Enolate Additions to a Chiral 3-Hydroxypropionate 2,3-Dication Equivalent. Enantioselective Synthesis of β,δ-Dihydroxy Esters

Article abstract of DOI:10.1021/jo9621940

The use of optically active dicarbonyl cyclopentadienyliron(vinyl ether) BF4 salts, 3 and 4, as enantioselective 3-hydroxypropionate 2,3-dication equivalents is outlined.Complexes 3 and 4 are readily available by exchange etherification of 2, and these have been transformed to enantiomeric dicarbonyl (η-cyclopentadienyliron)(η²-1-methoxypropene) BF4 5 and ent-5.Complex 5 has been converted to the corresponding p-methoxybenzyloxy vinyl ether complex 7 by exchange etherification.Condensation of this salt with a number of terminal and nonterminal enolates yields adducts, which are then transformed by redox-promoted alkoxycarbonylation, followed by alcohol deprotection, to optically active 2-methyl-3-hydroxy-5-keto esters. 1,3-Reduction of these ketols can be effected to give either syn- or anti-1,3-diols and thence their related pentanolides.

Full text of DOI:10.1021/jo9621940

3344
J . Org. Chem. 1997, 62, 3344-3354
En ola te Ad d ition s to a Ch ir a l 3-Hyd r oxyp r op ion a te 2,3-Dica tion
Equ iva len t. En a n tioselective Syn th esis of â,δ-Dih yd r oxy Ester s
W. Zhen, K.-H. Chu, and M. Rosenblum*
Department of Chemistry, Brandeis University, Waltham, Massachusetts 02254
Received November 25, 1996X
The use of optically active dicarbonyl cyclopentadienyliron(vinyl ether) BF4 salts, 3 and 4, as
enantioselective 3-hydroxypropionate 2,3-dication equivalents is outlined. Complexes 3 and 4 are
readily available by exchange etherification of 2, and these have been transformed to enantiomeric
dicarbonyl (η-cyclopentadienyliron)(η2-1-methoxypropene) BF4 5 and ent-5. Complex 5 has been
converted to the corresponding p-methoxybenzyloxy vinyl ether complex 7 by exchange etherification.
Condensation of this salt with a number of terminal and nonterminal enolates yields adducts, which
are then transformed by redox-promoted alkoxycarbonylation, followed by alcohol deprotection, to
optically active 2-methyl-3-hydroxy-5 keto esters. 1,3-Reduction of these ketols can be effected to
give either syn- or anti-1,3-diols and thence their related pentanolides.
In tr od u ction
We have earlier reported the preparation of the Fp-
(vinyl ether)BF4 salts 1 a -d (Fp ) dicarbonyl-η-cyclo-
pentadienyliron) and their use as vinyl, trans-propenyl,
isopropenyl, and R-carbomethoxyvinyl cation equivalents
in reactions with enolates to give â,γ-unsaturated ke-
tones1 and R-methylene-γ-lactones2 (Figure 1).
The closely related 1,2-diethoxyethylene complex 2,
obtained by exchange complexation of the olefin with Fp-
(isobutylene)BF4, has been shown to function as either a
cis- or trans-vinylene dication with stabilized and unsta-
bilized carbon nucleophiles.3
These transformations, summarized in Figure 2, take
advantage of the regio- and stereochemical control exer-
cised by the Fp group in nucleophile addition and
elimination reactions, and of the low-energy barrier
associated with rotation about the putative double bond
in Fp-(vinyl ether) salts, which enables ready conversion
of a trans-alkenyl ligand to its thermodynamically pre-
ferred cis form. Salt 2 thus provides a synthetic sequence
alternative to classical olefination reactions and, in
particular, provides a convenient route to cis- or trans-
â,γ-unsaturated carbonyl compounds.4
Complex 2 has been converted to the optically active
dioxino complexes 3 and 4, through exchange etherifi-
cation with (S)-propane-1,2-diol and (R,R)-butane-2,3-
diol, respectively (Figure 3), and these have been used
in the preparation of complexes 1a ,b in optically active
form.5 We have also shown that the absolute configura-
tions of Fp-(vinyl ether) and vinylene diether complexes
may be assigned through application of a simple CD
quadrant rule.6
F igu r e 1.
Although the diastereomers 3a ,b, formed in the reac-
tion of 2 and (S)-propane-1,2-diol, may be separated, this
is not necessary, since each adds nucleophiles regiose-
lectively (at C-3 for 3a and at C-2 for 3b) to give adducts
with the same configuration at the newly created tetra-
hedral centers.5b As shown in Scheme 1 below, these
adducts may be transformed, without isolation, through
successive low temperature protonation, and exchange
etherification, to enantiomeric vinyl ether complexes 5
and 6.5 A short paper reporting preliminary results in
this area was recently published.7 Structural assign-
ments for diastereomers 3a ,b are based on proton and
13C NMR analysis and on X-ray structure determination
of the parent dioxin complex5b and are summarized in
the Experimental Section.
* To whom correspondence should be addressed. Tel.: (617) 736-
2512. Fax: (617) 736-2516. E-mail: Rosenblum@binah.cc.brandeis.edu.
X Abstract published in Advance ACS Abstracts, April 15, 1997.
(1) (a) Chang, T. C-T.; Rosenblum, Samuels, S. B. J . Am. Chem. Soc.
1980, 102, 5930 (b) Chang, T. C-T.; Rosenblum, M. J . Org. Chem. 1981,
46, 4103. (c) Chang, T. C-T.; Rosenblum, M. Isr. J . Chem. 1984, 24,
99. (d) Chang, T. C-T., Coolbaugh, T. S.; Foxman, B. M.; Rosenblum,
M.; Simms, N.; Stockman, C. Organometallics 1987, 6, 2394.
(2) Chang, T. C-T.; Rosenblum, M. J . Org. Chem. 1981, 46, 4626.
Chang, T-C. T.; Rosenblum, M. Tetrahedron Lett. 1983, 24, 695.
(3) Marsi, M.; Rosenblum, M. J . Am. Chem. Soc. 1984, 106, 7264.
(4) Hudrlik, P. F.; Kulkarni, A. K. J . Am. Chem. Soc. 1981, 103,
6251 and references therein.
The present paper describes the use of complexes 3a ,b
as chiral 3-hydroxypropionate 2,3-dication equivalents
(Figure 4) and especially their application in the synthe-
sis of syn- and anti-â,δ-dihydroxy esters and their derived
δ-lactones, which are important structural elements in
(6) Begum, M. K.; Chu, K-H.; Coolbaugh, T. S.; Rosenblum, M. Zhu,
X-Y. J . Am. Chem. Soc. 1989, 111, 5252.
(7) Chu, K-H.; Zhen, W.; Zhu, X-Y.; Rosenblum, M. Tetrahedron Lett.
1992, 33, 1173.
(5) (a) Rosenblum, M.; Turnbull, M. M.; Foxman, B. M. Organome-
tallics 1986, 5, 1062. (b) Turnbull, M. M.; Foxman, B. M.; Rosenblum,
M. Organometallics 1988, 7, 200.
S0022-3263(96)02194-9 CCC: $14.00 © 1997 American Chemical Society

Enolate Additions to a 3-Hydroxypropionate 2,3-Dication
J . Org. Chem., Vol. 62, No. 10, 1997 3345
F igu r e 2.
Sch em e 1a
a large number of biologically active natural products.8
The retrosynthetic analysis shown in Figure 4 illustrates
the very different disconnections associated with the
synthesis of 2-alkyl-3-hydroxy esters following either the
reaction path involving synthons 5 and 6, derived from
3 or 4 or that involving a related aldol type reaction.9
a
Reaction conditions: (a) Nu1-, TEA, THF, -78 °C, 1h; (b)
HBF4, CH2Cl2, -78 °C; ROH, 25 °C.
and 6, from the planar chirality of the organometallic
reagent and the stereochemically enforced mode by which
it reacts with nucleophiles.
F igu r e 3.
Moreover, asymmetric induction and diastereoselection,
which is generally achieved in the aldol reaction through
control of the six-center cyclic transition state generally
associated with these reactions, is derived instead, for 5
Resu lts
In order to examine the use of 3a ,b as a chiral dication
synthetic equivalent, the mixture of diastereomers was
first converted to the optically active propenyl ether
complex 7 (Scheme 2). Experiments were also carried
out with the more accessible racemic salt rac-7, which is
readily prepared in multigram quantities by metalation
of bromopropionaldehyde diethyl acetal with FpNa, fol-
lowed by acid-promoted elimination of ethanol and ether
exchange10 (Scheme 2).
(8) Pettit, G. R. Pure Appl. Chem. 1994, 66, 2271. Omura, S.;
Tanaka, H. in Macrolide Antibiotics: Chemistry, Biology and Practice;
Omura, S.; Ed.; Academic Press: New York, 1984. Endo, A.; Kuroda,
M.; Tsujita, Y. J . Antibiot. 1976, 29, 1346. Harada, T.; Shintani, T.;
Oku, A. J . Am. Chem. Soc. 1995, 117, 12346 and references therein.
Martin, S.; Guinn, D. E. Synthesis 1991, 245. De Mico, A.; Piancatelli,
G.; Cacurri, S.; Sperandina, L. Gazz. Chim. Ital. 1992, 122, 415.
Stokker, G. E.; Alberts, A. W.; Anderson, P. S.; Cragoe, E. J .; Deana,
A. A.; Gilfillan, J . L.; Hirshfield, J .; Holtz, W. J .; Hoffman, W. F.; Huff,
J . W.; Lee, T. J .; Novello, F. C.; Prugh, J . D.; Rooney, C. S.; Smith, R.
L.; Willard, A. K. J . Med. Chem. 1986, 29, 170 and references therein.
(9) Heathcock, C. H. Comprehensive Organic Synthesis; Heathcock,
C. H., Ed.: Pergamon Press: New York, 1991; Vol. 2, p 181; Kim, B.
M.; Williams, S. F., Masamune, S. Ibid. Vol. 2, p 239; Patterson, I.
Ibid. Vol. 2, p 301.
Illustrative of the use of 7 as an optically active
R-methyl-â-hydroxypropionate â-cation equivalent is its
(10) Cutler, A.; Raghu, S.; Rosenblum, M. J . Organometal. Chem.
1974, 77, 381.

3346 J . Org. Chem., Vol. 62, No. 10, 1997
Zhen et al.
