Double diastereoselection in aldol reactions mediated by dicyclohexylchloroborane between chiral aldehydes and a chiral ethyl ketone derived from L-erythrulose. Synthesis of a C1-C9 fragment of the structure of the antifungal metabol

Article abstract of DOI:10.1021/jo051307p

Both matched and mismatched diastereoselections have been observed in the aldol reactions of a range of chiral aldehydes with the dicyclohexylboron enolate of a chiral ethyl ketone related to L-erythrulose. As was previously observed in the corresponding

Full text of DOI:10.1021/jo051307p

Double Diastereoselection in Aldol Reactions Mediated by
Dicyclohexylchloroborane between Chiral Aldehydes and a Chiral
Ethyl Ketone Derived from L-Erythrulose. Synthesis of a C1-C9
Fragment of the Structure of the Antifungal Metabolite
Soraphen A1r
Santiago D´ıaz-Oltra,† Juan Murga,*,† Eva Falomir,† Miguel Carda,† Gabriel Peris,‡ and
J. Alberto Marco*,§
Departamento de Quı´mica Inorga´nica y Orga´nica, and Servicios Centrales de Instrumentacio´n,
Universidad Jaume I, E-12080 Castello´n, Spain, and Departamento de Qu´ımica Orga´nica,
Universidad de Valencia, E-46100 Burjassot, Valencia, Spain
alberto.marco@uv.es
Received June 27, 2005
Both matched and mismatched diastereoselections have been observed in the aldol reactions of a
range of chiral aldehydes with the dicyclohexylboron enolate of a chiral ethyl ketone related to
L-erythrulose. As was previously observed in the corresponding aldol reactions with L-erythrulose
derivatives, the Felkin-Anh model provides an adequate explanation for the stereochemical outcome
of reactions with chiral R-methyl aldehydes. However, a satisfactory account of the results observed
with R-oxygenated aldehydes was only possible with the Cornforth model. As a practical application
of the methodology described herein, a C1-C9 fragment of the structure of the antifungal macrolide
soraphen A1R has been prepared in a convergent and stereoselective way.
Introduction
was that, in contrast to the previously documented
behavior of Chx2BCl, ketones 1 and 2 give rise to syn
aldols 3 and 4, respectively, with almost total stereose-
lectivity.5 In the case of 1, we were able to demonstrate
that this is due to the fact that Chx2BCl promotes the
formation of the boron Z-enolate rather than the expected
E-enolate3c (although not experimentally investigated, it
is reasonable to assume for 2 the same behavior and thus
the selective formation of the Z-enolate). We further
concluded that the boron Z-enolate of each ketone has a
distinct stereofacial bias for attacking the Re aldehyde
carbonyl face. These results are of interest because when
the aldol adducts are appropriately manipulated, 1 and
2 may be viewed as synthetic equivalents of chiral d2,
d3, and d4 synthons (see Scheme 1), the latter two of
which were reported for the first time in our study.3
These synthons, in turn, greatly facilitate the synthesis
of polyoxygenated, sugar-like chains and polypropionate
fragments, which are present in many biologically rel-
evant natural products.6
The aldol reaction is a powerful and general method
for the stereocontrolled construction of carbon-carbon
bonds.1 Among the many enolate types used for this kind
of reaction thus far, boron enolates are particularly
versatile because of their good reactivity and excellent
stereoselectivity.2 In recent years, we have investigated
the outcome of the aldol reactions of boron enolates
generated from dicyclohexylboron chloride, Chx2BCl, with
either the L-erythrulose derivative 13 or the structurally
related ketone 2.4 This line of research has led to several
different findings, with each result prompting us to
expand our investigative efforts. One of our first findings
concerning reactions with achiral aldehydes, for example,
* Corresponding author. Phone: 34-96-3544337. Fax: 34-96-
3544328.
† Departamento de Qu´ımica Inorga´nica y Orga´nica, Universidad
Jaume I.
‡ Servicios Centrales de Instrumentacio´n, Universidad Jaume I.
§ Universidad de Valencia.
10.1021/jo051307p CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/02/2005
8130
J. Org. Chem. 2005, 70, 8130-8139

Reactions of an Ethyl Ketone with Aldehydes
SCHEME 1. Aldol Additions of the Boron
Z-Enolates of 1 and 2 to Achiral Aldehydes
SCHEME 2. Aldol Additions of the Boron
Z-Enolate of 1 to r-Chiral Aldehydes
After obtaining these results, we extended our study
to the doubly diastereoselective1c aldol reactions of ketone
1 with R-chiral aldehydes (Scheme 2). We found that in
the case of R-methyl aldehydes 5a,b of either configura-
tion, the boron Z-enolate of 1 was able to exert the
stereocontrol over the reaction.7 As with achiral alde-
(1) (a) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem.
1982, 13, 1-115. (b) Mukaiyama, T. Org. React. 1982, 28, 203-331.
(c) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 1-30. (d) Heathcock, C. H. In Asymmetric
Synthesis; Morrison, J. D., Ed.; Academic Press: Orlando, FL, 1984;
Vol. 3, pp 111-212. (e) Heathcock, C. H. Aldrichimica Acta 1990, 23,
99-111. (f) Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Winterfeldt, E., Eds.; Pergamon Press: Oxford, 1993; Vol. 2. (g)
Mekelburger, H. B.; Wilcox, C. S. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Winterfeldt, E., Eds.; Pergamon Press:
Oxford, 1993; Vol. 2, pp 99-131. (h) Heathcock, C. H. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Winterfeldt, E., Eds.;
Pergamon Press: Oxford, 1993; Vol. 2, pp 133-179, 181-238. (i) Kim,
B. M.; Williams, S. F.; Masamune, S. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Winterfeldt, E., Eds.; Pergamon
Press: Oxford, 1993; Vol. 2, pp 239-275. (j) Rathke, M. W.; Weipert,
P. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Winterfeldt, E., Eds.; Pergamon Press: Oxford, 1993; Vol. 2, pp 277-
299. (k) Paterson, I. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Winterfeldt, E., Eds.; Pergamon Press: Oxford, 1993;
Vol. 2, pp 301-319. (l) Franklin, A. S.; Paterson, I. Contemp. Org.
Synth. 1994, 1, 317-338. (m) Braun, M. In Houben-Weyl’s Methods of
Organic Chemistry, Stereoselective Synthesis; Helmchen, G., Hoffmann,
R. W., Mulzer, J., Schaumann, E., Eds.; Georg Thieme Verlag:
Stuttgart, 1996; Vol. 3, pp 1603-1666, 1713-1735. (n) Mahrwald, R.
Chem. Rev. 1999, 99, 1095-1120. (o) Palomo, C.; Oiarbide, M.; Garc´ıa,
J. M. Chem.-Eur. J. 2002, 8, 36-44. (p) Palomo, C.; Oiarbide, M.;
Garc´ıa, J. M. Chem. Soc. Rev. 2004, 33, 65-75. (q) Modern Aldol
Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004.
(2) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1-200.
(3) (a) Carda, M.; Murga, J.; Falomir, E.; Gonza´lez, F.; Marco, J. A.
Tetrahedron 2000, 56, 677-683. (b) Murga, J.; Falomir, E.; Carda, M.;
Marco, J. A. Tetrahedron: Asymmetry 2002, 13, 2317-2327. (c) Murga,
J.; Falomir, E.; Gonza´lez, F.; Carda, M.; Marco, J. A. Tetrahedron 2002,
58, 9697-9707. (d) The d3 synthon of ketone 1 is conceptually related
to dihydroxyacetone enolates. See: Enders, D.; Voith, M.; Lenzen, A.
Angew. Chem., Int. Ed. 2005, 44, 1304-1325.
(4) Carda, M.; Murga, J.; Falomir, E.; Gonza´lez, F.; Marco, J. A.
Tetrahedron: Asymmetry 2000, 11, 3211-3220.
(5) This stereochemical outcome of aldol reactions mediated by
dicyclohexylboron chloride may be general in R-oxygenated ketones:
Murga, J.; Falomir, E.; Carda, M.; Gonza´lez, F.; Marco, J. A. Org. Lett.
2001, 3, 901-904.
hydes, the boron Z-enolate of 1 selectively attacked the
Re aldehyde carbonyl face. Thus, aldols 7a,b and 8a,b
were obtained as essentially single stereoisomers after
reaction with the (S) and (R) enantiomers, respectively,
of the aforementioned aldehydes (Scheme 2).8 In contrast,
a distinct match/mismatch dichotomy was found when
R-oxygenated aldehydes were used. Thus, while a highly
stereoselective aldol reaction occurred with aldehydes (S)-
6a-c,9 leading to aldols 9a-c, only complex aldol mix-
(6) (a) Recent Progress in the Chemical Synthesis of Antibiotics;
Lukacs, G., Ohno, M., Eds.; Springer: Berlin, 1990. (b) Norcross, R.
