Synthesis of stereopentad analogues of the C14-C22 segment of callystatin A through additions of chiral allenylzinc reagents to stereotriads

Article abstract of DOI:10.1021/jo015936k

The addition of (P)- and (M)-allenylzinc reagents, prepared in situ through Pd-catalyzed metalation of(R)- and (S)-3-butyn-2-ol mesylates, to diastereomeric stereotriad aldehydes 8, 13, 18, and 23 of syn,syn, syn,anti, anti,anti, and anti,syn stereochemis

Full text of DOI:10.1021/jo015936k

J . Org. Chem. 2001, 66, 7825-7831
7825
Syn th esis of Ster eop en ta d An a logu es of th e C14-C22 Segm en t of
Ca llysta tin A th r ou gh Ad d ition s of Ch ir a l Allen ylzin c Rea gen ts to
Ster eotr ia d s
J ames A. Marshall* and Gregory M. Schaaf
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904
jam5x@virginia.edu
Received J uly 17, 2001
The addition of (P)- and (M)-allenylzinc reagents, prepared in situ through Pd-catalyzed metalation
of (R)- and (S)-3-butyn-2-ol mesylates, to diastereomeric stereotriad aldehydes 8, 13, 18, and 23 of
syn,syn, syn,anti, anti,anti, and anti,syn stereochemistry was examined. Additions to the former
two aldehydes afforded the four anti adducts with high diastereoselectivity and negligible
mismatching. Significant mismatching was observed with the latter two aldehydes and the (M)-
allenylzinc reagent. An evaluation of possible transition states is presented in consideration of
steric and dipolar control elements.
In tr od u ction
upon allene chirality to favor one of the two possible
diastereomeric transition states in the addition and thus
differ in a fundamental way from the aforementioned
methods in which a chiral auxiliary or catalyst provides
the control element. The chiral allenylmetal methodology
provides access to all isomers of the homopropargylic
alcohol stereotriad adducts with excellent diastereo- and
enantioselectivity. In addition, the acetylenic grouping
of the adducts can be further elaborated, both function-
1
Polyketide natural products have played a major role
in the development of synthesis methodology for acyclic
stereocontrol. This remarkably diverse family possess a
wide range of important biological activity with proven
or potential use in medicine. The most common synthetic
1
approach for constructing the various stereotriad and
higher subunits of these compounds involves diastereo-
and enantioselective carbon-carbon bond forming reac-
tions related to variants of the aldol reaction. Allylborane
and boronate, allylsilane, and allyltitanate additions have
5
ally and for chain extension by a variety of protocols. The
overall utility of the methodology is reflected in applica-
6
tions to a number of important natural products.
2
also been applied with great success. Other less used,
but no less important, methods have also been developed
over the years, and new methodology continues to ap-
3
pear. Many of these approaches utilize a chiral auxiliary
or substrate to effect stereochemical control.
Additions of chiral nonracemic allenylmetal reagents
to chiral R-methyl propanal derivatives have also proven
useful for the assembly of stereotriad segments of
4
polyketide natural products (eq 1). These reagents rely
Chiral allenylzinc and indium reagents are readily
available through oxidative transmetalation of transient
allenylpalladium intermediates derived from sulfonic
*
Corresponding author. Fax + 01-804-924-7993.
(1) For an insightful review on polyketide natural product stereo-
chemistry and conformation, see Hoffmann, R. W. Angew. Chem., Int.
Ed. 2000, 39, 2054.
7
esters of (R)- or (S)-3-butyn-2-ol derivatives (eq 2). When
these transmetalations are conducted in the presence of
substrate aldehydes, anti homopropargylic alcohol ad-
ducts are formed with high diastereoselectivity. The
(2) Representative leading references. Aldol: Evans, D. A.; Carter,
P. H.; Carreira, E. M.; Prunet, J . A.; Charette, A. B.; Lautens, M.
Angew. Chem., Int. Ed. 1998, 37, 2354. Paterson, I.; Scott, J . P. J .
Chem. Soc., Perkin Trans. 1 1999, 1003. Allylmetalations: Boronate;
Scheidt, K. A.; Tasaks, A.; Bannister, T. D.; Wendt, W. R.; Roush, W.
R. Angew. Chem., Int. Ed. 1999, 38, 1652. Borane; Guo, J .; Duffy, K.
J .; Stevens, K. L.; Dalko, P. I.; Roth, R. M.; Hayward, M. M.; Kishi, Y.
Angew. Chem., Int. Ed. 1998, 37, 187. Silane; Panek, J . S.; J ain, N. F.
J . Org. Chem. 1998, 63, 4572. Titanate: Bouzbouz, S.; Popkin, M. E.;
Cossy, J . Org. Lett. 2000, 2, 3449.
