Formal total synthesis of fostriecin by 1,4-asymmetric induction with an alkyne-cobalt complex

Article abstract of DOI:10.1002/chem.201000795

The synthesis of a protected dephosphofostriecin, and thereby a formal synthesis of fostriecin, has been accomplished. The synthetic challenges were the construction of four stereogenic centers and the conformationally labile cis-cis-trans-triene moiety. Previous total syntheses have employed at least two asymmetric reactions that required the use of an external chiral auxiliary. Although remote stereoinduction in a 1,4-relationship is considered difficult, we have developed a notable 1,4-asymmetric induction that utilizes an alkyne-cobalt complex for the control of C5 stereochemistry by the C8 stereogenic center. The stereochemistry at C11 was established by 1,3-asymmetric induction with a higherorder alkynyl-zinc reagent. Thus, only one asymmetric reaction requiring an external chiral auxiliary was employed in this route. The labile cis-cis-transtriene unit was constructed at a late stage of the synthesis by diastereoselective coupling of a dienyne and an aldehyde unit, followed by reduction.

Full text of DOI:10.1002/chem.201000795

DOI: 10.1002/chem.201000795
Formal Total Synthesis of Fostriecin by 1,4-Asymmetric Induction
with an Alkyne–Cobalt Complex
Yujiro Hayashi,*[a] Hirofumi Yamaguchi,[a] Maya Toyoshima,[a] Kotaro Okado,[a]
Takumi Toyo,[a] and Mitsuru Shoji[a, b]
Abstract: The synthesis of a protected
dephosphofostriecin, and thereby
duction in a 1,4-relationship is consid-
ered difficult, we have developed a no-
table 1,4-asymmetric induction that uti-
lizes an alkyne–cobalt complex for the
control of C5 stereochemistry by the
C8 stereogenic center. The stereochem-
istry at C11 was established by 1,3-
asymmetric induction with a higher-
order alkynyl-zinc reagent. Thus, only
one asymmetric reaction requiring an
external chiral auxiliary was employed
in this route. The labile cis-cis-trans-
triene unit was constructed at a late
stage of the synthesis by diastereoselec-
tive coupling of a dienyne and an alde-
hyde unit, followed by reduction.
a
formal synthesis of fostriecin, has been
accomplished. The synthetic challenges
were the construction of four stereo-
genic centers and the conformationally
labile cis-cis-trans-triene moiety. Previ-
ous total syntheses have employed at
least two asymmetric reactions that re-
quired the use of an external chiral
auxiliary. Although remote stereoin-
Keywords: alkynes
·
asymmetric
synthesis · cobalt · diastereoselectiv-
ity · fostriecin
Introduction
peared in the literature,[6,7] as well as a number of synthetic
studies.[8]
Fostriecin (1, CI-920), a novel secondary metabolite isolated
from Streptomyces pulveraceus, along with analogues such as
PD113270 and PD113271,[1] is active in vitro against leuke-
mia, lung cancer, breast cancer, and ovarian cancer and
shows antitumor activity against L1210 and P388 leukemia
in vivo.[2] It is also known to be a selective inhibitor of pro-
tein phosphatase 2A (PP2A) and 4 (PP4).[3] This important
biological activity has attracted the attention of many syn-
thetic chemists. In 1997, the relative and absolute configura-
tions of fostriecin were determined by Boger and co-work-
ers by synthetic and degradation studies.[4] The first total
synthesis was accomplished by the same group in 2001.[5]
Since then several excellent asymmetric syntheses have ap-
Structurally, compound 1 has four stereogenic centers and
contains a conformationally labile cis-cis-trans-triene moiety.
A key issue for the synthesis of 1 is how to control the four
stereogenic centers. Most of the previous syntheses are
based on reagent-controlled methodology. For instance, all
of the previous syntheses employed reagent-based strategies
to control the stereogenic center at C5. These strategies in-
cluded Sharpless asymmetric dihydroxylation,[5] asymmetric
hetero-Diels–Alder reaction with a chiral Cr catalyst,[7a]
Brownꢀs asymmetric allylation,[7b,f,h,j,l,m] Yamamotoꢀs asym-
metric allylation,[7g,i] lithium 2,2’-dihydroxy-1,1’-binaphthyl-
ethoxyaluminum hydride (BINAL-H) asymmetric reduc-
tion,[7c,d] Sharpless kinetic resolution,[7e] and lipase-catalyzed
kinetic resolution.[7k] There are no reported methods for a
substrate-controlled strategy.
