General strategy for synthesis of C-19 methyl-substituted sarpagine / macroline / ajmaline indole alkaloids including total synthesis of 19(S),20(R)-dihydroperaksine, 19(S),20(R)-dihydroperaksine-17-al, and peraksine

Article abstract of DOI:10.1021/jo5016163

A detailed account of the development of a general strategy for synthesis of the C-19 methyl-substituted alkaloids including total synthesis of 19(S),20(R)-dihydroperaksine-17-al (1), 19(S),20(R)-dihydroperaksine (2), and peraksine (6) is presented. Efforts directed toward the total synthesis of macrosalhine chloride (5) are also reported. Important to success is the sequence of chemical reactions which include a critical haloboration reaction, regioselective hydroboration, and controlled oxidation (to provide sensitive enolizable aldehydes at C-20). In addition, the all-important Pd-catalyzed α-vinylation reaction has been extended to a chiral C-19 alkyl-substituted substrate for the first time. Synthesis of the advanced intermediate 64 completes an improved formal total synthesis of talcarpine (26) and provides a starting point for synthesis of macroline-related alkaloids 27-31. Similarly, extension of this synthetic strategy in the ring A oxygenated series should provide easy access to the northern hemisphere 32b of the bisindoles angustricraline, alstocraline, and foliacraline (Figure 4).

Full text of DOI:10.1021/jo5016163

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Article
General Strategy for the Synthesis of C-19 Methyl Substituted
Sarpagine/Macroline-Ajmaline Indole Alkaloids Including
the Total Synthesis of 19(S),20(R)-Dihydroperaksine,
19(S),20(R)-Dihydroperaksine-17-al and Peraksine
Rahul Vinod Edwankar, Chitra Rahul Edwankar, Jeffrey R Deschamps, and James M. Cook
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5016163 • Publication Date (Web): 23 Sep 2014
Downloaded from http://pubs.acs.org on September 28, 2014
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General Strategy for the Synthesis of Cꢀ19 Methyl Substituted
Sarpagine/MacrolineꢀAjmaline Indole Alkaloids Including the Total Synthesis
of 19(S),20(R)ꢀDihydroperaksine, 19(S),20(R)ꢀDihydroperaksineꢀ17ꢀal and
Peraksine
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†
†
‡
*†
Rahul V. Edwankar, Chitra R. Edwankar, Jeffrey R. Deschamps and James M. Cook
†
Department of Chemistry & Biochemistry, University of WisconsinꢀMilwaukee, Milwaukee, WI
53201
‡
Center for Biomolecular Science and Engineering, Naval Research Laboratory, Code 6930,
Washington, D. C 20375, USA
capncook@uwm.edu
TOC
Dꢀ(+)ꢀtryptophan
H
H
O
H
H
N
H
H
R
O
N
N
N
19
N
R
N
Me
H
Me
H
H
H
H
H
CHO
2
2a R = H
26 ( )ꢀtalcarpine
OH
22b R = Me
1
2
R = CHO, (+)ꢀdihydroperaksineꢀ17ꢀal
R = CH OH, (+)ꢀdihydroperaksine
2
H
H
R1
H
H
H
AcO
O
Cl
H
OH
O
N
OH
N
N
Me
H
N
H
N
N
H
H
H
H
H
5 (+)ꢀmacrosalhine chloride
H
R2
H
ajmaline alkaloids
0-17
6
(+)ꢀperaksine
1
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ABSTRACT
A detailed account of the development of a general strategy for the synthesis of the Cꢀ19 methyl
substituted alkaloids including the total synthesis of 19(S),20(R)ꢀdihydroperaksineꢀ17ꢀal (1),
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19(S),20(R)ꢀdihydroperaksine (2) and peraksine (6) is presented. Efforts directed toward the total
synthesis of macrosalhine chloride (5) are also reported. Important to success is the sequence of
chemical reactions which include a critical haloboration reaction, regioselective hydroboration
and controlled oxidation (to provide sensitive enolizable aldehydes at Cꢀ20). In addition, the allꢀ
important Pdꢀcatalyzed αꢀvinylation reaction has been extended to a chiral Cꢀ19 alkyl substituted
substrate for the first time. The synthesis of the advanced intermediate 32a completes an
improved formal total synthesis of talcarpine (26) and provides a starting point for the synthesis
of macrolineꢀrelated alkaloids 27ꢀ31. Similarly extension of this synthetic strategy in the ring A
oxygenated series should provide an easy access to the northern hemisphere 32b of the
bisindoles angustricraline, alstocraline and foliacraline (Figure 4).