Sch em e 4a
a
Reaction conditions: (a) -78 °C, 1 h, THF; (b) NaOAc, MeOH,
Ce(NH4)2(NO3)6, -78 °C to 25 °C, (c) THF, L-Selectride, -78 °C
to 25 °C.
aggregation pheromone.12 In order to examine the enan-
tioselectivity of the overall sequence, rac-7 was carried
through to rac-9a . Examination of the proton NMR
spectrum of this material in the presence of Eu(hfc)3
showed that the optically active ester is formed with
>98% ee.13
F igu r e 4.
conversion to the protected hydroxy ester 8 through
addition of ethyl Grignard, followed by in situ redox-
promoted methoxycarbonylation of the adduct (Scheme
3). A number of oxidizing reagents were examined as
The reaction of 7 with a number of enolates was also
examined. Although the lithium enolate of cyclohex-
anone had been used successfully with vinyl ether
complexes 1, it gave poor and irreproducible yields of
adduct in reactions with rac-7. Since we had earlier
observed that alkyl cuprates and higher order cyanocu-
prates gave better yields of addition product with a
number of Fp(vinyl ether) salts,3 lithium cyclohexanone
enolate was converted to the cuprate salt by treatment
with CuBr-Me2S,14 and this was added to 7. Under
these reaction conditions, the adduct 10 was obtained in
90% yield as a single diastereomer. The stereochemistry
of the adduct was determined by redox-promoted meth-
oxycarbonylation to give 11, which was reduced with
L-Selectride and cyclized to the lactone 12. Examination
of its proton NMR spectrum confirmed the structure of
the lactone (Scheme 4). The anti diastereochemistry ob-
served for 11 corresponds to that observed in the reac-
tions of a number of cyclohexanone enolates with complex
cation 1a 1d and is compatible with a preferred antiperi-
planar transition state 13 for the reacting components.
Sch em e 2a
a
Reaction conditions: (a) FpNa, THF, 25 °C, 3.5 h; (b) HBF4-
Et2O, (c) p-MeOC6H4CH2OH, 25 °C, 20 min.
Sch em e 3a
(12) Philips, J . K.; Miller, S. P. F.; Anderson, J . F.; Falles, H. M.;
Burkholder, W. E. Tetrahedron Lett. 1987, 28, 6145. Chong, J . M.
Tetrahedron 1989, 45, 623.
(13) In the racemic ester, the doublet proton resonance of the
R-methyl group is split into a double doublet at δ 1.20 by the chiral
shift reagent. This resonance remains unchanged in the optically active
ester.
a
Reaction conditions: (a) LiMe2Cu, Et3N. -78 °C, 4 h; (b)
CH2Cl2, HBF4-Et2O, -78 °C, p-MeOC6H4OH; (c) EtMgBr, Et3N,
THF/Et2O, -78 °C, 1 h; (d) Ce(NH4)2(NO3)6, NaOAc, MeOH, CO,
-78 °C to 25 °C; (e) DDQ, CH2Cl2, H2O, 25 °C, 2 h.
(14) Present experimental evidence suggests that metal enolates,
formed by conjugate addition of cuprates to enones, are better
represented as the lithium enolate: House, H. O.; Wilkins, J . M. J .
Org. Chem. 1978, 43, 2443; House, H. O.; Wilkins, J . M. J . Org. Chem.
1976, 41, 4031. Nevertheless, the species formed by treatment of
lithium enolates with copper(I) would appear to differ from these, and
we have represented this salt tentatively here as a copper enolate. For
example, while lithium dienolates derived from R,â-unsaturated acids
underwent preferential R-alkylation, the corresponding “copper dieno-
lates”, formed by treatment of the lithium salts with CuI were observed
to give selective γ-alkylation: Katzenellenbogen, J . A.; Crumrine, A.
L. J . Am. Chem. Soc. 1976, 98, 4925. Similarly, while the lithium
enolate of ethyl acetate was observed to react with propargyl bromide
to give ethyl 4-pentynoate, the “copper enolate” gave the corresponding
ethyl 3,4-pentadienoate: Amos, R. A.; Katzenellenbogen, J . A. J . Org.
Chem. 1978, 43, 555. Finally, the course of alkylation of â-aryl and
â-aralkylcyclopentanones and cyclohexanones in the presence or
absence of copper(I) was found to be distinctly different: Posner, G.
H.; Lentz, C. M. J . Am. Chem. Soc. 1979, 101, 934.
promoters of the carbonylation step, among them bro-
mine, chlorine, NBS, AgBF4, Ag2O, O2, and Ce(NH4)-
(NO3)6. Of these, the last proved the most effective. The
reaction sequence shown in Scheme 3, can alternatively
be carried through beginning with 3a ,b, without isolation
and purification of intermediates, to give 8 in 61% overall
yield. Deprotection of the hydroxyl group with DDQ gave
(2R,3S)-hydroxy ester 9a.11 When redox-promoted alkoxy-
carbonylation is carried out in the presence of 3-pentanol,
the sequence gives ent-sitophilate 9b, the granary weevil
(11) Heathcock, C. H.; Pirrung, M. C.; Sohn, J . E. J . Org. Chem.
1979, 44, 4294.

Enolate Additions to a 3-Hydroxypropionate 2,3-Dication
J . Org. Chem., Vol. 62, No. 10, 1997 3347
Sch em e 5a
Ta ble 1. Ca lcu la ted a n d Obser ved P r oton Cou p lin g
Con sta n ts for 20 a n d 21
J 2,3
lactone
obsda
calcdb
20a
20b
21a
21b
9.93
9.90
6.72
6.60
9.47
9.47
4.84
4.84
a
b
By decoupling experiments. For 20 and 21, R ) Me.
high stereoselectivity. The 1,3-diols were in turn trans-
formed to the δ-lactones 20a ,b and 21a ,b and the
stereochemistry of each of these was confirmed by
comparison of ring proton coupling constants observed
for these compounds with those calculated for the model
compounds 20 and 21 (R ) Me).17 These data are
summarized in Table 1. The proton NMR spectra of each
of the diastereomeric lactones did not show the presence
of the other diastereoisomer in the product. The syn-
thesis of cis-diols 18a ,b and the derived lactones 20a ,b
was carried out on optically active material, derived from
use of (2R,3S)-7, while the synthesis of diols 19a ,b and
their derived lactones 21a ,b was carried out with rac-7.
The diastereoselectivity of reactions involving rac-7
with nonterminal enolates was also of interest, and two
such enolates were examined (Scheme 6). (Z)-2-(Tri-
methylsiloxy)-2-heptene was prepared from 2-heptanone
and ethyl (trimethylsilyl)acetate, following the method
of Kuwajima,18 and converted to the copper enolate 22a .
Reaction of this with rac-7 gave a 3.5:1 mixture of
diastereoisomeric products, which were not separated but
converted through redox-promoted methoxycarbonylation
and alcohol deprotection to a mixture of keto esters 25a
and 26a (50%), from which the major isomer could be
separated and characterized. The mixture of keto esters
was in turn reduced to the anti-1,3-diols 27a and 28a
(95%) and cyclized to give lactones 30a and 31a . The
structures of the major and minor isomers (30a and 31a ,
respectively) were assigned from an analysis of their ring
proton coupling constants and a comparison of these with
coupling constants calculated for the model lactones 30
and 31 (R ) Et). These results, summarized in table 2
support the assignment of the major condensation prod-
uct as 23a . Analogously, syn-reduction of the mixture
of keto esters 25a and 26a resulted in the reduction of
the major isomer 25a alone (50%). The unreduced keto
ester 26a could not be separated from 29a , but cyclization
of this mixture led to the formation of lactone 32a , from
which 26a could be recovered. An analysis of the ring
proton coupling constants for this lactone (Table 2)
confirms its structural assignment and thence the as-
signment of structure 23a as the major product of the
condensation reaction.
a
Reaction conditions: (a) THF, -78 °C, 30 min; (b) CAN, THF,
NaOMe, CO, -60 °C; (c) DDQ, CH2Cl2/H2O, 25 °C, 2 h; (d) Et3B,
THF/MeOH, -78 °C, 30 min; NaBH4, 5 h; (e) Me4NBH(OAc)3,
CH3CN/HOAc, -40 °C, 18 h; (f) p-TsOH, C6H6, 25 °C, 18 h.
The reactions of 7 with two terminal enolates (14a and
14b) were also examined (Scheme 5). While the lithium
enolates yielded almost exclusively the product of O-
alkylation, the copper enolates gave C-alkylation prod-
ucts 15a and 15b, respectively, in high yield. Redox-
promoted methoxycarbonylation of these, using ceric
ammonium nitrate (CAN) in methanol at -60 °C, af-
forded the keto esters 16a and 16b, and these were
transformed to the deprotected hydroxy keto esters 17a
and 17b with DDQ. In the presence of a sufficient excess
of ceric reagent, both oxidative carbonylation of the
alkylFp intermediates 15a and 15b as well as deprotec-
tion of the alcohol function can be achieved. Thus, using
3-4 equiv of CAN with 15a and workup of the reaction
at -30 °C gave 16a and 17a (95:5) in 70% yield, while
the use of 6 equivs of CAN and workup at room temper-
ature gave these products in an inverted ratio of 5:95 in
65% yield. It is important to note here as well that,
whereas sodium acetate was used in the redox-promoted
alkoxycarbonylation reactions of Schemes 3 and 4, so-
dium methoxide proved to give better yields of product
in the transformation of 15 and was consequently used
in all subsequent oxidation reactions.
Similarly, (Z)-4-phenyl-2-(trimethylsiloxy)-2-butene was
prepared following House’s procedure,19 purified by spin-
ning band distillation, and converted to the copper
(15) Chen, K. M.; Gunderson, K. G.; Hardtmann, G. E.; Prasad, K.;
Repic, O.; Shapiro, J . M. Chemistry Lett. 1987, 1923. Kathawala, F.
G.; Prager, B.; Prasad, K.; Repic, O.; Shapiro, M. J .; Stabler, R. S.;
Widler, L. Helv. Chim. Acta 1986, 69, 803.
(16) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J . Am. Chem.
Soc. 1988, 110, 3560.
(17) Model version KS 2.99, obtained from Prof. K. Steliou, Boston
University, was used in the conformational search and MM2 calcula-
tions.
(18) Nakamura, E.; Hashimoto, K.; Kuwajima, I. Tetrahedron Lett.
1978, 24, 2079. Nakamura, E.; Murofushi, T. Shimizu; M.; Kuwajima,
I. J . Am. Chem. Soc. 1976, 98, 2346.
Further elaboration of 17a ,b to either the syn- or anti-
1,3-diols 18a ,b or 19a ,b was readily achieved by reduc-
tion of the ketol employing the methods of Prasad15 and
of Evans,16 respectively. In our hands, these were found
to give high yields of the requisite syn- or anti-diols with

3348 J . Org. Chem., Vol. 62, No. 10, 1997
Zhen et al.