[a] Prof. Dr. Y. Hayashi, H. Yamaguchi, M. Toyoshima, K. Okado,
T. Toyo, Dr. M. Shoji
Department of Industrial Chemistry, Faculty of Engineering
Tokyo University of Science, Kagurazaka, Shinjuku-ku
Tokyo 162-8601 (Japan)
Fax : (+81)3-5261-4631
E-mail: hayashi@ci.kagu.tus.ac.jp
[b] Dr. M. Shoji
For the construction of the stereogenic center at C11, two
syntheses employed the transfer of chirality from that of
natural sources, such as malic acid[7c,d] and glucose.[7j] Only
Hatakeyama et al. employed a substrate-controlled method-
Present address: Faculty of Pharmacy, Keio University
Shibakoen 1-5-30, Minato-ku, Tokyo 105-8512 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000795.
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FULL PAPER
ology; a 1,3-anti reduction di-
rected by the stereogenic center
at C9.[7f,m] Other total syntheses
used reagent-based strategies
such as Sharpless asymmetric
dihydroxylation,[5]
asymmetric
Sharpless
epoxidation,[7e]
Noyori
reduction,[7a,h,i,g]
Brownꢀs allylation reaction,[7b]
and lipase-catalyzed kinetic res-
olution.[7k]
The stereochemistry of all
four stereogenic centers was el-
egantly controlled by four dif-
ferent catalytic asymmetric re-
Scheme 2. Retrosynthetic analysis of fostriecin (1). TBDPS=tert-butyldiphenylsilyl.
actions by the groups of Shiba-
saki[7g,i] and Falck,[7b] whereas
three of the four stereogenic
centers were constructed by using asymmetric catalytic reac-
tions in the groups of Jacobsen,[7a] Imanishi,[7c,d] Kobaya-
shi,[7e] and Trost.[7h] In these syntheses, asymmetric catalytic
reactions were utilized at least twice (Scheme 1). Yadav
stereochemistry at C5 was to be controlled by the stereogen-
ic center at C8 by 1,4-asymmetric induction triggered by an
alkyne–cobalt complex, methodology recently developed in
this group (see below).[9] The only reaction requiring the use
of an external chiral auxiliary is the Sharpless asymmetric
dihydroxylation[10] of the homoallylic alcohol 8, which would
create the two successive stereogenic centers at C8 and C9.
To construct the labile triene unit in a synthetically efficient
manner, a large triene precursor can be introduced with the
creation of the C11 stereogenic center.
Herein, we report the realization of this scenario for the
synthesis of protected dephosphofostriecin 2,[11] the key in-
termediate from the synthesis reported by Imanishi and co-
workers.[7c,d]
Scheme 1. Summary of the control of the absolute configuration at C5
and C11 in previous syntheses of fostriecin (1). AD=asymmetric dihy-
droxylation, AE=asymmetric epoxidation.
Background to the 1,4-asymmetric induction: Chelation con-
trol of 1,2- and 1,3-stereorelationships is well established.