(4) Reviews: (a) Marshall, J . A. Chem. Rev. 1996, 96, 31. (b)
Marshall, J . A. Chem. Rev. 2000, 100, 3163.
(5) (a) Marshall, J . A.; Yanik, M. M. J . Org. Chem. 1999, 64, 3798.
(b) Marshall, J . A.; Yanik, M. M. Tetrahedron Lett. 2000, 41, 4717. (c)
Marshall, J . A.; Yanik, M. M. Org. Lett. 2000, 2, 2173.
(
3) Other imaginative, but to date less widely used, approaches to
(6) Natural products: (a) Zincophorin. Marshall, J . A.; Palovich, M.
R. J . Org. Chem. 1998, 63, 3701. (b) Discodermolide. Marshall, J . A.;
J ohns. B. A. J . Org. Chem. 1998, 63, 7885. (c) Callystatin A. Marshall,
J . A.; Fitzgerald, R. A. J . Org. Chem. 1999, 64, 4477. (d) Aplyronine
A. Marshall, J . A.; J ohns, B. A. J . Org. Chem. 2000, 65, 1501. (e)
Balifomycin. Marshall, J . A.; Adams, N. D. Organic Lett. 2000, 2, 2897.
Marshall, J . A.; Adams, N. D. J . Org. Chem., in press. (f) Tautomycin.
Marshall, J . A.; Yanik, M. M. J . Org. Chem. 2001, 66, 1373.
(7) (a) Allenylzinc reagents: Marshall, J . A.; Adams, N. D. J . Org.
Chem. 1999, 64, 5201. (b) Allenylindium reagents: Marshall, J . A.;
Grant, C. M. J . Org. Chem. 1999, 64, 8214. (c) Allenylsilicon re-
agents: Marshall, J . A.; Maxson, K. J . Org. Chem. 2000, 65, 630.
the stereocontrolled synthesis of polypropionate segments include the
following. Oxabicyclo[3.2.1] cleavage: Hunt, K. W.; Grieco, P. A. Org.
Lett. 2001, 3, 481. Kim, H.; Hoffmann, H. M. R. Eur. J . Org. Chem.
000, 2195. Epoxide rearrangement: J ung, M. E.; Marquez, R. Org.
Lett. 2000, 2, 1717. Ketene aldol: Calter, M. A.; Bi, F. C. Org. Lett.
000, 2, 1529. Hydroformylation: Breit, B.; Zahn, S. K. Tetrahedron
Lett. 1998, 39, 1901. 1,4-Additions: Hanessian, J .; Ma, J .; Wang, W.
Tetrahedron Lett. 1999, 40, 4627. Nitrile oxide cycloadditions: Bode,
J . W.; Fraefal, N.; Muri, D.; Carreira, E. M. Angew. Chem., Int. Ed.
2
2
2
001, 40, 2082. Hetero Diels-Alder: Myles, D. C.; Danishefsky, S. J .
Pure Appl. Chem. 1989, 61, 1235.
1
0.1021/jo015936k CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/12/2001

7
826 J . Org. Chem., Vol. 66, No. 23, 2001
Marshall and Schaaf
Sch em e 1
preference for anti over syn adducts can be attributed to
an unfavorable eclipsing interaction between the allenyl
Me and the aldehyde R substituent in the transition state
leading to the syn adduct (see B in eq 2).
stereotriads to afford various stereopentad adducts (eq
4). These arrays are present in a number of stereochemi-
cally complex polyketide natural products with potential
as medicinal agents.2 In the present study it was of
interest to determine both the effect of the longer chain
R-substituent on Felkin-Anh control of the addition and
the role of the â-oxygen substituent as a dipolar control
element. A previous investigation of such R,â-substituent
effects has been reported for Mukaiyama aldol and
allylmetal additions that proceed through acyclic transi-
tion states.9 The present investigation differs in two
important respects: (1) The additions proceed through
cyclic, as opposed to acyclic transition states; (2) The
reagents are allenic rather than allylic or enolic.
Interestingly, high diastereoselectivity is observed in
additions to both enantiomers of the aforementioned
R-methyl propanal derivatives to afford the anti,anti and
anti,syn adducts (eq 3). Thus, the preference for the anti
transition state overrides Felkin-Anh considerations in
these additions with a resulting absence of mismatching.8
For our aldehyde substrates, we selected the four
stereotriad isomers represented by 8, 13, 18, and 23
(Scheme 1). The choice of a â-OTBS ether was based on
the findings by Evans that such ethers exhibit a signifi-
9
cant dipole effect. The stereopentads resulting from the
planned additions to these aldehydes are related to the
C14-C22 segment of the marine-sponge derived antitu-
mor compound, callystatin A, and analogues thereof
(
Figure 1).10 Accordingly, these studies address practical
as well as fundamental stereochemical issues.