Sch em e 6a
Sch em e 7a
a
Reaction conditions: (a) THF, -78 °C, 2.5 h; (b) CAN, THF,
-60 °C to -30 °C, NaOMe, CO; (c) Et3B, THF/MeOH, -78 °C, 30
min; (d) Me4NBH(OAc)3, CH3CN/HOAc, -40 °C, 5 h; (e) p-TsOH,
C6H6, 25 °C, 18 h.
thence to the lactones 30b and 31b in a 2.5:1 ratio. As
before, we observed that corresponding syn-reduction14
of the mixture of keto esters 25b and 26b resulted in the
selective reduction of the major isomer 25b alone. The
resulting mixture of 29b and unchanged 26b was lac-
tonized, and 26b was separated from the lactone, which
was characterized by its PMR spectrum. As before, these
experiments establish 23b as the principal product
resulting from the condensation of 22b and 7.
a
Reaction conditions: (a) THF, -78 °C, 30 min; (b) CAN, THF,
NaOMe, CO, -60 °C to 25 °C; (c) DDQ, CH2Cl2/H2O, 25 °C, 2 h;
(d) Me4NBH(OAc)3, CH3CN/HOAc, -40 °C, 18 h; (e) Et3B, THF/
MeOH, -78 °C, 30 min; NaBH4, 5 h; (f) p-TsOH, C6H6, 25 °C, 18
h.
Ta ble 2. Ca lcu la ted a n d Obser ved Cou p lin g Con sta n ts
Finally, the effect of enolate geometry on the diaste-
reoselectivity of the condensation reaction was examined
(Scheme 7). Both the Z-18 and E-enolates20 of 3-pen-
tanone gave mixtures of syn- and anti-34, in which the
syn-isomer predominated (1.5:1). As before, these mix-
tures were transformed through redox-promoted meth-
oxycarbonylation, reduction, and lactonization to the
lactones 36-39, which were characterized by their ring
coupling constants (Table 3). The possibility that E- and
Z-copper enolates of 3-pentanone equilibrate under con-
ditions of their formation was examined, by conversion
of (Z)-(trimethylsiloxy)-2-pentene (99% Z) to the copper
enolate and quenching this with TMSCl. The product
was observed to be the (Z)-silyl ether free of detectable
amounts of the E-isomer.
for La cton es 30-32
J 2,3
J 3,4
J 4,5
lactone
obsda
calcdb
obsda
calcdb
obsda
calcdb
30a
31a
3a
9.8
8.6
7.9
-
9.7
8.3
8.1
8.3
5.6
7.6
4.1
8.3
5.6
7.6
9.6
4.2
4.1
-
10.1
4.2
3.4
8.4
3.4
2.1
2.6
8.4
3.4
2.1
7.7
3.0
3.2
-
9.8
3.0
3.2
8.3
4.0
1.9
9.8
8.3
4.0
1.9
A
30b
31b
32b
Discu ssion
a
b
By decoupling experiments. For 30-32, R ) Et.
The predominance of syn-product in the condensation
of nonterminal acyclic enolates with cationic vinyl ether
complex 7 forms a close parallel with the syn-selectivity
observed in reactions of tris(dialkylamino)sulfonium eno-
lates with aldehydes21 and in the reactions of cis- and
trans-allylic silanes and stannanes with aldehydes.22
Here, too, syn-selectivity in the product is largely inde-
enolate. Reaction of this with rac-7 gave a mixture of
diastereoisomer condensation products 23b and 24b in
a ratio of 2.5:1. The structure of these isomers was
determined, as before, by their conversion, through redox-
promoted methoxycarbonylation, to the esters 25b and
26b, which were in turn transformed to anti-1,3-diols and
(19) House, H. O.; Gall, M.; Olmstead, H. D. J . Org. Chem. 1971,
36, 2361. House, H. O.; Czuba, L. J .; Gall, M.; Olmstead, H. D. J . Org.
Chem. 1969, 34, 2324.
(20) Corey, E. J .; Gross, A. W. Tetrahedron. Lett. 1984, 25, 495.
(21) Noyori, R.; Nishida, I. Sakata, J . J . Am. Chem. Soc. 1983, 105,
1598.

Enolate Additions to a 3-Hydroxypropionate 2,3-Dication
J . Org. Chem., Vol. 62, No. 10, 1997 3349
allylsilanes and allylstannanes and aldehydes.23 What-
ever the precise orientational preference of reacting
components in these reactions, it seems that only small
energy differences separate idealized antiperiplanar and
synclinal transition states from one another. Indeed,
recent calculations indicate that the energies of such open
transition states for the condensation of acetaldehyde
enolate and formaldehyde are computationally indistin-
guishable.24 It has also been suggested that stereoelec-
tronic factors may favor a synclinal orientation of donor
and acceptor components in Michael reactions of nitro-
olefines with enamines.25 While the modest syn-diaste-
reoselectivity observed in the reactions of 7 with acyclic
Z- and E-enolates is in accord with a small difference in
energy between antiperiplanar and synclinal transition
states, the contrasting high anti-diastereoselectivity
observed in the reaction of cyclohexanone enolate with 7
suggests a clear preference for the antiperiplanar transi-
tion state 13. For the cyclic enolate, this conformation
is free of steric interactions involving the benzyloxy group
with either adjacent or across ring protons of the cyclo-
hexane ring, while none of the related synclinal confor-
mations are free of such interactions.
Ta ble 3. Ca lcu la ted a n d Obser ved Cou p lin g Con sta n ts
for La cton es 36-38
J 2,3
J 3,4
J 4,5
lactone
obsda
calcd
obsda
calcd
obsda
calcd
36
37
38
39
10.5
9.8
7.6
8.3 (B)
5.6 (C)
7.5 (D)
4.1 (A)
8.5
3.9
2.1
2.6
8.4 (B)
3.4 (C)
2.1 (D)
2.6 (A)
7.3
3.3
2.7
9.9
8.3 (B)
4.0 (C)
1.9 (D)
9.8 (A)
4.0
a
By decoupling experiments.
Con clu sion
In this and earlier publications,1d,5,8 the organometallic
salts 3a ,b and 4 have been shown to behave as stabilized,
enantioselective carbocations toward carbon nucleophiles.
The transformation of the resulting neutral complexes,
through ring opening and alcohol exchange, sets the stage
for addition of a second nucleophile. The present paper
has examined the diastereoselective addition of cyclic as
well as terminal and nonterminal acyclic enolates to the
vinyl ether complex 7, derived from 3a ,b. These reac-
tions, combined with chain functionalization through
stereospecific redox-promoted methoxycarbonylation, pro-
vide facile entry to optically active syn- and anti-â,δ-
dihydroxypropionates.
F igu r e 5.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. Solvents were freshly distilled
by standard procedures, maintained under a nitrogen atmo-
sphere, and degassed by passing through a stream of nitrogen
prior to use. All reactions and subsequent manipulations were
handled under either a nitrogen or argon atmosphere. Ele-
mental analyses were determined by Desert Analytics, Tucson,
AZ. Several of the products which were too unstable to submit
F igu r e 6.
1
for elemental analyses were characterized by their H and 13C
pendent of enolate or allylmetal geometry. These results
have been accounted for in terms of open or non-chelated
antiperiplanar transition states 40-43, in which steric
interactions of substituent groups (R1 and R2) at the
reaction center control the diastereofacial selectivity of
the reaction22 (Figure 5).
This construct cannot apply to the reactions of 7 with
enolates, since antiperiplanar transition states 44 and
45 should then lead to preferential formation of anti-
NMR spectra. All chemicals were purchased from Aldrich
Chemical Co. unless otherwise specified.
cis-1,2-Dim eth oxyeth ylen e. This was prepared by py-
rolysis of 2-methoxyacetaldehyde dimethyl acetal, following the
procedure of McElvain and Stammer,26 except that commercial
12-32 mesh alumina, purchased from EM Science, was used.
Separation of the cis- and trans-products was achieved by
spinning band distillation (cis-1,2-dimethoxyethylene, bp 92-
1
94 °C, trans-isomer bp 90-92 °C). cis-Isomer H NMR (CDCl3)
δ 5.30 (s, 1H), 3.62 (s, 3H); 13C NMR (CDCl3) δ 130.0, 60.2.
trans-Isomer 1H NMR (CDCl3) δ 6.30 (s, 1H), 3.48 (s, 3H), 13C
NMR (CDCl3) δ 134.5, 58.2. Dicarbonyl-η-cyclopentadienyliron
η2-cis-1,2-dimethoxyethylene tetrafluoroborate (11) was pre-
product from both Z- and E-enolates (Figure 6).
A
synclinal transition state for the reacting components
gives a better account of the experimental results for both
E- and Z-enolates, and such an orientation of reactants
has also been proposed for intramolecular reactions of
(23) Denmark, S. E.; Weber, E. J . J . Am. Chem. Soc. 1984, 106, 7970.
Denmark, S. E.; Weber, E. J . Helv. Chim. Acta 1983, 66, 1655.
(24) Li, Y.; Paddon-Row, M. N.; Houk, K. N. J . Am. Chem. Soc. 1988,
110, 3684.
(25) Seebach, D.; Golinski, J . Helv. Chim. Acta 1981, 64, 1413.
(26) McElvain, S. M.; Stammer, C. H. J . Am. Chem. Soc. 1951, 73,
915.
(22) (a)Mikami, K.; Kawamoto, K.; Loh, T. P.; Nakai, T. J . Chem.
Soc., Chem. Commun. 1990, 1164 and references therein. (b)Yama-
moto, Y.; Acc. Chem. Res. 1987, 20, 243. (c) Aoki, S.; Mikami, K.;
Masahiro, T.; Nakai, T. Tetrahedron 1993, 49, 1783.