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INTRODUCTION
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Figure 1. Sarpagineꢀajmaline alkaloids containing a Cꢀ19(S) methyl group.
The Cꢀ19 methyl substituted indole alkaloids represented in Figure 1 are a relatively rare
1
class of alkaloids belonging to the sarpagineꢀajmaline series with over seventeen members
2
isolated to date. In addition to the asymmetric centers at Cꢀ3(S), Cꢀ5(S) and Cꢀ15(R) of the
sarpagine/ajmaline framework, these alkaloids share a distinctive feature which is the presence
of a βꢀmethyl group at Cꢀ19. The sarpagine indole alkaloids (+)ꢀ19(S),20(R)ꢀdihydroperaksineꢀ
17ꢀal (1), (+)ꢀ19(S),20(R)ꢀdihydroperaksine (2) and (+)ꢀ10ꢀhydroxydihydroperaksine (3), were
3
isolated from the hairy root culture of Rauwolfia serpentina by Stöckigt et al. The root of
Rauwolfia serpentina Benth (N.0.Apocyanaciae) has been in use in India for hundreds of years
4
for a host of unrelated ailments. The plant has gained universal acclamation as a useful
5
therapeutic agent in the treatment of high blood pressure. The presence of high concentrations
of alkaloids and other phytochemicals has provided a basis for the ethnomedical use of this plant
6
in treating various medical conditions. Oꢀacetyl preperakine (4) was isolated from the stem bark
7
of Rauwolfia volkensii by Akinloye et al. However, the stereochemistry of the Cꢀ19 methyl and
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Cꢀ20 aldehydic groups were not determined the during isolation. The presence of a hexacyclic
hemiacetal ring is a unique feature of the Cꢀ19 methyl substituted alkaloids macrosalhine
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chloride 5 (isolated from Alstonia macrophylla), peraksine 6 (isolated from Rauwolfia
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10
perakensis), verticillatine 7 (isolated from Rauwolfia verticillata), and alstoyunine A (8) and B
1
1
12
9 (isolated from Alstonia yunnanensis) . Perakine 10 (isolated from Rauwolfia Vomitoria),
1
3
raucaffrinoline 11 (isolated from Rauwolfia Caffra), 10ꢀmethoxyperakine (12) and vincawajine
1
4
1
4 (isolated from Vinca Major), 10ꢀmethoxyraucaffrinoline 13 (isolated from Vinca
1
5
16
herbacea), rauvotetraphylline D 15 (isolated from Rauwolfia tetraphylla) as well as
11
alstoyunine C (16) and D 17 (isolated from Alstonia yunnanensis) are the eight ajmalineꢀ
related alkaloids which also belong to this group.
Scheme 1. Biomimetic and Biosynthetic relationship between the sarpagine, macroline and
ajmaline alkaloids.
(Me) SO , K CO ,
2
4
2
3
H
H
N
OR
benzene, heat;
TBAF, THF19
H
N
H
H
OH
O
b
O
ꢀorꢀ
N
Me
N
Me
MeI, THF; KOtBu,
H
H
H
EtOH, THF, reflux,
H
1
1
8a R = TBS,
8b R = TIPS
1
9 macroline
9
0%; TBAF, THF,
8
6%20
O
H
H
17
HO
acetyl CoA/vinorine
synthase21
H
N
N
N
H
N
H
H
H
H
H
2
0
21
1
6ꢀepivellosimine
deacetylvinorine
1a
The sarpagine group of alkaloids (represented by 18) is the largest class of natural
1
7
1b
products related to the macroline and ajmaline bases and both series originate from common
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biogenetic intermediates. Sarpagine alkaloids can be converted to macroline 19 by a retroꢀ
1
8
Michael reaction or a Hoffmann elimination reaction of the N ꢀmethyl intermediate of 18a/b, as
b
1
9
20
demonstrated by LeQuesne et al. and latter confirmed in Milwaukee, whereas a biogenetic
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connection between the sarpagine and ajmaline alkaloids was confirmed by the conversion of
2
1
16ꢀepivellosimine 20 into deacetylvinorine 21 by Stöckigt et al. (Scheme 1).