D.; Paterson, I. Chem. Rev. 1995, 95, 2041-2114. (c) Thirsk, C.;
Whiting, A. J. Chem. Soc., Perkin Trans. 1 2002, 999-1023. (d) Yeung,
K.-S.; Paterson, I. Angew. Chem., Int. Ed. 2002, 41, 4632-4653. (e)
Suenaga, K. Bull. Chem. Soc. Jpn. 2004, 77, 443-451.
(7) Marco, J. A.; Carda, M.; D´ıaz-Oltra, S.; Murga, J.; Falomir, E.;
Roeper, H. J. Org. Chem. 2003, 68, 8577-8582.
(8) In the aldol reaction of ketone 1 with (R)-5b, an approximately
4:1 mixture of syn aldols was formed, according to the NMR data of
the mixture. In our previous publication,7 we assumed that the not
isolated, minor stereoisomer was the “anti-Felkin” stereoisomer, which
resulted from attack to the aldehyde Si face. However, we later found
that aldehyde 5b is much more prone to racemization than its analogue
5a. We thus believe that the minor stereoisomer, which appears in
the reaction mixture in variable proportions, is formed from the small
proportion of the undesired enantiomer, generated adventitiously
during the synthesis and isolation of the aldehyde. The preparation of
aldehydes 5 has to be performed with extreme care, to keep racem-
ization to a minimum (the results presented in this paper and in refs
7 and 9 are part of the Ph.D. thesis of S.D.-O., Universidad Jaume I,
July 2005).
J. Org. Chem, Vol. 70, No. 20, 2005 8131

D´ıaz-Oltra et al.
TABLE 1. Stereochemical outcome of Aldol Additions
tures and extensive decomposition resulted when the (R)
enantiomers were used.
of Ketone 2 with Aldehydes (R)- and (S)-5
These results were not adequately explained with the
Felkin-Anh paradigm alone,10 as this mechanistic model
worked satisfactorily only in the reactions with R-methyl
aldehydes 5, but not with those involving R-oxygenated
aldehydes 6. Relying on recent results,11 we then pro-
posed Cornforth’s dipolar model as offering a more
adequate explanation for the stereochemical outcome of
aldol reactions of 1 with chiral aldehydes bearing polar
R-heteroatoms.12 This was the first time that this model
had been applied to a doubly diastereoselective aldol
reaction.1c In the present Article, we have extended the
same approach to chiral ethyl ketone 2 in the belief that
stereoselective aldol reactions of 2 with R-methyl alde-
hydes and R-oxygenated aldehydes will provide efficient
access to polypropionate fragments such as those present
in macrolides, polyether antibiotics, and related bioactive
metabolites.6
entry
aldehyde
% yield
dra
1
2
3
4
(S)-5a
(S)-5b
(R)-5a
(R)-5b
95
75
86
62
>95:5b
>95:5b
>95:5c
>95:5c
a dr > 95:5 means that the minor diastereoisomer was not
detected by means of 1H and 13C NMR. b The only diastereoisomer
detected was 10a,b. c The only diastereoisomer detected was
11a,b.
SCHEME 3. Aldol Additions of the Boron
Z-Enolate of 2 to Aldehydes (R)-5 and (S)-5
Results and Discussion
Aldol Reactions with r-Methyl Aldehydes. To
accomplish our objective, standard procedures were used
to prepare the four enantiomerically pure aldehydes 5a,b
and 6a,b that we had employed in our previous study
(Scheme 2).13 The aldol additions were performed under
the conditions described in our earlier reports.3,14-17 We
started with the aldol reactions of ketone 2 and R-methyl
aldehydes (R)-5 and (S)-5. The results are shown in
Scheme 3 and Table 1. The reactions with aldehydes (S)-5
were comparatively rapid at 0 °C (total conversion in
5 h) and completely diastereoselective, taking into ac-
count the detection limits of NMR spectroscopic methods
(dr > 95:5). Aldols 10 were thus formed via enolate attack
to the Re aldehyde carbonyl face. For aldehydes (R)-5,
the reactions were also completely diastereoselective and
gave rise to aldols 11, again resulting from enolate attack
to the Re aldehyde face.
These results lead to the conclusion that the facial bias
of this ketone enolate (attack to aldehyde Re faces) is
strong enough to overcome the inherent facial Felkin
preference of the carbonyl group in R-methyl aldehydes
5, a fact which greatly enhances the synthetic value of
this methodology.6 This can be understood within the
same mechanistic framework presented in our recent
publications.3c,7 Scheme 4 presents a proposal of favorable
cyclic transition structures (TSs) of the Zimmerman-
Traxler type,18,19 in which the different, previously dis-
cussed energetically relevant features7 are taken into
account. In order of increasing quantitative importance,
these factors are: (a) the inherent Felkin-Anh bias of
the aldehyde (nucleophilic attack anti-coplanar to either
the bulkiest aldehyde CR substituent or that having the
(9) The methodology described in ref 7 has been applied to the
stereoselective synthesis of the natural lactone anamarine: D´ıaz-Oltra,
S.; Murga, J.; Falomir, E.; Carda, M.; Marco, J. A. Tetrahedron 2004,
60, 2979-2985.
(10) (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
9, 2199-2204. (b) Anh, N. T. Top. Curr. Chem. 1980, 88, 145-162. (c)
Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191-1223. See also,
however: Smith, R. J.; Trzoss, M.; Bu¨hl, M.; Bienz, S. Eur. J. Org.
Chem. 2002, 2770-2775.
(11) Shortly before we concluded our investigation with ketone 1, a
paper by Evans and co-workers appeared in which the Cornforth model
was resurrected to provide a good explanation of the sterochemical
outcome of aldol reactions of achiral ketones with R-heteroatom-
substituted aldehydes: Evans, D. A.; Siska, S. J.; Cee, V. J. Angew.
Chem., Int. Ed. 2003, 42, 1761-1765.
(12) Cornforth’s model has been previously applied to reactions of
R-oxygenated aldehydes with achiral allylboron compounds: (a) Roush,
W. R.; Adam, M. A.; Walts, A. E.; Harris, D. J. J. Am. Chem. Soc. 1986,
108, 3422-3434. (b) Brinkmann, H.; Hoffmann, R. W. Chem. Ber. 1990,
123, 2395-2401. (c) Thadani, A. N.; Batey, R. A. Tetrahedron Lett.
2003, 44, 8051-8055. (d) The higher stability of Cornforth-like
transition structures in some additions of allylboron reagents to
R-oxygenated aldehydes has also received theoretical support: Gung,
B. W.; Xue, X. Tetrahedron: Asymmetry 2001, 12, 2955-2959. (e) For
more detailed accounts of the diastereoselective reactions of allylboron
compounds, see: Roush, W. R. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Winterfeldt, E., Eds.; Pergamon Press:
Oxford, 1993; Vol. 2, pp 1-54. Roush, W. R. In Houben-Weyl’s Methods
of Organic Chemistry, Stereoselective Synthesis; Helmchen, G., Hoff-
mann, R. W., Mulzer, J., Schaumann, E., Eds.; Georg Thieme Verlag:
Stuttgart, 1996; Vol. 3, pp 1410-1486, and references therein. (f) For
a related situation in the addition of an allenylstannane, see: Marshall,
J. A.; Wang, X.-J. J. Org. Chem. 1991, 56, 3211-3213.
(15) The stereostructures of two correlation compounds related to
aldols 10a and 11a (see Supporting Information) were established by
means of X-ray diffraction analyses. Crystallographic data (excluding
structure factors) have been deposited at the Cambridge Crystal-
lographic Data Center as supplementary material with references
CCDC-269222 and CCDC-269772. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cam-
bridge, CB2 1EZ, UK [fax, +44(0)-1223-336033 or e-mail, deposit@
ccdc.cam.ac.uk].
(13) See pertinent citations in our previous publication.7 Because
aldehydes 6c gave essentially the same results as 6b in aldol reactions
with 1, only the latter were used in the present work.
(14) The stereostructures of the aldol products were established with
the aid of the chemical correlation methodology used in our previous
papers3 and, in two cases, by means of X-ray diffraction analysis.15
Aldol adducts were reduced in situ with LiBH4 to yield the expected
syn-1,3-diols.16 These were subsequently converted into acetonides,
which were then studied by means of NMR.17 Standard manipulations
of the protecting groups further permitted the preparation of other
cyclic derivatives suitable for similar NMR studies. Descriptions of
these chemical correlations and analytical data for correlation products
are given in the Supporting Information.
(16) Paterson, I.; Channon, J. A. Tetrahedron Lett. 1992, 33, 797-
800.
(17) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9-17.
(18) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957,
79, 1920-1923.