3350 J . Org. Chem., Vol. 62, No. 10, 1997
Zhen et al.
pared from the cis-isomer in 90% yield, following the procedure
of Turnbull et al.5b
an oily crude product quantitatively (61-84%). This crude
product was redissolved in 5 mL of methylene chloride and
cooled to -78 °C. HBF4-Et2O (0.35 mL, 0.22 mmol) was added
and the formation of an orange solid was observed. After an
additional 15 min, 0.24 mL (6 mmol) of methanol was added
to dissolve the solid, and the solution was stirred at -40 °C
for 1 h and then allowed to warm to 0 °C. Ether was slowly
added to precipitate an orange solid (45.3 mg, 67%): 1H NMR
(acetone-d6/TMS) δ 7.95 (d, 1H, J cis ) 4.0 Hz), 5.76 (s, 5H),
4.18 (s, 3H), 3.70-3.95(dq, 1H, J ) 4.0, 6.1 Hz), 1.61 (d, 3H,
J ) 6.1 Hz); CD (CH2Cl2, -30 °C) ∆ꢀ455 ) -1.85 M-1 cm-1, ∆ꢀ
(5R)-(Dicar bon yl-η-cyclopen tadien yl ir on )-5,6-dih ydr o-
5-m eth yl-1,4-d ioxin Tetr a flu or obor a te (3a ) a n d (6R)-
(Dica r bon yl-η-cyclop en ta d ien yl)-5,6-d ih yd r o-6-m eth yl-
1,4-d ioxin Tetr a flu or obor a te (3b). The following procedure
represents an improvement of that given earlier5b for the
preparation of these complexes. To a 100 mL Schlenk reaction
flask containing Fp-dimethoxyethylene tetrafluoroborate 2
(5.28 g, 15 mmol) were added 10 mL of CH2Cl2 and 5.53 mL
of (S)-(+)-1,2-propanediol (5.70 g, 75 mmol) consecutively at
0 °C. The reaction changed from a dark orange suspension to
a dark brown solution quickly. A constant flow of argon was
applied to entrain the methanol side product. In 15 min, a
solid precipitated, and the stirred reaction suspension was
maintained at 0 °C for another hour. Over 20 mL of ether
was introduced and stirring was continued. The yellow solid
was then collected on a sintered glass funnel, washed repeat-
edly with ether, and dried to give the product as a bright yellow
solid, (5g, 92%) which was composed of two diastereomers, 3a
and 3b, in a ratio of 3:1. If the reaction is run using 30 mL of
solvent for the same scale of reactants, a 1:1 ratio of the same
two diastereomers is formed. A single diastereomer, 3a , can
be obtained in 50% yield from the mixture by simply washing
it (isomer ratio 3:1) with a small amount of cold methylene
chloride several times, which removes the more soluble isomer
3b.
) 3.41 M-1 cm-1
.
345
(1R,2R)-(Dica r bon yl-η-cyclop en ta d ien ylir on )(η2-1-[(p-
m eth oxyben zyl)oxy]p r op en e) Tetr a flu or obor a te (7). To
a 100 mL Schlenk reaction flask were added 260 mg (0.773
mmol) of (R,R)-Fp-(η2-1-methoxypropene) BF4 complex 5, 10
mL of methylene chloride, and 0.96 mL (7.73 mmol) of
p-methoxybenzyl alcohol at 0 °C. A constant flow of nitrogen
was applied during the reaction to entrain the methanol
byproduct. The system was flushed to dryness and the product
was redissolved in methylene chloride. This was repeated five
times over the course of 5 h. Finally, ether was added slowly
to precipitate a solid. The compound was filtered, washed with
ether, and dried in vacuo to give 282 mg of 7 (82%) as a yellow
powder. This compound could also be prepared and used
without isolation by adding p-methoxybenzyl alcohol to the
dioxin ring opening intermediate, as described in the synthesis
of ester 8: 1H NMR (CD3NO2/TMS) δ 7.81 (d, 1H, J ) 4.4 Hz),
7.46 (d, 2H, J ) 8.6 Hz), 7.02 (d, 2H, J ) 8.6 Hz), 5.51 (s, 5H),
5.37 (d, 1H, J ) 11.3 Hz), 5.31 (d, 1H, J ) 11.3 Hz), 3.84 (s,
3H), 3.65 (dq, 1H, J ) 4.4 Hz, J ) 6.2 Hz), 1.65 (d, 3H, J )
6.3 Hz); 13C NMR (CD3NO2/TMS) δ 213.1, 209.4, 162.0, 134.2,
132.0, 127.9, 115.5, 88.8, 78.2, 56.2, 47.5, 14.4; IR (CH2Cl2)
The structural assignments for 3a and 3b were made as
follows. It is known from the X-ray diffraction study of the
5b
parent Fp-(dioxin) BF4 that the Fp group is moved laterally
along the CdC bond axis in order to reduce steric interactions
between the syn-axial proton across the dioxine ring and an
Fp carbonyl ligand. This interaction is also relieved in part
by deflection of the carbon center bonded to the syn-axial
proton into the O-CdC-O plane, partly by bending of the Fp
group away and out from under the dioxin ring, and most
importantly for the present analysis by the lateral displace-
ment cited above. This displacement has the effect of increas-
ing positive charge density on the distal oxygen atom of the
complexed vinylene diether function (O1 in 3) and consequently
to the saturated carbon center (C6, Figure 3) bonded to this
oxygen center. Hence, the methylene carbon signals in 3a and
3b are at δ 69.5 and 68.7 respectively, while the corresponding
methine carbon resonances in 3a and 3b are at δ 70.4 and
71.7 respectively. Furthermore, the syn axial proton across
the heterocyclic ring, which interacts sterically with the Fp
group, lies in the shielding cone of the Fp group. In conformity
with this, the axial proton in 3a , the methylene proton, is
observed at δ 3.35 while that of 3b is at δ 3.64, while the axial
methine proton in 3b is more highly shielded than is the axial
methine proton in 3a (δ 3.91 vs 4.05). These same effects are
seen in 4.5b
2060, 2020 cm-1; CD (CH2Cl2, -30 °C) ∆ꢀ455 ) -1.17 M-1 cm-1
,
∆ꢀ365 ) 1.96 M-1 cm-1. Anal. Calcd for C18H19O4FeBF4: C,
48.91; H, 4.33. Found: C, 48.76; H, 4.12. The corresponding
rac-7 was prepared similarly by treating 3.50 g (10.0 mmol)
of rac-Fp-(η2-1-ethoxypropene) BF4 (rac-5) in 20 mL of meth-
ylene chloride with 12.5 mL (100 mmol) of p-methoxybenzyl
alcohol. After reacting for 12 h at 0 °C, rac-7 was precipitated,
filtered, washed with ether, and dried in vacuo to give 3.57 g
of product (81%) as a yellow powder.
(2R,3S)-Meth yl 2-Meth yl-3-[(p-m eth oxyben zyl)oxy]pen -
ta n oa te (8). Lithium dimethylcuprate, generated in situ from
0.411 g (2 mmol) of CuBr-SMe2 and 2.86 mL (4 mmol) of 1.4
M methyllithium in ether solution was added at -78 °C to a
solution of 3a ,b (0.728 g, 2 mmol) in 10 mL of THF containing
0.835 mL (606 mg, 6 mmol) of triethylamine. After 4 h at -78
°C, the reaction solution was transferred via cannula to a short
plug of alumina (Brockmann, Basic IV). The red filtrate was
concentrated in vacuo to give a dark oil. Column chromatog-
raphy of this oil on alumina, (Brockmann, Basic IV, 250 g),
eluting with ether:hexane, 1:1, afforded 518 mg (88.7%) of
adduct (Scheme 1, Nu ) Me), preceded by a small amount of
Fp-methyl. The product was redissolved in 10 mL of meth-
ylene chloride and cooled to -78 °C, and HBF4-Et2O (0.35
mL, 2.2 mmol) was added to give a light yellow precipitate of
5 (R ) OCH(Me)CH2OH, Nu ) Me). After 0.5 h, ether was
slowly added to precipitate additional product. Solvent was
removed by cannula filtration and was replaced by methylene
chloride (10 mL), followed by a solution of p-methoxybenzyl
alcohol in methylene chloride (2.76 g, in 5 mL) at -5 °C. After
stirring at 0 °C for 10 h, ether was added to precipitate the
yellow gummy product 7 (784 mg, 81%). This was taken up
in 10 mL of THF and cooled to -78 °C, and a solution of
ethylmagnesium bromide in THF/ether (2.0 mmol) containing
0.83 mL of triethylamine was added dropwise. After stirring
at -78 °C for 1 h, a solution of sodium acetate in methanol
(492 mg, in 5 mL of methanol) and a solution of ceric
ammonium nitrate in methanol (5.48 g, in 10 mL of methanol)
were added sequentially under a CO atmosphere. A color
change from orange to green was observed and the reaction
was allowed to warm up slowly. Water was added to quench
the reaction, and the organic layer was separated and con-
centrated to give a gummy residue. Exhaustive extraction of
this with ether and hexane, followed by removal of solvent in
r a c-(Dica r bon yl-(η-cyclop en ta d ien ylir on )(η2-1-eth oxy-
p r op en e) Tetr a flu or obor a te (r a c-5 R ) Et, Nu ) Me). This
was prepared following the procedure for the preparation of
the corresponding hexafluorophosphate10 from bromopropi-
onaldehyde diethyl acetal: 1H NMR (CD3NO2/TMS) δ 7.73 (d,
1H, J ) 4.5 Hz), 5.52 (s, 5H), 4.48 (dq, 1H, J ) 7.1, J ) 10.0
Hz), 4.42 (dq, 1H, J ) 7.1, J ) 10.0 Hz), 3.60 (dq, 1H, J ) 4.5
Hz, 6.2 Hz), 1.65 (d, 3H, J ) 6.2 Hz), 1.41 (dd, 3H, J ) 7.1, 7.1
Hz); 13C NMR (CD3NO2/TMS) δ 214.0, 212.5, 136.2, 88.8, 73.3,
46.7, 15.0, 14.4. Anal. Calcd for C12H15FeO3BF4: C, 41.19;
H, 4.32. Found: C, 40.92; H, 4.52.
