Enantiocontrolled synthesis of trialkyl-substituted stereogenic carbons. A general route to cis-3,5-dialkyl γ-lactones

Article abstract of DOI:10.1021/ol991287b

(Formula Presented) Lewis acid treatment of tertiary Co₂(CO)₆-propargylic alcohols having a stereochemically defined benzyloxy group at the γ-benzyl position yielded after cobalt demetalation sec-dialkyl bishomopropargylic alcohols in good yields. The reaction is highly stereoselective and predictable, providing pure stereoisomers. The use of benzyl-α,α′-d₂ ethers permitted the stereoselective d-labeling of methines and methylenes. Very simple chemical manipulations provided a general methodology to obtain the enantiomers of 3,5-dialkyl-γ-lactones.

Full text of DOI:10.1021/ol991287b

ORGANIC
LETTERS
2000
Vol. 2, No. 3
335-337
Enantiocontrolled Synthesis of
Trialkyl-Substituted Stereogenic
Carbons. A General Route to
cis-3,5-Dialkyl γ-Lactones
David D´ıaz and V´ıctor S. Mart´ın*
Instituto UniVersitario de Bio-Orga´nica “Antonio Gonza´lez”, UniVersidad de La
Laguna, C/Astrof´ısico Francisco Sa´nchez, 2, 38206 La Laguna, Tenerife, Spain
Vmartin@ull.es
Received November 30, 1999
ABSTRACT
Lewis acid treatment of tertiary Co2(CO)6-propargylic alcohols having a stereochemically defined benzyloxy group at the γ-benzyl position
yielded after cobalt demetalation sec-dialkyl bishomopropargylic alcohols in good yields. The reaction is highly stereoselective and predictable,
providing pure stereoisomers. The use of benzyl-r,r′-d2 ethers permitted the stereoselective d-labeling of methines and methylenes. Very
simple chemical manipulations provided a general methodology to obtain the enantiomers of 3,5-dialkyl-γ-lactones.
Carbon-carbon σ-bond formation is usually the main
objective in an organic synthesis.1 The coupling between an
acetylide and an alkylating agent could be considered to be
a standard procedure for the synthesis of dialkyl acetylenes.2
However, due to competitive elimination reactions, this
procedure is inefficient for the preparation of sec-dialkyl
acetylenes.2 One alternative procedure that overcomes this
difficulty is the reduction of the cobalt complex of R-acety-
lenic alcohols with sodium borohydride in trifluoroacetic
acid.3 Recently, we described a new procedure for the
synthesis of bishomopropargylic alcohols based on the Lewis
acid treatment of γ-benzyl-protected Co2(CO)6-R,γ-acetylenic
diols and further demetalation.4
In this paper, we present the possibility of extending such
an intramolecular reduction to the stereocontrolled synthesis
of sec-dialkyl bishomopropargylic alcohols (Scheme 1).5 The
γ-benzyl-protected R,γ-propargylic alcohols 1 were obtained
in accordance with Scheme 2. Chiral 2,3-epoxy alcohols 5
Scheme 1. Stereoselective Synthesis of sec-Dialkyl
Acetylenes
(1) ComprehensiVe Organic Synthesis; Trost, B. M., et al., Eds.;
Pergamon Press: Oxford, 1991; Vol. 3.
(2) (a) Brandsma, L. In PreparatiVe Acetylenic Chemistry; Elsevier:
Amsterdam, 1988. (b) Garratt, P. J. In ComprehensiVe Organic Synthesis;
Trost, B. M., et al., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp 271-
292.
10.1021/ol991287b CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/20/2000