Figure 2. Pentacyclic intermediates 22
Based on this, the Cꢀ19 methyl substituted basic sarpagine framework 22 (Figure 2)
could serve as the key template for the synthesis of the ajmaline alkaloids 10ꢀ17 and the
16,17,22
macroline bases 22ꢀ30 (Figure 3).
Extension of this synthetic strategy to the ringꢀA
oxygenated series should provide the macroline intermediate 32b, the northern hemisphere of the
2
2b,23
bisindoles (+)ꢀangusticraline, (+)ꢀalstocraline and (+)ꢀfoliacraline (Figure 4).
Herein we
would like to provide a detailed account of the development of a general strategy for the
synthesis of the Cꢀ19 methyl substituted alkaloids including the total synthesis of (+)ꢀ
2
4
1
9(S),20(R)ꢀdihydroperaksine (1), (+)ꢀ19(S),20(R)ꢀdihydroperaksineꢀ17ꢀal (2), (+)ꢀperaksine
6) and formal total synthesis of ( )ꢀtalcarpine (25) as well as the efforts directed toward the
total synthesis of (+)ꢀmacrosalhine chloride (5).
(
̶
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HO
MeO
H
N
H
N
H
H
H
OH
OH
O
16
N
R
N
Me
Me
H
H
H
CHO
0
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3 R = Me, ꢀH at Cꢀ16
2
5 ( )ꢀ19,20ꢀdehydroꢀ10ꢀ
methoxytalcarpine22b
+)ꢀrauvoyunine A22a
(
2
4 R = H, ꢀH at Cꢀ16
(+)ꢀrauvotetraphylline A16
H
H
H
H
O
O
N
R1
R2
N
N
N
Me
Me
Me
Me
H
H
H
H
R
2
9 R = CHO
2
6 R = H, R = CHO
1 2
)ꢀtalcarpine17
(
)ꢀsecotalcarpine17
(
27 R = H, R = CH OH
30 R = CH2OH
1
2
2
( )ꢀmacrocarpine B22c
(
)ꢀmacrocarpine A22c
2
8 R = OH, R = CH OH
31 R = CH2OAc
1
2
2
( )ꢀmacrocarpine C22c
(
)ꢀalstohentine22d
1
6,17,22
Figure 3. Macrolineꢀrelated indole alkaloids
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MeO
MeO
H
N
H
N
H
H
H
O
O
H
OH
H
H
O
N
Me
N
Me
CO Me
2
H
H
H
10
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N
Me
Me
H
N
H
MeO
Me
H
H
N
Me
(+)ꢀangusticraline
(+)ꢀalstocraline
MeO
MeO C
N
2
H
H
N
H
O
H
H
O
N
Me
H
H
Me
N
H
(+)ꢀfoliacraline
MeO C
N
2
H
(
(
A) Alstonia bisindoles
B) Proposed biogenesis of angusticraline and alstocraline
R
OR1
R, R = OMe
1
(+)ꢀangusticraline
(+)ꢀalstocraline
H
H
OH
N
N
Me
CHO
Me
N
R = OMe
H
H
H
H
R = H
1
Me
MeO C
N
3
3
2a = H
2
H
2b = OMe
macroline equivalents
R = H, norcabucraline
1
R = OMe, cabucraline
1
Figure 4. Alstonia bisindoles and their proposed biogenesis.