8132 J. Org. Chem., Vol. 70, No. 20, 2005

Reactions of an Ethyl Ketone with Aldehydes
SCHEME 4. Felkin-Anh TSs for Aldol Additions of the Boron Z-Enolate of 2 to Aldehydes (R)-5 and (S)-5
lowest lying σ*C-X orbital), including the most favorable
Bu¨rgi-Dunitz trajectory (approach nearer to the smallest
CR substituent, usually an H atom);10,20,21 (b) anticoplanar
orientation of the C-Oenolate and CR-O bonds (minimized
dipolar repulsion)1e,22 and the spatial allocation of the
dioxolane ring away from the bulky boron ligands (mini-
mized steric crowding); and (c) avoidance of syn pentane
repulsive interactions between the Me group at the
enolate CdC bond and one substituent at the stereogenic
R-aldehyde carbon.1a,12,23,24
still of the Felkin-Anh-type (enolate attack anti to the
bulky CH2OP group), but in which the enolate approaches
along a less favorable Bu¨rgi-Dunitz trajectory that
pushes the nucleophile toward the methyl group rather
than to the hydrogen atom, a feature of quantitatively
minor importance.7 The alternative, and unobserved,
attack of the enolate to the aldehyde Si face must take
place, under the assumed avoidance of syn pentane
interactions, through TS-1, which shows an unfavorable
steric crowding between the dioxolane ring and one of
the bulky boron ligands. This particular hindrance may
be alleviated by means of bond rotation, but only at the
cost of increasing the dipolar repulsion between the
C-Oenolate and CR-O bonds.22 In contrast, the aldol
reaction with aldehydes (R)-5 led mainly to the Felkin
stereoisomer 11 (Scheme 4). This stereochemical outcome
can be explained only if the aldol process occurs via the
“non-Anh” rotamer TS-4,21 again under avoidance of the
syn pentane interaction present in the Felkin-Anh
rotamer TS-5. Moreover, enolate attack to the aldehyde
Si face to yield the (not detected) epimer of 11 through
For the reactions of aldehydes (S)-5 yielding solely syn
aldols 10, we may assume a TS such as TS-2, which is
(19) For theoretical studies on boron aldol reactions, see: (a) Li, Y.;
Paddon-Row, M. N.; Houk, K. N. J. Org. Chem. 1990, 55, 481-493.
(b) Goodman, J. M.; Kahn, S. D.; Paterson, I. J. Org. Chem. 1990, 55,
3295-3303. (c) Bernardi, A.; Capelli, A. M.; Gennari, C.; Goodman, J.
M.; Paterson, I. J. Org. Chem. 1990, 55, 3576-3581. (d) Bernardi, A.;
Capelli, A. M.; Comotti, A.; Gennari, C.; Gardner, M.; Goodman, J.
M.; Paterson, I. Tetrahedron 1991, 47, 3471-3484. (e) Bernardi, F.;
Robb, M. A.; Suzzi-Valli, G.; Tagliavini, E.; Trombini, C.; Umani-
Ronchi, A. J. Org. Chem. 1991, 56, 6472-6475. (f) Gennari, C.; Vieth,
S.; Comotti, A.; Vulpetti, A.; Goodman, J. M.; Paterson, I. Tetrahedron
1992, 48, 4439-4458. (g) Vulpetti, A.; Bernardi, A.; Gennari, C.;
Goodman, J. M.; Paterson, I. Tetrahedron 1993, 49, 685-696. See also
ref 3c.
(20) Gawley, R. E.; Aube´, J. Principles of Asymmetric Synthesis;
Pergamon: New York, 1996; Chapters 4 and 5.
(23) Roush, W. R. J. Org. Chem. 1991, 56, 4151-4157. The
quantitative importance of the syn pentane interaction in these
reactions is underscored by the fact that pivalaldehyde does not react
with the boron Z-enolates of ketones 1 and 2.3,4 In fact, if a TS is drawn
for aldol reactions with this aldehyde, a steric interaction of the
aforementioned type will always be present for all rotamers around
the tBu-CO bond.
(24) The various factors that may influence the stereochemical
outcome of aldol reactions have been very lucidly analyzed by Dan-
ishefsky and co-workers in a recent publicaction: Lee, C. B.; Wu, Z.;
Zhang, F.; Chappell, M. D.; Stachel, S. J.; Chou, T.-C.; Guan, Y.;
Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 5249-5259.
(21) Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109,
3353-3361. The “non-Anh” label in Schemes 4 and 6 refers to
transition structures in which attack takes place anti to a substituent,
which neither has the lowest lying σ*C-X orbital (for R-heteroatom-
substituted aldehydes) nor is the sterically bulkiest one (for aldehydes
not bearing R-heteroatoms). See also ref 20.
(22) Van Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.; Heath-
cock, C. H. J. Org. Chem. 1991, 56, 2499-2506. For another example
of the importance of dipole alignment in aldol TSs, see: Boeckman, R.
K., Jr.; Connell, B. T. J. Am. Chem. Soc. 1995, 117, 12368-12369.
J. Org. Chem, Vol. 70, No. 20, 2005 8133

D´ıaz-Oltra et al.
SCHEME 5. Aldol Additions of the Boron
Z-Enolate of 2 to Aldehydes (R)-6 and (S)-6
cyclohexyl ligands. For its part, the Felkin-Anh TS-8
deviates from the Cornforth geometry. The fact that both
alternative TSs display energetically unfavorable fea-
tures explains why the corresponding aldol reaction is
slow and nonstereoselective.
All results therefore can be explained within the
framework of the same unified general concept we put
forth in our recent publication.7 Energetic factors in order
of decreasing quantitative importance are: (a) for R-het-
eroatom-substituted aldehydes and in contrast to R-meth-
yl aldehydes, Cornforth TSs are markedly preferred to
those of the Felkin-Anh type; (b) syn pentane repulsions
between the enolate Me group and one aldehyde non-
hydrogen R-substituent (Me in the lactaldehyde deriva-
tives used here) are energetically important interactions
that must be avoided through C-C bond rotation; (c)
steric crowding between the dioxolane ring and one
B-cyclohexyl group arises when attack takes place from
the enolate Si face; while suitable C-C bond rotation
relieves this interaction, it simultaneously increases the
dipolar repulsion between the C-Oenolate and CR-O bonds;
and (d) because the Felkin-Anh π-facial bias is not very
strong for aldehydes bearing only carbon R-substituents
(dr’s rarely g3:1),1,20 stereocontrol is frequently exerted
by the chiral enolate rather than by the aldehyde.
In summary, we propose that R-methyl aldehydes (S)-5
react with the dicyclohexylboron enolate of 2 to yield
aldols 10 selectively through TS-2 whereas aldehydes
(R)-5 generate aldols 11 through TS-4 (Scheme 4), with
stereocontrol coming from the chiral enolate in both
cases. The R-oxygenated aldehydes (S)-6, on the other
hand, react to yield aldols 12 through the Cornforth
transition state TS-7 (Scheme 6). Their enantiomers
(R)-6 react sluggishly and nonstereoselectively because
the energy of the Cornforth-type TS-9 (Scheme 6) is
increased by factor c. The energy of the alternative TS-8
is also increased by its deviation from the Cornforth
geometry, that is, dominance of factor a. Once again, the
Cornforth model proves useful in explaining the stereo-
chemical outcome of aldol additions to R-heteroatom-
substituted carbonyl groups.28-30
TS-3 would suffer from steric crowding between the
dioxolane ring and one of the B-cyclohexyl groups.
Aldol Reactions with r-Oxygenated Aldehydes.
We then investigated the aldol reactions of ketone 2 and
R-oxygenated aldehydes (R)-6 and (S)-6. The results are
given in Scheme 5. The reactions with aldehydes (S)-6
were highly diastereoselective and gave aldols 12a,b
(dr > 95:5), once again through enolate attack to the
aldehyde Re face. In contrast, the reactions of aldehydes
(R)-6 were very slow (less than 50% conversion after 12
h) and not only yielded complex mixtures of 3-4 stereo-
isomeric aldols but were also accompanied by extensive
decomposition.25
These results parallel those previously observed with
ketone 17 and may be explained within the same mecha-
nistic framework. Again, the Felkin-Anh model proves
unable to provide a satisfactory explanation of this
stereochemical outcome, as shown on the left-hand side
of Scheme 6.26,27 Reasonable explanations may be formu-
lated, however, by invoking the Cornforth model.11,12,28
This is illustrated on the right-hand side of Scheme 6,
where the proposed transition structures are reexamined
within this paradigm. Thus, the unfavorable non-Anh
TS-7 now becomes favorable within the framework of the
Cornforth model. Dipolar repulsions between the CdO
and CR-OP bonds are minimized in this TS, in which
nucleophilic attack takes place from the less hindered
carbonyl face. The alternative TS-6 not only deviates
from the Cornforth geometry, an unfavorable feature in
this case, but also shows a syn pentane repulsion between
the two methyl groups. As regards the aldol reactions of
2 with aldehydes (R)-6, a Cornforth transition structure
TS-9 may be formulated, but it suffers from steric
crowding between the dioxolane ring and the boron
Synthesis of the C1-C9 Soraphen A1r Fragment.