However, it is a synthetic challenge to control a more
remote stereocenter, such as in a 1,4-relationship, by using a
pre-existing stereogenic center.[12] In particular, the stereose-
lective nucleophilic addition of a 4-alkoxy-2-butenal or 2-bu-
tynal system is difficult because there are two sp2 or sp
carbon atoms between the stereogenic and pro-stereogenic
centers, thus, chelation control is not expected. Metal tem-
plates have been utilized for remote asymmetric induction,
for example, the elegant 1,5-asymmetric induction described
by Ley and co-workers used p-allyltricarbonyliron lactone
complexes in the total synthesis of taurospongin.[13] There
have been, however, no useful methods for efficient 1,4-
asymmetric induction that could be applied to the total syn-
thesis of fostriecin. Thus, we have developed a remote asym-
metric induction that uses an alkyne–cobalt complex as a
metal template.[9] The angle of the triple bond in alkyne 9 is
1808, whereas that in alkyne–cobalt complex 10 is about
1408 (Scheme 3).[14] On formation of a complex, the stereo-
genic and pro-stereogenic centers are be forced closer to-
gether and, thus, metal chelation could be expected, which,
in turn, would generate a high stereoselectivity. By the use
of alkyne–cobalt complexation, we have developed a stereo-
et al. employed d-glucose as a chiral starting material and
three of the four stereogenic centers were derived from this
chiral source.[7j]
Synthetic plan: For the construction of the labile C12–C18
triene moiety, all of the previous methods used a cross-cou-
pling reaction between a C12–C13 vinyl iodide unit and
C14–C18 diene metal unit. Though the triene alcohol
moiety (C11–C17 unit) would be unstable toward acid, we
thought the corresponding dienyne alcohol would be more
stable because alkynes are more electron withdrawing than
alkenes, and that the triene could be synthesized by stereo-
selective reduction at a later stage of the synthesis. Based on
these considerations, we planned the retrosynthetic analysis
outlined in Scheme 2.
Contrary to the previous syntheses, our synthetic strategy
is to employ reactions that use pre-existing stereogenic cen-
ters to control stereochemistry, if possible. The stereogenic
center at C11 was to be constructed, while a new carbon–
carbon bond was made between C11 and C12, by 1,3-asym-
metric induction directed by the C9 stereogenic center. The
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10151

Y. Hayashi et al.
Scheme 3. Change in alkyne bond angle on formation of an alkyne–
cobalt complex.
Scheme 5. Stereoselective ketone reduction in an alkyne–cobalt complex.
selective synthetic method for the generation of both the
anti and syn isomers. Excellent anti selectivity was obtained
in the reaction of alkyne–cobalt complex 11 with Me3ZnLi
(Scheme 4), whereas no selectivity was generated with the
the hydroxyl groups are protected with nonchelating tert-bu-
tyldimethylsilyl (TBS) and trimethylsilyl (TMS) groups. In
complex 16 one of the hydroxyl groups is TBS-protected
and the other is a free hydroxyl group. In 17 one of the hy-
droxyl groups is protected with a benzyloxymethyl (BOM)
group, from which chelation would be possible, and the
other hydroxyl group is unprotected. We thought that find-
ing the suitable combination of protecting group and nucleo-
phile to makes this unprecedented 1,4-asymmetric reaction
successful was the first key issue in our synthesis of 1.
Synthesis of alkyne–cobalt complexes 15–17: The synthesis
of 15 is described in Scheme 6. Mono-protection of 1,3-pro-
panediol (18) with para-methoxybenxyl chloride (PMBCl)
Scheme 4. Stereoselective addition of a alkyl-metal reagent to alkyne–
cobalt complex. MOM=methoxymethyl.
uncomplexed alkynyl aldehyde.
Reduction of alkyne–cobalt
complex 13 with NaBH4 gave
syn-14
stereoselectively
(Scheme 5) and, again, no selec-
tivity was observed in the reaction of uncomplexed ketone.
Although it is well known that alkyne–cobalt complexes
can be easily prepared under
followed by oxidation with SO3·pyridine complex[15] provid-
ed aldehyde 19. Wittig reaction, followed by reduction and
mild oxidative conditions in
high yield by treatment of the
corresponding
alkyne
with
[Co2(CO)8], to the best of our
knowledge, there is no litera-
ture precedent for the use of
alkyne–cobalt complexes for
1,4-asymmetric induction.
Results and Discussion
From our investigations of 1,4-
asymmetric
induction
in
alkyne–cobalt complexes, the
choice of nucleophile and pro-
tecting group for the hydroxyl
moiety was found to be impor-
tant to achieve high selectivity.