Resu lts
The synthesis of the stereotriad aldehyde substrates,
outlined in Scheme 1, utilizes methodology developed
The thrust of the present study was to examine
reactions of chiral allenylzinc reagents with isomeric
(
9) Evans, D. A.; Duffy, J . D.; Dart, M. J . Tetrahedron Lett. 1994,
(
8) Ch e´ rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
35, 8537. Evans, D. A.; Dart, M. J .; Duffy, J . L.; Yang, M. G. J . Am.
Chem. Soc. 1996, 118, 4322.
2
119. Anh, N. T.; Eisenstein, O. Nouv. J . Chem. 1977, 1, 61.

Synthesis of Stereopentad Analogues
J . Org. Chem., Vol. 66, No. 23, 2001 7827
derivatives (R)- or (S)-1 without isolation. This can be
accomplished through TMS cleavage with Amberlite-OH
resin in CH
is removed by stirring the mixture with 3 Å molecular
seives and MgSO . After filtration, the CH Cl solution
of 3-butyn-2-ol is treated with MsCl and Et N to form
2 2
Cl -MeOH solvent. The methanol cosolvent
4
2
2
3
the stable mesylate which can be isolated by extraction
in the usual way (eq 5).
F igu r e 1. Relationship of the present studies to the C14-
C22 segment of Callystatin A.
Sch em e 2
Exposure of the syn,syn aldehyde 8 to the (P)-allenyl-
zinc reagent, generated in situ from the propargylic
mesylate (R)-1 and diethylzinc in the presence of 10 mol
%
Pd(OAc)
2
3
‚PPh , afforded the anti adduct 27 with no
trace of the syn isomer 28, according to analysis of the
1
H NMR spectrum. However, a small amount of the
diastereomeric anti product 29 (ratio ) 91:9) was also
produced. This latter product most likely results from
partial racemization of the intermediate allenyl Pd
over the past several years in our laboratory.1,3 This
chemistry has been discussed in a number of reviews,4
and detailed pathways for the additions to aldehyde 2
need not be reiterated here. It suffices to say that the
syn,syn adduct 4 arises via an acyclic Felkin-Anh
transition state and the syn,anti adduct (right-to-left) 19
also results from an acyclic transition state but with
12,13
precursor of the allenylzinc reagent.
When this ex-
periment was repeated with mesylate (S)-1, a 92:8
mixture of the anti adducts 29 and 27 was formed free
of any syn adduct 30 (Scheme 3).
Additions to the syn,anti aldehyde 13 proceeded analo-
gously. Both the (P)- and (M)-allenylzinc reagents derived
from mesylates (R)- and (S)-1 afforded the anti adducts
31 and 33 as near-exclusive products. In the former case
the alternative anti adduct 33 derived from the (M)-
allenylzinc reagent (ratio ) 94:5) was also produced.
Barely detectable signals for what may be the syn adduct
6
d
6e
“chelation” control. The two anti adducts 9 and 14 are
reagent-controlled products resulting from cyclic transi-
tion states (see eq 3).
In our initial investigations of the allenylpalladium
transmetalation methodology we utilized (R)- and (S)-3-
butyn-2-ol from commercial sources. However, the in-
creasing cost of these alcohols prompted our search for a
more economical supply. To date, we have developed two
synthetic routes that fulfill our needs. The first employs
commercially available, and relatively inexpensive, (R)-
and (S)-lactic esters as the starting materials.6f The
second, which we selected for the present studies, utilizes
Amano AK lipase to effect a multigram scale kinetic
resolution of racemic, moderately priced 4-TMS-3-butyn-
1
32 were also observed in the H NMR spectrum of this
mixture. The reaction proceeding from mesylate (S)-1 and
aldehyde 13 afforded a 92:6:2 mixture of the anti products
33, 31, and the (presumed) syn isomer 34. Thus, to the
extent that negligible amounts of the syn isomers can
be detected, the foregoing additions resemble those
leading to the anti adducts 13 and 18 (Scheme 1) in which
reagent control overrides Felkin-Anh preferences.
The two R,â-anti aldehyde diastereomers 18 and 23
exhibited typical matched behavior with the (P)-allenyl-
zinc reagents derived from mesylate (R)-1 affording
negligible amounts of syn 36/40 or diastereomeric anti
byproducts (Scheme 4). Additions of the (M)-allenylzinc
reagent from mesylate (S)-1, on the other hand, were
significantly mismatched. In each case the combined syn
and ent-anti diastereomers 38/42 and 35/39 accounted
for approximately one-third of the total stereopentad
products.