(1R ,2R )-(Dica r b on yl-(η-cyclop e n t a d ie n ylir on )(η2-1-
m eth oxyp r op en e) Tetr a flu or obor a te (5, R ) Me, Nu )
Me). This was prepared following the procedure Turnbull et
al.5b used in the preparation of the enantiomeric (S,S)-triflate
salt. Lithium dimethyl cuprate was generated in situ from
123 mg (0.6 mmol) of CuBr-SMe2 and 0.86 mL (1.4 M, 1.2
mmol) of methyllithium in ether and 5 mL of THF at -78 °C
for 0.5 h. This was transferred via cannula to a suspension
of 3a ,b (72.8 mg, 0.2 mmol) in 10 mL of THF and 0.17 mL
(1.2 mmol) of triethylamine. The reaction was stirred at -78
°C for 1 h and then allowed to warm up to room temperature
and quenched with water. The solution was extracted with
ether, dried over magnesium sulfate, and concentrated to give

Enolate Additions to a 3-Hydroxypropionate 2,3-Dication
J . Org. Chem., Vol. 62, No. 10, 1997 3351
vacuo, gave 227 mg (61%) of 8 as a brown oil: 1H NMR (CDCl3/
TMS) δ 7.25 (d, 2H, J ) 8.7 Hz), 6.87 (d, 2H, J ) 8.7 Hz), 4.45
(bs, 1H), 4.46 (bs, 1H), 3.79 (s, 3H), 3.66 (s, 3H), 3.58-3.72
(m, 1H), 2.66 (dq, 1H, J ) 5.7, 7.1 Hz), 1.42-1.72 (m, 2H),
1.20 (d, 3H, J ) 7.2 Hz), 0.93 (t, 3H, J ) 7.4); 13C NMR (CDCl3/
TMS) δ 175.6, 159.1, 130.7, 129.4, 113.7, 81.0, 71.8, 55.3, 51.6,
mL of THF, prepared from benzyl acetone,19 was cooled to 0
°C, and n-butyllithium (0.90 mL, 2.5 M in hexane, 2.2 mmol)
was added dropwise to this solution. The solution was stirred
for 30 min and then cooled to -78 °C and transferred by
cannula to a slurry of CuBr-SMe2 (226 mg, 1.1 mmol) in 20
mL of THF at -78 °C. This solution was kept at -78 °C for
30 min and then transferred by cannula to a slurry of 7 (446
mg, 1.0 mmol) in 20 mL of THF at -78 °C. The reaction was
continued for 2 h at -78 °C and then was allowed to warmed
up to room temperature. The reaction solution was passed
through a short plug of alumina (Brockmann, Basic IV) to
remove excess enolate. The resulting clear olive-green solution
was cooled again to -78 °C and CO gas was bubbled in to
saturate the solution. NaOMe (0.54 g, 10 mmol) in 10 mL of
methanol was syringed in, followed by the slow addition of
CAN (2.74 g, 5 mmol) in 15 mL of methanol, while the solution
temperature was maintained at -60 °C. The solution turned
from light-green to dark-green when one-third of the CAN
solution had been added and remained that color until the
solution was allowed to warm up to -30 °C, at which point it
turned to clear brown. Solvent was removed in vacuo at this
temperature, and the product was extracted with a mixture
of hexane and water. Workup followed by flash chromatog-
raphy of the product on silica gel (Aldrich, 60-200 mesh, eluted
with ether:hexane, 1:1) gave 163 mg of 16a (43%) containing
5-10% of 17a and p-methoxybenzaldehyde: 1H NMR (CDCl3/
TMS) δ 7.18-7.35 (m, 5H), 7.25 (d, 2H, J ) 8.7 Hz), 6.83 (d,
2H, J ) 8.7 Hz), 4.45 (bs, 1H), 4.38 (bs, 1H), 4.24 (m, 1H),
3.77 (s, 3H), 3.66 (s, 3H), 2.7-2.9 (m, 7H), 1.15 (d, 3H, J ) 7.1
Hz); 13C NMR (CDCl3/TMS) δ 208.0, 174.6, 159.1, 140.8, 129.4,
128.4, 128.3, 128.2, 114.2, 113.6, 76.1, 72.2, 55.12, 51.6, 45.5,
45.3, 43.0, 29.4, 12.1.
43.0, 24.9, 11.9, 9.8; [R]25 ) -5.46° (0.90, CHCl3).
D
(2R,3S)-Meth yl 2-Meth yl-3-h yd r oxyp en ta n oa te (9a ).
To a solution of (2R, 3S)-methyl 2-methyl-3-(p-methoxyben-
zyloxy)pentanonate (8) (44 mg, 0.155 mmol) in 5 mL of
methylene chloride was added 39 mg (0.17 mmol) of 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone at room temperature.
After stirring for 10 min, 2 mL of water was added and the
reaction was stirred for an additional 2 h. Ether was added
to extract the methylene chloride solution and the solvent was
removed in vacuo to give 15.2 mg (70%) of product 9a : 1H
NMR (CDCl3/TMS) δ 3.76-3.88 (m, 1H), 3.71 (s, 3H), 2.55 (dq,
1H, J ) 3.6, 7.2 Hz), 2.47 (d, 1H, J ) 4.8 Hz), 1.42-1.56 (m,
2H), 1.18 (d, 3H, J ) 7.2 Hz), 0.97 (t, 3H, J ) 7.5 Hz); 13C
NMR (CDCl3/TMS) δ 176.6, 73.2, 51.8, 43.8, 26.7, 10.5, 10.4;
[R]25 ) -2.70° (0.65, CHCl3). Both the 1H and 13C NMR
D
spectrum data are identical with the data reported in the
literature.11
(2S*,3S*,4S*)-Meth yl 2-Meth yl-3-[4-(m eth oxylben zyl)-
oxy]-3-(2-oxocycloh exyl)p r op ion a te (r a c-11). Lithium cy-
clohexanone enolate (2.0 mmol) was prepared by slow addition
of n-butyllithium (0.8 mL, 2.5 M in hexane, 2.0 mmol) to a
solution of 1-cyclohexenyl-trimethylsilyl ether (0.340 g, 2.0
mmol) in THF. After stirring for 0.5 h the mixture was
transferred to a suspension of CuBr-SMe2 (0.205 g, 1.0 mmol),
cooled to -78 °C. The resulting mixture was stirred for an
additional 0.5 h and transferred by cannula to a suspension
of rac-Fp-(1-[(p-methoxybenzyl)oxy]propene) BF4 (7) (0.442 g,
1.0 mmol) in 20 mL of THF, cooled to -78 °C. After stirring
for 1 h, a solution of sodium acetate in methanol (0.984 g in
10 mL) was added, followed by dropwise addition of a methanol
solution of ceric ammonium nitrate (2.74 g, 5 mmol), under a
CO atmosphere. The reaction was then allowed to warm up
to room temperature without removing the cold bath. During
this period, the color of the solution, which had turned green
after one-third of the oxidizing reagent had been added,
changed to brown at -50 °C. Solvent was removed in vacuo
and the resulting gum was taken up in ether solution, which
was washed with a solution of sodium bicarbonate and dried.
Removal of solvent left an oil which was purified by prepara-
tive TLC (1500 µm silica plate, eluted with ether:hexane, 1:1)
to give 0.152 g (46%) of rac-11 as a clear oil: 1H NMR (CDCl3/
TMS) δ 7.21 (d, 2H, J ) 8.6 Hz), 6.83 (d, 2H, J ) 8.6 Hz), 4.59
(d, 1H, J ) 10.3 Hz), 4.38 (d, 1H, J ) 10.3 Hz), 4.34 (dd, 1H,
J ) 3.9, 7.8 Hz), 3.77 (s, 3H), 3.69 (s, 3H), 2.63 (dq, 1H, J )
4.0, 7.1 Hz), 2.52-2.70 (m, 1H), 2.28-2.42 (m, 2H), 1.44-2.08
(m, 6H), 1.20 (d, 3H, J ) 7.1 Hz); 13C NMR (CDCl3/TMS) δ
211.2, 175.6, 159.1, 130.7, 129.5, 113.7, 78.0, 73.3, 55.2, 54.4,
51.7, 42.5, 40.8, 30.1, 28.0, 24.8, 10.5. Anal. Calcd for
C19H26O5: C, 68.26; H, 7.78. Found: C, 68.36; H, 8.06.
r a c-La cton e (r a c-12). To a solution of rac-keto ester 11
(0.100 g, 0.3 mmol) in 5 mL of THF was added 0.33 mL of
L-Selectride (1.1 mmol, 1.0 M in THF) dropwise at -78 °C.
The reaction was stirred at -78 °C for 1 h, allowed to warm
up to room temperature, and then quenched with aqueous
sodium bicarbonate. Workup gave the crude product as a
brown oil. This was purified by preparative TLC (1500 µm
silica plate, ether:hexane, 3:7) to give 0.064 g (70%) of rac-12
as a clear oil. A minor impurity which was separated by
preparative TLC (1000 µm silica plate, acetate:hexane, 2:8)
was determined not to be a diastereomer. 1H NMR (CDCl3/
TMS) δ 7.26 (d, 2H, 8.7 Hz), 6.89 (d, 2H, J ) 8.7 Hz), 4.60 (d,
1H, J ) 11.1 Hz), 4.37 (d, 1H, J ) 11.1 Hz), 4.26-4.42 (m,
1H), 3.81 (s, 3H), 3.46 (dd, 1H, J ) 4.6, 10.3 Hz), 2.56 (dq, 1H,
J ) 7.02, 10.25 Hz), 2.07-2.22 (m, 1H), 1.86-1.18 (m, 8H),
1.36 (d, 3H, J ) 7.02 Hz); 13C NMR (CDCl3/TMS) δ 174.3,
159.4, 129.8, 129.4, 113.9, 80.1, 75.2, 70.4, 55.3, 38.7, 36.7, 30.7,
24.5, 19.9, 19.1, 14.8.
(2R,3S)-Meth yl 2-Meth yl-3-h yd r oxy-5-k eto-7-p h en yl-
h ep ta n oa te (17a ). Deprotection of 16a , obtained above (163
mg, 0.43 mmol), was carried out with DDQ/H2O/CH2Cl2 as
described in detail for the preparation of 9. The product was
purified by flash column chromatography on silica gel (ether/
hexane, 1:1) to afford 74 mg of 17a (60%): 1H NMR (CDCl3/
TMS) δ 7.15-7.35 (m, 5H), 4.25-4.35 (m, 1H), 3.69 (s, 3H),
3.28 (bs, 1H), 2.48-2.93 (m, 7H), 1.05 (d, 3H, J ) 7.1 Hz); 13
C
NMR (CDCl3/TMS) δ 209.9, 175.4, 140.6, 128.5, 128.2, 126.1,
68.1, 51.8, 46.3, 45.0, 44.1, 29.4, 12.0; [R]27 ) -3.40° (3.20,
D
CHCl3). Anal. Calcd for C15H20O4: C, 68.18; H, 7.63. Found:
C, 67.72; H, 7.69.
(2R,3S,5S)-Met h yl 2-Met h yl-3,5-d ih yd r oxy-7-p h en yl-
h ep ta n oa te (18a ). A 1 M THF solution of Et3B (1.1 mL) was
added to a mixture of THF (8 mL) and methanol (2 mL) at
room temperature under argon. After stirring for 1 h, the
mixture was cooled to -78 °C and 17a (265 mg, 1.0 mmol)
was added. Reaction was continued for 30 min and sodium
borohydride (1.1 mmol) was then added. After 5 h, the reaction
mixture was diluted with ethyl acetate (20 mL) and quenched
with aqueous ammonium chloride solution, and the organic
phase was separated. Methanol (5 mL) and saturated aqueous
ammonium chloride solution (5 mL) were added, and the
solution was stirred at room temperature overnight. Workup
gave an oil, which was purified by column chromatography
on silica gel. Elution with 100% ether followed by ethyl acetate
gave 172 mg (65%) of 18a . The first fraction, about 40 mg
was the boron dihydroxy intermediate, which could be recycled
to the desired product by stirring overnight in methanol/THF/
saturated aqueous ammonium):
1H NMR (CDCl3/TMS) δ
7.15-7.35 (m, 5H), 4.10-4.20 (m, 1H), 3.85-3.95 (m, 1H), 3.69
(s, 3H), 3.55 (d, 1H, J ) 3.4 Hz), 3.45 (d, 1H, J ) 1.9 Hz),
2.6-2.85 (m, 2 H), 2.40-2.50 (m, 1H), 1.40-1.80 (m, 4H), 1.19
(d, 3H, J ) 7.23 Hz); 13C NMR (CDCl3/TMS) δ 176.6, 142.3,
128.8, 128.7, 126.2, 73.2, 72.0, 52.3, 45.0, 39.9, 39.8, 32.0, 11.1.