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RESULTS AND DISCUSSION
Scheme 2. Retrosynthetic Analysis
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7
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As illustrated in Scheme 2, in a retrosynthetic sense, dihydroperaksineꢀ17ꢀal (1), and
dihydroperaksine
(2)
could
presumably
be
obtained
from
36
by
an
oxidation/epimerization/reduction sequence. The βꢀprimary alcohol in 36 could also serve as the
precursor for peraksine (6) and can be expected to originate from the terminal olefinic moiety in
aldehyde 35a via a regioselective hydroboration process. The thermodynamically stable αꢀ
aldehydes at Cꢀ17 would arise via homologation of the pentacylic ketones 22a/b, which should
be accessible via the recently modified αꢀvinylation process from iodides 34a/b. The chiral
methyl group could be introduced by alkylating the asymmetric N ꢀH tetracylic ketones 33a/b
b
with a suitably substituted optically active unit.
As planned, the basic tetracyclic core of the N ꢀH/N ꢀMe tetracyclic ketones 33a/b, which
a
a
contained rings ABCD required for the synthesis of the Cꢀ19 methyl substituted sarpagine indole
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alkaloids was constructed enantiospecifically and stereospecifically via the asymmetric Pictetꢀ
Spengler/Dieckmann protocol on a 400 g scale (from the commercially available Dꢀ(+)ꢀ
2
5
tryptophan) following the procedure developed in Milwaukee. The inclusion of the Cꢀ19 βꢀ
methyl group in the sarpagine skeleton required the synthesis of a suitably protected Rꢀ
acetylenic alcohol 40 in high optical purity (Scheme 3). Several methods have been reported for
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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26
the synthesis of enantiomerically enriched alkynols. However, many of these approaches are
not completely satisfactory because of low or moderate chemical yields and/or enantioselectivity,
especially those observed for the substrate, 1ꢀalkynꢀ3ꢀol, which has been attributed to the small
27
difference between the medium and large substitutents. Although the enzymatic resolution of
1ꢀalkynꢀ3ꢀols with a long alkyl chain, was successful, this method was difficult to apply to short
2
6g
chain analogs such as 3ꢀbutynꢀ2ꢀol because of poor enantioselectivities. This prompted us to
employ the 1ꢀtrialkylsilylꢀ1ꢀalkynꢀ3ꢀols instead as the chiral unit for introduction of the Cꢀ19
methyl group into the sarpagine framework. The 1ꢀtrialkylsilylꢀ1ꢀalkynꢀ3ꢀols have been
synthesized in higher enantiomeric excess (ee) and high yield by lipase mediated kinetic
28
resolutions of the racemic alcohols, as well as by asymmetric reduction of the corresponding
2
4,26e,h,29
ketone.
Because of the potential loss of material which results from the low volatility of
the TMSꢀpropargylic alcohols, it was decided to synthesize the more stable TIPS. Our initial
report on the synthesis of the optically active TIPS propargylic alcohol 40 began with the
asymmetric Noyori hydrogenation, which when performed on a 25 g scale resulted in 40 with an
24
erosion of ee (80% ee). In this paper, the lipase mediated kinetic resolution has been developed
as an alternative approach for the synthesis of 40 which can be performed on a large scale with
higher ee (>95%). As illustrated in Scheme 3, the synthesis of 40 began with the large scale
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2
2
2
2
2
2
2
3
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5
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preparation of the racemic TIPSꢀacetylenic alcohol 37 from commercially available TIPS
3
0
acetylene, following the procedure of Jones et al.
Scheme 3. Lipase mediated kinetic resolution of racemic alcohol 37
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
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9
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3
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7
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9
0
1
2
3
4
5
6
7
8
9
0
OH
nꢀBuLi, CH CHO,
3
CH3
THF, ꢀ40 °C
TIPS
H
95%
Triisopropyl acetylene
TIPS
37
(104 g scale)
OAc
Me
OH
OH
Me
lipase AK 20 (crude)
Me
H
H
H
vinyl acetate, dry hexanes,
MS 4 Å, rt, 72 h
TIPS
TIPS
39
TIPS
(104 g scale)
3
7
38
Rꢀacetate, 46%
Sꢀalcohol, 44%
(95% ee)
(94% ee)
OH
sat K CO in
PPh , DEAD, PhCO H,
3 2
THF, 0 °C to rt, 2 h;
2
3
Me
MeOH/H O, rt, 2 h
2
38
H
39
NaOH/H O/MeOH, rt, 2 h,
96%
2
TIPS
40
90% (over two steps)
Rꢀalcohol
OTs
OH
Me
TsCl, Et N, DMAP, CH Cl ,
ꢀ25 °C for 0.5 h, rt, 2 h,
Me
3
2
2
H
H
TIPS
TIPS
41
99%
40
Rꢀalcohol
The racemic alcohol 37 on treatment with vinyl acetate in distilled hexanes under
catalysis by crude lipase AK20 provided the desired (R)ꢀacetate 38 in 95% ee and 46% yield.