Based on these results, we se-
lected three alkyne–cobalt com-
plexes with different protecting
groups to investigate the 1,4-
asymmetric induction for the
synthesis of 1. In complex 15 Scheme 6. Synthesis of alkyne–cobalt complex 15. (DHQD)2PHAL=Bis(dihydroquinidino)phthalazine.
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Formal Total Synthesis of Fostriecin
FULL PAPER
oxidation gave 20. The Corey–Fuchs alkyne synthesis[16] af-
forded alkyne 21, which was oxidized to diol 22 in good
yield with excellent enantioselectivity (93% enantiomeric
excess (ee))[17] under Sharpless dihydroxylation condi-
then gave aldehyde 29. The treatment of 29 with [Co2(CO)8]
provided alkyne–cobalt complex 17 in good yield.
Reaction of allyl-metal reagents with alkyne–cobalt com-
plexes 15–17: With complexes 15–17 in hand, the diastereo-
selective allylation reaction was investigated. First, reaction
with Grignard reagent allylmagnesium bromide was exam-
ined (Table 1). Only marginal selectivity was observed in
the reaction of 17 (Table 1, entry 3) and almost no selectivi-
ty was detected in the cases of 15 and 16 (Table 1, entries 1
and 2). Allyl metal reagents (CH2=CHCH2)2Zn, (CH2=
CHCH2)2TiCl2, (CH2=CHCH2)2AlEt, and a combination of
CH2=CHCH2MgBr and CeCl3 also did not afford the de-
sired isomer predominately (Table 1, entries 4–7). In com-
plexes 15–17 the stereogenic center C8 is a quaternary
carbon atom and there is an alkoxy group at C9 (fostriecin
numbering). Thus, there are several possibilities of chelation
and the transition state may be quite different from that of
the model reaction in Scheme 4.
tions[10]
. Protection of the diol 22 with TBS triflate
(TBSOTf) and TMSOTf in the presence of 2,6-lutidine gave
23. Treatment of 23 with BuLi and 4-formylmorpholine gave
aldehyde 24, which was treated with [Co2(CO)8] to provide
alkyne–cobalt complex 15 in good yield.
The alkyne–cobalt complex 16 was synthesized from 24 in
two steps. Selective removal of the TMS group on the tert-
alcohol in the presence of the secondary TBS ether by treat-
ment with LiBF4, followed by complexation with [Co2(CO)8]
gave 16 in good yield (Scheme 7).
As the desired results were not obtained with allyl metal
reagents, the Hosomi–Sakurai allylation,[18] which proceeds
by a Lewis acid activated mechanism, was investigated. The
results are summarized in Table 2. There are reports of the
Lewis acid mediated allylation[19] and Mukaiyama-aldol re-
actions[20] of the dicobalt hexacarbonyl complex of a,b-ace-
tylenic aldehyde, and BF3·OEt2 is a suitable promoter in the
reaction with allyl stannanes.[19] The model alkyne–cobalt
complex 17 was treated with allyl triphenyl stannane in the
presence of several Lewis acids. Whereas low selectivity was
Scheme 7. Synthesis of alkyne–cobalt complex 16.
The alkyne–cobalt complex 17 was synthesized from 22
(Scheme 8). Protection of both hydroxyl groups of 22 with
triethylsilyl triflate (TESOTf) and 2,6-lutidine, followed by
treatment with BuLi and ClCO2Me gave ester 26. The pro-
tecting group on the secondary alcohol was changed from
TES to BOM in two steps to give 27; treatment with pyridi-
nium p-toluenesulfonate (PPTS) in MeOH, then BOMCl
and iPr2NEt. Reduction with diisobutylaluminum hydride
(DIBAL-H), followed by treatment with tetra-n-butylammo-
nium fluoride (TBAF) gave diol 28. Oxidation with MnO2
observed with HfCl4, ZnCl2, BF3·OEt2, TiCl
3ACHTUNGTRENN(UNG OiPr), and
TiCl(OiPr)3 (Table 2, entries 1–3, 5, and 6), moderate selec-
AHCTUNGTRENNUNG
tivity (73:27) was obtained when MgBr2·OEt2 was employed
(Table 2, entry 4). Good selectivity (80:20) was obtained in
the presence of TiCl2ACHTNUTRGNE(NUG OiPr)2 (Table 2, entry 7). The selectivi-
ty increased to 92:8 when the reaction was performed at
lower temperature (À408C, Table 2, entry 8). It should be
mentioned that the bulkiness of the allyl stannane reagent is
important. Whereas Ph3SnCH2CH=CH2 gave an excellent
result, the corresponding Bu3Sn
analogue gave poor selectivity
(Table 2, entry 8 versus 9). The
absolute configuration of the
newly generated stereocenter at
C5 of 32 was determined by the
advanced Mosherꢀs a-methoxy-
a-trifluoromethylphenylacetic
acid (MTPA) method[21] after
conversion to the (R)- and (S)-
mono-MTPA esters of 32.