[R]27
) -3.40° (1.30, CHCl3).
D
(2R,3S,5S)-3-Hydr oxy-2-m eth yl-5-(2-ph en yleth yl)-5-pen -
ta n olid e (20a ). To a solution of 18a (80 mg, 0.30 mmol) in 5
mL of dry benzene was added p-TsOH (6 mg, 0.03 mmol), and
the reaction was allowed to continue at room temperature for
8 h. Solvent was removed in vacuo and the product was
purified by flash column chromatography on silica gel (Aldrich,
60-200 mesh, ethyl acetate:hexane, 1:1 (Rf ) 0.25 on TLC
plate), to give 62 mg (88%) of 20a : 1H NMR (CDCl3/TMS) δ
(2R,3S)-Meth yl 2-Meth yl-3-[(4-m eth oxyben zyl)oxy]-5-
k eto-7-p h en ylh ep ta n oa te (16a ). A solution of 2-[(trimeth-
ylsilyl)oxy]-4-phenyl-1-butene (14a ) (484 mg, 2.2 mmol) in 20

3352 J . Org. Chem., Vol. 62, No. 10, 1997
Zhen et al.
7.17-7.32 (m, 5H), 4.51-4.62 (m, 1H), 3.84-3.94 (m, 1H),
2.82-2.92 (m, 2H), 2.53-2.62 (m, 1H), 1.80-2.10 (m, 4H), 1.32
(d, 3H, J ) 7.0 Hz); 13C NMR (CDCl3/TMS) δ 174.4, 140.9,
brown. Solvent was removed in vacuo and the product was
extracted with hexane and water. Workup followed by flash
column chromatography of the crude product on silica gel
(Aldrich, 60-200 mesh, eluted with ether:hexane, 1:1) afforded
161 mg of 17b (35% based on 7) and 25 mg of 16b. 17b: 1H
NMR (CDCl3/TMS) δ 4.30 (m, 1H), 3.71 (s, 3H), 2.40-2,70 (m,
5H), 1.22-1.65 (m, 6H), 1.21 (d, 3H, J ) 7.2 Hz), 0.89 (t, 3H,
J ) 7.1 Hz); 13C NMR (CDCl3/TMS) δ 211.4, 175.4, 68.38,
51.82, 45.9, 44.2, 43.6, 31.3, 23.2, 22.4, 13.8, 12.2.
128.5, 128.4, 126.1, 74.3, 69.2, 42.8, 37.1, 36.7, 31.1, 14.1; [R]27
D
) -7.06° (1.0, CHCl3). Anal. Calcd for C14H18O3: C, 71.72;
H, 7.74. Found: C, 71.77; H, 7.74.
(2R*,3S*,5R*)-Meth yl 2-Meth yl-3,5-dih ydr oxy-7-(2-ph en -
yleth yl)h ep ta n oa te (r a c-19a ). To a solution of 716 mg (2.72
mmol) of tetramethylammonium triacetoxyborohydride in 1.5
mL of anhydrous acetonitrile was added 1.5 mL of anhydrous
acetic acid. The solution was stirred at ambient temperature
for 30 min and then cooled to -40 °C, and a solution of 90 mg
(0.34 mmol) of rac-methyl 2-methyl-3-hydroxy-5-keto-7-phe-
nylheptanoate (rac-17a ) in 1 mL of anhydrous acetonitrile was
added via cannula. The mixture was stirred at -40 °C for 18
h. The reaction was quenched with 4.0 mL of 0.5 N aqueous
sodium potassium tartrate, and the mixture was allowed to
warm slowly to ambient temperature and was then diluted
with dichloromethane and washed with saturated aqueous
sodium bicarbonate. Further workup gave 90 mg (99%) of the
product diol as a colorless oil: (The NMR spectrum of this
product did not show any detectable amount of the syn isomer.)
1H NMR (CDCl3/TMS) δ 7.15-7.35 (m, 5H), 4.15-4.25 (m, 1H),
3.90-4.00 (m, 1H), 3.70 (s, 3H), 3.10 (bs, 1H), 2.45 (bs, 1H),
2.5-2.85 (m, 3H), 1.40-1.90 (m, 4H), 1.21 (d, 3H, J ) 7.2 Hz);
13C NMR (CDCl3/TMS) δ 176.3, 141.9, 128.4, 128.4, 125.8, 68.9,
68.7, 51.8, 44.6, 39.8, 39.0, 32.0, 11.5. This compound cyclized
rapidly to the lactone 21a in the NMR tube in CDCl3 solu-
tion.
(2R*,3S*,5R*)-3-Hyd r oxy-2-m eth yl-5-p en tyl-5-p en ta n o-
lid e (r a c-21b). To a solution of 716 mg (2.72 mmol) of
tetramethylammonium triacetoxyborohydride in 1.5 mL of
anhydrous acetonitrile was added 1.5 mL of anhydrous acetic
acid. The solution was stirred at ambient temperature for 30
min and then cooled to -40 °C, and a solution of 78.2 mg (0.34
mmol) of (2R*,3S*)-methyl 2-methyl-3-hydroxy-5-keto de-
canonate (rac-17b) in 1 mL of anhydrous acetonitrile was
added via cannula. The mixture was stirred at -40 °C for 18
h. The reaction was quenched with 4.0 mL of 0.5 N aqueous
sodium potassium tatrate, and the mixture was allowed to
warm slowly to ambient temperature. The mixture was then
diluted with dichloromethane and the organic solution was
washed with aqueous saturated sodium bicarbonate. Workup
gave 78 mg (99%) of the diol rac-19b as a colorless oil. The
NMR spectrum of this product did not show any detectable
amount of the syn isomers. To a solution of rac-19b (70 mg,
0.30 mmol) in 5 mL dry benzene was added p-TsOH (6 mg,
0.03 mmol). The reaction was continued for 8 h at room
temperature. Solvent was removed in vacuo and the product
was purified by flash column chromatography on silica gel
(60-200 mesh, ethyl acetate:hexane, 1:1), to give 54 mg (90%)
of rac-21b: 1H NMR (CDCl3/TMS) δ 4.17-4.29 (m, 1H), 3.70-
3.81 (m, 1H), 2.35 (dq, 1H, J ) 7.1, 9.7 Hz), 2.16-2.24 (m,
1H, J gem ) 13.3, 3.8, 3.2 Hz), 1.95 (d, 1H, J ) 4.9 Hz), 1.27-
1.75 (m, 9H), 1.41 (d, 3H, J ) 7.1 Hz), 0.89 (t, 3H, J ) 6.7
Hz); 13C NMR (CDCl3/TMS) δ 173.3, 76.6, 70.3, 45.1, 38.2, 35.8,
22.5, 24.4, 31.5, 13.5, 13.9. Anal. Calcd for C11H20O3: C, 65.96;
H, 10.06. Found: C, 65.62; H, 9.85.
(2R,3S)-Met h yl 2-Met h yl-3-h yd r oxy-5-k et od eca n oa t e
(17b). Step w ise Oxid a tion of 15b. The condensation of
copper enolate 14b with 112 g (2.50 mmol) of 7 was carried as
described earlier for the preparation of 17b. After passing the
solution of the crude product through a short plug of alumina
(Brockmann, Basic IV) to remove excess enolate, the clear
olive-green solution was cooled to -78 °C and CO gas was
bubbled in to saturate the solution. NaOCH3 (0.675 g, 12.5
mmol) in 30 mL of methanol was syringed in, followed by the
slow addition of CAN (6.8 g, 12.5 mmol) in 40 mL of methanol,
while the solution was kept at -60 °C. The solution was
allowed to warm slowly to -30 °C. Solvent was removed in
vacuo at this temperature, and the product was taken up in a
mixture of 50 mL of hexane and 20 mL of water. Further
workup, followed by flash column chromatography of the crude
product on silica gel (Aldrich, 60-200 mesh, eluted with 1:1
ether:hexane) afforded 350 mg of 16b (39% yield). Deprotec-
tion of 16b was carried out with DDQ/H2O/CH2Cl2 as described
in detail for the preparation of 9a . The product was purified
by flash column chromatography on silica gel (Aldrich, 60-
200 mesh, ether:hexane, 1:1) to afford 161 mg of 17b (70%).
(2R,3S,5S)-3-H yd r oxy-2-m et h yl-5-p en t yl-5-p en t a n o-
lid e (20b). A 1.0 M THF solution of Et3B (0.55 mL) was added
to a mixture of dry THF (4 mL) and methanol (1 mL) at room
temperature under argon. After stirring for 1 h, the mixture
was cooled to -78 °C and 17b (115 mg, 0.50 mmol) in 1 mL
THF was added. Reaction was continued for 30 min and
sodium borohydride (0.55 mmol) was then added. After 5 h,
the reaction mixture was diluted with ethyl acetate (10 mL
and quenched with aqueous ammonium chloride solution, and
the organic phase was separated. Methanol (3 mL) and
saturated aqueous ammonium chloride solution (3 mL) were
added, and the solution was stirred at room temperature
overnight. Workup gave an oil, which was purified by column
chromatography on silica gel, first eluted with 100% ether and
followed by ethyl acetate to give 75 mg of 18b (65%). To a
solution of 18b (69 mg, 0.30 mmol) in 5 mL of dry benzene
was added p-TsOH (6 mg, 0.03 mmol) and the reaction was
(2R*,3S*,5R*)-3-Hyd r oxy-2-m eth yl-6-(2-p h en yleth yl)-5-
p en ta n olid e (r a c-21a ). To a solution of rac-19a (80 mg, 0.30
mmol) in 5 mL of dry benzene was added p-TsOH (6 mg, 0.03
mmol). The reaction was continued for 8 h at room temper-
ature. Solvent was removed in vacuo and the product was
purified by flash column chromatography on silica gel (60-
200 mesh, ethyl acetate:hexane 1:1), to give 62 mg (88%) of
rac-21a : 1H NMR (CDCl3/TMS) δ 7.15-7.35 (m, 5H), 4.17-
4.25 (m, 1H), 3.68-3.71 (m, 1H), 2.70-2.90 (m, 2H), 2.35-
2.43 (m, 1H, J ) 7.1, 9.9, 1.4 Hz), 2.15-2.24 (m, 1H), 1.86-
2.13 (m, 2H), 1.69-1.80 (m, 1H), 1.40 (d, 3H, J ) 7.1 Hz); 13
C
NMR (CDCl3/TMS) δ 176.3, 140.7, 128.5, 128.4, 126.1, 75.5,
70.0, 45.0, 38.2, 37.5, 30.9, 13.5. Anal. Calcd for C14H18O3:
C, 71.72; H, 7.74. Found: C, 71.45; H, 7.54.