As noted above, the unprecedented d3 and d4 synthons
depicted in Scheme 1 may be particularly useful for the
synthesis of polyhydroxy and polypropionate chains such
as those present in bioactive, natural polyketides. To
(25) This was established upon examination of NMR data for the
crude aldol mixtures. In view of this synthetically useless result, we
did not attempt to isolate individual compounds.
(29) Doubly diastereoselective aldol reactions of chiral enolates with
chiral R-oxygenated aldehydes are not extensively documented in the
literature. Matched and mismatched processes have been reported,
with the full range from total stereocontrol by the enolate to complete
dominance of the aldehyde being observed. See refs 1 and 2 and, for
further cases: (a) Nicolaou, K. C.; Piscopio, A. D.; Bertinato, P.;
Chakraborty, T. K.; Minowa, N.; Koide, K. Chem.-Eur. J. 1995, 1, 318-
333. (b) Sibi, M. P.; Lu, J.; Edwards, J. J. Org. Chem. 1997, 62, 5864-
5872. (c) Kobayashi, S.; Furuta, T. Tetrahedron 1998, 54, 10275-10294.
(d) Esteve, C.; Ferrero`, M.; Romea, P.; Urp´ı, F.; Vilarrasa, J. Tetra-
hedron Lett. 1999, 40, 5083-5086. (e) Nicolaou, K. C.; Pihko, P. M.;
Diedrichs, N.; Zou, N.; Bernal, F. Angew. Chem., Int. Ed. 2001, 40,
1262-1265. (f) Forsyth, C. J.; Hao, J.; Aiguade, J. Angew. Chem., Int.
Ed. 2001, 40, 3663-3667. (g) Davies, S. G.; Nicholson, R. L.; Smith,
A. D. Org. Biomol. Chem. 2004, 2, 3385-3400. For a recent review on
doubly and multiply stereoselective reactions, see: Kolodiazhnyi, O.
I. Tetrahedron 2003, 59, 5953-6018.
(26) Provided that chelation is not involved in the transition state,
achiral enolates react with R-oxygenated aldehydes to yield predomi-
nantly, albeit with variable diastereoselectivity, the Felkin aldols. See
refs 1 and 2. For more recent cases, see, for example: (a) Esteve, C.;
Ferrero`, M.; Romea, P.; Urp´ı, F.; Vilarrasa, J. Tetrahedron Lett. 1999,
40, 5079-5082. (b) Lu, L.; Chang, H.-Y.; Fang, J.-M. J. Org. Chem.
1999, 64, 843-853. However, it is worth noting that Felkin aldols have
been found to predominate in some reactions where chelation is likely
to occur: Grandel, R.; Kazmaier, U.; Rominger, F. J. Org. Chem. 1998,
63, 4524-4528.
(27) For nucleophilic additions to aldehydes bearing R-heteroatoms
other than oxygen, see, for example: (a) Reetz, M. T. Chem. Rev. 1999,
99, 1121-1162 (R-amino aldehydes). (b) Enders, D.; Piva, O.; Burkamp,
F. Tetrahedron 1996, 52, 2893-2908 (R-sulphenyl aldehydes). (c)
Enders, D.; Adam, J.; Klein, D.; Otten, T. Synlett 2000, 1371-1384
(R-silyl aldehydes). See also: Enders, D.; Burkamp, F. Collect. Czech.
Chem. Commun. 2003, 68, 975-1006.
(28) Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem. Soc.
1959, 112-127. See also: Paddon-Row, M. N.; Rondan, N. G.; Houk,
K. N. J. Am. Chem. Soc. 1982, 104, 7162-7166.
(30) Excluded from this discussion are chiral enolates in which the
chirality resides in the ligands bound to the heteroatom. In these cases,
stereocontrol by the chiral auxiliary is usually observed. See, for
example: Gennari, C.; Pain, G.; Moresca, D. J. Org. Chem. 1995, 60,
6248-6249.
8134 J. Org. Chem., Vol. 70, No. 20, 2005

Reactions of an Ethyl Ketone with Aldehydes
SCHEME 6. Felkin-Anh and Cornforth TSs for Aldol Additions of the Boron Z-Enolate of 2 to Aldehydes
(R)-6 and (S)-6
illustrate this, we have prepared a fragment of the
molecular structure of the antifungal metabolite sora-
phen A1R (Scheme 7). This naturally occurring compound
is the main member of a macrolide family isolated from
cultures of a strain of the myxobacterium Sorangium
cellulosum. It exhibits a marked antifungal activity due
to its ability to inhibit the fungal acetyl-CoA carboxyl-
ase.31 Recent studies have established that the product
is basically a polyketide as regards its biosynthetic origin,
even though the presence of an unsubstituted phenyl ring
also relates it to the shikimic acid pathway.32 Only a total
synthesis has been reported thus far for soraphen A1R,33
but other synthetic approaches to fragments of its
structure or analogues thereof have recently appeared
in the literature.34
Our main retrosynthetic concept for soraphen A1R is
depicted in Scheme 7. The macrolide system is to be
constructed by means of a Julia olefination-macrolacton-
ization sequence. This retrosynthetic cleavage gives rise
to fragments A and B, the latter comprising carbon atoms
C-1 to C-9. In this paper, we present a stereoselective
synthesis of compound 13 (depicted in Scheme 7 in both
the cyclic hemiacetal and the open form), a precursor to
fragment B. Functional modification of compound 13
produces intermediate C (Scheme 8), the disconnection
of which via retro-aldol reaction generates D. Compound
D in turn is easily available via our aldol methodology
from ketone 2 and one of the aldehydes (S)-5 (depending
on the protective group selected), whereby the former
product functions as a chiral d4 synthon, thus maximizing
atom economy.35 The process is highly convergent and
leads to compound 13, which has six stereocenters (seven
in the hemiacetal form), from two chiral precursors, 2
and (S)-5, with one stereocenter each.
(31) (a) Bedorf, N.; Schomburg, D.; Gerth, K.; Reichenbach, H.; Ho¨fle,
G. Liebigs Ann. Chem. 1993, 1017-1021. (b) Gerth, K.; Bedorf, N.;
Irschik, H.; Ho¨fle, G.; Reichenbach, H. J. Antibiot. 1994, 47, 23-31.
(c) Gerth, K.; Pradella, S.; Perlova, O.; Beyer, S.; Mu¨ller, S. J.
Biotechnol. 2003, 106, 233-253.
(32) (a) Hill, A. M.; Thompson, B. L.; Harris, J. P.; Segret, R. Chem.
Commun. 2003, 1358-1359. (b) Hill, A. M.; Thompson, B. L. Chem.
Commun. 2003, 1360-1361.
(33) Abel, S.; Faber, D.; Hu¨ter, O.; Giese, B. Synthesis 1999, 188-
197.
(34) (a) Loubinoux, B.; Sinnes, J.-L.; O’Sullivan, A. C.; Winkler, T.
J. Org. Chem. 1995, 60, 953-959. (b) Loubinoux, B.; Sinnes, J.-L.;
O’Sullivan, A. C. J. Chem. Soc., Perkin Trans. 1 1995, 521-525. (c)
Gurjar, M. K.; Mainkar, A. S.; Srinivas, P. Tetrahedron Lett. 1995,
36, 5967-5968. (d) Cao, Y.; Eweas, A. F.; Donaldson, W. A. Tetrahedron
Lett. 2002, 43, 7831-7834. (e) Park, S. H.; Lee, H. W.; Park, S.-U.
Bull. Korean Chem. Soc. 2004, 25, 1613-1614.
The specific steps of the synthesis are depicted in
Scheme 9. Thus, aldol reaction of 2 with aldehyde (S)-
5b, followed by in situ reduction16 with LiBH4, afforded
syn-1,3-diol 14, which was subsequently transformed into
its benzylated derivative 15.36 Cleavage of the cyclohex-
(35) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259-
281. (b) Trost, B. M. Acc. Chem. Res. 2002, 35, 695-705. See also:
Eissen, M.; Mazur, R.; Quebbemann, H.-G.; Pennemann, K.-H. Helv.
Chim. Acta 2004, 87, 524-535.
J. Org. Chem, Vol. 70, No. 20, 2005 8135

D´ıaz-Oltra et al.
