scheme 1, where Aux
represents a suitable chiral auxiliary) were investigated
in this work. The aldol-like reaction between Aux-CO-
Et and OHC-CHMe-CH2O-PG was not contemplated;
it is a well-known method,10 but it requires two addi-
tional steps for the removal of the central hydroxy
group.
Attempted asymmetric double methylation of pentane-
dioic acid derivatives (Scheme 1, route a). From glutaric
anhydride we prepared derivatives 10 and 11,11 which
were treated with an excess of base and methylating
agent. For the sake of comparison, methylation of 12,
prepared by Michael addition of the corresponding
N-propanoyloxazolidinone to methyl acrylate,12 was
also attempted under similar conditions.13 In practice,
all the experiments performed with 10 and 11, using
two or more equiv. of LDA or NaHMDS (either added
from the beginning or in two steps) and a large excess
of methyl iodide or methyl triflate, in THF at different
temperatures, led to complex mixtures which did not
contain the desired dimethylated product. In the case of
Asymmetric Michael addition to methacrylates (Scheme
1, route b). Reaction of titanium enolates of chiral
N-propanoyl-2-oxazolidinones with ethyl acrylate or
acrylonitrile had been reported to afford conjugate
adducts in excellent yields and diastereoselectivities
(>99% de),12 which we confirmed in our lab. However,
less reactive Michael acceptors such as 2-methyl-
propenoate (methacrylate) derivatives did not react;
changes in temperature, solvent, enolisation conditions
and addition of methyl methacrylate previously com-
plexed with Lewis acids did not afford any
improvement.
By sharp constrast, as shown in Scheme 2, reaction of
the titanium enolate of propanoyl-oxazolidone 13 and
S-2-pyridyl 2-methylthiopropenoate 14 gave rise to the
desired thiol esters 15+15%,15 which could be readily
converted (by isolation and treatment with MeOH and
a trace of toluene-4-sulphonic acid or by addition of
MeOH in situ) to the corresponding methyl esters
16+16%, in 85% overall yield, as a 1:1 diastereomeric
mixture not easily separable by flash chromatography.
Attempts to control the stereochemistry of the methyl
group at Cg by using (−)-sparteine instead of ethyldiiso-
propylamine in the enolisation step or by quenching the
Scheme 1.
Scheme 2.

G. Mas et al. / Tetrahedron Letters 44 (2003) 8805–8809
8807
Scheme 3.
Scheme 4.
reaction at −78°C with chiral aminoalcohols such as
quinine and (−)-N-methylephedrine before the addition
of MeOH, were unsuccessful, as only modest improve-
ments in the diastereoselection were noted. This is a
drawback of the approach, despite the fact that the
performance of 14 is an encouraging result.
Asymmetric alkylation of N-propanoylpseudoephedrine
enolates with O-benzyl-3-iodo-2-methylpropan-1-ol
(Scheme 1, route d). Myers et al. reported the use of
pseudoephedrine as a practical chiral auxiliary for the
alkylation of the corresponding amide enolates.18a,b
Standard, non-activated alkyl iodides, which do not
react with enolates of imides (i.e. when the N atom is
linked to a second EWG), react efficiently with pseu-
doephedrine amides such as 20. The alkylating agent
required by us, (S)-3-iodo-2-methylpropan-1-ol, pro-
tected as its benzyl ether 21,19 was prepared from
methyl (S)-3-hydroxy-2-methylpropanoate.20 Reaction
of the lithium enolate of 20 with 21 (see Scheme 4) in
THF at rt afforded, in 87% yield and with a ]99% de,
the syn-dimethyl derivative 22, which was quantita-
tively reduced with lithium amidotrihydroborate18 to
the syn-dimethyl alcohol 23.
Reaction of a chiral enolate with 3-bromo-2-methyl-
propene followed by hydroboration and oxidation
(Scheme 1, route c).16 The sodium enolate of 13 and
3-bromo-2-methylpropene afforded the allylation
product 17, which was treated with different achiral
and chiral boranes (BH3–Me2S, 9-BBN, catecholbo-
rane/(Ph3P)3RhCl, thexylborane, dicyclohexylborane,
diisopinocampheylborane, isopinocampheylborane) fol-
lowed by oxidation (H2O2/NaOH, H2O2/NaHCO3,
H2O2/NaHCO3/glycerol) to afford diastereomeric alco-
hols 18 (syn) and 18% (anti). The best isolated yield
(82% overall yield) was obtained using an excess of
Chx2BH and oxidising the C–B bonds in the presence
of glycerol, but no significant asymmetric induction was
detected. On the other hand, moderate enrichment in
18 was achieved with thexylborane, but the yields were
poor. The remaining experiments afforded worse results
(yields and diastereoselectivities). Separation of 18 and
18% by flash chromatography or by MPLC was not
feasible, but we took advantage of the easier cyclisation
of the syn-dimethyl derivative 18 into lactone 8,17 in
Et3N/CH3CN, to isolate the anti diastereomer (18%),
which was protected as its tert-butyldimethylsilyl ether
(TBSCl, imidazole, CH2Cl2, 85%) and reduced (LiBH4,
MeOH, THF, 98%) to enantiopure 19% (Scheme 3). The
diastereomeric ratio of 19% (anti) to 19 (syn isomer, not
depicted) was shown by GC to be 95:5.