2
-ol (R,S)-24 through enantioselective acetylation with
vinyl acetate to afford unchanged (S)-4-TMS-3-butyn-2-
ol ((S)-24) and the acetate of (R)-4-TMS-3-butyn-2-ol (25),
both of >95% ee (Scheme 2).11 The two are readily
separated through treatment of the mixture with succinic
anhydride and extraction of the (S)-succinate 26 with
aqueous NaHCO
3 4
. Reduction of each ester with LiAlH
or DIBAL-H affords the enantiomeric butynols (S)- and
(R)-24 of high ee.
Because of their volatility and water solubility the
parent butynols are best converted to the mesylate
Str u ctu r e Cor r ela tion s
The configurational relationships between propargylic
mesylates and the derived allenylzinc reagents have been
well established as has the stereochemistry of the ensu-
(10) Previous syntheses. (a) Kobayashi, M.; Higuchi, K.; Murakami,
N.; Tajima, H.; Aoki, S. Tetrahedron Lett. 1997, 38, 2859. (b) Mu-
rakami, N.; Wang, W.; Aoki, M.; Tsutsui, Y.; Sugimoto, M.; Kobayashi,
M. Tetrahedron Lett. 1998, 39, 2349. (c) Crimmins, M. T.; King, B. W.
J . Am. Chem. Soc. 1998, 120, 9084. (d) Smith, A. B., III; Brandt, B.
M. Org. Lett. 2001, 3, 1685.
4,6,7
ing homopropargylic alcohol products (see eqs 2 and 3).
(12) Chiral allenylpalladium compounds are racemized by Pd(0)
catalysts. Elsevier: C. J .; Vermeer, P. J . Org. Chem. 1985, 50, 3042.
See also Marshall, J . A.; Wolf, M. A.; Wallace, E. M. J . Org. Chem.
1997, 62, 367.
(13) Poisson and Normant have found that chiral allenylzinc
bromide reagents are configurationally stable to ca. -10 °C. Poisson,
J .-F.; Normant, J .-F. Synlett 2001, 305.
(11) Cf. Burgess, K.; J ennings, L. D. J . Am. Chem. Soc. 1991, 113,
6
129. Beresis, R. T.; Solomon, J . S.; Yang, M. G.; J ain, N. F.; Panek,
J . S. Org. Synth. 1997, 75, 78. The kinetic resolution sequence leading
to the enantiomeric TMS butynols was developed by Matt Yanik in
our laboratory. Details will be disclosed in due course pending further
investigations on applications of the derived allenylsilane reagents.

7
828 J . Org. Chem., Vol. 66, No. 23, 2001
Marshall and Schaaf
Sch em e 3
Sch em e 4
Nonetheless, we elected to confirm our assignments
through correlation of the newly formed carbinol stereo-
center and the resident OTBS center of the aldehyde
stereotriad substrates. Such a correlation would confirm
our assumption that the major product was formed via
the anti pathway (eq 2). The fact that the major product
of the (P)-allenylzinc addition was present as a minor
product in the analogous addition of the (M)-allenylzinc
reagent (by virtue of the racemization side reaction)
provides additional support for this assumption.
Assignment of the 1,3-diol stereochemistry was achieved
through conversion of the stereopentad adducts to the
acetonides 44, 46, 48, 50, 52, and 54 derived from the
syn,syn and syn,anti aldehydes 8 and 13 and the two
matched adducts 35 and 39 from additions to the anti,-
anti and anti,syn aldehyde adducts 18 and 23 (Scheme
5). The syn acetonides 44 and 48 showed distinctly
different chemical shifts for the acetonide methyl groups
in the range of 20 and 30 ppm whereas the corresponding
signals for the anti isomers 46, 50, 52, and 54 were
closely spaced near 25 ppm.14 The inseparable diastere-
omeric mixture of acetonides obtained from the mis-
matched adducts 37 and 41 could not be analyzed
because of overlapping signals. However, small samples
of 37 and 38 could be isolated through careful chroma-
tography. Upon oxidation15 each gave rise to ketone 55
in accord with the assigned structures.
(14) Rychnovsky, S. D.; Skalitzky, D. J . J . Org. Chem. 1993, 58,
3511.

Synthesis of Stereopentad Analogues
J . Org. Chem., Vol. 66, No. 23, 2001 7829
Sch em e 5
Transition state representations illustrating the rela-
tionship of these four factors are presented in Figure 2.
In all cases the avoidance of an allenic methyl/aldehyde
substituent eclipsing interaction, denoted as “steric,”
results in a preference for the anti adducts. Felkin-Anh
orientation, while not crucial, likely plays a more impor-
tant role than is seen in additions leading to the anti
triads (eq 3) by virtue of the longer â-carbon chain in the
triad aldehydes compared to propanal 2. The most serious
mismatching occurs when the transition state for the anti
adduct lacks two of the four favorable orientational
factors as in AAA while the corresponding syn arrange-
ment, SSA, lacks only one (steric), albeit perhaps the
most important of the four.
In view of the highly selective additions to the two R,â-
syn aldehydes 8 and 13, it can be surmised that the anti
vs gauche orientation of the extended carbon chain, as
in ASS vs. AAS, is a relatively unimportant conforma-
tional factor. It should be noted that rotation of the CR-
Câ bond in ASS or AAA to place R in the anti position
would lead to 1,3-dipole repulsion between the aldehyde
CdO and the â-OR substituent. Dipole repulsion is
assumed to be an important control element but its effect
is not directly measurable in these studies. It seems
unlikely that the stereochemistry of the γ-position exerts
a significant influence, given the comparable steric and
electronic attributes of the ethyl and methyl substituents.
Although the foregoing conclusions regarding transition
state preferences may prove useful in predicting the
stereochemical outcomes of related additions, perhaps of
greatest practical import is the finding that the allenylz-
inc methodology provides a workable route to six of the
eight possible R,â anti stereopentad diastereomers.
Exp er im en ta l Section
(
R)-3-Bu tyn -2-yl Meth a n esu lfon a te (R)-1. To a stirring
solution of (R)-TMS-butynol (4.00 g, 0.281 mmol) in 9:1 CH
Cl :MeOH (14 mL) was added Amberlite IRA-400 (OH) (2.4 g,
0 wt %), and the mixture was stirred overnight. Molecular
sieves (3 Å) and MgSO were added, and stirring was contin-
ued for 30 min. The mixture was filtered through Celite, and
the solids were rinsed with additional CH Cl until a total
volume of ∼140 mL was obtained. After the solution was cooled
to -78 °C, triethylamine (15.6 mL, 1.12 mmol, 4 equiv) and
MsCl (6.6 mL, 0.844 mmol, 3 equiv) were added and the
solution was stirred for 1.5 h. The reaction was quenched with
2
-
2
6
4
2
2
Tr a n sition Sta te An a lysis
In our analysis of probable transition states we incor-
porate conclusions reached by Evans and co-workers in
their proposed stereochemical model for merged 1,2- and
NaHCO
organic extract was dried over MgSO
reduced pressure, and chromatographed (elution with 3:1
pentane/ether) to give 3.14 g (75%) of a clear oil, [R] ) +108.1
3
, extracted with CH
2
Cl
2
, and washed with brine. The
1
,3-asymmetric induction in Mukaiyama aldol and re-
, concentrated under
9
4
lated additions to aldehydes. Thus, we assume that the
orientation of the â-stereocenter will favor conformers in
which (1) dipole repulsion between the carbonyl oxygen
and the OR substituent is minimized and (2) the â-alkyl
substituent (R in Figure 2) preferentially adopts an anti
vs gauche conformation relative to the main carbon chain
for steric reasons. We assume that dipole considerations
will override conformational preferences when the two
factors are in conflict. The other factors that play a role
in the present addition reactions are (1) steric interac-
tions between the allenic methyl group and the aldehyde
R-substituent, as illustrated in eq 2 (A vs B), and (2)
Felkin-Anh orientation of the aldehyde R-methyl sub-
stituent. Of these, the allenic methyl steric interactions
are considered paramount in view of the absence of a
mismatched syn adduct from additions leading to 9 and
D
16
(
c 3.0, CHCl
(2R,3R,4S)-(-)-1-(ter t-Bu t yld im et h ylsilyloxy)-2,4-d i-
m eth yl-5-h exyn -3-ol (4). To a stirring solution of aldehyde
(4.00 g, 19.8 mmol) in CH Cl (200 mL) at -78 °C was added
allenylstannane (M)-3 (7.79 g, 22.7 mmol, 1.15 equiv). After
min, BF ‚OEt (7.32 mL, 3.00 equiv) was added over 10 min,
and the mixture was stirred for 1 h and quenched with
saturated NaHCO . The aqueous layer was extracted with
Et O, washed with brine, and dried over MgSO . The solution
3
); lit. [R]
D
) +108.8 (c 3.12 CHCl
3
).
2
2
2
1
7
5
3
2
3
2
4
was filtered, concentrated under reduced pressure, and chro-
matographed on silica gel (elution with 2.5% EtOAc/hexanes)
to give 4.47 g (88%) of product as a separable 88:12 mixture
1
of diastereomers. H NMR (CDCl
3
, 300 MHz) δ 3.9 (d, J ) 3.0
Hz, 1H), 3.72 (m, 2H), 3.52 (br, 1H), 2.52 (m, 1H), 2.16 (m,
H), 2.06 (d, J ) 3 Hz, 1H), 1.31 (d, J ) 9.0 Hz, 3H), 1.01 (d,
J ) 9.0 Hz, 3H), 0.91 (m, 9H), 0.081 (s, 6H).
1
1
4 (Scheme 1 and eq 2).
(
16) Marshall, J . A.; Adams, N. D. J . Org. Chem., in press.
(17) Marshall, J . A.; Lu, Z.-H.; J ohns, B. A. J . Org. Chem. 1998, 63,
817.
(15) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155; Meyer,
S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549.

7
830 J . Org. Chem., Vol. 66, No. 23, 2001
Marshall and Schaaf
F igu r e 2. Possible transition state arrangements for additions of (P)- and (M)-allenylzinc reagents to the diastereomeric aldehyde
stereotriads 8, 13, 18, and 23. The discriptors “anti” and “gauche” refer to the conformation of the aldehyde backbone (heavy
lines), “+” and “-”designate favorable and unfavorable steric or dipolar relationships.
(
2R,3R,4S)-(-)-1,3-Bis(ter t-bu tyld im eth ylsilyloxy)-2,4-
concentration under reduced pressure afforded 3.29 g (93%)
d im eth yl-5-h exyn e (5). Gen er a l P r oced u r e for Alcoh ol
Silyla tion s. To a solution of alcohol 4 (2.17 g, 8.45 mmol) in
CH
mmol, 2.5 equiv) and TBSOTf (5.02 g, 19.0 mmol, 2.25 equiv).
The mixture was allowed to warm to room temperature and
stirred for an additional 1 h. The reaction was quenched with
saturated NaHCO
CH Cl , washed with brine, and dried over MgSO
of the reduced product as a clear oil that was used without
1
further purification. H NMR (CDCl
3
, 300 MHz); δ 3.67 (dd, J
2
Cl
2
(84 mL) at 0 °C was added 2,6-lutidine (2.4 mL, 21.1
) 1.2, 4.5 Hz, 1H), 3.47 (dd, J ) 7.2, 9.6, 1H), 3.36 (dd, J )
6.3, 9.6 Hz, 1H), 1.76 (m, 1H), 1.49 (m, 2H), 1.04 (m, 1H), 0.84-
0.96 (m, 27H), 0.032 (m, 12H).
(2R,3R,4S)-(-)-3-(ter t-Bu t yld im et h ylsilyloxy)-2,4-d i-
m eth yl-1-h exa n ol (7). Gen er a l P r oced u r e for Selective
Desilyla tion . To a solution of silyl ether 6 (3.24 g, 8.65 mmol)
in 95% EtOH (87 mL) was added PPTS (217 mg, 0.865 mmol,
0.100 equiv). The mixture was stirred for 18 h, quenched with
TEA (1 mL), and concentrated under reduced pressure. The
residue was chromatographed on silica gel (gradient elution
3
, and the aqueous layer was extracted with
. The
2
2
4
solution was filtered, concentrated under reduced pressure,
and chromatographed on silica gel (elution with 1% EtOAc/
hexanes) to give 2.60 g (83%) of a clear oil. H NMR (CDCl
1
3
,
3
(
6
7
9
00 MHz); δ 3.76 (dd, J ) 1.8, 7.5 Hz, 1H), 3.43 (m, 2H), 2.59
m, 1H), 2.12 (m, 1H), 2.04 (d, J ) 2.7 Hz, 1H), 1.19 (d, J )
with 5% to 25% EtOAc/hexanes) to give 1.87 g (83%) of alcohol
.9 Hz, 3H), 0.90 (m, 21H), 0.08 (m, 12H); 13C NMR (CDCl
,
7 as a clear oil. [R]
20
-3.82 (c 1.96, CHCl
); IR (neat) v 3353,
, 300 MHz); δ 3.63 (m,
3
D
-
3
1 1
5 MHz) ppm 86.3, 78.3, 69.9, 69.5, 69.4, 36.2, 30.2, 25.8, 17.7,
.3, -5.6. -5.7.
(
d im eth ylh exa n e (6). Gen er a l P r oced u r e for th e Hyd r o-
gen a tion of Alk yn es. To a stirring solution of alkyne 5 (3.50
g, 9.44 mmol) in dry EtOH (50 mL) was added 5% Pt-C (1.84
g). The mixture was stirred under a hydrogen atmosphere for
2960, 2951, 2855 cm ; H NMR (CDCl
2H), 3.45 (dd, J ) 6.0, 10.5 Hz, 1H), 2.20 (s, 1H) 1.91 (m, 1H),
1.49 (m, 2H), 1.14 (m, 1H), 0.94 (m, 18H), 0.08 (m, 6H);
NMR (CDCl , 75 MHz) ppm 77.2, 66.4, 39.5, 38.1, 27.3, 26.0,
25.6, 18.3, 15.3, 12.6, 12.2, -4.1, -4.2. Anal. Calcd for
Si: C, 64.55; H, 12.38. Found: 64.63, 12.57.
(2S,3R,4S)-3-(ter t-Bu tyld im eth ylsilyloxy)-2,4-d im eth -
3
13
2R,3R,4S)-(-)-1,3-Bis(ter t-bu tyld im eth ylsilyloxy)-2,4-
C
3
14 32 2
C H O
4
h followed by addition of Norite decolorizing charcoal.
ylh exa n a l (8). Gen er a l P r oced u r e for Sw er n Oxid a tion
Filtration through a column of Celite on silica gel and
of Alcoh ols (Oxid a tion P r oced u r e A). To a stirring solution

Synthesis of Stereopentad Analogues
J . Org. Chem., Vol. 66, No. 23, 2001 7831
of oxalyl chloride (0.080 mL, 0.92 mmol, 1.5 equiv) in CH
2
Cl
2
(1.1 mL) was added 6 N HCl (1.1 mL). The reaction mixture
(
5 mL) at -78 °C was added DMSO (0.131 mL, 1.84 mmol,
was stirred for 4 h, quenched with NaHCO
with Et O. The extracts were washed with brine, dried over
MgSO , and concentrated under reduced pressure. The residue
was chromatographed on silica gel (elution with 25% EtOAc/
hexanes) and concentrated under reduced pressure to give 14.2
mg (67%) of crude diol 43, which was used without further
purification.
To a stirring solution of diol 43 (14.2 mg, 0.0720 mmol) in
2,2-dimethoxypropane (0.21 mL) at room temperature was
added CSA (16.6 mg, 0.0720 mol, 1.00 equiv). The reaction
mixture was stirred for 3 h, quenched with water, and
extracted with ether. The extracts were washed with brine,
3
, and extracted
3
.00 equiv). The mixture was stirred for 15 min, and then
Cl (1 mL) was added
over 15 min, followed by triethylamine (0.385 mL, 2.70 mmol,
.50 equiv) addition over 10 min. After 3 h, the temperature
was raised to -40 °C, and the reaction was quenched with
NaHCO . The layers were separated, and the CH Cl layer was
washed with water, dried over MgSO , and filtered. After
2
alcohol 7 (160 mg, 0.614 mmol) in CH
2
2
4
4
3
2
2
4
concentration under reduced pressure, the oil was triturated
with hexanes, filtered, and concentrated uder reduced pressure
to give 119 mg (75%) of aldehyde 8 as a pale yellow oil which
1
was used without further purification. H NMR (CDCl
3
, 300
MHz); δ 9.82 (s, 1H), 3.99 (m, 1H), 2.52 (m, 1H), 1.49 (m, 2
4
dried over MgSO , and concentrated under reduced pressure.
The product was chromatographed on silica gel (elution with
H), 1.15 (m, 1H), 1.07 (d, J ) 6.6 Hz, 3H), 0.89 (m, 15H), 0.05
(m, 6H).
5% EtOAc/hexanes) to give 9.9 mg (58%) of acetonide 44 as a
(
2R,3R,4R)-1-ter t-Bu tyld im eth ylsilyloxy-2,4-d im eth yl-
clear oil. 13C NMR (CDCl
3
, 75 MHz) ppm 99.1, 87.4, 77.7, 68.3,
5
-h exyn -3-ol (9). Sta n d a r d P r oced u r e for Allen ylzin c
35.3, 30.4, 29.9, 28.5, 23.5, 19.3, 15.9, 15.4, 10.8, 4.3.
Ad d ition . To a stirring solution of Pd(OAc)
mmol, 0.050 equiv) in THF (4.9 mL) at -78 °C was added PPh
6.5 mg, 0.025 mmol, 0.050 equiv), aldehyde 8 (100 mg, 0.49
2
(5.5 mg, 0.025
syn -1,3-Diol Aceton id e 48. Gen er a l P r oced u r e for
Aceton id e F or m a tion (P r oced u r e B). To a stirring solution
of homopropargylic alcohol 31 (43.3 mg, 0.138 mmol) in THF
(0.6 mL) was added TBAF (0.2 mL, 1 M in THF). The reaction
mixture was stirred for 1 h, quenched with sat. NaCl (aq), and
3
(
mmol), and mesylate (R)-1 (109 mg, 0.74 mmol, 1.50 equiv).