1,3-Asymmetric induction: As
the crucial 1,4-asymmetric in-
duction had been successful,
the next key issue was the cou-
pling of the C1–C11 and C12–
C18 units, which generates the
stereogenic center at C11
Scheme 8. Synthesis of alkyne–cobalt complex 17.
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10153

Y. Hayashi et al.
Table 1. The effect of allyl metal reagent on the 1,4-asymmetric induction in alkyne–cobalt complexes 15–17.[a]
cleophile, and additive would
be important for the success of
this 1,3-asymmetric induction.
Three aldehydes (33–35) with
different protecting groups
were selected as model alde-
hydes for the C1–C11 unit.
Entry
Complex
Reagent
T [8C]
t [min]
Yield [%][b]
Ratio R/S[c]
Synthesis of aldehydes 33–35:
Aldehyde 33 was synthesized
from the C1–C11 unit inter-
mediate 21 as shown in
Scheme 9. Sonogashira cou-
pling[25] of alkyne 21 with
1
2
3
4
5
6
7
15
16
17
17
17
17
17
allylMgBr
allylMgBr
allylMgBr
À90
À90
À78
À78
À78
À78
À78–0
30
20
30
10
360
10
38
50
87
87
80
82
80
50:50
50:50
55:45
60:40
50:50
51:49
51:49
T
AHCTUNGTRENNUNG
E
600
phenyl
iodide
proceeded
[a] Alkyne–cobalt complex (0.04 mmol), allyl metal reagent (0.09 mmol), Et2O (0.30 mL), 20 min. [b] Isolated
yield. [c] R/S ratio at C5 (fostriecin numbering), determined by H NMR spectroscopic analysis.
smoothly to afford enyne 36.
Dihydroxylation promoted by a
catalytic amount of OsO4 af-
forded diol 37 in good yield.
The TES-protection of both hy-
droxyl groups, followed by se-
lective removal from the secon-
dary alcohol gave 39. Treatment
of 39 with BOMCl then remov-
al of the PMB group with 2,3-
dichloro-5,6-dicyanobenzoqui-
none (DDQ)[26] afforded pri-
mary alcohol 41. Oxidation of
alcohol 41 with tetrapropylam-
1
Table 2. The effect of the Lewis acid on 1,4-asymmetric induction in the reaction between 17 and allyl stanna-
nes.[a]
Entry
R
Lewis acid
T [8C]
t
Yield [%][b]
Ratio R/S[c]
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bu
HfCl4
ZnCl2
BF3·OEt2·OEt2
MgBr2·OEt2
À78
0.5 h
15
45
40
86
20
78
60
60
86
50:50
55:45
64:36
73:27
60:40
60:40
80:20
92:8
À78
4 h
10 min
8 h
0.5 h
8 h
4 h
46 h
12 h
À78
monium
perruthenate
À78 to 0
À78
(TPAP)[27] gave aldehyde 33 in
good yield.
TiCl
TiCl
TiCl
TiCl
TiCl
G
E
À78 to 0
À20
Aldehyde 34 was prepared
from diol 37 (Scheme 10). Re-
moval of the PMB protecting
group with trifluoroacetic acid
(TFA), followed by treatment
with benzaldehyde dimethyl
À40
À45
45:55
[a] Alkyne–cobalt complex 17 (0.04 mmol), allyl stannane (0.40 mmol), Lewis acid (0.40 mmol), CH2Cl2
(2 mL). [b] Isolated yield. [c] R/S ratio at C5 (fostriecin numbering), determined by HPLC analysis.
through 1,3-asymmetric induction directed by the C9 stereo-
genic center (see Scheme 2).