SCHEME 7. Structure and Retrosynthetic
Analysis of Soraphen A1r
18. Desilylation of the latter compound with TBAF
followed by Swern oxidation40 afforded aldehyde 20. The
absolute configurations of all five stereocenters present
in compounds 14-20 were unequivocally established as
described in the Supporting Information.14 The remaining
carbon chain, which comprises two stereocenters, was
added with the aid of the asymmetric Evans aldol
methodology.41 Thus, oxazolidinone 21 was transformed
into its boron Z-enolate and added to aldehyde 20. This
provided adduct 22, which has seven consecutive stereo-
centers, as an essentially single diastereomer. The con-
figurations of the two new stereocenters were predicted
on the basis of the reliable outcome of Evans aldol
methodology, aided here in a matched way by the
intrinsic Felkin bias of the aldehyde.29b,42 Reductive
cleavage of the chiral auxiliary followed by selective
protection and oxidation with Dess-Martin periodinane43
afforded ketone 25 in good yield. Ketone 25 was then
converted into the targeted intermediate 13,44 precursor
to one of the key fragments of soraphen A1R.
Experimental Section
General Features. These are described in detail in the
Supporting Information.
General Experimental Procedure for Aldol Additions
of Ketone 2 Mediated by Dicyclohexyl Boron Chloride.
Chx2BCl (neat, 395 µL, ca. 1.8 mmol) was added under N2 via
syringe to an ice-cooled solution of Et3N (280 µL, 2 mmol) in
anhydrous Et2O (5 mL). Ketone 2 (198 mg, 1 mmol) was
dissolved in anhydrous ether (5 mL) and added dropwise via
syringe to the reagent solution. The reaction mixture was then
stirred for 30 min. After addition of a solution of the appropri-
ate aldehyde (1.5 mmol) in ether (6 mL), the reaction mixture
was stirred at 0 °C for 5 h. Phosphate buffer solution (pH 7, 6
mL) and MeOH (6 mL) were then added, followed by 30% aq
H2O2 solution (3 mL). After being stirred for 1 h at room
temperature, the mixture was worked up (extraction with
Et2O). Solvent removal in vacuo and column chromatography
of the residue on silica gel (hexanes-EtOAc mixtures) afforded
the corresponding aldol addition product. Chemical yields and
dr’s (the latter determined by means of 1H and 13C NMR) are
given in the text.
SCHEME 8. Retrosynthetic Analysis of
Intermediate 13, a C1-C9 Fragment of Soraphen
A1r
(39) Meerwein, H. Organic Syntheses; Wiley: New York, 1973; Coll.
Vol. V, pp 1096-1098. See also: Pichlmair, S. Synlett 2004, 195-196.
(40) (a) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185. (b)
Tidwell, T. T. Org. React. 1990, 39, 297-572.
(41) (a) Evans, D. A. Aldrichimica Acta 1982, 15, 23-32. (b) Kim,
B. M.; Williams, S. F.; Masamune, S. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Winterfeldt, E., Eds.; Pergamon
Press: Oxford, 1993; Vol. 2, pp 239-276. See also ref 2.
anone acetal was initially attempted under the usual
aqueous acidic conditions, but yields were only moder-
ate.37 An excellent 87% yield was obtained, however,
under aprotic conditions with anhydrous ZnBr2 in CH2-
Cl2.38 Diol 16 was selectively silylated in its primary
alcohol group and then methylated in the secondary
hydroxyl with trimethyloxonium tetrafluoroborate39 to
(42) At least one case is known where the strong Felkin stereofacial
bias of an R-oxygenated aldehyde forced the formation of an anti aldol
from the Z-boron enolate of a chiral N-acyloxazolidinone: Evans, D.
A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem.
Soc. 1990, 112, 7001-7031. In the present case, however, a matched
double diastereoselection can be expected between the known facial
preference of the boron enolate of 21 and the Felkin bias of aldehyde
20: both factors predict here a predominant enolate attack to the
aldehyde carbonyl Si face. For a very similar situation, see ref 29b.
(43) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-
4156. (b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287.
(44) Our efforts to perform hydrogenolytic debenzylation of 25, while
providing the desired 13 (as its hemiacetal form in the assumedly most
stable anomer), have not yet given satisfactory and reproducible yields
(<30%), even if various reaction conditions have been tried. Unfortu-
nately, many otherwise useful debenzylating reagents (e.g., Na in liquid
NH3 or Li di-tert-butyldiphenylide) are precluded here due to the
presence of the R-alkoxy ketone moiety. We are presently investigating
other methods to improve the yield of this critical deprotection step,
as well as the use of alternative protecting groups.
(36) In our first approach to 13, MOM protecting groups were used
for the hydroxyl functions of diol 14. However, they proved incompat-
ible with the acidic reaction conditions necessary for the deprotection
of the cyclohexanone acetal: a great amount of decomposition was
observed under a variety of conditions, as well as formation of
formaldehyde acetals as byproducts.
(37) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons: New York, 1999; pp 215-
217. (b) Kocienski, P. J. Protecting Groups, 3rd ed.; Georg Thieme
Verlag: Stuttgart, 2004; pp 133-137. For instance, acidic conditions
such as 80% aq AcOH or PPTS/MeOH gave yields of around 50-60%
(based on recovered starting material), together with ill-defined
byproducts.
(38) Ribes, C.; Falomir, E.; Murga, J. Submitted for publication.
8136 J. Org. Chem., Vol. 70, No. 20, 2005

Reactions of an Ethyl Ketone with Aldehydes
SCHEME 9. Stereoselective Synthesis of Intermediate 13
(2R,3S,4S)-5-(tert-Butyldiphenylsilyloxy)-1-[(2S)-(1,4-
dioxaspiro[4.5]dec-2-yl)]-3-hydroxy-2,4-dimethylpentan-
1-one (10a). Oil, [R]D -36.5 (c 1.4; CHCl3). IR 3490 (br), 1715
(50 mL). Ketone 2 (1.98 g, 10 mmol) was dissolved in
anhydrous ether (50 mL) and added dropwise via syringe to
the reagent solution. The reaction mixture was then stirred
for 30 min. After addition of a solution of freshly prepared
aldehyde (S)-5b (2.67 g, 15 mmol) in ether (60 mL), the
reaction mixture was stirred at 0 °C for 5 h. The solution was
cooled to -78 °C and treated dropwise with a 2 M solution of
LiBH4 in THF (15 mL, 30 mmol). The stirring was then
continued at -78 °C for 2 h. The reaction was quenched with
pH 7 phosphate buffer (60 mL) and MeOH (60 mL), followed
by a 30% aq H2O2 solution (30 mL). After being stirred for 1 h
at room temperature, the mixture was poured into saturated
aq NaHCO3 and extracted with Et2O. The organic layer was
washed with brine and dried on anhydrous Na2SO4. Solvent
removal in vacuo afforded an oily residue, which was chro-
matographed on silica gel (hexanes-EtOAc mixtures) to yield
syn-1,3-diol 14 (2.8 g, 74% overall): oil; [R]D +15.8 (c 3.1,
1
cm-1. H NMR (500 MHz) δ 7.70-7.65 (4H, br m), 7.45-7.35
(6H, br m), 4.64 (1H, dd, J ) 7.7, 5.7 Hz), 4.24 (1H, dt, J )
8.8, 3 Hz), 4.20 (1H, dd, J ) 8.5, 7.7 Hz), 4.10 (1H, dd, J )
8.5, 5.7 Hz), 3.84 (1H, dd, J ) 10.2, 4 Hz), 3.74 (1H, dd, J )
10.2, 7.2 Hz), 3.60 (1H, br d, J ) 3 Hz, OH), 3.27 (1H, dq, J )
3, 7 Hz), 1.84 (1H, m), 1.65-1.55 (8H, br m), 1.40 (2H, m),
1.10 (3H, d, J ) 7 Hz), 1.07 (9H, s), 0.87 (3H, d, J ) 7 Hz); 13
C
NMR (125 MHz) δ 212.8, 132.9, 132.8, 111.3, 19.1 (C), 135.6,
135.5, 129.9, 129.8, 127.7, 127.6, 79.1, 74.7, 45.1, 37.7 (CH),
68.8, 66.3, 35.8, 34.6, 25.1, 24.0, 23.8 (CH2), 26.9 (×3), 13.4,
7.5 (CH3). HR FABMS m/ z 525.3043 (M + H+). Calcd for
C31H45O5Si, 525.3036. Anal. Calcd for C31H44O5Si: C, 70.95;
H, 8.45. Found: C, 70.80; H, 8.49.