The unreacted (S)ꢀalcohol 39 was also recovered in 94% ee in 44% yield. The reaction was
found to be reproducible on a 104 g scale with no change in the ee’s of the isolated products. To
our knowledge this is the first report of a lipase catalyzed resolution of the TIPS analog 37 on a
1
large scale. The ee of the (R)ꢀacetate 38 was determined by Eu(hcf) aided analysis of the Hꢀ
3
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NMR spectrum. Saponification of the acetoxy group in 38 with K CO /MeOH provided the
2
3
(
R)ꢀalcohol 40 without loss of stereochemical integrity. The recovered (S)ꢀalcohol 39 was
recycled to the (R)ꢀalcohol 40 by a Mitsunobu inversion (following the procedure of Crimmins et
10
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al.), followed by saponification of the ester thereby increasing the efficiency of the process. In
order to perform the S 2 reaction, the secondary alcohol in 40 was converted to propargyl
N
tosylate 41, which was employed for alkylation without any further purification.
Scheme 4. Synthesis of the Acetylenic Ketones 43a/b
The N ꢀalkylation of the secondary amines 33a/b (individually) with optically active (R)ꢀ
b
tosylate 41 either in THF/DMF/ethanol with K CO resulted in very little conversion or complete
2
3
consumption of 33a/b accompanied by baseline impurities. Since it was well known that the
3
2
nucleophilic strength was dependent on the solvent employed in the reaction, accordingly
acetonitrile proved to be the most suitable solvent for this process as the reaction went to
completion in 12ꢀ14 h under refluxing conditions to give 42a and 42b (individually) along with
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2
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2
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2
2
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3
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their minor diastereomers 42a′/b′ in a combined yield of 89% and 94% in N ꢀH and the N ꢀMe
a
a
series, respectively. Both diastereomers (major vs minor) were completely separable both in the
N ꢀH and N ꢀMe series by silica gel column chromatography.
a
a
0
1
2
3
4
5
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7
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9
0
Desilylation of 42a/b with tetrabutylammonium fluoride (TBAF·xH O) at 0 °C in THF
2
provided the acetylenic compounds 43a/b, respectively, in 96% yield (Scheme 4). The ‘S’
configuration at Cꢀ12 (Cꢀ19 for the sarpagine skeleton) was confirmed by Xꢀray crystal analysis
in the N ꢀMe series (Scheme 4). With the successful introduction of the chiral methyl group into
a
the developing sarpagine framework, attention now turned to the synthesis of ring E via the
vinyl iodides 34a/b.
The simplest method for converting terminal alkynes to vinyl iodides in a single step is
3
3
by the use of HI which is not useful especially for sensitive substrates. Although other methods
34
are reported there are very few reports on the direct synthesis of αꢀvinyl iodides from terminal
3
5
36
alkynes. Suzuki et al. reported a single step conversion of terminal alkynes into 2ꢀhaloꢀ1ꢀ
alkenes in excellent yields and very high regioselectivity by using Bꢀbromoꢀor Bꢀiodoꢀ9ꢀBBN
[
BBN: borabicyclo(3.3.1)nonane].
Initial attempts at haloboration of 43a/b with BꢀIꢀ9ꢀBBN resulted in very liitle
conversion. Attempts to improve this included: heating it to reflux, or increasing the equivalents
of the reagent (1.2 to 8 eq), use of freshly distilled reagent, portion wise addition, but none of
them provided any significant improvement on the outcome of the reaction. At best only 30%
yield of the desired vinyl iodides 34a/b could be achieved. It was felt that addition of the first
few equivalents of the borane reagent resulted in complexation of the boron reagent to the ketone
in 43a/b and created a steric cloud, which prevented another molecule of BꢀIