A Study Directed to the Asymmetric Synthesis of the Antineoplastic Macrolide Acutiphycin under Enantioselective Acyclic Stereoselection Based on Chiral Oxazaborolidinone-Promoted Asymmetic Aldol Reactions

Article abstract of DOI:10.1021/jo990342r

A shortening of the reaction path can be realized by using a series of the chiral oxazaborolidinone-promoted aldol reaction with respect to the practical synthesis of the (+)-acutiphycin seco acid derivative 5. The linear strategy is based on the utilizat

Full text of DOI:10.1021/jo990342r

J . Org. Chem. 1999, 64, 5511-5523
5511
A Stu d y Dir ected to th e Asym m etr ic Syn th esis of th e
An tin eop la stic Ma cr olid e Acu tip h ycin u n d er En a n tioselective
Acyclic Ster eoselection Ba sed on Ch ir a l
Oxa za bor olid in on e-P r om oted Asym m etic Ald ol Rea ction s
Syun-ichi Kiyooka* and Mostofa A. Hena
Department of Chemistry, Kochi University Akebono-cho, Kochi 780-8520, J apan
Received February 24, 1999
A shortening of the reaction path can be realized by using a series of the chiral oxazaborolidinone-
promoted aldol reaction with respect to the practical synthesis of the (+)-acutiphycin seco acid
derivative 5. The linear strategy is based on the utilization of five aldol reactions with a sequence
of silyl nucleophiles, 7, 8, 35, 10, and 11, in the presence of stoichiometric amounts of the promoter,
1 or 2. The construction of the relative configuration between the stereogenic centers is
diastereoselectively controlled by the stereochemistry of the promoter used in the enantioselective
aldol reaction, which is nearly independent of that of the substrate (promoter control).
The chiral Lewis acid-promoted aldol reaction in which
activated aldehydes react with silyl nucleophiles is
generally considered to be more practical and useful for
the enantioselective construction of aldol skeletons,
compared with asymmetric aldol reactions involving
chiral auxiliaries. When a chiral Lewis acid can be used
successfully as a catalyst, the asymmetric aldol reaction
is the reaction of choice. Even in the case where the chiral
Lewis acid does not function as a catalyst, the stoichio-
metric process is still quite useful (in this case the Lewis
acid is called a promoter) and more advantageous than
the cases of requiring the binding and removal of chiral
auxiliaries. This is because the chiral ligands contained
by the promoter are recycled in nearly all cases. After
the first report by Reetz, who converted a prototype of
the Mukaiyama aldol reaction into an asymmetric ver-
sion by introducing a chiral Lewis acid,1a a number of
other successful examples appeared in this field; among
these are the divalent tin-catalyzed asymmetric aldol
reactions found and developed by Mukaiyama and
Kobayashi1b and the chiral borane (CAB)-catalyzed asym-
metric aldol reaction reported by Yamamoto.1c Reactions
using a titanium reagent, reported by Carreira,1d and a
copper reagent, reported by Evans,1e recently have also
led to significantly higher levels of enantioselectivity.
During this period, we also described a highly enanti-
oselective aldol reaction, which is promoted by chiral
oxazaborolidinones.2a,b Similar reactions have also been
reported by Masamune2c,d and Corey.2e
(S)- and (R)-Oxazaborolidinones, 1 and 2, respectively,
were easily obtained in situ via the reaction of (S)- and
(R)-N-tosylvalines with 1 equiv of BH3‚THF which pro-
motes the aldol reaction of a variety of aldehydes with
silyl ketene acetals with very high enantioselectivity
(Scheme 1). The scope and limitation of the oxazaboro-
lidinone-promoted aldol reaction has been summarized
by surveying the stereochemical outcome of reactions
which involve enantioselectivities which are acceptable
for practical syntheses, even though a stoichiometric
amount of the promoter is required.3 In a stable confor-
mation in the ground state of (S)-oxazaborolidinone 1,
as optimized using MOPAC-AM1,4 one methyl group of
the isopropyl substituent is necessarily located at the
upper position of the five-membered ring (Figure 1). The
stereochemical outcome (si facial selectivity) observed in
the reaction using 1 can be explained based on the
assumption that carbon-carbon bond formation takes
place at the bottom of the five-membered ring, thus
avoiding steric hindrance by the methyl group. Corey
extended this view by suggesting that the conformation
is fixed by a hydrogen bonding interaction between the
Lewis acid and the aldehyde.5 Thus, our oxazaborolidi-
none-promoted aldol reaction presumably proceeds via
a transition state assembly, as depicted in Figure 1, in
which no π-π interactions between the aromatic moiety
of the promoter and the aldehyde are involved.
Acyclic stereoselection methods, which have been
developed in the past two decades, have been largely
attained via the diastereoselective inter- and/or intramo-
lecular chirality transfer of the stereochemistry of the
first chiral center so that stereoselective construction of
acyclic systems, which involve multiple chiral centers,
is always affected by the stereochemistry of the sub-
strates used in the reaction.6 It might be expected that
(1) (a) Reetz, M. T.; Kyung, S.-H.; Bolm, C.; Zierke, T. Chem. Ind.
(London) 1986, 824. (b) Kobayashi, S.; Uchio, H.; Fujishita, Y.; Shiina,
I.; Mukaiyama, T. J . Am. Chem. Soc. 1991, 113, 4247-4252. (c)
Ishihara, K.; Maruyama, T.; Mouri, M.; Gao, Q.; Furuta, K.; Yamamoto,
H. Bull. Chem. Soc. J pn. 1993, 66, 3483-3491. (d) Carreira, E. M.;
Singer, R. A.; Lee, W. J . Am. Chem. Soc. 1994, 116, 8837-8838. (e)
Evans, D. A.; Murry, J . A.; Kozlowski, M. C. J . Am. Chem. Soc. 1996,
118, 5814-5815.
(2) (a) Kiyooka, S.-i.; Kaneko, Y.; Komura, M.; Matsuo, H.; Nakano,
M. J . Org. Chem. 1991, 56, 2276-2278. (b) Kiyooka, S.-i.; Kaneko, Y.;
Kume, K. Tetrahedron Lett. 1992, 33, 4927-4930. (c) Parmee, E. R.;
Tempkin, O.; Masamune, S.; Abiko, A. J . Am. Chem. Soc. 1991, 113,
9365-9366. (d) Parmee, E. R.; Hong, Y.; Tempkin, O.; Masamune, S.
Tetrahedron Lett. 1992, 33, 1729-1732. (e) Corey E. J .; Cywin, C. L.;
Roper, T. D. Tetrahedron Lett. 1992, 33, 6907-6910.
(3) Kiyooka, S.-i. Rev. Heteroatom Chem. 1997, 17, 245-270.
(4) Dewar, M. J . S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J . J . P.
J . Am. Chem. Soc. 1985, 107, 3902-3909.
(5) (a) Corey, E. J .; Rohde, J . J . Tetrahedron Lett. 1997, 38, 37-40.
(b) Corey, E. J .; Barnes-Seeman, D.; Lee, T. W. Tetrahedron Lett. 1997,
38, 4351-4354.
(6) (a) Gawly, R. E.; Aube´, J . Principles of Asymmetric Synthesis,
Pergamon: Oxford, 1996. (b) Santelli, M.; Pons, J .-M. Lewis Acids and
Selectivity in Organic Synthesis, CRC Press: Boca Roton, 1995.
10.1021/jo990342r CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

5512 J . Org. Chem., Vol. 64, No. 15, 1999
Kiyooka and Hena
Sch em e 1. Gen er a l F ea tu r e of th e Oxa za bor o-
lid in on e-P r om oted Asym m etr ic Ald ol Rea ction
the use of a series of chiral oxazaborolidinone-promoted
aldol reactions toward a practical synthesis of (+)-
acutiphycin (3).
Resu lts a n d Discu ssion
Acutiphycin (3) has been shown to be cytotoxic to KB
and NIH/3T3 cells and has significant antineoplastic in
vivo against murine Lewis lung carcinoma. The struc-
tural elucidation of this novel macrolide, which was
isolated from the alga Osillatoria Acutissima, its biologi-
cal activity,9 and spectral analysis, was reported origi-
nally by Moore in 1984.10 The only known route for the
synthesis of this macrolide was reported by Smith in
1995.11 In this route Smith employed a Brown asym-
metric allylboration, chelation-controlled introduction of
a methyl group, a Still [2,3]-sigmatropic rearrangement,
and a Cram enolate addition to generate the stereogenic
centers of (+)-acutiphycin.
Despite the report of this macrolide synthesis it ap-
peared to us that the acyclic stereocontrol for the creation
of the chiral centers remains a challenging synthetic
objective. The complex structure of marine macrolides
such as acutiphycin serves as an exciting stage for
exhibiting creative synthetic methodology.12 Aldol reac-
tions, which are auxiliary-, reagent-, and/or substrate-
controlled, have been employed for constructing the
acyclic structures which contain numerous stereogenic
centers.8 However, few precedents exist for the synthetic
approaches using catalyst and/or promoter-controlled
aldol reactions. When the stereochemistry of the catalyst
(promoter) controls the newly created stereocenter, in
preference to that of the substrate in the chiral catalyst
and/or promoter-controlled aldol reaction, the reaction
proves to be remarkably straightforward for achieving
enantioselective acyclic stereoselection.
With our continuing studies on the chiral oxazaboro-
lidinone-promoted asymmetric aldol reaction our aim was
to achieve substantial shortening of paths toward com-
plex targets by repeated aldol reactions. The methodology
is based on promoter control where enantiomerically pure
diastereomers can be provided by repeating the asym-
metric aldol reactions controlled by the stereochemistry
of the promoter.8 Thus, our goal is to construct the seco
acid 4 (Scheme 2) with a linear strategy using a series
of five aldol reactions at the carbon-carbon bonds
indicated with slanted lines in the seco acid derivative 6
of acutiphycin in Table 1. The key aldol reactions for this
very simple and straightforward synthesis are listed,
along with necessary reagents in the presence of a
stoichiometric amount of the promoters.
High ly E n a n t ioselect ive Syn t h esis of t h e C11-
C22 Su bu n it. The introduction of the first stereogenic
center into the acyclic system is very important because
the initial enantiomerical purity will affect the selectivity
of each of the subsequent reactions. As a result, an
especially high enantioselectivity is demanded for the
first reaction. In undertaking the construction of the (R)-
stereogenic center at C17 of the C11-C22 segment, the
reaction started with commercially available hexanal.
F igu r e 1.
acyclic stereoselection might evolve to highly efficient
levels provided that the enantioselective carbon-carbon
bond formation reactions proceed under complete pro-
moter (catalyst) control with no stereochemical effects
caused by substrates. During the development of the
chiral oxazaborolidinone (1 and 2)-promoted asymmetric
aldol reaction, we reported an interesting catalyst and/
or promoter control7 on reaction stereochemistry, in
which the newly stereogenic center is created by the
stereochemistry of the promoter and which is nearly
independent of the substrate aldehyde even in the
presence of an R-chiral center in the aldehyde.8 This
promoter control has proved to be remarkably straight-
forward for achieving enantioselective acyclic stereose-
lection.8
We report herein a highly enantioselective synthesis
of a seco acid derivative via shortened reaction paths with
(7) The term “Catalyst control” was first introduced by Mukaiya-
ma: (a) Kobayashi, S.; Ohtsubo, A.; Mukaiyama, T. Chem. Lett. 1991,
831-834. (b) Soai, K.; Shimada, C.; Takeuchi, M. Itabashi, M. J . Chem.
Soc., Chem. Commun. 1994, 567-568.
(8) (a) Kiyooka, S.-i.; Kira, H.; Hena, M. A. Tetrahedron Lett. 1996,
37, 2597-2600. (b) Kiyooka, S.-i.; Maeda, H. Tetrahedron: Asymmetry
1997, 8, 3371-3374. (c) Kiyooka, S.-i.; Maeda, H.; Hena, M. A.; Uchida,
M.; Kim, C.-S.; Horiike, M. Tetrahedron Lett. 1998, 39, 8287-8290.
(d) Hena, M. A.; Kim, C.-S.; Horiike, M.; Kiyooka, S.-i. Tetrahedron
Lett. 1999, 40, 1161-1164.
(9) Moore, R. E. Pure Appl. Chem. 1982, 54, 1919-1934.
(10) Barchi, J . J ., J r.; Moore, R. E.; Patterson, G. M. L. J . Am. Chem.
Soc. 1984, 106, 8193-8197.
(11) Smith, A. B., Chen, S. S.-Y.; Nelson, F. C.; Reichert, J . M.;
Salvatore, B. A. J . Am. Chem. Soc. 1995, 117, 12013-12014.
(12) Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041-2114.