oisomer regardless the stereochemistry of the carbinol
propargylic center (entries 1 and 2).9 Even when the R2
substituent was a phenyl group, the reduction provided only
one stereoisomer (entry 3). These products represent com-
pounds in which the chirality of the γ-carbon has been
completely transferred to the sec-position relatiVe to the
acetylene. When the R2 increased the steric influence
(isopropyl group), a tiny amount of 4d was isolated (entry
4). The reaction lacks stereoselectivity when R2 is a tert-
butyl group. These facts are consistent with our previously
reported mechanism based on a hydride transfer of one
benzylic proton to the propargylic carbocation (Scheme 3).4
Scheme 2. Synthesis of γ-Benzyl Protected R,â-Propargylic
Alcohols
Scheme 3. Proposed Mechanism for the Stereoselective
were regioselectively opened to the corresponding 1,3-diols.
Benzylidene protection and regioselective reduction provided
the secondary benzyl ether. Oxidation of the primary alcohol
furnished the aldehyde 6, which was treated with a suitable
Grignard reagent to yield the secondary alcohols 7. Oxidation
to the corresponding ketone and lithium acetylide addition
provided 1 as a mixture of diastereoisomers.6
Hydride Transfer to Co2(CO)6-Propargylic Cations
The Co2(CO)6-acetylenic complex 2 was obtained by
simple treatment of 1 with Co2(CO)8 in a CH2Cl2 solution.
The addition of 1 equiv of BF3‚OEt2 to a CH2Cl2 solution
of the Co2(CO)6-acetylenic complex 2, at -20 °C, provided
within minutes the corresponding complexed bishomopro-
pargylic alcohol in a straightforward manner.7 In all cases,
the Co2(CO)6-bishomopropargylic alcohols were satisfactorily
demetalized in the standard manner (Ce(NO3)6(NH4)2, ac-
etone, 0 °C) to obtain the free acetylenes. Representative
examples with different R2 groups are outlined in Table 1.8
The chairlike transition state locates the bulkiest group in a
pseudoequatorial position. The cobalt complex substituent
is such a group when R2 is not highly demanding from a
steric viewpoint. However, when the size of R2 was very
large, as occurred, for example, with a tert-butyl group,
competition between the group and the complexed acetylene
led to poor selectivity.
To establish the stereochemistry of the newly created
stereocenter, we envisioned the possibility of transforming
3 into a 3,5-disubstituted γ-lactone. Thus, 3 was selectively
hydrogenated to the cis-olefin 8 that after acetylation and
cleavage of the olefin afforded the corresponding carboxylic
acid. Alkaline hydrolysis of the acetate group and further
acid treatment afforded in excellent yield the corresponding
γ-lactone (Table 2). The methodology was quite general,
except for the case for R2 ) phenyl, in which we had to
cleave the double bond via the formation of the correspond-
ing cis-diol (OsO4, NMO) and further oxidative fragmenta-
tion (KMnO4, K2CO3, NaIO4). The cis relationship between
Table 1. Stereoselective Intramolecular Propargylic Reduction
in γ-Benzyl-Protected Co2(CO)6-R,γ-Acetylenic Diols under
Lewis Acid Treatment
entry
2 (R1 ) C13H27-n, R3 ) C5H11-n)
3:4
(yield, %)a
1
2
3
4
5
2a , R2 ) CH3
2b, R2 ) C5H11-n
2c, R2 ) Ph
100:0
100:0
100:0
30:1
89 (79)
86 (82)
87 (84)
81 (72)
79 (70)
2d , R2 ) Pr-i
2e, R2 ) Bu-t
1:1
a Yields are not optimized (the overall yield from 1 to 3 + 4 is given in
parentheses).
As can be seen from Table 1, the configuration of the
stereogenic center in which the benzyl-protected group was
located remains unaffected. However, the most interesting
feature of our process was that the reduction of a tertiary
propargylic alcohol, when the R2 is not very bulky, provided
the corresponding sec-dialkyl acetylene as a sole diastere-
(6) The propargylic alcohol is usually obtained as a mixture in which
one of the diastereoisomers slightly predominates (ca. 1.5:1).
(7) Blank experiments performing the acidic treatment over 1 gave
inseparable mixtures, and in any case, traces of 3 were detected.
(8) In our previous work, we have shown that the propargylic reduction
is compatible with a broad kind of functional group.
(9) We have performed the reaction with both diastereoisomers of 2b
leading to 3b as the sole isolated product.
(10) Prepared by the method shown in: Rodr´ıguez, C. M.; Mart´ın, T.;
Ram´ırez, M. A.; Mart´ın, V. S. J. Org. Chem. 1994, 59, 4461.
(11) Evans, D. A. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1985; Vol. 4, pp 2-110 and references therein.
(12) The dibenzyl alcohol 18 was obtained in accordance with the method
described in Scheme 2, with the exception of the step relative to the
reduction of the benzylidene derivative. In this case, we had to use
NaBH3(CN)-(CH3)3SiCl, in CH3CN, to obtain the secondary benzyl ether
since the use of DIBAL provided the benzyl ether in the primary position.
Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1992, 2371.
(3) Nicholas, K. M.; Siegel, J. J. Am. Chem. Soc. 1985, 107, 4999.
(4) D´ıaz, D. D.; Mart´ın, V. S. Tetrahedron Lett. 1999, in press.
(5) For other examples of “ionic hydrogenations” of alcohols, see: (a)
Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633 and
references therein. (b) Adlington, M. G.; Orfanopoulos, M.; Fry, J. L.
Tetrahedron Lett. 1976, 2955. (c) Carey, F. A.; Tremper, H. S. J. Org.
Chem. 1971, 36, 758. (d) Olah, G. A.; Arvanaghi, M.; Ohannecian, L.
Synthesis 1987, 770. (e) Smonou, I.; Orfanopoulos, M. Tetrahedron Lett.
1988, 29, 5793 and references therein.
336
Org. Lett., Vol. 2, No. 3, 2000