There are several reports on chelation-controlled 1,3-
asymmetric induction in the literature. Reetz and Jung re-
ported that 1,3-asymmetric induction in the reaction of 3-
benzyloxybutanal and MeTiCl3 afforded the anti isomer of
the product with 80% diastereomeric excess (de).[22] Mar-
shall and Jahns observed anti-selective addition of an alkyn-
yl lithium reagent to b-tert-butyldimethylsiloxyaldehyde in
the presence of LiBr,[23] and the anti isomer was predomi-
nately obtained in the Lewis acid mediated addition of al-
kynyl stannanes to b-siloxyaldehydes reported by Evans and
co-workers.[24]
The stereoselective coupling of the C1–C11 and C12–C18
units was expected to be facile because of this precedent,
however, this was not the case and a model study had to be
carried out. The results obtained by Evans et al.[24] suggested
that the combination of the hydroxyl-protecting group, nu-
acetal in the presence of toluene sulfonic acid (TsOH) af-
forded 43. Protection of the tert-alcohol with TESOTf and
2,6-lutidine gave 44. Reduction of 44 with DIBAL-H afford-
ed primary alcohol 45, which was oxidized with TPAP to
afford 34.
Aldehyde 35 was also synthesized from diol 37
(Scheme 11). Successive protection of the secondary and ter-
tiary hydroxyl groups of 37 with TBSOTf and TESOTf, re-
spectively, afforded 47. Removal of the PMB group and oxi-
dation of the primary hydroxyl group with TPAP provided
35.
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Formal Total Synthesis of Fostriecin
FULL PAPER
Next, the Lewis acid was in-
vestigated. Me2AlCl, MeAlCl2
or BF3·OEt2 were selected be-
cause BF3·OEt2 is reported to
afford the desired selectivity.[24]
As shown in Table 4, the reac-
tion proceeds in some cases, but
the desired anti isomer was
only obtained with low selectiv-
ity (Table 4, entry 4) or as the
minor isomer.
These inferior results can be
explained by the presence of
bulky substituents at C8 (fos-
triecin numbering). That is, be-
cause the chair transition state
53 cannot be formed as a result
of the steric bulk at C8, the ex-
pected 1,3-asymmetric induc-
Scheme 9. Synthesis of model aldehyde 33 (NMO=N-methylmorpholine-N-oxide).
tion
cannot
be
realized
(Scheme 12).
To realize the 1,3-asymmetric
induction, we thought as fol-
lows: If the hydroxyl groups at
C8 and C9 were protected as a
cyclic acetal the conformation
would be fixed. If the reaction
proceeds through transition
state 55 (shown in Scheme 13),
in which chelation would be
possible, the desired anti isomer
should be generated predomi-
nantly. With this transition state
in mind, model aldehyde 54 was
synthesized from the previous
precursor 37 by formation of
acetal 57 with acetone dimethyl
acetal, followed by the removal
of PMB and oxidation of alco-
Scheme 10. Synthesis of model aldehyde 34.
hol
58
with
TEMPO[28]
Scheme 11. Synthesis of model aldehyde 35.
(Scheme 14).
The crucial 1,3-asymmetric
induction was investigated in
1,3-Asymmetric induction: Reaction of 33–35 with phenyla-
cetylene: Phenylacetylene was selected as a model for the
C12–C18 dienyne unit and the coupling reaction with alde-
hydes 33–35 was investigated. Chelation would be expected
in the reactions of 33 and 34, whereas it would not be ex-
pected in the case of bis-silyl-protected ether 35. The results
are summarized in Table 3. Use of LiBr in addition to the
alkynyl lithium reagent gave low diastereoselectivity
(Table 3, entries 1 and 2) and alkynyl titanium reagents, pre-
detail with model aldehyde 54. After several trials, the
choice of the metal was found to be important. Whereas
lithium and titanium acetylide gave no selectivity (Table 5,
entries 1 and 2), reaction with the zinc derivative gave good
results (Table 5, entry 3). The ratio of alkynyl lithium to
ZnBr2 is crucial to achieve the best selectivity (Table 5, en-
tries 3–5) and dialkynyl zinc was found the most suitable nu-
cleophile (Table 5, entry 4), which was also used by Fukuya-
ma and co-workers in the total synthesis of leustroduc-
sin B.[29] Excellent anti selectivity and good yield were ob-
tained with a 2:1 ratio of alkynyl lithium/zinc additive
(Table 5, entry 4).