Synthesis of the Antineoplastic Macrolide Acutiphycin
J . Org. Chem., Vol. 64, No. 15, 1999 5513
Sch em e 2. A Retr osyn th esis of Acu tip h ycin
Sch em e 3
Sch em e 4
Ta ble 1. A Lin ea r Str a tegy tow a r d th e Seco Acid 6 of
Acu tip h ycin on th e Ba sis of Ch ir a l Oxa za bor oli-
d in on e-P r om oted Asym m etr ic Ald ol Rea ction s
methylsilyl ether 14, followed by subsequent reduction
with DIBAL to directly give the corresponding aldehyde
15.
The olefinic bond between C14-C15 was introduced
via a Wittig reaction (Scheme 4) using (R-carbethoxyeth-
ylidene)triphenylphosphorane (16). The resulting olefin
17 showed a E/Z ratio of 200:1. The E/Z geometry was
identified by comparing the olefinic proton chemical shift
with the data available in the literature.15 The reduction
of the ester group of 17 with DIBAL gave the correspond-
ing aldehyde 18. To reduce the number of the reaction
steps, we used (R-formylethylidene)triphenylphosphorane
(19)16 to prepare the desired aldehyde 18 in one step. This
reaction also showed an excellent E/Z ratio.
a
At the beginning of this study we have considered that the
planned third aldol reaction proceeds with the sense of anti
selectivity.
Our previous results promised a high enantioselectivity
for the second chiral oxazaborolidinone-promoted aldol
reaction using a silyl ketene acetal derived from ethyl
isobutyrate.2a,b The reaction of olefinic aldehyde 18 with
silyl nucleophile 20 proceeded well in the presence of
chiral promoter 1 to give the TBS-acetal derivative 21
(the stereochemistry at the acetal carbon, however, was
unclear) in 70% yield (Scheme 5). The resulting acetal
21 was converted to the corresponding aldehyde 23 by
treatment with 80% AcOH. However, an attempt to
protect the hydroxy group of 23 with TBSCl, unfortu-
nately, failed. The protection of 21 was then carried out
by using TBSOTf and 2,6-lutidine in CH2Cl2 to give the
multiple TBS-protected compound 22. However, hydroly-
sis of the acetal group of 22 with 80% AcOH did not give
the desired products.
The (S)-oxazaborolidinone (1)-promoted aldol reaction
between a variety of aldehydes and dithiolane silyl ketene
acetal is known to provide the corresponding dithiolane
aldols with very high enantioselectivities.13 The necessity
of using a dithiolane aldol rests in the fact that the
reaction, without steric bulk at the R-position of the silyl
ketene acetal, provides low enantiometric acetate aldols
under conditions of the chiral oxazaborolidinone-promot-
ed aldol reaction.2a,b
The dithiolane substituent of the silyl ketene acetal 7,
derived from ethyl dithiolane-2-carboxylate, enhanced the
enantiometric purity of the aldol 13 up to >98% ee under
the conditions mentioned above. Treatment of 12 with a
large excess of nickel boride (prepared in situ from NiCl2
14
and NaBH4) for desulfurization, provided the acetate
aldol 13 (Scheme 3). The hydroxy group of 13 was
protected with TBSCl-imidazole to give tert-butyldi-
(15) (a) Semmelhack, M. F.; Tomesch, J . C.; Czarny, M.; Boettger,
S. J . Org. Chem. 1978, 43, 1259-1262. (b) Nagaoka, H.; Kishi, Y.
Tetrahedron 1981, 37, 3873-3888. (c) Still, W. C.; Gennari, C.
Tetrahedron Lett. 1983, 24, 4405-4408.
(16) (a) Schlessinger, R. H.; Pross, M. A.; Richardson, S.; Lin, P.
Tetrahedron Lett. 1985, 26, 2391-2394. (b) Trippet, S.; Walker, D. M.
J . Chem. Soc. 1961, 1266-1272.
(13) Kiyooka, S.-i.; Hena, M. A. Tetrahedron: Asymmetry 1996, 7,
2181-2184.
(14) Flippin, L. A.; Dombroski, M. A. Tetrahedron Lett. 1985, 26,
2977-2980.

5514 J . Org. Chem., Vol. 64, No. 15, 1999
Kiyooka and Hena
Sch em e 5
Sch em e 8
Sch em e 9
Sch em e 6
alcohol 29, which, after Swern oxidation, gave the desired
aldehyde 30. However, the third chiral oxazaborolidi-
none-promoted aldol reaction of 30 with silyl ketene
acetal 9 did not proceed, due presumably to steric
hindrance around the aldehyde function which restricted
the minimal approach required for coordination between
the aldehyde and the chiral oxazaborolidinone (Scheme
8). Thus it became obvious that a smaller protecting
group might lead to the expected result.
The subsequent direct reduction of â-trimethylsiloxy
ester 27 to the corresponding aldehyde 32 by DIBAL
under conditions at -78 °C proved to be more difficult
than anticipated because of steric factors. Ester 27 was
then reduced to alcohol 31, followed by Swern oxidation
to give the desired aldehyde 32 in good yield (Scheme
9).
Sch em e 7
Un exp ected Selectivity in th e Ald ol Rea ction
w ith P iva la ld eh yd e a s a Mod el of High ly Hin d er ed
Ald eh yd es. At the initial stage of our investigations we
believed that the chiral oxazaborolidinone-promoted aldol
reactions of the highly hindered aldehyde 32 with silyl
nucleophile 9 proceed according to the mode of selectivity
of anti preference on the basis of observations that follows
(Scheme 10). The asymmetric aldol reaction of isobu-
tyraldehyde with silyl nucleophile 9, which gives largely
the E-isomer (92%), resulted in a slight excess of anti
diastereoselectivity with relatively lower enantioselec-
tivity, compared with that of the minor syn isomer.2b In
addition, we observed that the aldol reaction of pivalal-
dehyde with silyl nucleophile 10 proceeds with extremely
high enantioselectivity (98% ee). On the basis of these
two results, we strongly expected that the aldol reaction
of pivalaldehyde with silyl nucleophile 35 (E/Z ) 85:15)
instead of 9 would preferentially give the anti isomer
with very high enantioselectivity. However, the reaction
with 9 did not proceed because of excess steric hindrance.
We then explored the aldol reaction of pivaldehyde with
35 as a model reaction of 32 with 35.
Thus, in the second chiral oxazaborolidinone-promoted
aldol reaction trimethylsily ketene acetal 8 was used
instead of tert-butyldimethylsilyl ketene acetal 20 to
construct the isobutyrate aldol 25. As expected, this
reaction proceeded smoothly to give the corresponding
aldol 25 as a single diastereomer in high yield (88%)
(Scheme 6). Protection of the hindered hydroxy group of
25 was carried out with three different reagents to give
methyl, trimethylsilyl, and tert-butyldimethylsilyl ethers
(26, 27, and 28), respectively (Scheme 7). The TBS-
protected ether 28 was treated with DIBAL in an usual
manner (-78 °C, 2 h, quenched at -78 °C), but instead
of giving the corresponding aldehyde remained largely
unchanged with only a small portion converted to the
corresponding alcohol. The protected aldol 28 was treated
with DIBAL for 2 h at -78 °C, allowed to warm to room
temperature, and quenched to give the corresponding
Very surprisingly, and contrary to our expectation, the
syn isomer was obtained as the major product (22:1) in
96% ee. The diastereochemistry of the products was

Synthesis of the Antineoplastic Macrolide Acutiphycin
J . Org. Chem., Vol. 64, No. 15, 1999 5515
Sch em e 10
Sch em e 11
F igu r e 2. The NOEs detected for syn-38 and anti-38.
assigned by a comparison of the acetonides, syn-38 and
anti-38,17 derived from syn-36 and anti-36, respectively.
The NOEs of these compounds also confirmed the struc-
tures (Figure 2). anti-38 was alternatively prepared via
anti aldol 40 by a known stereoselective procedure using
the enolate of 3918 (Scheme 11).
The result, which involved an unexpected switching
of diastereoselectivity along with very high enantiose-
lectivity in the reaction with pivaldehyde, was very
surprising. This unexpected switching of diastereoselec-
tivity observed in the reaction of the bulky aldehyde can
be explained on the basis of Corey’s hydrogen bond model
between the aldehyde hydrogen and the promoter borane-
ring oxygen5 that the reaction presumably proceeds
through A or C, shown in Figure 3 where B is destabi-
lized by gauche interactions between the methyl and tert-
butyl groups and between the tert-butyl and enol groups.18
In any event the validity of the aldol reaction with 35
was verified on introducing, in a syn-selective manner,
a methyl group into such a highly sterically hindered
skeleton in acyclic systems.
Con str u ction of th e Ster eocen ter a t C10. In the
presence of a stoichiometric amount of chiral borane 1,
aldehyde 32 smoothly underwent an aldol condensation
with 3 equiv of 35 at -78 °C for 24 h to give a mixture of
the aldols, 41-44, in 92% yield. An extended reaction
time (>20 h) is necessary in order to obtain acceptable
yields. The results are summarized in Scheme 12 and
Table 2. The stereochemistry of the products was as-
signed by a comparison of the observed J values indicat-
ing the relative stereochemistry between C2 and C3. In
F igu r e 3. Transition state assemblies to syn aldol.
this system, adjacent to a quaternary carbon, the cou-
pling constants of syn isomers are larger than those of
anti isomers, contrary to common cases,19 as shown in
Table 3. The NOE experiments of the acetonide 46
derived from 41 confirmed the stereochemistry (Scheme
13, Figure 4). The ratio of 41 + 43 to 42 + 44 corresponds
to the diastereofacial selectivity while each ratio of 41 to
43 and 42 to 44 corresponds to the enantiofacial selectiv-
ity in the reaction. High syn (10:1) predominance was
observed and each syn and anti product showed a
(17) Pirrung, M. C.; Heathcock, C. H. J . Org. Chem. 1980, 45, 1727-
1732.
(18) Gennari, C. Selectivities in Lewis Acid Promoted Reactions;
Schinzer, D., Ed.; Kluwer Academic Publishers: Dordrecht, 1988; pp
53-71.
(19) Mulzer, J .; Zippel, M.; Bru¨ntrup, G.; Segner, J .; Finke, J . Liebigs
Ann. Chem. 1980, 1108-1134.

5516 J . Org. Chem., Vol. 64, No. 15, 1999
Kiyooka and Hena
Sch em e 12
Sch em e 13
F igu r e 4. The NOEs detected for compund 46.
Sch em e 14
Ta ble 2. Ch ir a l Oxa za bor olid in on e-P r om oted Ald ol
Rea ction w ith Ald eh yd e 32
chiral borane yield (%) syn/antia synb 41/43 antib 42/44
1 (L-valine)
2 (D-valine)
92
54
10:1
4.5:1
12:1
4:1
10:1
1.5:1
a
The syn/anti ratio (41 + 43/42 + 44) is corresponding to the
diastereoselectivity of the reaction. b The each syn (41/43) and anti
(42/44) ratio is corresponding to the enantioselectivity of the
reaction.
Ta ble 3. Th e List of th e Ch a r a cter istic Vicin a l Cou p lin g
Con sta n ts (J 2,3) Rela ted to th e Rela tive Ster eoch em istr y
betw een C2 a n d C3 in th e System Ha vin g a Ter tia r y
Su bstitu en t a t C3
Ta ble 4. P r od u ct Ra tios Obser ved in th e BF 3-Ca ta lyzed
Ald ol Rea ction of 32 w ith 35 (Sch em e 14)
45:47:48:51 ) 1:1:1:1
2,3-syn/2,3-anti ) 1:1
3,5-syn/3,5-anti ) 1:1
a
The relative stereochemistry of C2 and C3 of 41 was confirmed
on the basis of NOE experiments of the acetonide derivative, which
was prepared from LAH reduction of 41 followed by acetonization.
configuration at C3 of the products in the reaction with
2, we carried out the reaction of 32 with 35 in the
presence of achiral Lewis acid, BF3‚OEt2. The BF3-
catalyzed reaction gave four products, 45, 47, 48, and 51,
as shown in Scheme 14. It was obvious that no substrate
control appears, relative to C2 and C3 (Table 4). Conse-
quently, the syn preference observed in the presence of
chiral promoter 2 cannot be ascribed to any type of
substrate control.
The enhanced syn selectivity in the presence of chiral
promoter 1 can be rationally explained by using Figure
5. The spatial orientation of the siloxy group at C3 is
presumably fixed by the introduction of two methyl
considerably high enantiofacial selectivity which can be
attributed to the inherent si-facial selectivity of the chiral
oxazaborolidinone 1. Promoter control apparently exists,
which is independent of the stereochemistry of the
substrate. However, when chiral borane 2, derived from
D-valine, was used, the yield was considerably lower
(54%). The stereochemical response was poor for each
diastereo- and enantioselevtivity; but a similar prepon-
derance was observed for the each selectivity, compared
with the reaction with 1. To explore the possibility that
substrate control operates as giving a preference to (S)-

Synthesis of the Antineoplastic Macrolide Acutiphycin
J . Org. Chem., Vol. 64, No. 15, 1999 5517
Sch em e 16
F igu r e 5. A transition state model explaining the unexpected
switch of diastereoselectivity.
Sch em e 17
Sch em e 15
groups at C2, which affect the conformation of the entire
aldehyde, and, when the chiral borane coordinates to the
aldehyde, an adequate fit between the stereocenters of
the catalyst and the substrate (at C3) might be achieved
to provide stereochemical outcome expected from pro-
moter control. An effective approach of the silyl nucleo-
phile may take place via a path, such as A for the case
of promoter control with 1 where an adequate space is
open to the nucleophile. On the other hand, the reaction
with 2 (from D-valine) diminished promoter control and
substrate control because of stereochemically unsuitable
interactions where the TMSO group and oxazaborolidi-
none moiety reversely locate relative to the face of the
five-membered ring involving the carbonyl group, shown
in B.
use it for this step because the desulfurization process
under a hydrogen atmosphere reduces the double bonds
in the acyclic subtrate 55. The reaction of 55 with
unsubstituted silyl nucleophile 10 in the presence of
chiral borane 1 proceeded smoothly to give aldol 56 in
84% yield with 85% de. Fortunately, the undesired isomer
was easily separated by flash column chromatography.
After TES protection, the last aldehyde 57 was prepared
via a two-step procedure (DIBAL reduction and Swern
oxidation) in good yield (Scheme 17).
The stereochemistry at C2 of the major product 41 was
opposite relative to that at C10 in acutiphycin. From the
standpoint of the total synthesis of acutiphycin, this is
not necessarily a serious disadvantage. After cyclization
to the macrolactone, epimerization at C10 would over-
come this problem.
We alternatively considered the epimerization at C10
related to the target molecule at this stage. When the
major isomer 46 from the aldol reaction was treated with
sodium ethoxide under thermodynamic conditions, the
expected isomer 52 was isolated in 33% yield along with
recovered 46 (Scheme 15).
En a n tioselective Bon d Exten sion to th e C1-C10
Su bu n it. The economic homologation of the aldehyde
moiety, which is accompanied by double bond formation,
was addressed in the next step. An effective reagent 54
for this purpose has been reported.20 The aldehyde 53,
directly obtained by the DIBAL reduction of 46, was
treated with the R-silyl imine 54 under LDA conditions
to give the R,â-unsaturated aldehyde 55 with very high
E geometry (16:1) in 74% yield (Scheme 16).
Provided that an acetoacetate unit can be enantiose-
lectively introduced by the fifth aldol reaction, the
synthesis of the linear seco acid of acutiphycin can now
be realized. Adequate reagents, such as silyl nucleophile
5821 and disilyl nucleophile 11,22 have been prepared.
Highly enantioselective chiral Lewis acid-catalyzed aldol
reactions using 58 have been reported by two groups,23
but the reagent 58 gave unacceptable results in our chiral
oxazaborolidinone-promoted aldol reaction, only 16% ee
of 59 for benzaldehyde, as shown in Scheme 18. The fifth
aldol reaction for the final stage was achieved using
disilyl nucleophile 11. The reaction of benzaldehyde in
the presence of chiral borane 1 gave aldol 60 in 72% yield
with 61% ee in a model reaction. After protection and
reduction, the fifth aldol reaction of 57 with disilyl
The next step is the introduction of an acetate aldol
unit by a fourth aldol reaction. Although the best reagent
for high enantioselectivity is generally considered to be
the dithiolane silyl nucleophile 7, we were not able to
(21) Grunwell, J . R.; Karipides, A.; Wigal, C. T.; Heinzman, S. W.;
Parlow, J .; Surso, J . A.; Clayton, L.; Fleitz, F. J .; Daffner, M.; Stevens,
J . E. J . Org. Chem. 1991, 56, 91-95.
(22) Yamamoto, K.; Suzuki, S.; Tsuji, J . Chem. Lett. 1978, 649-
652.
(20) (a) Corey, E. J .; Weigel, L. O.; Floyd, D.; Bock, M. G. J . Am.
Chem. Soc. 1978, 100, 2916-2918. (b) Corey, E. J .; Enders, D.; Bock,
M. G. Tetrahedron Lett. 1976, 7-10.
(23) (a) Sato, M. Sunami, S.; Sugita, Y.; Kaneko, C. Chem. Pham.
Bull. 1994, 42, 839-845. (b) Singer, R. A.; Carreira, E. M. J . Am. Chem.
Soc. 1995, 117, 12360-12361.

5518 J . Org. Chem., Vol. 64, No. 15, 1999
Kiyooka and Hena
from sodium/benzophenone immediately prior to use. Dichlo-
romethane, diisopropylamine, and triethylamine were distilled
from calcium hydride under a nitrogen atmosphere. Dimethyl
sulfoxide (DMSO), N,N-dimethylformamide (DMF), and 2,6-
lutidine were distilled from calcium hydride under reduced
pressure. Oxalyl chloride was distilled prior to use. All
reactions involving organometallic reagents were conducted
under an argon atmosphere. Infrared spectra are reported in
wavenumber (cm-1). All proton NMR spectra were measured
in CDCl3 solvent, and chemical shifts are reported as δ values
in parts per million relative to tetramethylsilane (δ 0.00) as
internal standard. Data are tabulated in the following order:
multiplicity, coupling constants in hertz, number of protons.
All carbon NMR spectra were measured in CDCl3 solvent, and
chemical shifts are reported as δ values in parts per million
relative to CDCl3 (δ 77.0) as internal standard.
Sch em e 18
1-Eth oxy-1-(tr im eth ylsiloxy)-2,2-(eth ylen ed ith io)eth -
en e (7). To a solution of diisopropylamine (0.77 mL, 5.5 mmol)
in dry THF (25 mL) at 0 °C was added n-BuLi (3.45 mL, 5.5
mmol, 1.6 M in hexane) dropwise. The solution was cooled to
-78 °C, and ethyl dithiolanecarboxylate (0.70 mL, 5.0 mmol)
was added dropwise over 30 min. After 25 min, chlorotri-
methylsilane (1.27 mL, 10 mmol) was added, and the solution
was allowed to warm to room temperature and stirred over-
night. After evaporation of the solvent in vacuo, the residue
was diluted with dry hexane and filtered through Celite. After
removal of the hexane in vacuo, the residual oil was distilled
(bp 108-109 °C/ 0.1 mmHg) to give the pure silyl nucleophile
7 as a yellow oil (937 mg, 75%). IR (film) 1655 cm-1; 1H NMR
(CDCl3, 90 MHz) δ (ppm) 3.82 (q, J ) 7.0 Hz, 2H), 3.21 (brs,
4H), 1.20 (t, J ) 7.0 Hz, 3H), 0.19 (s, 9H).
Sch em e 19
E t h yl (3R)-2,2-(E t h ylen ed it h io)-3-h yd r oxyoct a n oa t e
(12). To a solution of N-(p-toluenesulfonyl)-(S)-valine (298 mg,
1.1 mmol) in dry CH2Cl2 (3 mL) at 0 °C was added BH3‚THF
(1.0 mL, 1.0 mmol, 1 M in THF). The solution was allowed to
stir for 30 min at 0 °C and then additionally for 30 min at
room temperature. The solution was cooled to -78 °C, and
hexanal (100.1 mg, 1 mmol) in CH2Cl2 (1 mL) was added slowly
over 5 min. After stirring for 5 min, 7 (275 mg, 1.1 mmol) in
CH2Cl2 (1 mL) was added dropwise over 5 min, the reaction
mixture was stirred for 3 h, and a buffer solution (5 mL, pH
6.86) was added to quench the reaction. The reaction mixture
was allowed to warm to room temperature. After phases were
separated, the organic phase was diluted with ether, washed
with sat. aq NaHCO3 solution and brine, dried over MgSO4,
and evaporated in vacuo. Flash column chromatography (10%
ethyl acetate/hexane) provided the pure aldol 12 (180.9 mg,
65%, 98% ee, CHIRALCEL OD, 1.5% 2-propanol/hexane, 1.0
F igu r e 6. Each selectivity found in the reaction sequence.
nucleophile 11 in the presence of 2 permitted a straight-
forward synthesis of the C10-epi seco acid derivative 61
of acutiphycin with 83% de. The final compound 61 was
easily separated from the isomer by flash column chro-
matography (Scheme 19).
mL/min, Rf 20.5 min, λ 210 nm). [R]24 +10.0 (c 1.4, CHCl3).
D
IR (film) 3490, 1730 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm)
4.25 (q, J ) 7.0 Hz, 2H), 4.05 (d, J ) 9.7 Hz, 1H), 3.33-3.42
(m, 4H), 2.82 (brs, 1H), 1.33-1.67 (m, 8H), 1.32 (t, J ) 7.0
Hz, 3H), 0.88 (t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
δ (ppm) 171.8, 75.8, 75.5, 62.2, 39.9, 39.8, 34.0, 31.4, 26.1, 22.4,
13.9, 13.8. Anal. Calcd for C12H22O3S2: C, 51.76; H, 7.96.
Found: C, 51.70; H, 8.01.
Con clu sion
The synthesis of the (+)-acutiphycin seco acid deriva-
tive 5 having six stereogenic centers was achieved from
hexanal by a linear strategy using the chiral oxazaboro-
lidinone-promoted asymmetric aldol reaction in only 16
steps. The excellent to good enantioselectivities in the
five aldol reaction sequences and the high E selection in
the two olefination steps were obtained, as shown in
Figure 6. On the route to the synthesis of 61 no special
separation of isomers was required, presumably because
of the high purity of each reaction product. Such high
selective reactions allow for the shortening of the path-
way to this complex target. It is clear that the chiral
oxazaborolidinone-promoted asymmetric aldol reaction is
practical for the construction of the carbon backbones
having multichiral centers with enantioselective acyclic
stereoselection.
Eth yl (3R)-3-Hyd r oxyocta n oa te (13). To a solution of 12
(1.1 g, 4.0 mmol) in ethanol (40 mL) was mixed anhydrous
NiCl2 (25.9 g, 0.2 mol), and the mixture was kept under H2
pressure. Then the mixture was cooled to -10 °C, and NaBH4
(3.8 g, 0.1 mol) was added in portions while the mixture was
stirred vigorously with a mechanical stirrer. The same tem-
perature was maintained until the evolution of gas was ceased.
The resulting black mixture was allowed to warm to room
temperature and stirred vigorously for 16 h. The reaction
mixture was filtered, and the solvent ethanol was removed in
vacuo. The concentrated residue was diluted with ether,
washed with water, and dried over MgSO4. After evaporation
of the ether, the crude material was purified by flash column
chromatography to give acetate aldol 13 (640 mg, 85%, 98%
ee, CHIRALCEL OD, 5% 2-propanol/hexane, 0.5 mL/min, Rf
Exp er im en ta l Section
11.9 min, λ 210 nm) as a colorless oil. [R]24 -22.0 (c 1.0,
D
Gen er a l. Unless otherwise noted, materials were obtained
from commercial suppliers and were used without further
purification. Ether and tetrahydrofuran (THF) were distilled
CHCl3); IR (film) 3485, 1728 cm-1; 1H NMR (CDCl3, 400 MHz)
δ (ppm) 4.17 (q, J ) 7.0 Hz, 2H), 3.97-4.12 (m, 1H), 3.05 (brs,
1H), 2.49 (dd, J ) 16.3, 3.4 Hz, 1H), 2.39 (dd, J ) 16.3, 9.0

Synthesis of the Antineoplastic Macrolide Acutiphycin
J . Org. Chem., Vol. 64, No. 15, 1999 5519
Hz, 1H), 1.27 (t, J ) 7.0 Hz, 3H), 1.25-1.54 (m, 8H), 0.89 (t,
J ) 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 172.9,
67.9, 60.5, 41.3, 36.4, 31.6, 25.0, 22.5, 14.1, 13.9. Anal. Calcd
for C10H20O3: C, 63.80; H, 10.71. Found: C, 63.82; H, 10.68.
Eth yl (3R)-3-(ter t-Bu tyld im eth ylsiloxy)octa n oa te (14).
To a solution of imidazole (0.82 g, 12.0 mmol) in DMF (5 mL)
was added TBSCl (0.91 g, 6.0 mmol) in DMF (2 mL) over 2.5
min. The solution was stirred at room temperature for 10 min.
A solution of 13 (0.75 g, 4.0 mmol) in DMF (1 mL) was
introduced dropwise, and the solution was allowed to stir
overnight. The reaction mixture was poured into ice-water,
extracted with ether, washed with sat. aq NH4Cl solution and
brine, and dried over anhydrous MgSO4. After evaporation of
the solvent, the crude residue was purified by flash column
chromatography (2.5% ethyl acetate/hexane) to give TBS ether
NMR (CDCl3, 100 MHz) δ (ppm) 194.9, 151.1, 140.2, 71.1, 37.3,
36.6, 31.8, 25.7, 24.9, 22.5, 17.9, 13.8, 9.3, -4.6. Anal. Calcd
for C17H34O2Si: C, 68.39; H, 11.48. Found: C, 68.26; H, 11.51.
Aldehyde 18 was also obtained from 17, employing a DIBAL
reduction procedure similar to that for aldehyde 15. 17 (342
mg, 1 mmol) and DIBAL (1.2 mL, 1.2 mmol, 1 M in toluene)
in CH2Cl2 (10 mL) at -78 °C for 2 h afforded aldehyde 18 (256
mg, 89%) after flash column chromatography (1% ethyl
acetate/hexane) as a colorless oil.
(r-F or m yleth ylid en e)tr ip h en ylp h osp h or a n e (19). n-
Butyllithium (6.9 mL, 11.0 mmol, 1.6 M in toluene) was added
dropwise to a stirred suspension of ethyltriphenylphosphonium
iodide (10.0 mmol) in THF (33 mL) at 22 °C under a nitrogen
atmosphere. The resulting red solution was stirred for 1 h and
then cooled to 0 °C. Freshly sublimed potassium tert-butoxide
(1.24 g, 11.0 mmol) was added followed by a rapid addition of
ethyl formate (2.02 mL, 25 mmol). The buff-colored reaction
mixture was kept at 0 °C for 15 min and then quenched with
1 M HCl (12.5 mL). Dichloromethane (75 mL) was added to
the reaction mixture and the pH of the aqueous layer adjusted
to pH 8 by adding 10% NaOH (aq) solution, followed by stirring
at 0 °C for 0.5 h. The aqueous layer was separated and
extracted further with CH2Cl2 (50 mL). The combined organic
extracts were dried and evaporated in vacuo to give an oil that
was crystallized from CH2Cl2/Et2O to afford a white solid (84%,
mp 180-182 °C). Recrystallization from benzene/hexane af-
forded a material (overall 78%, mp 213-217 °C). 1H NMR
(CDCl3, 400 MHz) δ (ppm) 8.04 (d, J ) 2.4 Hz, 1H), 7.50-7.71
(m, 15H), 1.88 (dd, J ) 13.6, 2.4 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ (ppm) 178.9, 178.7, 133.7, 133.6, 132.7, 132.5,
129.0, 128.9, 124.5, 123.6, 10.6.
14 (1.10 g, 90%) as a colorless oil. [R]24 -15.0 (c 1.2, CHCl3);
D
IR (film) 1739 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm) 4.11
(q, J ) 7.0 Hz, 2H), 4.07 (m, 1H), 2.38 (dd, J ) 14.6, 7.1 Hz,
1H), 2.33 (dd, J ) 14.6, 5.9 Hz, 1H), 1.25 (t, J ) 7.0 Hz, 3H),
1.21-1.44 (m, 8H), 0.89 (t, J ) 6.8 Hz, 3H), 0.86 (s, 9H), 0.06
(s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 171.8,
69.4, 60.1, 42.6, 37.5, 31.8, 25.7, 24.5, 22.5, 17.9, 14.1, 13.9,
-4.5, -4.8. Anal. Calcd for C16H34O3Si: C, 63.52; H, 11.33.
Found: C, 63.47; H, 11.41.
(3R)-3-(ter t-Bu tyldim eth ylsiloxy)octan al (15). To a cooled
(-78 °C) solution of ester 14 (302 mg, 1.0 mmol) in CH2Cl2 (5
mL) was added DIBAL (1.2 mL, 1.2 mmol, 1 M in toluene)
over a period of 30 min, the reaction mixture was allowed to
stir at -78 °C for 2 h, and MeOH was added to quench the
reaction. After 15 min water (2 mL) was added, the resulting
mixture was then allowed to warm to room temperature and
stirred vigorously to form a precipitate. Workup procedures
were carried out with filtration of precipitate, separation of
phases, washing with water and brine, drying over MgSO4,
and evaporation of the solvent. Purification of the residue by
flash column chromatography (2.5% ethyl acetate/hexane)
(4E,3R,7R)-1,7-Bis(ter t-bu tyld im eth ylsiloxy)-1-eth oxy-
3-h yd r oxy-2,2,4-tr im eth yld od ec-4-en e (21). The aldol con-
densation procedure described for the preparation of aldol 12
was employed with aldehyde 18 (298 mg, 1 mmol), 20 (253
mg, 1.1 mmol), BH3‚THF (1.0 mL, 1.0 mmol, 1 M in THF),
N-(p-toluenesulfonyl)-(S)-valine (298 mg, 1.1 mmol), and CH2-
Cl2 (5 mL) at -78 °C for 3 h to give 21 (371 mg, 70%) after
flash column chromatography (1% ethyl acetate/hexane) as a
provided aldehyde 15 (219 mg, 85%) as a colorless oil. [R]24
D
-5.0 (c 1.0, CHCl3); IR (film) 1728 cm-1; 1H NMR (CDCl3, 400
MHz) δ (ppm) 9.75 (t, J ) 2.4 Hz, 1H). 4.13 (quin, J ) 5.8 Hz,
1H), 2.45 (dd, J ) 5.6, 2.4 Hz, 2H), 1.22-1.51(m, 8H), 0.85 (t,
J ) 6.8 Hz, 3H), 0.84 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ (ppm) 202.4, 68.2, 50.7, 37.7, 31.7,
25.6, 24.7, 22.5, 17.9, 13.9, -4.5, -4.7. Anal. Calcd for
colorless oil. [R]23 +25.0 (c 1.0, CHCl3); IR (film) 3516 cm-1
;
D
1H NMR (CDCl3, 90 MHz) δ (ppm) 5.32 (t, J ) 7.0 Hz, 1H)
4.50 (s, 1H), 4.32 (s, 1H), 3.84 (q, J ) 7.0 Hz, 2H), 3.35 (quin,
J ) 5.8 Hz, 1H), 2.16 (t, J ) 6.1 Hz, 2H), 1.89 (brs, 1H), 1.60
(s, 3H), 1.20-1.45 (m, 8H), 1.25 (t, J ) 7.0 Hz, 3H), 1.09 (s,
3H), 0.89 (s, 9H), 0.87 (t, J ) 6.5 Hz, 3H), 0.84 (s, 9H), 0.72 (s,
3H), 0.08 (s, 3H), 0.06 (s, 3H), 0.01 (s, 6H).
C
14H30O2Si: C, 65.06; H, 11.70. Found: C, 65.12; H, 11.78.
Eth yl (2E,5R)-5-(ter t-Bu tyld im eth ylsiloxy)-2-m eth yl-
d ec-2-en oa te (17). A mixture of aldehyde (258 mg, 1.00 mmol)
and (R-carbethoxyethylidene)triphenylphosphorane (402 mg,
1.1 mmol) in dry benzene (10 mL) was heated at 60-65 °C
under a nitrogen atmosphere with stirring. After 3 h the
solution was cooled to room temperature and evaporated to
dryness, and ether (10 mL) was mixed. The precipitate was
removed by filtration and evaporation of the filtrate gave a
(4E,3R,7R)-1,3,7-Tr is(ter t-bu tyldim eth ylsiloxy)-1-eth oxy-
2,2,4-tr im eth yld od ec-4-en e (22). Employing a similar pro-
cedure described for the preparation of TMS ether 27 with a
change in reaction time (7 h), alcohol 21 (531 mg, 1 mmol),
2,6-lutidine (0.44 mL, 3.8 mmol), TBSOTf (0.41 mL, 1.8 mmol),
and CH2Cl2 (5 mL) afforded TBS ether 22 (613 mg, 95%) after
flash column chromatography (1% ethyl acetate/hexane) as a
1
crude product (E:Z, 200:1; H NMR). The crude was purified
1
by flash chromatography (10% ethyl acetate/hexane) to give
(E)-olefin 17 (291 mg, 85%) as a colorless oil. 1H NMR (CDCl3,
90 MHz) δ (ppm) 6.76 (t, J ) 6.6 Hz, 1H) 4.14 (q, J ) 7.0 Hz,
2H), 3.64-3.72 (m, 1H), 2.26 (t, J ) 6.6 Hz, 2H), 1.79 (s, 3H),
1.24 (t, J ) 7.0 Hz, 3H), 1.20-1.39 (m, 8H), 0.84 (brs, 12H),
0.01 (s, 6H). Anal. Calcd for C19H38O3Si: C, 66.61; H, 11.18.
Found: C, 66.73; H, 11.23.
colorless oil. H NMR (CDCl3, 90 MHz) δ 5.34 (t, J ) 7.0 Hz,
1H), 4.57 (s, 1H), 4.13 (s, 1H), 3.68 (q, J ) 7.0 Hz, 2H), 3.28
(quin, J ) 5.8 Hz, 1H), 2.15 (t, J ) 6.8 Hz, 2H), 1.57 (s, 3H),
1.22-1.45 (m, 8H), 1.17 (t, J ) 7.0 Hz, 3H), 1.04 (s, 3H), 0.88
(s, 27H), 0.87 (t, J ) 6.8 Hz, 3H), 0.69 (s, 3H), 0.05 (brs, 18H).
E t h yl (4E,3R,7R)-7-(ter t-Bu t yld im et h ylsiloxy)-3-h y-
d r oxy-2,2,4-tr im eth yld od ec-4-en oa te (25). The aldol con-
densation procedure described for aldol 12 was employed using
aldehyde 18 (298 mg, 1.0 mmol), 8 (207 mg, 1.1 mmol), BH3‚
THF (1.0 mL, 1.0 mmol, 1 M in THF), N-(p-toluenesulfonyl)-
(S)-valine (298 mg, 1.1 mmol), and CH2Cl2 (5 mL) at -78 °C
for 3 h to give aldol 25 (282 mg, 68%, ∼100% de; 1H NMR)
after flash column chromatography (5% ethyl acetate/hexane)
(2E,5R)-5-(ter t-Bu t yld im et h ylsiloxy)-2-m et h yld ec-2-
en a l (18). A mixture of aldehyde 15 (258 mg, 1.00 mmol) and
(R-formylethylidene)triphenylphosphorane (350 mg, 1.1 mmol)
in dry benzene (15 mL) was refluxed under
a nitrogen
atmosphere with stirring for 18 h. The solution was then
allowed to cool to room temperature, the benzene was removed
in vacuo, and the concentrated material was diluted with ether
(10 mL). The solid was removed by filtration, and evaporation
as a colorless oil. [R]24 +12.0 (c 1.0, CHCl3); IR (film) 3442,
D
1728 cm-1; H NMR (CDCl3, 400 MHz) δ (ppm) 5.40 (t, J )
1
1
of the filtrate gave a crude product (E:Z, 99:1; H NMR). The
7.0 Hz, 1H), 4.16 (dq, J ) 7.0, 1.2 Hz, 2H), 4.05 (d, J ) 6.0 Hz,
1H), 3.69 (quin, J ) 6.3 Hz, 1H), 3.22 (d, J ) 6.0 Hz, 1H), 2.18
(brt, J ) 6.8 Hz, 2H), 1.57 (s, 3H), 1.28 (t, J ) 7.0 Hz, 3H),
1.22 (s, 3H), 1.19-1.40 (m, 8H), 1.12 (s, 3H), 0.88 (s, 9H), 0.87
(t, J ) 6.5 Hz, 3H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ (ppm) 177.9, 135.3, 126.0, 83.0, 71.9, 60.7, 46.1,
36.6, 35.6, 31.9, 25.8, 25.0, 24.1, 22.5, 20.9, 18.0, 13.9, 13.0,
crude was purified by flash chromatography to give (E)-olefin
18 (268 mg, 90%) as a colorless oil. [R]23D +14.0 (c 1.5, CHCl3).
IR (film) 1698 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm) 9.35
(s, 1H). 6.55 (t, J ) 7.3 Hz, 1H), 3.81 (quin, J ) 5.8 Hz, 1H),
2.48 (t, J ) 6.8 Hz, 2H), 1.72 (s, 3H), 1.17-1.45 (m, 8H), 0.86
(s, 9H), 0.84 (t, J ) 6.5 Hz, 3H), 0.03 (s, 3H), 0.01 (s, 3H); 13
C

5520 J . Org. Chem., Vol. 64, No. 15, 1999
Kiyooka and Hena
-4.4, -4.6. Anal. Calcd for C23H46O4Si: C, 66.61; H, 11.18.
Found: C, 66.53; H, 11.09.
1H NMR (CDCl3, 90 MHz) δ (ppm) 5.38 (t, J ) 6.8 Hz, 1H),
3.92 (s, 1H), 3.63-3.67 (m, 1H), 3.46 (dd, J ) 34.0, 10.7 Hz,
2H), 2.95 (brs, 1H), 2.35 (t, J ) 6.6 Hz, 2H), 1.62 (s, 3H), 1.20-
1.50 (m, 8H), 1.03 (s, 3H), 0.93 (t, J ) 6.6 Hz, 3H), 0.92 (s,
18H), 0.69 (s, 3H), 0.05 (s, 12H); 13C NMR (CDCl3, 22.5 MHz):
δ (ppm) 136.6, 125.2, 86.5, 78.4, 71.0, 39.7, 36.6, 35.5, 32.0,
25.9, 25.2, 23.5, 22.6, 22.2, 18.1, 14.0, -4.3, -4.5, -4.6, -5.3.
Anal. Calcd for C27H58O3Si2: C, 66.60; H, 12.01. Found: C,
66.58; H, 12.04.
Eth yl (4E,3R,7R)-7-(ter t-Bu tyld im eth ylsiloxy)-3-m eth -
oxy-2,2,4-tr im eth yld od ec-4-en oa te (26). To a stirred solu-
tion of alcohol 25 (414 mg, 1 mmol) in DMF (5 mL) at room
temperature was added MeI (0.19 mL, 3 mmol). Silver(I) oxide
(463 mg, 2.0 mmol) was added to the reaction mixture in
portions over a period of 1.5 h. After stirring the mixture
overnight at room temperature, CH2Cl2 (20 mL) was poured
into the mixture which was concentrated in vacuo. The
resulting residue was diluted with ether and washed with
water and brine. After drying over MgSO4, the solvent was
evaporated to a crude resedue. The crude was purified by flash
chromatography (2% ethyl acetate/hexane) to give ether 26
(4E,3R,7R)-3,7-Bis(ter t-bu tyld im eth ylsiloxy)-2,2,4-tr i-
m eth yld od ec-4-en a l (30). To a stirred and cooled (-78 °C)
solution of (COCl)2 (0.13 mL, 1.5 mmol) in CH2Cl2 (10 mL)
was added DMSO (0.14 mL, 2 mmol). After 10 min, 29 (487
mg, 1 mmol) in dry CH2Cl2 (3 mL) was added. The mixture
was stirred for 20 min and Et3N (0.42 mL, 3.0 mmol) was
added. The temperature of the mixture was allowed to rise to
0 °C. After stirring for an additional 30 min, a mixture of water
(0.5 mL), ether (10 mL), and benzene (2.5 mL) was added. The
organic phase was separated, washed with water and brine,
dried over MgSO4, and evaporated in vacuo. Flash chroma-
tography of the crude residue (1% ethyl acetate/hexane) gave
30 (461 mg, 95%) as a pure colorless oil. IR (film) 2710, 1726
(205 mg, 48%) as a colorless oil. [R]24 +30.0 (c 1.0, CHCl3);
D
IR (film) 1736 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm) 5.44
(t, J ) 7.0 Hz, 1H), 4.13 (ddq, J ) 30.4, 10.8, 7.0 Hz, 2H), 3.77
(s, 1H), 3.72 (quin, J ) 6.0 Hz, 1H), 3.16 (s, 3H), 2.24 (dt, J )
6.6, 6.4 Hz, 2H), 1.58 (s, 3H), 1.26 (t, J ) 7.0 Hz, 3H), 1.23-
1.45 (m, 8H), 1.14 (s, 3H), 1.06 (s, 3H), 0.88 (s, 9H), 0.87 (t, J
) 6.6 Hz, 3H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ (ppm) 176.8, 132.7, 127.8, 90.9, 71.9, 60.2, 56.7, 47.6,
36.6, 35.8, 31.9, 25.8, 25.0, 23.0, 22.6, 20.1, 18.1, 14.2, 14.0,
13.5, -4.3, -4.5. Anal. Calcd for C24H48O4Si: C, 67.24; H,
11.28. Found: C, 67.27; H, 11.26.
1
cm-1; H NMR (CDCl3, 90 MHz) δ (ppm) 9.66 (s,1H), 5.37 (t,
J ) 6.8 Hz, 1H), 4.09 (s, 1H), 3.68 (quin, J ) 5.0 Hz, 1H), 2.15
(t, J ) 6.8 Hz, 2H), 1.52 (s, 3H), 1.20-1.48 (m, 8H), 0.98 (s,
3H), 0.96 (s, 3H), 0.87 (t, J ) 6.8 Hz, 3H), 0.86 (s, 18H), 0.03
(s, 12H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 206.3. 135.7,
125.9, 83.8, 71.8, 51.0, 36.7, 35.5, 32.0, 25.9, 25.8, 25.2, 22.7,
20.6, 18.1, 14.0, 13.4, -4.2, -4.4, -4.6, -5.3.
Eth yl (4E,3R,7R)-7-(ter t-Bu tyld im eth ylsiloxy)-2,2,4-tr i-
m eth yl-3-(tr im eth ylsiloxy)d od ec-4-en oa te (27). To a solu-
tion of alcohol 25 (414 mg, 1 mmol) and 2,6-lutidine (0.44 mL,
3.8 mmol) in CH2Cl2 (5 mL) was added TMSOTf (0.33 mL, 1.8
mmol). The mixture was stirred at room temperature for 20
min. Water (1 mL) was added to quench the reaction. The
solution was extracted with ether, dried over MgSO4, and
evaporated in vacuo. The crude was purified by flash column
chromatography (2% ethyl acetate/hexane) to give ether 27
(4E,3R,7R)-7-(ter t-Bu tyldim eth ylsiloxy)-2,2,4-tr im eth yl-
3-(tr im eth ylsiloxy)d od ec-4-en ol (31). Using a procedure
similar to that for the preparation of alcohol 29, ester 27 (486.8
mg, 1 mmol), DIBAL (3.0 mL, 3.0 mmol, 1 M in toluene), and
CH2Cl2 (5 mL) gave alcohol 31 (391.4 mg, 88%) after flash
column chromatography (10% ethyl acetate/hexane) as a
(477 mg, 98%) as a colorless oil. [R]24 +21.0 (c 1.0, CHCl3);
D
IR (film) 1736 cm-1 ; 1H NMR (CDCl3, 400 MHz) δ (ppm) 5.38
(t, J ) 7.0 Hz, 1H), 4.29 (s, 1H), 4.08 (ddq, J ) 25.1, 10.7, 7.0
Hz, 2H), 3.69 (quin, J ) 6.0 Hz, 1H), 2.17 (m, 2H), 1.57 (s,
3H), 1.25 (t, J ) 7.0 Hz, 3H), 1.22-1.40 (m, 8H), 1.12 (s, 3H),
1.03 (s, 3H), 0.89 (s, 9H), 0.88 (t, J ) 6.5 Hz, 3H), 0.07 (s, 3H),
0.05 (s, 3H), 0.03 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ (ppm)
177.1, 136.1, 125.3, 82.3, 72.0, 60.3, 48.8, 36.4, 35.8, 32.0, 25.9,
25.3, 22.7, 22.1, 20.8, 18.2, 14.2, 14.1, 13.9, 0.0, -4.2, -4.4.
Anal. Calcd for C26H54O4Si2: C, 64.14; H, 11.18. Found: C,
64.03; H, 11.22.
colorless oil. [R]24 +23.0 (c 0.3, CHCl3); IR (film) 3422 cm-1
;
D
1H NMR (CDCl3, 400 MHz) δ (ppm) 5.36 (t, J ) 7.0 Hz, 1H),
3.89 (s, 1H), 3.70 (quin, J ) 5.6 Hz, 1H), 3.59 (dd, J ) 10.2,
3.6 Hz, 1H), 3.33 (dd, J ) 6.6, 3.6 Hz, 1H),), 3.28 (dd, J )
10.2, 6.6 Hz, 1H), 2.19 (t, J ) 6.3 Hz, 2H), 1.65 (s, 3H), 1.20-
1.38 (m, 8H), 0.97 (s, 3H), 0.88 (s, 9H), 0.87 (t, J ) 5.1 Hz,
3H), 0.76 (s, 3H), 0.08 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C
NMR (CDCl3, 100 MHz): δ (ppm) 136.6, 125.4, 87.1, 72.0, 71.8,
39.4, 36.7, 35.7, 32.1, 26.0, 25.3, 23.8, 22.7, 21.8, 18.2, 14.1,
13.9, 0.0, -4.2, -4.4. Anal. Calcd for C24H52O3Si2: C, 64.80;
H, 11.78. Found: C, 64.89; H, 11.85.
E t h yl (4E,3R,7R)-3,7-Bis(ter t-b u t yld im et h ylsiloxy)-
2,2,4-tr im eth yld od ec-4-en oa te (28). Employing a similar
procedure to that for the preparation of TMS ether 27 with
the exception in reaction time (7 h), alcohol 25 (414 mg, 1
mmol), TBSOTf (0.41 mL, 1.8 mmol), and 2,6-lutidine (0.44
mL, 3.8 mmol) in CH2Cl2 (5 mL) afforded TBS ether 28 (501
mg, 95%) after flash column chromatography (1% ethyl
(4E,3R,7R)-7-(ter t-Bu tyldim eth ylsiloxy)-2,2,4-tr im eth yl-
3-(tr im eth ylsiloxy)d od ec-4-en a l (32). Employing the oxida-
tion procedure described for the preparation of aldehyde 30,
alcohol 31 (445 mg, 1.0 mmol), (COCl)2 (0.13 mL, 1.5 mmol),
DMSO (0.14 mL, 2.0 mmol), Et3N (0.42 mL, 3.0 mmol), and
CH2Cl2 (10 mL) gave aldehyde 32 (354 mg, 80%), after flash
column chromatography (2.5% ethyl acetate/hexane), as a
acetate/hexane) as a colorless oil. IR (film): 1736 cm-1 1H
.
NMR (CDCl3, 90 MHz) δ (ppm) 5.35 (t, J ) 7.0 Hz, 1H), 4.25
(s, 1H), 4.06 (q, J ) 7.0 Hz, 2H), 3.63-3.65 (m, 1H), 2.11 (t, J
) 6.8 Hz, 2H), 1.55 (s, 3H), 1.22 (t, J ) 7.0 Hz, 3H), 1.18-
1.40 (m, 8H), 1.02 (s, 3H), 0.98 (s, 3H), 0.83 (t, J ) 6.8 Hz,
3H), 0.82 (s, 18H), 0.01 (s, 12H); 13C NMR (CDCl3, 22.5 MHz)
δ (ppm) 176.7, 136.0, 125.5, 82.4, 71.9, 60.2, 48.8, 36.6, 35.7,
35.5, 32.0, 25.9, 25.8, 25.2, 22.7, 22.3, 21.1, 18.1, 14.1, 14.0,
13.9, -4.2, -4.5, -4.8, -5.4.
colorless oil. [R]24 +19.4 (c 1.0, CHCl3); IR (film) 1710 cm-1
;
D
1H NMR (CDCl3, 400 MHz) δ (ppm) 9.67 (s, 1H), 5.39 (t, J )
7.0 Hz, 1H), 4.07 (s, 1H), 3.69 (quin, J ) 5.6 Hz, 1H), 2.17 (t,
J ) 6.2 Hz, 2H), 1.54 (s, 3H), 1.20-1.41 (m, 8H), 1.00 (s, 3H),
0.97 (s, 3H), 0.89 (s, 9H), 0.87 (t, J ) 7.0 Hz, 3H), 0.07 (s, 9H),
0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ (ppm)
206.9, 135.8, 125.7, 83.6, 71.9, 50.9, 36.4, 35.6, 32.0, 31.9, 25.9,
25.2, 22.7, 20.5, 18.1, 18.0, 14.1, 13.3, 0.0, -4.2, -4.4. Anal.
Calcd for C24H50O3Si2: C, 65.10; H, 11.38. Found: C, 64.97;
H, 11.42.
(4E,3R,7R)-3,7-bis(ter t-Bu tyld im eth ylsiloxy)-2,2,4-tr i-
m eth yld od ec-4-en ol (29). To a stirred (-78 °C) solution of
ester 28 (528 mg, 1 mmol) in CH2Cl2 (10 mL) was added
DIBAL (3.0 mL, 3.0 mmol, 1M in toluene) over a period of 30
min. After stirring for 2 h at the same temperature, the
solution was allowed to warm to room temperature and stirred
additionally for 2 h. Methanol (2.0 mL) was added to the
reaction mixture at room temperature, after 15 min water (2
mL) was added, and the resulting solution was stirred vigor-
ously until a precipitate was formed. The precipitate was
filtered off, and layers were separated. The organic phase was
dried over MgSO4, and evaporated. The crude material was
purified by column chromatography (10% ethyl acetate/hexane)
P h en yl (3S)-3-Hyd r oxy-4,4-d im eth ylp en ta n oa te (34).
The aldol condensation procedure described for the preparation
of aldol 12 was employed with pivalaldehyde (258 mg, 3 mmol),
10 (687 mg, 3.3 mmol), BH3‚THF (3.0 mL, 3.0 mmol, 1 M in
THF), N-(p-toluenesulfonyl)-(S)-valine (298 mg, 1.1 mmol), and
CH2Cl2 (15 mL) at -78 °C for 3 h to give acetate aldol 34 (500
mg, 75%, 98% ee, CHIRALCEL OD, 1% 2-propanol/hexane,
0.5 mL/min, Rf 22.2 min, λ 254 nm), after flash column
chromatography (10% ethyl acetate/hexane), as a colorless oil.
[R]24D -36.0 (c 1.0, CHCl3); IR (film) 3489, 1751 cm-1; 1H NMR
(CDCl3, 400 MHz) δ (ppm) 6.85-7.25 (m, 5H), 3.69 (brd, J )
10.4 Hz, 1H), 2.64 (dd, J ) 16.3, 2.2 Hz, 1H), 2.57 (brs, 1H),
to give 29 (443 mg, 91%) as a colorless oil. IR (film) 3445 cm-1
;