(2R,3S)-Met h yl 2-Met h yl-3-h yd r oxy-5-k et od eca n oa t e
(17b). Con cu r r en t Ca r bom eth oxyla tion -Dep r otection
of 15b. 2-[(Trimethylsilyl)oxy]-1-heptene was prepared ac-
cording to House’s procedure and purified by distillation (bp
40 °C/0.2 mm). A solution of the silyl ether (1.025 g, 5.5 mmol)
in 30 mL of THF was cooled to 0 °C, and n-butyllithium (2.25
mL, 2.5 M in hexane, 5.5 mmol) was added dropwise to this
solution. The solution was stirred for 30 min and then cooled
to -78 °C and transferred by cannula to a slurry of CuBr-
SMe2 (0.56 g, 2.75 mmol) in 30 mL of THF at -78 °C. This
solution was kept at -78 °C for 30 min and then transferred
by cannula to a slurry of 7 (1.12 g, 2.50 mmol) in 30 mL of
THF at -78 °C. The reaction was continued for 2 h at -78
°C and then was allowed to warm up to room temperature.
The reaction solution was passed through a short plug of
alumina (Brockmann, Basic IV) to remove excess of enolate.
An NMR spectrum of an aliquot of the addition product 15b
showed it to be 85-90% pure (80-85% yield): 1H NMR
(acetone-d6/TMS) δ 7.30 (d, 2H, J ) 8.8 Hz), 6.87 (d, 2H, J )
8.8 Hz), 4.93 (s, 5H), 4.40 (bs, 1H), 4.41 (bs, 1H), 3.90-4.05
(m, 1H), 3.77 (s, 3H), 2.40-2.85 (m, 4H), 1.15-1.60 (m, 4H),
1.26 (d, 3H, J ) 7.2 Hz), 0.87 (t, 3H, J ) 6.7 Hz); 13C NMR
(CDCl3/TMS) δ 206.0, 160.1, 132.0, 130.2, 114.2, 86.9, 85.9,
71.4, 55.4, 47.5, 44.5, 32.1, 24.3, 24.0, 22.5, 14.2, 14.2. The
clear olive-green solution of the adduct 15b was cooled again
to -78 °C and CO gas was bubbled in to saturate the solution.
NaOCH3 (0.540 g, 10 mmol) in 30 mL of methanol was added
by syringe, followed by the slow addition of CAN (8.16 g, 15
mmol) in 40 mL of methanol, while the solution was kept at
-60 °C. The solution color turned from light-green to dark-
green when one-third of the CAN solution had been added and
remained that color until the solution was allowed to warm
up to room temperature, at which point it turned to clear

Enolate Additions to a 3-Hydroxypropionate 2,3-Dication
J . Org. Chem., Vol. 62, No. 10, 1997 3353
allowed to continue at room temperature for 8 h. Solvent was
removed in vacuo and the product was purified by flash column
chromatography on silica gel to give 53 mg (88%) of 20b: 1H
NMR (CDCl3/TMS) δ 4.48-4.62 (m, 1H), 3.82-3.94 (m, 1H),
2.58-2.68 (m, 1H), 1.84-2.04 (m, 2H), 1.40-1.75 (m, 8H), 1.32
(d, 3H, J ) 6.9 Hz), 0.89 (t, 3H, J ) 6.8 Hz); 13C NMR (CDCl3/
TMS) δ 174.2, 75.3, 69.5, 42.9, 37.2, 31.5, 26.6, 22.5, 14.1,
J ) 6.5, 8.3 Hz), 1.85-1.96 (m, 1H), 1.36 (d, 3H, J ) 7.0 Hz),
1.30 (d, 3H, J ) 7.5 Hz); 13C NMR (CDCl3) δ 173.5, 140.1,
129.3, 128.7, 126.4, 76.9, 73.7, 48.7, 44.4, 41.4, 18.4, 14.9.
(2R*,3S*,4R*,5S*)-3-n -Bu tyl-3-h yd r oxy-2,5-d im eth yl-5-
p en ta n olid e (32a ). (Z)-[(Trimethylsilyl)oxy]-2-heptene was
prepared from 2-heptanone (5 mL, 35.2 mmol) by treatment
with ethyl (trimethylsilyl)acetate (1.1 equiv 7.2 mL, 39 mmol)
in the presence of a catalytic amount of tetra-n-butylammo-
nium fluoride (1.06 mmol).18 The product was further purified
by spinning band distillation to give a product with 98% purity.
This (2.2 mmol) was converted to the copper enolate as
described earlier and added to 1.0 mmol of rac-51. A PMR
spectrum of this adduct showed two singlet resonances at δ
2.19 and 2.22, assigned to the acetyl function of 23a and 24a ,
respectively, formed in a ratio of 3.5:1. This mixture of adducts
was converted to a mixture of diastereomeric esters 25a and
26a , (115 mg, 50%) through redox-promoted migratory inser-
tion and deprotection. Some of the major isomer 25a was
isolated and purified by flash column chromatography on silica
gel from the diastereomeric mixture: 1H NMR (CDCl3/TMS)
δ 4.05-415 (m, 1H), 3.71 (s, 3H), 2.98 (d, 1H, J ) 3.2 Hz),
2.5-2.7 (m, 2H), 2.19 (s, 3H), 1.20-1.80 (m, 6H), 1.23 (d, 3H,
J ) 7.2 Hz), 0.89 (t, 3H, J ) 7.1 Hz); 13C NMR (CDCl3/TMS)
δ 215.0, 176.2, 71.1, 55.0, 51.9, 42.3, 30.5, 29.6, 27.2, 22.9, 13.8,
11.80. cis-Reduction of the mixture of 25a and 26a 14 and then
lactonization, following the procedure given earlier for the
preparation of 20 and 21, gave 42 mg (51%) of 32a and 20 mg
of unchanged 26a . The lactone 32a : 1H NMR (CDCl3/TMS) δ
4.74 (dq, 1H, J ) 3.2, J ) 7.0 Hz), 3.48-3.56 (m, 1H, J ) 4.1,
7.9 Hz), 2.49-2.61 (m, 1H), 1.90 (d, 1H, J ) 4.1 Hz),1.70-
1.80 (m, 1H), 1.2-1.5 (m, 6H), 1.33-1.37 (t, J ) 6.4 Hz, 6H),
0.91 (t, 3H, J ) 7.0 Hz); 13C NMR (CDCl3/TMS) δ 174, 74.8,
73.9, 47.0, 42.8, 29.2, 25.7, 22.8, 17.1, 13.9 (2). Anal. Calcd
for C11H20O3: C, 65.96; H, 10.06. Found: C, 65.92; H, 9.91.
The hydroxy ketone 26a , (2R*,3S*,4R*)-m eth yl 2-m eth yl-
3-h yd r oxy-4-n -bu tyl-5-k etoh exa n a ote: 1H NMR (CDCl3/
TMS) δ 3.91-4.03 (m, 1H), 3.71 (s, 3H), 3.22 (d, 1H, J ) 6.81
Hz), 2.54-2.67 (m, 2H), 2.22 (s, 3H), 1.25-1.60 (m, 6H), 1.24
(d, 3H, J ) 7.1 Hz), 0.894 (t, 3H, J ) 6.9 Hz); 13C NMR (CDCl3/
TMS) δ 214.2, 176.0, 73.1, 53.6, 51.9, 42.9, 31.5, 29.3, 28.8,
22.7, 13.8, 11.7.
(2R*,3S*,4S*(R*),5R*)-n -Bu tyl-3-h yd r oxy-2,5-d im eth yl-
5-p en ta n olid e (30a a n d 31a ). The mixture of 115 mg of
adducts 25a and 26a , prepared as described above, was
reduced to a mixture of 110 mg (95%) of trans-1,3-diols 27a
and 28a by the method of Evans. Lactonization of these diols
with benzenesulfonic acid in benzene gave 99 mg (85%) of 30a
and 31a . Separation of these two lactones was achieved by
flash column chromatography on silica gel. These products
were assigned the (2R*,3S*,4S*(R*),5R*) configuration from
their PMR spectrum. (2R*,3S*,4S*,5R*)-n -Bu tyl-3-h ydr oxy-
2,5-d im eth yl-5-p en ta n olid e (31a ): 1H NMR (CDCl3/TMS)
δ 4.48 (dq, 1H, J ) 3.0, 6.7 Hz), 3.84 (q, 1H, J ) 4.2, 8.6 Hz),
2.52 (q, 1H, J ) 7.1 Hz, 8.6 Hz), 1.86-1.94 (m, 1H), 1.80 (d,
1H, J ) 4.14 Hz), 1.2-1.5 (m, 6H), 1.41 (d, 3H, J ) 6.7), 1.39
(d,3H, J ) 7.1 Hz), 0.92 (t, 3H, J ) 6.8 Hz); 13NMR (CDCl3/
TMS) δ 173.6, 76.9, 74.1, 43.1, 40.9, 32.1, 23.0, 22.2, 18.3, 14.8,
13.9. (2R*,3S*,4R*,5R*)-n -Bu tyl-3-h yd r oxy-2,5-d im eth yl-
5-p en ta n olid e (30a ): 1H NMR (CDCl3/TMS) δ 4.20 (dq, 1H,
J ) 6.4, 7.7 Hz), 3.46-3.58 (m, 1H, J ) 9.6, 9.8 Hz), 2.38-
2.48 (m, 1H, J ) 6.9, 9.8 Hz), 1.85 (d, 1H, J ) 4.1 Hz), 1.50-
1.68 (m, 1H), 1.42 (d, 3H, J ) 6.4 Hz), 1.40 (d, 3H, J ) 6.9
Hz), 1.2-1.5 (m, 6H), 0.91 (t, 3H, J ) 7.0 Hz); 13C NMR (CDCl3/
TMS) δ 173.1, 76.9, 73.0, 47.3, 44.7, 27.6, 27.4, 25.7, 23.2, 20.3,-
13.9, 13.7.