By using (1S,2S)-pseudoephedrine derivative (ent-20)
and 21, the anti-dimethyl alcohol 23% was similarly
prepared, also in excellent overall yield. Compounds 23
and 23%,21,22 by suitable manipulations, can afford every
stereoisomer of each substructural unit 1–3.23 Alcohol
23% is synthetically equivalent to 24, the C1–C5 synthon
or building block required in our total synthesis of
(−)-amphidinolide K.5
In summary, among the five chemical methods of
obtaining the set of enantiopure fragments of type 1–3
(2,4-dimethylpentanedioates, 2,4-dimethylpentane-1,5-
diols, etc.) investigated by us, the alkylation of pseu-
doephedrine-derived amides18 turned out to be the most
appropriate procedure.
Analogously, ent-19% and ent-8 were prepared starting
from ent-13, via ent-17. Thus, pure anti isomers 19% and
ent-19% can be obtained by appropriate allylation and
hydroboration reactions. Pure syn isomers 8 and ent-8
can be prepared via the same process (an alternative to
the above-mentioned procedure from meso-glutaric
anhydride).
Acknowledgements
Thanks are due to the Ministerio de Educacio´n y
Cultura (PM95-0061 and PB98-1272) for financial sup-
port, as well as for a doctoral studentship to G.M. and
a postdoctoral fellowship to L.G. The suggestions of

8808
G. Mas et al. / Tetrahedron Letters 44 (2003) 8805–8809
Professor David A. Evans (Merendero de la Mari,
Barcelona, January 1998) regarding asymmetric Michael
reactions studied in this work are also acknowledged.
J.V. dedicates this work to Prof. Enrique Mele´ndez
(Universidad de Zaragoza) and Prof. Marcial Moreno
(Universitat Auto`noma).
values are variable, according to Ref. 7. Also see: (b)
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amide, by using a chiral 1,3-thiazolidine-2-thione, fol-
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1985, 1717–1719; (f) Hiratake, J.; Inagaki, M.;
Yamamoto, Y.; Oda, J. J. Chem. Soc. Perkin Trans. 1,
1987, 1053–1058 (reaction with methanol, catalysed by
cinchona alkaloids); (g) Dyer, U. C.; Robinson, J. A. J.
Chem. Soc., Perkin Trans. 1 1988, 53–59 (formation of a
hemiester and resolution by crystallisation with chiral
1-phenylethylamine). For a comparison of the ring open-
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1998, 63, 1190–1197. Also see Ref. 3k, and references cited
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the anion of (S)-4-benzyl-1,3-oxazolidin-2-one (butyl-
lithium, THF, −78°C) afforded 10, in 64% overall yield. (b)
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due to Professor Williams for communicating these results
before publication.
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13. There is a previous report on the double alkylation of
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auxiliaries: Trova, M. P.; Wang, Y. Tetrahedron 1993, 49,
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14. The 1H NMR signal at l 3.01 (t, J=7.2, 2H), correspond-
ing to the CH2CO group linked to Evans’ auxiliary of the
starting material (10), was shifted to l 3.80–3.72 (m, 1H)
in the methylation product, whereas the signal at 2.84 (t,
J=7.2, 2H), due to the CH2CO group linked to Oppolzer’s
auxiliary, remained. Only one new methyl signal appeared,
at 1.25 ppm (d, J=6.9, 3H). Comparison of the 13C NMR
spectra and MS corroborated that the major compound
was the monomethylated product.
9. (a) Enzyme-catalysed desymmetrisation of meso-2,4-
dimethylglutaric acid derivatives is also feasible, but the ee

G. Mas et al. / Tetrahedron Letters 44 (2003) 8805–8809
8809
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15. It is worth noting that (i) S-phenyl and S-4-pyridyl
thiomethacrylates did not react under identical conditions
and that (ii) when S-2-pyridyl methacrylate was previ-
ously complexed with a second equiv. of TiCl4, all the
starting material was recovered. It suggests that coordina-
tion of the pyridine nitrogen atom to the titanium atom
of the enolate (or its chelation by N and O of the thiol
ester) is the key point.