Synthesis of the Antineoplastic Macrolide Acutiphycin
J . Org. Chem., Vol. 64, No. 15, 1999 5521
2.48 (dd, J ) 16.3, 10.7 Hz, 1H), 0.82 (s, 9H); 13C NMR (CDCl3,
100 MHz) δ (ppm) 172.3, 150.4, 129.4, 125.9, 121.4, 75.5, 36.8,
34.4, 25.5. Anal. Calcd for C13H18O3: C, 70.24; H, 8.16.
Found: C, 70.31; H, 8.10.
3.99 (s, 1H), 3.93 (dd, J ) 6.6, 1.7 Hz, 1H), 3.71 (d, J ) 1.7
Hz, 1H), 3.70 (quin, J ) 5.5 Hz, 1H), 2.65 (dq, J ) 7.0, 6.6 Hz,
1H), 2.18 (brt, J ) 6.8 Hz, 2H), 1.59 (s, 3H), 1.25 (t, J ) 7.0
Hz, 3H), 1.23 (d, J ) 7.0 Hz, 3H), 1.22-1.41 (m, 8H), 0.92 (s,
3H), 0.89 (s, 9H), 0.88 (t, J ) 7.0 Hz, 3H), 0.70 (s, 3H), 0.10 (s,
9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
(ppm) 176.7, 136.3, 126.3, 87.5, 77.7, 71.8, 60.2, 43.0, 41.6, 36.7,
35.6, 32.0, 25.9, 25.2, 22.6, 21.5, 18.1, 16.9, 14.1, 14.0, 13.8,
0.0, -4.3, -4.5. Anal. Calcd for C29H60O5Si2: C, 63.92; H, 11.10.
1-Eth oxy-1-(tr im eth ylsiloxy)p r op -1-en e (35). Using a
similar procedure to that described for the preparation of silyl
ketene acetal 7, ethyl propionate (1.4 mL, 10.0 mmol), lithium
diisopropylamide (11.0 mmol), TMSCl (3.2 mL, 25.0 mmol),
and THF (15 mL) at -78 °C gave silyl ketene acetal 35 (1.48
g, 75%, E:Z, 24:1) on bulb to bulb distillation (bp 60-61 °C/20
mmHg) as a colorless oil. IR (film) 1658 cm-1; 1H NMR (CDCl3,
400 MHz) δ 3.82 (q, J ) 7.0 Hz, 2H), 3.72 (q, J ) 6.6 Hz, 1H),
1.49 (d, J ) 6.6 Hz, 3H), 1.21 (t, J ) 7.0 Hz, 3H), 0.2 1 (s, 9H).
Eth yl (2S,3S)-3-Hydr oxy-2,4,4-tr im eth ylpen tan oate (syn -
36) a n d E t h yl (2R,3S)-3-H yd r oxy-2,4,4-t r im et h ylp en -
ta n oa te (a n ti-36). Using the aldol condensation procedure
identical to that described for aldol 12, pivalaldehyde (258 mg,
3.0 mmol), 35 (575 mg, 3.3 mmol), BH3‚THF (3.0 mL, 3.0 mmol,
1 M in THF), N-(p-toluenesulfonyl)-(S)-valine (0.90 g, 3.3
mmol), and CH2Cl2 (5 mL) at -78 °C for 3 h afforded acetate
aldol anti-36 (17 mg, 3%, 96% ee, CHIRALPAC AD, 2%
2-propanol/hexane, 0.5 mL/min, Rf 23.5 min, λ 210 nm) and
syn-36 (367 mg, 65%, 96% ee, CHIRALPAC AD, 2% 2-propanol/
hexane, 0.5 mL/min, Rf 22.2 min, λ 210 nm) after flash column
Found: C, 64.02; H, 11.15. Ald ol 42. [R]24 +21.0 (c 0.5,
D
CHCl3); IR (film) 3485, 1712 cm-1; 1H NMR (CDCl3, 400 MHz)
δ (ppm) 5.37 (t, J ) 7.0 Hz, 1H), 4.25 (d, J ) 5.6 Hz, 1H), 4.15
(q, J ) 7.0 Hz, 2H), 4.00 (s, 1H), 3.70 (quin, J ) 6.0 Hz, 1H),
3.63 (dd, J ) 5.3, 4.1 Hz, 1H), 2.69 (dq, J ) 7.0, 4.1 Hz, 1H),
2.20 (brt, J ) 7.0 Hz, 2H), 1.65 (s, 3H), 1.27 (d, J ) 7.0 Hz,
3H), 1.28 (d, J ) 7.0 Hz, 3H), 1.22-1.41 (m, 8H), 0.89 (s, 9H),
0.88 (t, J ) 7.0 Hz, 3H), 0.85 (s, 3H), 0.82 (s, 3H), 0.07 (s, 9H),
0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ (ppm)
176.8, 136.3, 125.8, 85.5, 78.7, 71.9, 60.4, 42.8, 40.8, 36.7, 35.8,
32.1, 26.0, 25.3, 22.7, 21.3, 18.2, 17.6, 14.5, 14.2, 14.1, 0.0, -4.3,
-4.5. Anal. Calcd for C29H60O5Si2: C, 63.92; H, 11.10. Found:
C, 63.87; H, 11.21.
Eth yl (6E,2R,3R,5R,9R)-9-(ter t-Bu tyld im eth ylsiloxy)-
3-h ydr oxy-2,4,4,6-tetr am eth yl-5-(tr im eth ylsiloxy)tetr adec-
6-en oa te (43) a n d Eth yl (6E,2S,3R,5R,9R)-9-(ter t-Bu tyl-
d i m e t h y ls i lo x y )-3-h y d r o x y -2,4,4,6-t e t r a m e t h y l-5-
(tr im eth ylsiloxy)tetr a d ec-6-en oa te (44). Using the aldol
condensation procedure identical to that described for aldol
12, aldehyde 32 (0.90 g, 2.0 mmol), 35 (0.70 g, 4 mmol), BH3‚
THF (3.0 mL, 3.0 mmol, 1 M in THF), N-(p-toluenesulfonyl)-
(R)-valine (0.45 g, 3.3 mmol), and CH2Cl2 (12 mL) at -78 °C
for 24 h afforded aldol 43 (479 mg, 44%) and aldol 44 (109
mg, 10%) after flash column chromatography (2.5% ethyl
acetate/hexane) as colorless oils. Ald ol 43. [R]24D +10.0 (c 0.5,
CHCl3). IR (film) 3481, 1714 cm-1; The 1H NMR spectra
suggested the existence of three rotamers (4:2:1). The peaks
of the major rotamer are presented here. 1H NMR (CDCl3, 400
MHz) δ (ppm) 5.36 (dd, J ) 12.9, 6.8 Hz, 1H), 4.12 (ddq, J )
10.7, 7.0, 1.9 Hz, 2H), 3.29 (s, 1H), 3.89 (s, 1H), 3.71 (quin, J
) 6.8 Hz, 1H), 3.65 (d, J ) 1.9 Hz, 1H), 2.65 (quin, J ) 6.8
Hz, 1H), 2.18 (brt, J ) 5.8 Hz, 2H), 1.65 (s, 3H), 1.22-1.41
(m, 8H), 1.25 (t, J ) 7.0 Hz, 3H), 1.24 (d, J ) 7.0 Hz, 3H),
0.96 (s, 3H), 0.89 (s, 9H), 0.88 (t, J ) 7.0 Hz, 3H), 0.77 (s, 3H),
0.10 (s, 3H), 0.08 (s, 9H), 0.05 (s, 3H); 13C NMR (CDCl3, 100
MHz): δ (ppm) 176.9, 136.6, 125.4, 87.0, 77.9, 72.0, 60.4, 43.1,
41.8, 36.7, 35.7, 32.1, 26.0, 25.3, 23.8, 22.9, 22.7, 18.2, 16.9,
chromatography (2% ethyl acetate/hexane). a n ti-36. [R]24
D
+10.0 (c 0.5, CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 4.15
(dq, J ) 7.0, 0.7 Hz, 2H), 3.71 (d, J ) 9.7 Hz, 1H), 3.17 (dd, J
) 9.5, 2.0 Hz, 1H), 2.73 (dq, J ) 7.0, 2.0 Hz, 1H), 1.36 (d, J )
7.0 Hz, 3H), 1.28 (t, J ) 7.0 Hz, 3H), 0.90 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ (ppm) 177.4, 82.5, 60.5, 38.2, 35.9, 26.0,
18.0, 13.8. syn -36. [R]24D -12.0 (c 1.0, CHCl3); 1H NMR (CDCl3,
400 MHz) δ (ppm) 4.06 (q, J ) 7.0 Hz, 2H), 3.56 (t, J ) 4.6
Hz, 1H), 2.60 (dq, J ) 7.0, 4.6 Hz, 1H), 2.37 (brs, 1H), 1.19 (t,
J ) 7.0 Hz, 3H), 1.16 (d, J ) 7.0 Hz, 3H), 0.88 (s, 9H); 13C
NMR (CDCl3, 100 MHz) δ (ppm) 177.0, 78.0, 60.4, 41.1, 35.4,
26.4, 13.9, 12.9.
(2S,3S)-1,3-Isop r op ylid en e-2,4,4-tr im eth ylp en ta n e-1,3-
d iol (a n ti-38). To a stirred solution of diol anti-37 (131 mg,
0.9 mmol) in dry acetone (5 mL) was added successively
acetone dimethylacetal (0.22 mL, 1.8 mmol) and camphor-10-
sulfonic acid (23 mg, 0.1 mmol), and the reaction mixture was
stirred for 20 min at room temperature. The reaction was
quenched by adding Et3N (0.21 mL, 0.15 mmol). The solution
was evaporated. The resulting residue was dissolved in ether.
The solution was washed with water and dried over MgSO4.
After evaporation of the solvent, the crude material was
purified by column chromatography (2% ethyl acetate/hexane)
14.1, 14.0, 13.9, 0.0, -4.2, -4.4. Ald ol 44. [R]24 +22.0 (c 0.5,
D
to give acetonide anti-38 (182 mg, 98%) as a colorless oil. H
CHCl3); IR (film) 3484, 1712 cm-1; The 1H NMR spectra
suggested the existence of two rotamers (1.5:1). The peaks of
1
NMR (CDCl3, 400 MHz) δ (ppm) 3.63 (dd, J ) 11.2, 4.6 Hz,
1H), 3.23 (dd, J ) 11.2, 5.4 Hz, 1H), 2.96 (d, J ) 8.4 Hz, 1H),
1.69-1.79 (m, 1H), 1.27 (s, 3H), 1.24 (s, 3H), 0.88 (d, J ) 6.8
Hz, 3H), 0.84 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 98.7,
81.4, 65.3, 34.6, 31.7, 27.3, 26.2, 21.7, 17.5.
(2R,3S)-1,3-Isop r op ylid en e-2,4,4-tr im eth ylp en ta n e-1,3-
d iol (syn -38). Using the above procedure described for anti-
38, syn-38 was prepared (178 mg, 96%) from syn-37. 1H NMR
(CDCl3, 400 MHz) δ (ppm) 3.98 (dd, J ) 11.2, 2.7 Hz, 1H),
3.45 (dd, J ) 11.2, 1.7 Hz, 1H), 3.44 (brs, 1H), 1.52 (ddq, J )
7.0, 2.2, 1.9 Hz, 1H), 1.32 (s, 3H), 1.31 (s, 3H), 1.06 (d, J ) 6.8
Hz, 3H), 0.84 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 98.6,
78.4, 69.4, 34.0, 31.2, 29.6, 26.5, 18.6, 13.0.
1
the major rotamer are presented here. H NMR (CDCl3, 400
MHz) δ (ppm) 5.38 (dd, J ) 15.1, 7.5 Hz, 1H), 4.21 (d, J ) 5.6
Hz, 1H), 4.15 (q, J ) 7.0 Hz, 2H), 4.00 (s, 1H), 3.70 (quin, J )
5.6 Hz, 1H), 3.63 (dd, J ) 5.7, 5.6 Hz, 1H), 2.70 (dq, J ) 7.0,
3.9 Hz, 1H), 2.18 (brt, J ) 6.8 Hz, 2H), 1.65 (s, 3H), 1.27 (d, J
) 7.0 Hz, 3H), 1.28 (t, J ) 7.0 Hz, 3H), 1.21-1.45 (m, 8H),
0.89 (s, 9H), 0.87 (t, J ) 7.0 Hz, 3H), 0.86 (s, 3H), 0.72 (s, 3H),
0.06 (s, 3H), 0.05 (s, 9H), 0.04 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ (ppm) 177.6, 136.5, 125.6, 83.6, 79.1, 72.1, 60.6, 44.1,
39.0, 36.8, 35.9, 32.1, 26.0, 25.2, 22.7, 21.3, 19.8, 19.5, 17.9,
14.3, 14.2, 14.1, 0.1, -4.2, -4.4.
Eth yl (6E,2S,3S,5R,9R)-9-(ter t-Bu tyld im eth ylsiloxy)-
3,5-d ih yd r oxy-2,4,4,6-tetr a m eth yltetr a d ec-6-en oa te (45).
To a stirred solution of TMS ether 41 (97.5 mg, 0.179 mmol)
in anhydrous MeOH (10 mL) was added anhydrous citric acid
(166 mg, 0.86 mmol). The reaction mixture was stirred at 23
°C for 15 min, and then the solvent was removed in vacuo.
The residue was partitioned between H2O (5 mL) and ether
(20 mL), the organic layer was separated, and the aqueous
layer was extracted with ether. The combined organic layers
were washed with sat. aq NaHCO3 aq solution and brine, dried
over MgSO4, and concentrated in vacuo. The crude residue
afforded diol 45 (82.9 mg, 98%) after flash column chroma-
Eth yl (6E,2S,3S,5R,9R)-9-(ter t-Bu tyld im eth ylsiloxy)-3-
h yd r oxy-2,4,4,6-tetr a m eth yl-5-(tr im eth ylsiloxy)tetr a d ec-
6-en oa te (41) a n d Eth yl (6E,2R,3S,5R,9R)-9-(ter t-Bu tyl-
d i m e t h y ls i lo x y )-3-h y d r o x y -2,4,4,6-t e t r a m e t h y l-5-
(tr im eth ylsiloxy)tetr a d ec-6-en oa te (42). Using the aldol
condensation procedure identical to that described for aldol
12, aldehyde 32 (1.80 g, 4 mmol), 35 (1.4 g, 8 mmol), BH3‚
THF (6.0 mL, 6.0 mmol, 1 M in THF), N-(p-toluenesulfonyl)-
(S)-valine (1.80 g, 6.6 mmol), and CH2Cl2 (12 mL) at -78 °C
for 24 h afforded aldol 41 (1.78 g, 84%) and aldol 42 (174 mg,
8%) after flash column chromatography (2.5% ethyl acetate/
hexane) as colorless oils. Ald ol 41. [R]24 +8.0 (c 1.0, CHCl3);
tography (15% ethyl acetate/hexane) as a colorless oil. [R]24
D
D
IR (film) 3485, 1712 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm)
5.37 (t, J ) 6.8 Hz, 1H), 4.13 (ddq, J ) 19.7, 10.7, 7.0 Hz, 2H),
+25.0 (c 0.2, CHCl3); IR (film) 3383, 1734 cm-1
;
1H NMR
(CDCl3, 400 MHz) δ (ppm) 5.43 (t, J ) 7.0 Hz, 1H), 4.14 (q, J