Diethylzinc (1.5 mL, 1 M in hexane, 3.00 equiv) was added
over 10 min, and after stirring for 5 min the mixture was
warmed to -20 °C and stirred overnight. The reaction was
extracted with Et
2
O. The extracts were washed with brine,
dried over MgSO , and concentrated under reduced pressure.
4
quenched with NH
rated. The Et O layer was washed with brine and stirred with
MgSO and Norite decolorizing charcoal. The solution was
4
Cl:Et
2
O (1:1), and the layers were sepa-
The residue was chromatographed on silica gel (elution with
25% EtOAc/hexanes) and concentrated under reduced pressure
to give 18.1 mg (94%) of diol 47, which was used without
further purification.
To a stirring solution of diol 47 (25.9 mg of combined
samples from two experiments, 0.131 mmol) in 2,2-dimeth-
oxypropane (5 mL) at room temperature was added CSA (30.3
mg, 0.131 mol, 1.00 equiv). The reaction mixture was stirred
for 1 h, quenched with water, and extracted with ether. The
2
4
filtered and concentrated, followed by purification by column
chromatography on silica gel (elution with 2.5% EtOAc/
hexanes) to give 86.4 mg (68%) of product as a separable 95:5
mixture of alcohol 9 and its diastereomer 14 as a light yellow
1
oil. The H NMR spectrum was identical to that of a sample
previously prepared through allenylindium addition to alde-
6
d
hyde 8.
3R,4R,5R,6R,7S)-(+)-6-(ter t-Bu t yld im et h ylsilyloxy)-
,5,7-tr im eth yl-1-n on yn -4-ol (29). The general procedure for
allenylzinc addition reactions was employed with Pd(OAc)
35.0 mg, 0.155 mmol, 0.050 equiv), THF (31 mL), PPh (41.0
4
extracts were washed with brine, dried over MgSO , and
(
concentrated under reduced pressure. The product was chro-
matographed on silica gel (elution with 2.5% EtOAc/hexanes)
3
1
3
2
to give 26.2 mg (79%) of acetonide 48 as a clear oil. C NMR
(CDCl , 75 MHz) ppm 99.1, 87.4, 77.2, 76.9, 68.3, 35.1, 30.5,
(
3
3
mg, 0.155 mmol, 0.050 equiv), aldehyde 8 (800 mg, 3.10 mmol),
mesylate (S)-1 (690 mg, 4.65 mmol, 1.50 equiv), and diethylzinc
29.9, 28.5, 25.2, 19.3, 15.9, 13.4, 10.3, 4.1.
(
9.30 mL, 1 M in hexane) to give 619 mg (64%) of product as
Ack n ow led gm en t. This research was supported by
NIH Grant R01 CA90383-01 and NSF Grant CHE-
901319. We thank Professor J ames Panek for helpful
advice regarding the lipase kinetic resolution.
a separable 92:8 mixture of alcohol 29 and its diastereomer
2
0
2
7 as a light yellow oil. [R]
v 3481, 3301, 2960, 2925, 2846 cm ; H NMR (CDCl
MHz); δ 3.80 (m, 1H), 3.41 (m, 1H), 2.61 (m, 1H), 2.03 (m, 2H),
D
+8.72 (c 2.12, CHCl
3
); IR (neat)
9
-
1
1
3
, 300
1
3
.41 (m, 1H), 1.28 (d, J ) 7.2 Hz, 3H), 0.96 (d, J ) 6.9 Hz,
H), 0.87 (m, 12H), 0.81 (d, J ) 6.9 Hz, 3H), 0.11 (s, 3H), 0.07
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for 10-13, 16-23, 27, 31, 33, 35, 37, 39, 41, 46, 50,
1
3
(s, 3H); C NMR (CDCl
3
, 75 MHz) ppm 84.7, 78.6, 75.8, 70.3,
1
5
2
4
2, 54, and 55; H NMR spectra for 4-8, 10-13, 16-18, 20-
4
-
1.5, 37.2, 30.2, 28.0, 30.0, 18.2, 17.8, 15.6, 12.9, 12.0, -4.2,
4.6.
syn -1,3-Diol Aceton id e 44. Gen er a l P r oced u r e for
13
3, 27, 29, 31, 33, 35, 37, 39, 41, and 55; C NMR spectra for
4, 46, 48, 50, 52, and 54. This information is available free
of charge via the Internet at http://pubs.acs.org.
Aceton id e F or m a tion (P r oced u r e A). To a stirring solution
of homopropargylic alcohol 27 (33.2 mg, 0.106 mmol) in THF
J O015936K