of the suitable benzyl-R,R′-d2 ethers 14 and further applica-
tion of our methodology provided cleanly the corresponding
deutero compounds 15 (Scheme 5).
Table 2. Stereoselective Synthesis of cis-3,5-Disubstituted
γ-Lactones
From a practical viewpoint, the high regioselectivity of
the reaction is another very important feature since only those
benzyl ethers located at the γ-position are able to participate
in the reduction of the propargylic alcohol. Thus, we prepared
the dibenzyl alcohol 18 from S-malic acid in accordance with
Scheme 6,12 and it was then submitted to the above-
entry 3 (R1 ) C13H27-n, R3 ) C5H11-n) 3 (yield, %) 9 (yield, %)
1
2
3
4
3a , R2 ) CH3
3b, R2 ) C5H11-n
3c, R2 ) Ph
88
85
87
85
72
71
64
63
3d , R2 ) Pr-i
the 3,5-substituents was clearly determined by NOE experi-
ments over the γ-lactones 9 (Scheme 4). To ensure that such
Scheme 6. Only Benzyl Groups Located in the
BisHomopropargylic Position Are Able to Transfer Hydrides
Scheme 4. Stereoselective Synthesis of 3,5-Disubstituted
γ-Lactones
studies were reliable, we prepared the alternative trans-
lactone by a different procedure. Thus, the 4-benzoyloxy-
R,â-unsaturated ester 1010 was submitted to catalytic hydro-
genation to yield the saturated diester 11 that was submitted
to basic hydrolysis and further acidic treatment to afford the
lactone 12. The alkylation under standard basic conditions
led mainly to the expected trans-3,5-disubtituted γ-butyro-
lactone 13.11 The NMR studies were in accord with the
stereochemistry.
mentioned conditions, yielding only the reduced compound
19.
In summary, the intramolecular hydride transfer from a
secondary γ-benzyloxy group with defined absolute stereo-
chemistry to a Co2(CO)6-complexed propargylic cation
generated under Nicholas conditions occurs with excellent
stereoselectivity, providing a new method to obtain sec-
dialkyl acetylenes with absolute stereochemical control. Since
the stereochemistry of the reduction is highly predictable,
the judicious choice of the different substituents may provide
access to stereochemically defined tricarbon-substituted
methines in their enantiomeric forms. Application of this
methodology to the synthesis of some natural products is
underway and will be published in due course.
One exciting option of our method is the stereoselective
d-labeling of methines and methylenes. The only preparation
Scheme 5. Stereoselective d-Labeling of Methines and
Methylenes
Acknowledgment. This research was supported by the
DGES (PB95-0751) of Spain and the Consejer´ıa de Educa-
cio´n, Cultura y Deportes del Gobierno de Canarias. D. D.
thanks the M. E. C. of Spain for a F. P. I. fellowship.
Supporting Information Available: 1H NMR and 13C
NMR spectra for 3a-e, 4e, 9a-d, 15, and 19. NOE studies
for 9a-d. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL991287B
Org. Lett., Vol. 2, No. 3, 2000
337