5522 J . Org. Chem., Vol. 64, No. 15, 1999
Kiyooka and Hena
) 7.0 Hz, 2H), 4.05 (s, 1H), 3.99 (d, J ) 5.1 Hz, 1H), 3.70 (brs,
1H), 3.69 (quin, J ) 6.1 Hz, 1H), 3.01 (brs, 1H), 2.72 (dq, J )
7.0, 5.1 Hz, 1H), 2.20 (brt, J ) 7.0 Hz, 2H), 1.66 (s, 3H), 1.26
(t, J ) 7.0 Hz, 3H), 1.25 (d, J ) 7.0 Hz, 3H), 1.22-1.43 (m,
8H), 0.99 (s, 3H), 0.88 (s, 9H), 0.87 (t, J ) 7.0 Hz, 3H), 0.68 (s,
3H), 0.04 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 177.0,
136.4, 126.3, 86.6, 79.2. 72.0, 60.5, 42.3, 41.2, 36.7, 35.6, 31.9,
25.8, 25.0, 22.6, 22.1, 18.0, 15.5, 14.6, 14.1, 14.0, 13.3, -4.3,
-4.5. Anal. Calcd for C26H52O5Si: C, 66.05; H, 11.09. Found:
C, 66.02; H, 11.13.
Eth yl (6E,2S,3S,5R,9R)-9-(ter t-Bu tyld im eth ylsiloxy)-
3,5-d ih yd r oxy-3,5-isop r op ylid en e-2,4,4,6-tetr a m eth yltet-
r a d ec-6-en oa te (46). Using a similar procedure to that
described for the preparation of acetonide syn-38, diol 45 (472
mg, 1 mmol), acetone dimethylacetal (0.25 mL, 2.0 mmol) and
camphor-10-sulfonic acid (23 mg, 0.1 mmol) in dry acetone (5
mL) afforded acetonide 46 (502 mg, 98%) after flash column
chromatography (1% ethyl acetate/hexane) as a colorless oil.
[R]24D -5.7 (c 0.7, CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm)
5.38 (t, J ) 7.0 Hz, 1H), 4.11 (dq, J ) 7.0, 1.0 Hz, 2H), 3.97,
(s, 1H), 3.86 (d, J ) 8.0 Hz, 1H), 3.69 (quin, J ) 5.8 Hz, 1H),
2.61 (dq, J ) 8.0, 7.0 Hz, 1H), 2.20 (t, J ) 6.3 Hz, 2H), 1.65 (s,
3H), 1.46 (s, 3H), 1.42 (s, 3H), 1.26 (t, J ) 7.0 Hz, 3H), 1.22-
1.44 (m, 8H), 1.16 (d, J ) 6.8 Hz, 6H), 0.91 (s, 3H), 0.88 (s,
9H), 0.87 (t, J ) 7.0 Hz, 3H), 0.60 (s, 3H), 0.04 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ (ppm) 176.0, 133.1, 127.0, 98.7, 83.9,
78.0, 71.9, 60.4, 40.1, 38.2, 36.9, 35.6, 31.9, 29.9, 25.9, 25.0,
22.6, 21.3, 19.4, 18.0, 15.0, 14.9, 14.7, 14.1, 14.0, -4.3, -4.5.
Anal. Calcd for C29H56O5Si: C, 67.92; H, 11.01. Found: C,
68.01; H, 11.08.
BF 3‚OEt2-Ca ta lyzed Ald ol Con d en sa tion betw een Al-
d eh yd e 32 a n d Silyl Nu cleop h ile 35. To a cooled (-78 °C)
and stirred solution of aldehyde 32 (354 mg, 0.8 mmol) in CH2-
Cl2 (4 mL) was added freshly distilled BF3‚OEt2 (0.21 mL, 1.6
mmol) dropwise, and after an interval of 10 min silyl nucleo-
phile 35 (169.5 mg, 0.9 mmol) in CH2Cl2 (1 mL) was added
dropwise. After 2 h a buffer solution (2 mL, pH 6.86) was added
to quench the reaction. Workup procedures were carried out
with separation of phases, drying over MgSO4, and evaporation
in vacuo. Flash chromatography afforded 45, 47, and 48 as a
mixture (40 mg) with a ratio of 1:1:1 (the ratio was determined
from 1H NMR) and 51 (10 mg).
E t h yl (6E,2R,3R,5R,9R)-9-(ter t-Bu t yld im et h ylsiloxy)-
3,5-d ih yd r oxy-2,4,4,6-tetr a m eth yltetr a d ec-6-en oa te (47).
1H NMR (CDCl3, 400 MHz) δ (ppm) 5.43 (t, J ) 7.0 Hz, 1H),
4.14 (q, J ) 7.0 Hz, 2H), 4.10 (d, J ) 3.4 Hz, 1H), 3.87 (dd, J
) 5.4, 5.1 Hz, 1H), 3.69 (quin, J ) 6.1 Hz, 1H), 3.50 (d, J )
5.1 Hz, 1H), 2.80 (d, J ) 3.4 Hz, 1H), 2.72 (m, 1H), 2.21 (brs,
2H), 1.70 (s, 3H), 1.30 (d, J ) 7.0 Hz, 3H), 1.26 (t, J ) 7.0 Hz,
3H), 1.22-1.43 (m, 8H), 0.93 (s, 3H), 0.88 (s, 9H), 0.87 (t, J )
7.0 Hz, 3H), 0.04 (s, 6H). Anal. Calcd for C26H52O5Si: C, 66.05;
H, 11.09. Found: C, 66.07; H, 11.12.
Eth yl (6E,2R,3S,5R,9R)-9-(ter t-Bu tyld im eth ylsiloxy)-
3,5-d ih yd r oxy-2,4,4,6-tetr a m eth yltetr a d ec-6-en oa te (48).
IR (film) 3420, 1712 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm)
5.37 (t, J ) 7.0 Hz, 1H), 4.50 (d, J ) 8.5 Hz, 1H), 4.17 (q, J )
7.0 Hz, 2H), 3.94 (d, J ) 6.8 Hz, 1H), 3.69 (quin, J ) 6.1 Hz,
1H), 3.62 (dd, J ) 8.5, 2.2 Hz, 1H), 3.49 (d, J ) 6.8 Hz, 1H),
2.69 (dq, J ) 7.0, 2.2 Hz, 1H), 2.19 (brt, J ) 7.0 Hz, 2H), 1.70
(s, 3H), 1.34 (d, J ) 7.0 Hz, 3H), 1.29 (t, J ) 7.0 Hz, 3H), 1.22-
1.43 (m, 8H), 0.89 (s, 3H), 0.88 (s, 9H), 0.87 (t, J ) 7.0 Hz,
3H), 0.84 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ (ppm) 177.7, 136.4, 125.5, 85.0, 80.3, 72.0, 60.9,
42.2, 38.5, 36.7, 35.8, 31.9, 25.8, 25.1, 22.6, 22.2, 20.6, 18.0,
14.4, 14.0, 13.9, -4.3, -4.5. Anal. Calcd for C26H52O5Si: C,
66.05; H, 11.09. Found: C, 65.98; H, 11.13.
(6E,2S,3R,5R,9R)-9-(ter t-Bu t yld im et h ylsiloxy)-3-h y-
d r oxy-2,4,4,6-tr im eth yltetr a d ec-6-en -5-olid e (51). 1H NMR
(CDCl3, 400 MHz) δ (ppm) 5.46 (t, J ) 7.0 Hz, 1H), 4.29 (s,
1H), 3.72 (quin, J ) 5.5 Hz, 1H), 3.37 (dd, J ) 10.2, 4.4 Hz,
1H), 2.48 (dq, J ) 10.2, 7.0 Hz, 1H), 2.23 (brt, J ) 7.0 Hz,
2H), 1.86 (d, J ) 4.4 Hz, 1H), 1.69 (s, 3H), 1.42 (d, J ) 7.0 Hz,
3H), 1.20-1.44 (m, 8H), 0.97 (s, 3H), 0.93 (s, 3H), 0.89 (t, J )
7.0 Hz, 3H), 0.88 (s, 9H), 0.05 (s, 6H).
Eth yl (6E,2R,3S,5R,9R)-9-(ter t-Bu tyld im eth ylsiloxy)-
3,5-d ih yd r oxy-3,5-isop r op ylid en e-2,4,4,6-tetr a m eth yltet-
r a d ec-6-en oa te (52). To a solution of NaOEt (544 mg, 8.0
mmol) in ethanol (20 mL) was added 46 (410 mg, 0.8 mmol)
in EtOH (5 mL). After refluxing for 2 h, the solution was
concentrated, diluted with ether, washed with water, and dried
over MgSO4. After removal of the solvent, a crude residue was
purified by flash column chromatography (2% ethyl acetate/
hexane) to give 52 (164 mg, 40%) as a colorless oil. [R]24D +13.0
(c 0.8, CHCl3); 1H NMR (CDCl3, 400 MHz): δ (ppm) 5.39 (t, J
) 7.0 Hz, 1H), 4.12 (ddq, J ) 21.4, 10.7, 7.0 Hz, 2H), 3.94, (s,
1H), 3.70 (quin, J ) 5.8 Hz, 1H), 3.69 (d, J ) 7.8 Hz, 1H), 2.69
(dq, J ) 7.5, 7.0 Hz, 1H), 2.21 (t, J ) 6.3, 2H), 1.65 (s, 3H),
1.40 (s, 3H), 1.36 (s, 3H), 1.25 (t, J ) 7.0 Hz, 3H), 1.22-1.34
(m, 8H), 1.19 (d, J ) 7.0 Hz, 3H), 0.98 (s, 3H), 0.88 (s, 9H),
0.87 (t, J ) 7.0 Hz, 3H), 0.82 (s, 3H), 0.04 (s, 6H); 13C NMR
(CDCl3, 100 MHz) δ (ppm) 175.0, 133.0, 127.4, 98.3, 83.8, 80.4,
71.9, 60.0, 42.6, 37.4, 35.6, 31.9, 31.5, 29.8, 25.8, 25.0, 22.6,
22.0, 18.9, 18.0, 16.4, 14.8, 14.2, 14.1, 14.0, -4.4, -4.5. Anal.
Calcd for C29H56O5Si: C, 67.92; H, 11.01. Found: C, 67.85; H,
10.97.
(6E,2S,3S,5R,9R)-9-(ter t-Bu tyld im eth ylsiloxy)-3,5-d ih y-
d r oxy-3,5-isop r op ylid en e-2,4,4,6-tetr a m eth yltetr a d ec-6-
en a l (53). Employing a similar reduction procedure to that
described for aldehyde 15, ester 46 (342 mg, 1 mmol), and
DIBAL (1.2 mL, 1.2 mmol, 1 M in toluene) in CH2Cl2 (10 mL)
at -78 °C for 2 h afforded aldehyde 53 (417 mg, 89%) after
flash column chromatography (2% ethyl acetate/hexane) as a
1
colorless oil. [R]24 -5.0 (c 0.8, CHCl3); H NMR (CDCl3, 400
D
MHz) δ (ppm) 9.60 (d, J ) 2.2 Hz, 1H), 5.39 (t, J ) 7.0 Hz,
1H), 4.01 (d, J ) 4.8 Hz, 1H), 4.00 (s, 1H), 3.70 (quin, J ) 5.8
Hz, 1H), 2.54 (ddq, J ) 7.0, 4.8, 2.2 Hz, 1H), 2.21 (t, J ) 6.3
Hz, 2H), 1.66 (s, 3H), 1.45 (s, 3H), 1.38 (s, 3H), 1.20-1.44 (m,
8H), 1.16 (d, J ) 7.0 Hz, 3H), 0.92 (s, 3H), 0.87 (s, 9H), 0.86 (t,
J ) 7.0 Hz, 3H), 0.71 (s, 3H), 0.04 (s, 6H); 13C NMR (CDCl3,
100 MHz) δ (ppm) 203.7, 133.0, 127.0, 98.7, 83.8, 75.5, 71.9,
46.8, 38.1, 36.9, 35.6, 31.9, 29.8, 25.9, 25.1, 22.6, 22.0, 19.2,
18.1, 15.6, 14.9, 14.0, 10.2, -4.3, -4.5. Anal. Calcd for
C
27H52O4Si: C, 69.18; H, 11.18. Found: C, 69.51; H, 11.22.
r-Tr ieth ylsilyl ter t-Bu tylim in e of P r op a n a l (54). To a
cooled (-78 °C) solution of lithium diisopropylamide (1.1 equiv)
in THF (7 mL) was added the tert-butylimine of propanal (113
mg, 1.0 mmol). The resulting yellow solution was stirred for
30 min, TESCl (0.14 mL, 1.0 mmol) was added. The resulting
mixture was stirred with gradual warming to 0 °C over a
period of 3.5 h. The reaction was quenched with water and
extracted with ether. The combined ether extracts were
washed with brine and dried over K2CO3. Removal of the ether,
followed by distillation (bp 54-55 °C/0.22 mmHg) gave 54 (141
mg, 71%) as a clear oil. IR (neat) 1657 cm-1; 1H NMR (CDCl3,
400 MHz) δ (ppm) 7.56 (d, J ) 7.0 Hz, 1H), 2.05 (quin, J ) 7.0
Hz, 1H), 1.16 (d, J ) 7.0 Hz, 3H), 1.15 (s, 9H), 0.95 (t, J ) 7.5
Hz, 9H), 0.58 (q, J ) 7.5 Hz, 6H); 13C NMR (CDCl3, 100 MHz)
δ (ppm) 29.8, 29.0, 12.8, 7.4, 6.5, 5.7, 2.2.
(2E,8E,4R,5S,7R,11R)-11-(ter t-Bu t yld im et h ylsiloxy)-
5,7-d ih yd r oxy-5,7-isop r op ylid en e-2,4,6,6,8-p en ta m eth yl-
h exa d eca -2,8-d ien a l (55). To a solution (0 °C) of lithium
diisopropylamide (1.0 equiv) was added 54 (199 mg, 1.0 mmol)
dropwise over a period of 5 min. The resulting yellow to red
solution was stirred for 15 min. The solution was cooled to
-78 °C, and aldehyde 53 (468 mg, 1.0 mmol) in THF (1 mL)
was added. The resulting mixture was stirred with gradual
warming to -20 °C over a period of 2.5 h. The reaction was
quenched with water (2 mL), and oxalic acid was added to
reach the pH at 4.5 and stirred for 30 min. The solution was
poured into brine (10 mL) and extracted with ether. The
combined ether extracts were washed with sat. aq NaHCO3
solution, dried over MgSO4, and evaporated to give a crude
material (E:Z, 16:1; 1H NMR). Purification by flash column
chromatography (1% ethyl acetate/hexane) afforded aldehyde
55 (376 mg, 74%) as a clear oil. [R]24 -5.5 (c 0.9, CHCl3); IR
D
(film) 1691 cm-1; H NMR (CDCl3, 400 MHz) δ (ppm) 9.41 (s,
1
1H), 6.44 (d, J ) 10.4 Hz, 1H), 5.38 (t, J ) 7.0 Hz, 1H), 3.93
(s, 1H), 3.69 (quin, J ) 5.6 Hz, 1H), 3.47 (d, J ) 7.0 Hz, 1H),
2.93 (ddq, J ) 10.4, 7.0, 6.8 Hz, 1H), 2.20 (brt, J ) 6.3 Hz,