(2R,3S,4S)-5-Benzyloxy-1-[(2S)-(1,4-dioxaspiro[4.5]dec-
2-yl)]-3-hydroxy-2,4-dimethylpentan-1-one (10b). Oil; [R]D
1
CHCl3); IR 3470 (br) cm-1; H NMR δ 7.35-7.25 (5H, br m),
1
-42.6 (c 1.5; CHCl3). IR 3480 (br), 1718 cm-1. H NMR (500
4.52 (2H, s), 4.20 (1H, dt, J ) 8, 6 Hz), 4.00 (1H, dd, J ) 8, 6
Hz), 3.70 (3H, m), 3.57 (1H, dd, J ) 10, 5 Hz), 3.54 (1H, dd,
J ) 10, 7 Hz), 3.10 (2H, br s, OH), 1.96 (1H, m), 1.65-1.55
(9H, br m), 1.40 (2H, m), 0.97 (3H, d, J ) 6.5 Hz), 0.81 (3H, d,
J ) 6.5 Hz); 13C NMR δ 137.9, 110.1 (C), 128.5, 127.8, 127.7,
79.3, 76.9, 76.7, 37.3, 36.0 (CH), 75.5, 73.5, 65.9, 36.4, 35.1,
25.2, 24.1, 23.9 (CH2), 13.5, 6.3 (CH3). HR EIMS m/z (rel int.)
378.2350 (M+, 1), 141 (20), 91 (100). Calcd for C22H34O5,
378.2406.
(2S)-2-[(1S,2R,3S,4S)-1,3,5-Tris(benzyloxy)-2,4-dimeth-
ylpentyl]-1,4-dioxaspiro[4.5]decane (15). A 30% commer-
cial suspension of potassium hydride in mineral oil (3.2 g,
equivalent to ca. 24 mmol of KH) was stirred under N2 with
dry hexane (20 mL). The suspension was decanted, and the
supernatant liquid was removed with a syringe. This operation
was repeated once more with dry hexane and then again with
dry THF. After addition of dry THF (20 mL), the flask was
MHz) δ 7.35-7.25 (5H, br m), 4.59 (1H, dd, J ) 8, 5.5 Hz),
4.52, 4.49 (2H, AB system, J ) 11.7 Hz), 4.16 (1H, t, J ) 8
Hz), 4.10 (1H, br dd, J ) 8.5, 3 Hz), 4.05 (1H, dd, J ) 8, 5.5
Hz), 3.62 (1H, dd, J ) 9, 4 Hz), 3.55-3.50 (2H, m), 3.25 (1H,
dq, J ) 3.5, 7 Hz), 1.94 (1H, m), 1.65-1.50 (8H, br m), 1.40
(2H, m), 1.05 (3H, d, J ) 7 Hz), 0.92 (3H, d, J ) 7 Hz); 13C
NMR (125 MHz) δ 212.8, 137.7, 111.4 (C), 128.5, 127.9, 127.7,
79.1, 75.2, 45.1, 36.1 (CH), 75.5, 73.6, 66.3, 35.8, 34.6, 25.1,
24.0, 23.9 (CH2), 13.7, 7.8 (CH3). HR EIMS m/z (rel int.)
376.2227 (M+, 1), 198 (12), 141 (50), 91 (100). Calcd for
C22H32O5, 376.2249. Anal. Calcd for C22H32O5: C, 70.18; H,
8.57. Found: C, 70.09; H, 8.70.
(1S,2R,3S,4S)-5-Benzyloxy-1-[(2S)-1,4-dioxaspiro[4.5]-
dec-2-yl]-2,4-dimethylpentane-1,3-diol (14). Chx2BCl (neat,
4 mL, ca. 18 mmol) was added under N2 via syringe to an ice-
cooled solution of Et3N (2.8 mL, 20 mmol) in anhydrous Et2O
J. Org. Chem, Vol. 70, No. 20, 2005 8137

D´ıaz-Oltra et al.
cooled in an ice bath. A solution of diol 14 (2.27 g, 6 mmol) in
dry THF (20 mL) was then added via syringe and stirred for
30 min at the same temperature. Benzyl bromide (5.7 mL, ca.
48 mmol, 8 equiv) and tetra-n-butylammonium iodide (185 mg,
0.5 mmol) were then added to the reaction mixture, which was
stirred for 2 h at room temperature. Workup (extraction with
CH2Cl2) and column chromatography on silica gel (hexanes-
Et2O, 19:1) furnished 15 (3.11 g, 93%): oil; [R]D -11.1 (c 1.8,
CHCl3); 1H NMR δ 7.40-7.25 (15H, br m), 4.82 (1H, d, J ) 12
Hz), 4.63 (1H, d, J ) 12 Hz), 4.58 (2H, AB system, J ) 11.5
Hz), 4.44 (2H, s), 4.28 (1H, m), 3.87 (1H, dd, J ) 8, 6 Hz), 3.58
(1H, dd, J ) 9, 5.5 Hz), 3.50 (1H, dd, J ) 7.3, 3 Hz), 3.45-
3.40 (2H, m), 3.34 (1H, dd, J ) 9, 6.3 Hz), 2.00 (1H, m), 1.83
(1H, m), 1.65-1.25 (10H, br m), 1.05 (3H, d, J ) 7 Hz), 0.99
(3H, d, J ) 7 Hz); 13C NMR δ 139.2, 139.1, 138.6, 109.8 (C),
128.3, 128.2, 128.1, 127.7, 127.5, 127.4, 83.9, 80.8, 79.0, 38.7,
36.2 (CH), 75.2, 73.5, 73.1, 72.0, 65.9, 36.5, 35.5, 25.3, 24.1,
24.0 (CH2), 16.2, 10.7 (CH3). HR EIMS m/z (rel int.) 558.3380
(M+, 1), 309 (10), 269 (16), 181 (42), 91 (100). Calcd for
C36H46O5, 558.3345.
(2S,3S,4R,5S,6S)-3,5,7-Tris(benzyloxy)-4,6-dimethyl-
heptane-1,2-diol (16). Anhydrous ZnBr2 (6.75 g, 30 mmol)
was added under N2 to a solution of acetal 15 (2.8 g, ca. 5
mmol) in dry CH2Cl2 (60 mL). The mixture was stirred at room
temperature until consumption of the starting material (ca. 3
h, TLC monitoring!). Workup (extraction with CH2Cl2) and
column chromatography on silica gel (hexanes-EtOAc, 7:3)
provided diol 16 (2.08 g, 87%): oil; [R]D +7.7 (c 1.8, CHCl3);
IR 3440 (br) cm-1; 1H NMR δ 7.40-7.25 (15H, br m), 4.67 (1H,
d, J ) 11.5 Hz), 4.63 (1H, d, J ) 11.5 Hz), 4.60-4.55 (4H, m),
3.80 (1H, m), 3.65 (1H, dd, J ) 9, 5 Hz), 3.60-3.55 (3H, m),
3.53 (1H, dd, J ) 11.5, 4.5 Hz), 3.48 (1H, dd, J ) 7, 4 Hz),
2.80 (1H, br s, OH), 2.30 (1H, br s, OH), 2.25 (2H, m), 1.14
(3H, d, J ) 7 Hz), 1.09 (3H, d, J ) 7 Hz); 13C NMR δ 138.9,
138.4, 138.1 (C), 128.3, 128.2, 128.1, 127.7, 127.5, 127.4, 81.2,
80.8, 72.3, 37.4, 36.6 (CH), 74.5, 74.0, 73.2, 72.4, 64.5 (CH2),
15.0, 10.4 (CH3). HR FAB MS m/z 479.2824 (M + H)+. Calcd
for C30H39O5, 479.2797.
J ) 7 Hz), 1.13 (9H, s), 1.08 (3H, d, J ) 7 Hz); 13C NMR δ
139.2, 138.8, 138.7, 133.4, 133.3, 19.2 (C), 135.6, 135.5, 129.7,
128.3, 128.2, 128.1, 127.7, 127.5, 127.4, 127.2, 83.0, 82.0, 80.5,
37.2, 37.1 (CH), 74.7, 74.3, 73.0, 72.4, 63.3 (CH2), 59.2, 26.9
(×3), 15.4, 10.3 (CH3). HR EIMS m/z (rel int.) 730.4010 (M+,
1), 639 (M+ - Bn, 1), 269 (36), 181 (100), 91 (84). Calcd for
C47H58O5Si, 730.4053.