pared by addition of TiClACHTNUTRGENN(GU OiPr)3 or TiCl2ACHTUGNTERN(NUGN OiPr)2, afforded
the undesired syn isomer predominately (Table 3, entries 3–
8). Alkynyl zinc (Table 3, entries 9 and 10) and aluminum
reagents (Table 3, entries 11 and 12) also did not afford
good results.
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10155

Y. Hayashi et al.
Table 3. The effect of the alkynyl-metal reagent on the 1,3-asymmetric induction.[a]
Synthesis of the aldehyde (C1–
C11) unit: With conditions for
the coupling reaction estab-
lished for the model compound
54, the synthesis of the C1–C11
coupling unit 68 from alkyne–
cobalt complex 32 was investi-
gated (Scheme 15). Cobalt was
quantitatively removed from 32
by treatment with NMO and
Entry
Aldehyde
Additive
X/Y[b]
Solvent
Yield [%][c]
Ratio anti/syn[d]
1
2
3
4
5
6
7
8
33
35
33
34
35
33
34
35
33
33
33
35
LiBr
LiBr
1:3
1:3
1:1
1:1
1:1
1:1
1:1
1:1
2:1
1:1
1:1
1:1
THF
THF
50
63
99
99
90
80
90
90
99
45
85
90
50:50
58:42
14:86
47:53
17:83
22:78
52:48
25:75
33:67
38:62
50:50
60:40
TiCl
TiCl
TiCl
TiCl
TiCl
TiCl
N
toluene/THF
toluene/THF
toluene/THF
toluene/THF
toluene/THF
toluene/THF
Et2O
Et2O
THF
THF
subsequent
reduction
with
sodium bis(2-methoxyethoxy)a-
luminum hydride (Red-Al)
gave trans alkene 62 selectively,
in good yield. The unsaturated
lactone moiety 63, which was
constructed by acylation with
acryloyl chloride, was exposed
to the Grubbs second-genera-
tion catalyst[30] to afford 64 in
quantitative yield. Cleavage of
the BOM group afforded the
diol 65, which is an intermedi-
ate from the synthesis of Hata-
keyama et al.[7f,l,m] Compound
65 was protected as its dimethyl
acetal 66 and subsequent re-
moval of the PMB protecting
group, followed by TEMPO ox-
idation[28] afforded key inter-
mediate 68.
CHTUNGTRENNUNG
CHTUNGTRENNUNG
CHTUNGTRENNUNG
9
ZnBr2
ZnBr2
Me2AlCl
Me2AlCl
10
11
12
[a] Phenylacetylene (0.30 mmol), BuLi (0.20 mmol), Lewis acid (0.11 mmol), aldehyde (5.50 mmol), solvent
(0.30 mL), À788C, 2 h. [b] Ratio of alkynyl lithium/additive. [c] Isolated yield. [d] Determined by 1H NMR
spectroscopy of the crude product.
Table 4. The effect of Lewis acid in the 1,3-asymmetric induction.[a]
Entry
Aldehyde
Lewis acid
T [8C]
Yield [%][b]
Ratio anti/syn[c]
1
2
3
4
5
6
33
35
33
34
35
33
Me2AlCl
Me2AlCl
MeAlCl2
MeAlCl2
MeAlCl2
BF3·OEt2
À90
À90
À78
À78
À78
À78
70
21:79
nd[e]
23:77
69:31
nd
decomp.[d]
70
60
decomp.