Synthesis of the Antineoplastic Macrolide Acutiphycin
J . Org. Chem., Vol. 64, No. 15, 1999 5523
2H), 1.77 (s, 3H), 1.65 (s, 3H), 1.45 (s, 3H), 1.44 (s, 3H), 1.22-
1.47 (m, 8H), 1.06 (d, J ) 6.8 Hz, 3H), 0.90 (s, 3H), 0.88 (s,
9H), 0.87 (t, J ) 7.0 Hz, 3H), 0.70 (s, 3H), 0.03 (s, 6H); 13C
NMR (CDCl3, 100 MHz) δ (ppm) 195.4, 158.5, 135.9, 133.0,
127.2, 98.5, 83.8, 80.6, 71.9, 38.3, 36.9, 35.6, 34.9, 31.9, 29.9,
25.9, 25.1, 22.6, 22.4, 19.2, 18.1, 16.6, 15.4, 14.9, 14.0, 9.1, -4.3,
-4.5. Anal. Calcd for C30H56O4Si: C, 70.81; H, 11.09. Found:
C, 70.67; H, 11.13.
M in THF), N-(p-toluenesulfonyl)-(S)-valine (0.60 g, 2.2 mmol),
and CH2Cl2 (10 mL) at -78 °C for 3 h afforded 59 (377 mg,
76%, 16% ee, CHIRALPAK AD, 7% 2-propanol/hexane, Rf 26.0
min, 1 mL/min, λ 254 nm), after flash column chromatography,
as a colorless oil. IR (film) 3376, 1721, 1628 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ (ppm) 7.27-7.37 (m, 5H), 5.29 (s, 1H),
4.97 (br quin, J ) 4.1 Hz, 1H), 2.68 (dd, J ) 14.6, 8.7 Hz, 1H),
2.59 (dd, J ) 14.6, 4.9 Hz, 1H), 2.57 (br s, 1H), 1.66 (s, 3H),
1.65 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 168.8, 161.6,
142.7, 128.0, 127.4, 125.3, 106.2, 94.5, 70.1, 42.5, 24.7, 23.9.
Anal. Calcd for C14H16O4: C, 67.73; H, 6.50. Found: C, 67.82;
H, 6.59.
P h en yl (4E,10E,3S,6R,7S,9R,13R)-13-(ter t-Bu tyld im e-
th ylsiloxy)-7,9-isop r op ylid en e-3,7,9-tr ih yd r oxy-4,6,8,8,10-
p en ta m eth ylocta d eca -4,10-d ien oa te (56). Employing an
aldol condensation procedure described for the preparation of
aldol 12, aldehyde 55 (508 mg, 1 mmol), 10 (229 mg, 1.1 mmol),
BH3‚THF (1.0 mL, 1.0 mmol, 1 M in THF), N-(p-toluenesulfo-
nyl)-(S)-valine (298 mg, 1.1 mmol), and CH2Cl2 (5 mL) at -78
Meth yl (5S)-5-Hyd r oxy-3-oxo-5-p h en ylp en ta n oa te (60).
Using a similar procedure described above, benzaldehyde (106
mg, 1.0 mmol), 11 (286 mg, 1.1 mmol), BH3‚THF (1.0 mL, 1.0
mmol, 1 M in THF), N-(p-toluenesulfonyl)-(S)-valine (298 mg,
1.1 mmol), and CH2Cl2 (10 mL) at -78 °C for 3 h afforded 60
(160 mg, 72%, 61% ee, CHIRALPAK AD, Rf 51.5 min, 4%
2-propanol/hexane, 1 mL/min, λ 254 nm), after flash column
1
°C for 3 h afforded acetate aldol 56 (541 mg, 84%, 85% de, H
NMR) after flash column chromatography (2% ethyl acetate/
hexane) as a colorless oil (the undesired counter isomer was
separated during flash column chromatography). [R]24 +5.0
D
(c 0.8, CHCl3); IR (film) 3439, 1759 cm-1; 1H NMR (CDCl3, 400
MHz) δ (ppm) 7.37 (t, J ) 7.3 Hz, 2H), 7.22 (d, J ) 7.3 Hz,
1H), 7.08 (d, J ) 8.2 Hz, 2H), 5.47 (d, J ) 10.0 Hz, 1H), 5.35
(t, J ) 7.0 Hz, 1H), 4.52 (br d, J ) 8.8 Hz, 1H), 3.89 (s, 1H),
3.68 (quin, J ) 5.6 Hz, 1H), 3.33 (d, J ) 7.0 Hz, 1H), 2.78 (dd,
J ) 16.1, 9.3 Hz, 1H), 2.68 (dd, J ) 16.1, 3.4 Hz, 1H), 2.62 (br
s, 1H), 2.61-2.65 (m, 1H), 2.19 (br t, J ) 6.3 Hz, 2H), 1.74 (s,
3H), 1.64, (s, 3H), 1.42, (s, 3H), 1.40, (s, 3H), 1.19-1.42 (m,
8H), 0.96 (d, J ) 6.6 Hz, 3H), 0.88 (s, 3H), 0.87 (s, 9H), 0.86 (t,
J ) 7.0 Hz, 3H), 0.72 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ (ppm) 170.9, 150.4, 133.2, 132.4,
131.5, 129.4, 126.9, 125.9, 121.4, 98.2, 83.9, 81.2, 73.3, 72.0,
40.0, 38.1, 36.8, 35.7, 33.5, 31.9, 30.0, 25.8, 25.0, 22.6, 19.2,
18.0, 17.8, 15.3, 14.9, 14.0, 11.8, -4.3, -4.5. Anal. Calcd for
chromatography, as a colorless oil. IR (film) 3476, 1744 cm-1
;
1H NMR (CDCl3, 400 MHz) δ (ppm) 7.24-7.36 (m, 5H), 5.18
(dt, J ) 9.0, 3.2 Hz, 1H), 3.72 (s, 3H), 3.48 (s, 2H), 2.99 (dd, J
) 17.3, 3.2 Hz, 1H), 2.94 (d, 3.2 Hz, 1H), 2.90 (dd, J ) 17.3,
1.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 202.7, 167.2,
142.4, 128.6, 127.8, 125.6, 69.8, 52.5, 51.5, 49.6. Anal. Calcd
for C12H14O4: C, 64.85; H, 6.35. Found: C, 65.02; H, 6.40.
Met h yl (8E,14E,5S,7S,10R ,11S,13R,17R)-17-(ter t-Bu -
t yld im et h ylsiloxy)-5,11,13-t r ih yd r oxy-11,13-isop r op yl-
id en e-8,10,12,12,14-p en ta m eth yl-3-oxo-7-(tr ieth ylsiloxy)-
docosa-8,14-dien oate (61). Using a similar aldol condensation
procedure described, aldehyde 57 (600 mg, 0.9 mmol), 11 (260
mg, 1.0 mmol), BH3‚THF (0.9 mL, 0.9 mmol, 1 M in THF),
N-(p-toluenesulfonyl)-(R)-valine (271 mg, 1.0 mmol), and CH2-
Cl2 (4 mL) at -78 °C for 3 h afforded aldol 61 (528 mg, 75%,
C
38H64O6Si: C, 70.76; H, 10.00. Found: C, 70.33; H, 10.04.
1
(4E,10E,3S,6R,7S,9R,13R)-13-(ter t-Bu tyldim eth ylsiloxy)-
83% de, H NMR), after flash column chromatography (2.5%
7,9-d ih yd r oxy-7,9-isop r op ylid en e-4,6,8,8,10-p en ta m eth yl-
3-(tr ieth ylsiloxy)octa d eca -4,10-d ien a l (57). Employing a
procedure analogous to that for the preparation of TMS ether
27, alcohol 56 (645 mg, 1 mmol), TESOTf (0.31 mL, 1.8 mmol),
2,6-lutidine (0.44 mL, 3.8 mmol), and CH2Cl2 (5 mL) afforded
TES ether (purified by flash column chromatography, 1% ethyl
acetate/hexane). The TES ether was then reduced to the
corresponding alcohol using a procedure similar to that
described for the preparation of alcohol 29. The alcohol was
then oxidized using a Swern oxidation procedure described for
the preparation of aldehyde 30 to give aldehyde 57 (534 mg,
79% overall) after flash column chromatography (1% ethyl
acetate/hexane) as a colorless oil. 1H NMR (CDCl3, 400 MHz):
δ (ppm) 9.74 (t, J ) 2.4 Hz, 1H), 5.36 (t, J ) 7.0 Hz, 1H), 5.34
(d, J ) 10.2 Hz, 1H), 4.53 (dd, J ) 8.2, 4.3 Hz, 1H), 3.88 (s,
1H), 3.68 (quin, J ) 5.6 Hz, 1H), 3.30 (d, J ) 7.0 Hz, 1H), 2.67
(ddd, J ) 15.3, 8.2, 2.6 Hz, 1H), 2.58 (ddq, J ) 10.2, 7.0, 6.8
Hz, 1H), 2.33 (ddd, J ) 15.3, 4.3, 2.4 Hz, 1H), 2.19 (br t, J )
6.3 Hz, 2H), 1.64 (s, 3H), 1.62 (s, 3H), 1.43 (s, 3H), 1.41 (s,
3H), 1.20-1.44 (m, 8H), 0.95 (d, J ) 6.8 Hz, 3H), 0.92 (t, J )
7.8 Hz, 9H), 0.88 (t, J ) 7.0 Hz, 3H), 0.87 (s, 9H), 0.86 (s, 3H),
0.67 (s, 3H), 0.57 (q, J ) 7.8 Hz, 6H), 0.04 (s, 6H); 13C NMR
(CDCl3, 100 MHz) δ (ppm) 201.8, 133.2, 132.7, 132.0, 126.9,
98.2, 83.9, 81.1, 74.0, 72.0, 49.5, 38.1, 36.9, 35.7, 33.4, 31.9,
30.0, 25.9, 25.0, 22.6, 22.5, 19.2, 18.0, 17.3, 15.3, 14.9, 14.0,
10.9, 6.7, 4.7, -4.3, -4.5. Anal. Calcd for C38H74O5Si2: C, 68.41;
H, 11.18. Found: C, 68.31; H, 11.21.
ethyl acetate/hexane), as a colorless oil. [R]24 +16.6 (c 0.3,
D
CHCl3); IR (film) 3503, 1747, 1700, 1653 cm-1
;
1H NMR
(CDCl3, 400 MHz) δ (ppm) 5.36 (t, J ) 7.0 Hz, 1H), 5.35 (d, J
) 10.0 Hz, 1H), 4.31 (dd, J ) 7.0, 2.2 Hz, 1H), 4.23-4.30 (m,
1H), 3.89 (s, 1H), 3.73 (s, 3H), 3.69 (quin, J ) 5.6 Hz, 1H),
3.48 (s, 2H), 3.32 (d, J ) 7.0 Hz, 1H), 3.27 (d, J ) 2.9 Hz, 1H),
2.67 (d, J ) 6.0 Hz, 2H), 2.60 (ddq, J ) 10.0, 7.0, 6.6 Hz, 1H),
2.20 (brt, J ) 6.4 Hz, 2H), 1.64 (s, 3H), 1.58 (s, 3H), 1.43 (s,
3H), 1.41, (s, 3H), 1.20-1.40 (m, 10H), 0.95 (d, J ) 6.6 Hz,
3H), 0.94 (t, J ) 7.8 Hz, 9H), 0.89 (s, 3H), 0.88 (s, 9H), 0.87 (t,
J ) 7.0 Hz, 3H), 0.70 (s, 3H), 0.59 (q, J ) 7.8 Hz, 6H), 0.04 (s,
3H), 0.03 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 202.8,
167.3, 133.3, 133.0, 131.1, 126.8, 98.1, 83.9, 81.1, 75.2, 72.0,
64.5, 52.3, 50.1, 49.5, 41.3, 38.1, 36.8, 35.7, 33.4, 31.9, 30.0,
25.9, 25.0, 22.6, 22.5, 19.2, 18.0, 17.4, 15.3, 14.9, 14.0, 11.7,
6.8, 4.7, -4.4, -4.5. Anal. Calcd for C43H82O8Si2: C, 65.94; H,
10.55. Found: C, 65.03; H, 10.61.
Ack n ow led gm en t. This work was supported by the
Grant-in-Aid for Scientific Research on Priority Area
Nos. 8245239, 9231236, 10125229, and 9554046 from
the Ministry of Education, Science, and Culture, J apan
and partly supported by the Sasakawa Scientific Re-
search Grant from the J apan Science Society (M.A.H.
10-123).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra (28
pages). This material is available free of charge via the
Internet at http://pubs.acs.org.
6-(2-Hyd r oxy-2-p h en ylet h yl)-2,2-d im et h yl-1,3-d ioxin -
4-on e (59). Using the aldol condensation procedure identical
to that described for aldol 12, benzaldehyde (212 mg, 1.0
mmol), 58 (472 mg, 2.2 mmol), BH3‚THF (2.0 mL, 2.0 mmol, 1
J O990342R