14.00; [R]27 ) -2.0° (0.42, CHCl3). Anal. Calcd for
D
C11H20O3: C, 65.96; H, 10.06. Found: 65.62; H,10.18.
(2R*,3S*,4S*,5S*)-4-Ben zyl-3-h yd r oxy-2,5-d im eth yl-5-
p en ta n olid e (32b). 3-[(Trimethylsilyl)oxy]-1-phenyl-2-butene
was prepared by refluxing benzylacetone, triethylamine, tri-
methylsilyl chloride in DMF for 48 h.19 This afforded a product
with Z:E:T(terminal) isomers in a ratio of 5:3:4. The Z-isomer
was further separated and concentrated by spinning band
distillation in vacuo to give a product with Z:E:T ) 10:1:0.4.
This silyl enol ether (484 mg, 2.2 mmol) was converted to the
lithium enolate with n-butyllithium and then to the cuprous
enolate by treatment with CuBr-SMe2 as described earlier
in the preparation of 11. Addition to rac-7, followed by redox-
promoted carboxymethylation and deprotection of the p-
methoxybenzyloxy function, afforded a mixture of diastereo-
meric ester products 25b and 26b in
a ratio of 2.5:1,
respectively. These could be distinguished by a pair of
doublets at δ 1.83 and 1.93. The diastereomers could not be
separated, but cis reduction of this mixture as for 17a with
Et3B, MeOH, NaBH4 resulted in the reduction of the major
isomer (δ 1.83) alone. Cyclization of the mixture, and purifica-
tion by flash chromatography afforded the titled compound 32b
(50 mg, 21%) and 26b. 1H NMR 32b: (CDCl3/TMS) δ 7.15-
7.35 (m, 5H), 4.77 (dq, 1H, J ) 6.6, 3.2 Hz), 3.45-3.55 (m,
1H, J ) 3.4, 8.1 Hz, (coupling constants derived from spectra
taken in D2O)), 2.92 (dd, 1H, J ) 14.0, 5.4 Hz), 2,52-2.62 (m,
1H, J ) 6.7, 3.4 Hz, (coupling constants derived from spectra
taken in D2O)), 2.42 (dd, 1H, J ) 14.0, 11.2 Hz), 2.16-2.28
(m, 1H), 1.79 (d, 1H, J ) 4.2 Hz), 1.45 (d, 3H, J ) 6.6 Hz),
1.33 (d, 3H, J ) 6.6 Hz); 13C NMR (CDCl3/TMS) δ 174.0, 138.4,
129.0, 128.9, 126.7, 73.4, 73.6, 48.7, 42.2, 32.1, 17.2, 13.8.
26b: 1H NMR (CDCl3/TMS) δ 7.14-7.35 (m, 5H), 3.82-3.94
(m, 1H), 3.69 (s, 3H), 3.38 (d, 1H, J ) 7.5 Hz), 2.75-2.95 (m,
3H), 2.52-2.68 (m, 1H), 1.94 (s, 3H), 1.26 (d, 3H, J ) 7.1 Hz);
13C NMR (CDCl3/TMS) δ 207.0, 175.7, 138.1, 128.9, 128.4,
126.7, 73.6, 55.2, 51.9, 45.5, 42.2, 35.8, 12.3.
(2R*,3S*,4R*(S*),5R*)-4-Ben zyl-3-h ydr oxy-2,5-dim eth yl-
5-p en ta n olid e (30b a n d 31b). The mixture of 120 mg of
diastereomeric hydroxy keto esters 25b and 26b, prepared as
described above in the preparation of 32, from 484 mg (2.2
mmol) of silyl enol ether 22b, was reduced to give a mixture
of trans-1,3-diols 27b and 28b, following the procedure of
Evans, employed in the preparation of 19a . Purification and
cyclization of these esters, as for 19a , gave a mixture of
lactones in a ratio of 2.5:1. These were purified and separated
from other impurities by flash column chromatography and
cyclized in dry benzene with a trace amount of p-TsOH to
afford 90 mg (77%, two steps) of 30b and 31b. These products
were assigned the relative configurations on the basis of their
PMR. The major isomer is assigned as (2R*,3S*,4R*,5R*)-
4-ben zyl-3-h yd r oxy-2,5-d im eth yl-5-p en ta n olid e (30b): 1H
NMR (CDCl3/TMS) δ 7.15-7.35 (m, 5H), 4.15 (dq, 1H, J ) 6.4,
9.8 Hz), 3.42-3.54 (m, 1H, J ) 10.1, 9.7 Hz, (coupling
constants derived from spectra taken in D2O)), 2.86-3.04 (m,
2H), 2,38-2.50 (m, 1H, J ) 7.1, 9.7 Hz, (coupling constants
derived from spectra taken in D2O)), 1.92-2.04 (m, 1H), 1.44
(d, 3H, J ) 6.4 Hz), 1.36 (d, 3H, J ) 7.1 Hz); 13C NMR (CDCl3/
TMS) δ 172.8, 137.8, 129.4, 128.9, 126.8, 76.8, 72.6, 48.7, 44.2,
34.5, 20.9, 13.5. Anal. Calcd for C14H18O3: C, 71.72; H, 7.74.
Found: C, 72.02; H, 7.79. The minor isomer was not isolated
in pure form, and its structure as (2R*,3S*,4S*,5R*)-4-
ben zyl-3-h yd r oxy-2,5-d im eth yl-5-p en ta n olid e (31b) was
assigned from its NMR spectrum, obtained by subtraction of
the spectrum of purified 30b from that of the mixture of the
two isomers: 1H NMR (CDCl3/TMS) δ 7.15-7.35 (m, 5H), 4.51
(dq, 1H, J ) 7.0, 3.1 Hz), 3.78-3.86 (m, 1H, J ) 4.2, 8.3 Hz
(coupling constants derived from spectrum taken in D2O)),
2.86-3.04 (m, 1H), 2.74 (dd, 1H, J ) 14.3, 7.0 Hz, (coupling
constants derived from spectrum taken in D2O)), 2.62 (dd, 1H
(2R*,3S*,4R*,5S*)-5-E t h yl-3-h yd r oxy-2,4-d im et h yl-5-
pen tan olide (38) an d (2R*,3S*,4S*,5S*)-5-Eth yl-3-h ydr oxy-
2,4-d im eth yl-5-p en ta n olid e (39). n-Butyllithium (0.90 mL,
2.5 M in hexane, 2.2 mmol) was added dropwise to (Z)-3-
[(trimethylsilyl)oxy]-2-pentene18 (347.9 mg, 2.2 mmol) in 20
mL of THF, cooled to 0 °C. The solution was stirred for 30
min, cooled to -78 °C, and then transferred by cannula to a
slurry of CuBr-SMe2 (226 mg, 1.1 mmol) in 20 mL of THF
cooled to -78 °C. This solution was kept at -78 °C for 30
min and then transferred by cannula to a slurry of rac-7 (446
mg, 1.0 mmol) in 20 mL of THF at -78 °C. After 30 min, an

3354 J . Org. Chem., Vol. 62, No. 10, 1997
Zhen et al.
1
aliquot of the reaction mixture was taken for H NMR analysis.
73.4, 42.3, 42.3, 40.7, 34.3, 25.7, 24.5, 15.8, 15.7, 14.2, 13.9,
12.7, 12.5, 12.0, 10.2, 8.7. Anal. Calcd for C9H16O3: C, 62.91;
H, 9.30. Found: C, 63.30; H, 9.27.
The presence of two isomers (34) is evidenced by two pairs of
singlets, one at δ 4.95 and 4.90, assigned to Cp ring protons,
and another at δ 3.72 and 3.75, assigned to the p-methoxy-
phenyl protons. Both pairs show a relative intensity of 1.5:
1.0. After an additional 2 h at -78 °C, the solution was
allowed to come to room temperature and was passed through
a short plug of alumina (Brockmann, Basic IV), to remove
excess enolate. The resulting clear olive-green solution was
cooled again to -78 °C and CO was bubbled in until the
solution was saturated. Sodium methoxide (270 mg, 5 mmol)
in 10 mL of methanol was added by syringe, followed by the
slow addition of CAN (3.28 g, 6 mmol) in 15 mL of methanol,
keeping the solution temperature at -60 °C. During this
period, the solution turned from light green to dark-green
when one-half of the CAN solution had been added and
remained that color until the solution was allowed to warm
up to -30 °C, at which point it turned to a clear brown color.
Solvent was removed in vacuo and the product was extracted
with hexane and water. Workup and removal of solvent left
a residue, which after flash chromatography on silica gel
(Aldrich, 60-200 mesh, eluted with ether:hexane, 1:1), gave
130 mg of hydroxy keto esters 35 (40% yield). This was
reduced to the mixture of cis-1,3 diols14 and then cyclized (p-
TsOH, benzene) to give the titled compounds in 50% yield.
These two stereoisomeric lactones (38 and 39) could not be
separated. 1H NMR (CDCl3/TMS) δ 4.38-4.46 and 4.28-4.36
(m, 1H), 3.72-3.78 and 3.38-3.46 (m, 1H), 2.66-2.74 and
2.52-2.60 (m, 1H), 1.6-2.4 (m, 3H), 1.35 (pseudo triplet, 3H),
0.90-1.15 (m, 6H); 13C NMR δ 174.3, 174.4, 81.1, 79.3, 73.4,
(2R*,3S*,4S*(R*),5R*)-5-Eth yl-3-h yd r oxy-2,4-d im eth yl-
5-p en t a n olid e (36 a n d 37). The mixture of hydroxy keto
esters (76.4 mg, 0.40 mmol) 35, prepared as above, was reduced
to the corresponding trans-1,3-diols16 following the procedure
given for the preparation of 19a . This was then cyclized (p-
TsOH, benzene) to give the titled products in 85% yield. These
two stereoisomers are very difficult to separate and NMR
analysis was carried out on the mixture: 1H NMR (CDCl3/
TMS) δ 4.10-418 and 3.88-3.94 (m, 1H), 3.76-3.84 and 3.32-
3.38 (m, 1H), 2.36-2.50 (m, 2H), 1.6-2.2 (m, 3H), 1.41 (d, 3H,
J ) 7.1 Hz), 1.41 (d, 3H, J ) 7.1 Hz), 0.9-1.12 (m, 6H); 13C
NMR δ 173.6, 173.3, 82.8, 81.8, 75.3, 73.9, 44.5, 39.9, 39.8,
36.7, 25.7, 25.2, 14.3, 14.1, 13.8, 13.1, 9.9, 8.5.
Ack n ow led gm en t. This research was supported by
a grant from the National Institutes of Health (GM-
37067), which is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 8, 11, 16a , 18a , 18b, 25a , 26a , 26b, 30a , 31a , 32b,
36, and 37 (12 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9621940