90
Synthesis of the dienyne (C12–
C18) unit: The coupling part-
ner, dienyne 5, was synthesized
stereoselectively from cis-1,2-di-
52:48
[a] Phenylacetylene (0.30 mmol), BuLi (0.20 mmol), Lewis acid (0.11 mmol), aldehyde (5.50 mmol), Et2O
(0.30 mL), 2 h. [b] Isolated yield. [c] Determined by 1H NMR spectroscopy of the crude product. [d] Decompo- chloroethene (69) by two suc-
sition of the starting material. [f] Not determined.
cessive Sonogashira reactions
with 2-propyne-1-ol and trime-
thylsilylacetylene to generate
enyne derivative 71 in good yield (Scheme 16). Stereoselec-
tive reduction with Red-Al,[31] followed by protection of the
hydroxyl group with TBDPSCl and deprotection of the
TMS group with K2CO3 afforded 5 in good yield.
Coupling of the C1–C11 and
Scheme 12. Postulated transition state for the reaction of 52.
C12–C18 units and completion
of the formal total synthesis of
1: The crucial coupling reaction
of aldehyde 68 and dienyne 5
was performed by using the
conditions developed with the
model substrates (Scheme 17).
The alkynylzinc reagent gener-
ated from 5 reacted smoothly
with 68 to give 74 in good yield,
Scheme 13. Postulated transition state for the reaction of 54.
with excellent diastereoselectiv-
10156
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Chem. Eur. J. 2010, 16, 10150 – 10159

Formal Total Synthesis of Fostriecin
FULL PAPER
Scheme 14. Synthesis of model aldehyde 54.
ity. Treatment of 74 with TFA removed both the acetal and
TBDPS groups to yield tetraol 75. Protection of the primary
alcohol with TBDPSCl gave 76. The labile triene unit 2 was
successfully constructed in good yield by reduction with
Rieke Zn[32] in the presence of buffer solution. The conver-
Scheme 16. Synthesis of the C12–C18 dienyne unit 5.
Conclusion
Table 5. The effect of the nucleophile in the reaction of 54 with alkynyl metal.[a]
We have accomplished the syn-
thesis of protected dephospho-
fostriecin 2, and thereby
a
formal synthesis of fostriecin
Ratio anti/syn[c] (1). Two of the four stereogenic
Entry
Additive
none
X/Y
Solvent
T [8C]
Yield [%][b]
centers were generated with an
1
2
3
4
5
–
THF
toluene/THF
Et2O
Et2O
Et2O
À78
60
90
70
90
50
45:55
TiCl
N
1:1
1:1
2:1
3:1
À78
50:50
72:28
91:9
external chiral reagent by
Sharpless asymmetric dihydrox-
ylation. The other two were
ZnBr2
ZnBr2
ZnBr2
À78 to À20
À78 to À20
À78 to À50
90:10
synthesized
stereoselectively:
[a] Phenylacetylene (0.29 mmol), BuLi (0.20 mmol), Lewis acid (0.11 mmol), aldehyde (19.2 mmol), solvent
one by a novel 1,4-asymmetric
induction within an alkyne–
cobalt complex developed by
(0.30 mL). [b] Isolated yield. [c] Determined by HPLC.
sion of 2 to 1 has been demonstrated by Imanishi and co-
workers,[7c,d] thus, the formal total synthesis of 1 has been ac-
complished.
our group,[9] the second by 1,3-asymmetric induction. Al-
though cobalt has been used in many types of reaction,[33–40]
the present reaction is the first successful example of the
use of a cobalt complex in 1,4-
asymmetric induction.
Acknowledgements
This work was partially supported by a
Grant-in-Aid for Scientific Research
from MEXT.
Scheme 15. Synthesis of the C1–C11 aldehyde unit 68 from alkyne–cobalt complex 32.
Chem. Eur. J. 2010, 16, 10150 – 10159
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www.chemeurj.org
10157

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Chem. Eur. J. 2010, 16, 10150 – 10159

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Received: March 30, 2010
Published online: July 19, 2010
Chem. Eur. J. 2010, 16, 10150 – 10159
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www.chemeurj.org
10159