(2S,3S,4R,5S,6S)-3,5,7-Tris(benzyloxy)-2-methoxy-4,6-
dimethylheptan-1-ol (19). Compound 18 (1.83 g, ca. 2.5
mmol) was dissolved under N2 in dry THF (9 mL). Tetra-n-
butylammonium fluoride trihydrate (TBAF, 788 mg, 3 mmol)
dissolved in dry THF (3 mL) was then added. The reaction
mixture was stirred at rt until consumption of the starting
material (TLC monitoring). After addition of an aq saturated
NH4Cl solution (5 mL), the mixture was stirred for 5 min,
worked up, and chromatographed on silica gel (hexanes-
EtOAc mixtures). This furnished 19 (1.05 g, 85%): oil; [R]D
1
-2.7 (c 3.3, CHCl3); IR 3450 (br) cm-1; H NMR δ 7.40-7.30
(15H, br m), 4.82 (1H, d, J ) 11.5 Hz), 4.66 (1H, d, J ) 11.5
Hz), 4.62 (2H, AB system, J ) 11.5 Hz), 4.55 (2H, AB system,
J ) 12 Hz), 3.76 (1H, dd, J ) 12, 4 Hz), 3.69 (2H, m), 3.59
(1H, dd, J ) 12, 5 Hz), 3.50 (3H, s), 3.50-3.45 (3H, m), 2.30
(1H, br s, OH), 2.20 (2H, m), 1.16 (3H, d, J ) 7 Hz), 1.05 (3H,
d, J ) 7 Hz); 13C NMR δ 139.1, 138.8, 138.4 (C), 128.3, 128.2,
128.1, 127.7, 127.5, 127.4, 127.2, 83.3, 82.8, 80.2, 37.4, 36.5
(CH), 74.5, 74.3, 72.9, 72.0, 61.1 (CH2), 58.4, 15.6, 10.2 (CH3).
HR FAB MS m/z 493.2919 (M + H)+. Calcd for C31H41O5,
493.2948.
Oxidation of Alcohol 19 to Aldehyde 20. DMSO (350 µL,
5 mmol) was dissolved under N2 in dry CH2Cl2 (10 mL), cooled
to -78 °C, and treated with oxalyl chloride (330 µL, 2.5 mmol).
After the mixture was stirred at this temperature for 15 min,
a solution of alcohol 19 (985 mg, 2 mmol) in dry CH2Cl2 (10
mL) was added dropwise. The stirring was continued by
further 15 min, followed by addition of triethylamine (1.4 mL,
10 mmol). The reaction mixture was then heated to 0 °C and
stirred for 15 min at this temperature. Workup (CH2Cl2) and
evaporation in vacuo provided 20 as an oily product, which
was directly used in the next step. For weight calculations in
the next step, the oxidation is assumed to be quantitative.
Oxazolidinone 22. A solution of 21 (466 mg, 2 mmol) in
dry CH2Cl2 (2 mL) was cooled to -78 °C under N2 and treated
successively with triethylamine (560 µL, 4 mmol) and di-n-
butylboron triflate (3.6 mL of a 1 M solution in CH2Cl2, 3.6
mmol, 1.8 equiv). The mixture was stirred for 30 min at the
same temperature, then for 1 h at 0 °C, and recooled to -78
°C. The crude aldehyde 20 from above was dissolved in dry
CH2Cl2 (10 mL) and added dropwise at -78 °C to the boron
enolate mixture. The reaction was then heated to -20 °C and
stirred for 14 h at this temperature. The reaction was
quenched through sequential addition of pH 7 buffer solution
(15 mL), MeOH (15 mL), and 30% aqueous H2O2 (8 mL),
followed by stirring for 30 min at room temperature. The
reaction mixture was subsequently worked up (extraction with
CH2Cl2) and chromatographed on silica gel (hexanes-EtOAc,
4:1) to yield compound 22 (1.11 g, 77% overall yield from 19):
oil; [R]D +8.1 (c 1.2, CHCl3); IR 3490 (br), 1781, 1694 cm-1; 1H
NMR δ 7.40-7.25 (20H, br m), 4.72 (1H, d, J ) 11.3 Hz), 4.66
(1H, d, J ) 11.3 Hz), 4.65-4.50 (5H, m), 4.24 (1H, m), 4.13
(1H, dd, J ) 9, 2.7 Hz), 4.05 (2H, m), 3.92 (1H, dd, J ) 7.7, 2.8
Hz), 3.61 (2H, m), 3.51 (1H, dd, J ) 7.8, 2.8 Hz), 3.47 (1H,
overlapped m), 3.46 (3H, s), 3.30 (1H, br s, OH), 3.25 (1H, dd,
J ) 13.5, 3.5 Hz), 2.80 (1H, dd, J ) 13.3, 9.5 Hz), 2.40 (1H,
m), 2.14 (1H, m), 1.37 (3H, d, J ) 7 Hz), 1.19 (3H, d, J ) 7
Hz), 1.10 (3H, d, J ) 7 Hz); 13C NMR δ 177.1, 152.8, 139.2,
138.8, 138.4, 135.2 (C), 129.4, 128.9, 128.3, 128.2, 128.1, 127.7,
127.5, 127.4, 127.3, 81.8, 81.0, 80.0, 71.0, 55.0, 39.6, 37.4, 37.2
(CH), 74.5, 74.1, 73.0, 72.6, 66.0, 37.8 (CH2), 59.6, 15.3, 12.1,
10.1 (CH3). HR FAB MS m/z 724.3770 (M + H)+. Calcd for
C44H54NO8, 724.3849.
(2S,3S,4R,5S,6S)-3,5,7-Tris(benzyloxy)-1-(tert-butyldi-
phenylsilyloxy)-4,6-dimethylheptan-2-ol (17). A solution
of alcohol 16 (1.92 g, ca. 4 mmol) and imidazole (680 mg, 10
mmol) in dry CH2Cl2 (15 mL) was treated dropwise under N2
with a solution of TPS chloride (1.55 g, 6 mmol) in dry CH2Cl2
(10 mL). The reaction mixture was stirred overnight at rt, then
diluted with CH2Cl2 and worked up. Column chromatography
on silica gel (hexanes-EtOAc, 9:1) afforded 17 (2.72 g, 95%):
oil; [R]D -9.6 (c 2.1, CHCl3); IR 3500 (br) cm-1 1H NMR δ
;
7.75-7.70 (4H, m), 7.45-7.25 (21H, br m), 4.71 (1H, d, J )
11.5 Hz), 4.66-4.58 (3H, m), 4.55 (2H, AB system, J ) 12 Hz),
4.05 (1H, m), 3.81 (1H, dd, J ) 10, 6.5 Hz), 3.75-3.70 (2H,
m), 3.65-3.60 (3H, m), 2.60 (1H, d, J ) 7 Hz, OH), 2.32 (1H,
m), 2.23 (1H, m), 1.19 (3H, d, J ) 7 Hz), 1.16 (9H, s), 1.13
(3H, d, J ) 6.5 Hz); 13C NMR δ 139.1, 138.7, 138.4, 133.3,
133.2, 19.2 (C), 135.6, 135.5, 129.7, 128.3, 128.2, 128.1, 127.7,
127.5, 127.4, 127.2, 81.1, 80.0, 72.0, 37.2, 37.0 (CH), 74.6, 74.0,
73.1, 72.5, 65.2 (CH2), 26.9 (×3), 15.0, 10.5 (CH3). HR FAB
MS m/z 717.3998 (M + H)+. Calcd for C46H57O5Si, 717.3970.
(2S,3S,4R,5S,6S)-3,5,7-Tris(benzyloxy)-1-(tert-butyldi-
phenylsilyloxy)-2-methoxy-4,6-dimethylheptane (18). Al-
cohol 17 (2.15 g, ca. 3 mmol) and 1,8-bis(N,N-dimethylamino)-
naphthalene (3.9 g, ca. 18 mmol) were dissolved under N2 in
dry CH2Cl2 (50 mL) and treated with trimethyloxonium
tetrafluoroborate (2.22 g, ca. 15 mmol). The solution was
stirred for 3 h at rt. Workup (extraction with CH2Cl2) and
column chromatography on silica gel (hexanes-EtOAc, 19:1)
yielded methyl ether 18 (1.95 g, 89%): oil; [R]D -17.3 (c 1.5,
CHCl3); 1H NMR δ 7.75-7.70 (4H, m), 7.45-7.30 (21H, br m),
4.72 (1H, d, J ) 11.3 Hz), 4.66 (2H, d, J ) 11.3 Hz), 4.60 (1H,
d, J ) 11.3 Hz), 4.52 (2H, AB system, J ) 12 Hz), 3.91 (1H,
dd, J ) 10.5, 6 Hz), 3.87 (1H, dd, J ) 10.5, 5.7 Hz), 3.71 (1H,
dd, J ) 7.4, 4 Hz), 3.65-3.60 (3H, m), 3.52 (1H, dd, J ) 7.4,
3.4 Hz), 3.49 (3H, s), 2.30 (1H, m), 2.18 (1H, m), 1.16 (3H, d,
Alcohol 23. A solution of LiBH4 (2 M in THF, 0.9 mL, 1.8
mmol) was cooled under N2 to -10 °C and treated with
8138 J. Org. Chem., Vol. 70, No. 20, 2005

Reactions of an Ethyl Ketone with Aldehydes
absolute EtOH (105 µL, 1.8 mmol). After the mixture was
stirred for 10 min at this temperature, a solution of compound
22 (1.08 g, ca. 1.5 mmol) in dry Et2O (20 mL) was added
dropwise via syringe, followed by stirring for 2 h at -10 °C.