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20. We prepared 21 in four simple high-yielding steps, as
follows (Ref. 5): protection of the hydroxy group of
commercially available methyl (S)-3-hydroxy-2-methyl-
propanoate with benzyl 2,2,2-trichloroacetidimidate and
Me3SiOTf; reduction of the ester group with an excess of
iBu2AlH; activation of the hydroxy group as its mesylate;
and treatment with NaI in acetone. Also see Ref. 19.
These four steps can be shortened to three if a direct
iodo–dehydroxylation reaction is utilised (cf. Larock, R.
C. Comprehensive Organic Transformations; Wiley: New
York, 1999, pp 696–697).
21. Compound 23: oil; Rf (3:1 CH2Cl2–EtOAc) 0.61; 1H
NMR (CDCl3, 200 MHz) l 7.33 (br s, 5H), 4.50 (s, 2H),
3.50–3.40 (m, 2H), 3.30–3.20 (m, 2H), 1.92–1.82 (m, 1H),
1.75–1.63 (m, 1H), 1.52–1.40 (m, 2H), 0.96 (d, J=6.6,
3H), 0.93 (d, J=6.6, 3H); 13C NMR (CDCl3, 75.4 MHz)
l 138.5, 128.3, 127.5, 127.4, 75.8, 73.0, 68.0, 37.6, 33.2,
31.0, 18.1, 17.5; GC (SE-30, 50°C 1 min, 4°C/min“
250°C 10 min) tr=27.42 min, tr (minor diast.)=26.98
min, diastereomeric ratio=98:2. Compound 23%: oil; Rf
17. In fact, a 4:1 cis/trans mixture, from which the enantiop-
ure cis isomer could be isolated by crystallisation from
diethyl ether–pentane (cf. Ref. 3j).
18. (a) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L.
J. Am. Chem. Soc. 1994, 116, 9361–9362; (b) Myers, A.
G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D.
J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496–
6511. For an application of this protocol to a total
synthesis of the Sch 58516 macrolactam, see: (c) Mart´ın,
M.; Mas, G.; Urp´ı, F.; Vilarrasa, J. Angew. Chem., Int.
Ed. 1999, 38, 3086–3089. For an application of pseu-
doephedrine in aldol-like reactions, see: (d) Vicario, J. L.;
Badia, D.; Dom´ınguez, E.; Carrillo, L. Tetrahedron Lett.
1998, 39, 9267–9270; (e) Vicario, J. L.; Badia, D.;
Dom´ınguez, E.; Rodr´ıguez, M.; Carrillo, L. J. Org.
Chem. 2000, 65, 3754–3760. For an alternative, efficient
asymmetric alkylation procedure (not evaluated or com-
pared in the present study), which uses alkyl triflates
instead of alkyl iodides, see Ref. 3h.
1
(3:1 CH2Cl2–EtOAc) 0.60; H NMR (CDCl3, 300 MHz)
l 7.33 (br s, 5H), 4.50 (s, 2H), 3.49–3.37 (m, 2H),
3.33–3.24 (m, 2H), 1.94–1.82 (m, 1H), 1.80–1.71 (m, 1H),
1.29–1.18 (m, 2H), 0.91 (d, J=6.7, 3H), 0.89 (d, J=6.7,
3H); 13C NMR (CDCl3, 75.4 MHz) l 138.5, 128.3, 127.5,
127.4, 76.6, 73.0, 68.8, 37.2, 33.0, 30.5, 16.9, 16.3; CIMS
(NH4+) m/z 240 (M+18, 100), 223 (M+1, 53); GC (50°C
1 min, 4°C/min“250°C 10 min) tr=27.01 min, tr (minor
diast.)=27.40 min, diastereomeric ratio=98:2.
22. These compounds are known: (a) Hale, M. R.; Hoveyda,
A. H. J. Org. Chem. 1992, 57, 1643–1645; (b) Sefkow,
M.; Neidlein, A.; Sommerfeld, T.; Sternfeld, F.; Maestro,
M. A.; Seebach, D. Liebigs Ann. Chem. 1994, 719–729; (c)
Abiko, A.; Moriya, O.; Filla, S. A.; Masamune, S.
Angew. Chem., Int. Ed. 1995, 34, 793–795.
23. Alternatively, the use of ent-21 would give the enan-
tiomers of the compounds shown in Scheme 4.
19. Both enantiomers (21 and ent-21) are known. See: (a)
White, J. D.; Kawasaki, M. J. Org. Chem. 1992, 57,