The reaction was quenched through addition of 1 M NaOH (4
mL), with continued stirring for further 15 min at 0 °C.
Workup (extraction with Et2O) and column chromatography
on silica gel (hexanes-EtOAc, 4:1) furnished compound 23
(1H, m), 2.36 (1H, m), 2.10 (1H, m), 1.10 (3H, d, J ) 6.8 Hz),
1.04 (3H, d, J ) 7 Hz), 1.03 (9H, s), 0.95 (3H, d, J ) 6.8 Hz);
13C NMR δ 212.1, 139.3, 138.8, 138.3, 133.1, 133.0, 19.2 (C),
135.5, 135.4, 129.8, 128.3, 128.2, 128.1, 128.0, 127.8, 127.5,
127.4, 127.3, 127.2, 127.1, 88.3, 81.4, 80.0, 45.4, 37.4, 36.1 (CH),
74.2, 73.1, 72.6, 70.8, 67.6 (CH2), 59.1, 26.9 (×3), 15.1, 12.8,
9.8 (CH3). HR FAB MS m/ z 787.4353 (M + H)+. Calcd for
C50H63O6Si, 787.4393.
Hemiacetal 13. A solution of compound 25 (393 mg, 0.5
mmol) in EtOAc (100 mL) was mixed with 10% Pd/C (1.6 g)
and placed under H2 in a pressure flask at 35 atm. After being
stirred for 16 h, the crude mixture was filtered through Celite,
all volatiles were removed in vacuo, and the residue was
chromatographed on silica gel (hexanes-EtOAc, 7:3). This
gave 13 in very variable and not reproducible yields (always
<30%) as a somewhat unstable oil. Rf on silica gel, 0.2 (elution
with hexanes-EtOAc, 1:1): oil; [R]D -3.3 (c 0.2, CHCl3); IR
3430 (br) cm-1; 1H NMR (CDCl3 + D2O) δ 7.70-7.65 (4H, m),
7.40-7.30 (6H, br m), 4.03 (1H, dd, J ) 9.4, 3.6 Hz), 3.76 (1H,
m), 3.65-3.65 (1H, m), 3.56 (3H, s), 3.50-3.45 (2H, m), 3.05
(2H, m), 2.25 (1H, m), 1.88 (2H, m), 1.15 (3H, d, J ) 7 Hz),
1.05 (9H, s), 0.97 (3H, d, J ) 6.7 Hz), 0.80 (3H, d, J ) 6.8 Hz);
13C NMR δ 134.1, 134.0, 100.4, 19.2 (C), 135.7, 135.6, 129.5,
129.4, 127.5, 127.3, 84.4, 78.3, 73.6, 42.4, 40.3, 29.6 (CH), 63.6,
63.5 (CH2), 61.1, 26.9 (×3), 18.0, 12.1, 11.5 (CH3). HR EIMS
m/z (rel int.) 441.1928 (M+ - H2O - tBu, 6), 423 (M+ - 2H2O
- tBu, 11), 391 (M+ - 2H2O - MeOH - tBu, 6), 285 (41), 265
(62), 199 (100). Calcd for C29H44O6Si-H2O-tBu, 441.2091.
(735 mg, 89%): oil; [R]D -27.2 (c 2.6, CHCl3); IR 3430 (br) cm-1
;
1H NMR δ 7.40-7.30 (15H, m), 4.70 (1H, d, J ) 11.5 Hz), 4.66
(1H, d, J ) 11.5 Hz), 4.61 (1H, d, J ) 11.5 Hz), 4.58 (1H, d,
J ) 11.5 Hz), 4.55 (2H, s), 4.04 (1H, dd, J ) 9, 1.7 Hz), 3.88
(1H, dd, J ) 6.6, 3.4 Hz), 3.73 (1H, dd, J ) 10.6, 4 Hz), 3.66
(2H, m), 3.57 (2H, m), 3.43 (3H, s), 3.41 (1H, dd, J ) 9, 3.4
Hz), 3.30 (1H, br s, OH), 2.70 (1H, br s, OH), 2.38 (1H, m),
2.16 (1H, m), 2.00 (1H, m), 1.20 (3H, d, J ) 7 Hz), 1.09 (3H, d,
J ) 7 Hz), 1.03 (3H, d, J ) 7 Hz); 13C NMR δ 139.2, 138.5,
138.1 (C), 128.3, 128.2, 128.1, 127.7, 127.5, 127.4, 127.2, 82.1,
80.3, 79.7, 73.1, 37.0, 36.8, 35.5 (CH), 73.9, 73.8, 73.0, 72.5,
67.6 (CH2), 59.4, 15.4, 10.1, 9.6 (CH3). HR FAB MS m/z
551.3405 (M + H)+. Calcd for C34H47O6, 551.3372.
Alcohol 24. This was obtained in 89% yield through
silylation of 23 under the conditions described above for 17:
oil; [R]D -24 (c 2, CHCl3); IR 3500 (br) cm-1; 1H NMR δ 7.75-
7.70 (4H, m), 7.50-7.30 (21H, br m), 4.82 (1H, d, J ) 11.6
Hz), 4.71 (1H, d, J ) 11.6 Hz), 4.69 (1H, d, J ) 11.4 Hz), 4.60
(1H, d, J ) 11.4 Hz), 4.56 (2H, br s), 4.23 (1H, br d, J ) 8.8
Hz), 3.98 (1H, dd, J ) 7.4, 2.8 Hz), 3.85-3.80 (2H, m), 3.68
(1H, dd, J ) 8.8, 3.8 Hz), 3.64 (1H, dd, J ) 8.8, 5.8 Hz), 3.60
(1H, dd, J ) 7.7, 3.1 Hz), 3.50 (1H, overlapped m), 3.50 (3H,
s), 3.10 (1H, br s, OH), 2.42 (1H, m), 2.20 (1H, m), 2.10 (1H,
m), 1.23 (3H, d, J ) 7 Hz), 1.15 (9H, s), 1.12 (3H, d, J ) 7 Hz),
1.10 (3H, d, J ) 7 Hz); 13C NMR δ 139.3, 138.7, 138.6, 133.3,
133.2, 19.2 (C), 135.6, 135.5, 129.7, 128.3, 128.2, 128.1, 128.0,
127.8, 127.5, 127.4, 127.3, 127.2, 127.1, 82.1, 80.8, 80.0, 72.2,
37.3, 37.2, 35.6 (CH), 74.4, 74.2, 73.0, 72.6, 69.1 (CH2), 59.7,
26.9 (×3), 15.3, 10.0, 9.8 (CH3). HR FAB MS m/z 789.4546
(M + H)+. Calcd for C50H65O6Si, 789.4550.
Ketone 25. Alcohol 24 (552 mg, 0.7 mmol) was dissolved
under N2 in dry CH2Cl2 (5 mL). After successive addition of
solid NaHCO3 (0.12 g, ca. 1.4 mmol) and Dess-Martin perio-
dinane (0.6 g, ca. 1.4 mmol), the mixture was stirred at room
temperature until consumption of the starting material (ca.
45 min, TLC monitoring!). Workup (extraction with CH2Cl2)
and column chromatography on silica gel (hexanes-EtOAc,
19:1) afforded compound 25 (468 mg, 85%): oil; [R]D -62.2 (c
0.8, CHCl3); IR 1725 cm-1; 1H NMR δ 7.65-7.60 (4H, m), 7.45-
7.20 (21H, br m), 4.62 (1H, d, J ) 11.6 Hz), 4.58 (1H, d, J )
11.6 Hz), 4.55-4.45 (4H, m), 4.35 (1H, d, J ) 3.4 Hz), 4.07
(1H, dd, J ) 8.3, 3.4 Hz), 3.80 (1H, dd, J ) 9.3, 8.3 Hz), 3.60-
3.55 (3H, m), 3.50 (1H, dd, J ) 8.3, 2.5 Hz), 3.42 (3H, s), 3.05
Acknowledgment. Financial support has been
granted by the Spanish Ministry of Education and
Science (project BQU2002-00468), and by the AVCyT
(projects GRUPOS03/180 and GV05/52). J.M. thanks the
Spanish Ministry of Education and Science for a con-
tract of the Ramo´n y Cajal program. S.D.-O. thanks the
Conseller´ıa de Educacio` de la Generalitat Valenciana
for a predoctoral fellowship. We further thank the
S.C.S.I.E. at the University of Valencia for performing
the mass spectral measurements.
Supporting Information Available: Description of the
general features and chemical correlations, including reaction
conditions, used to establish the configurations of the aldols
and spectral data of some selected correlation products.
Graphical NMR spectra of compounds 10a, 10b, 11a, 11b, 12a,
12b, 13-19, and 22-25, as well as of some correlation
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO051307P
J. Org. Chem, Vol. 70, No. 20, 2005 8139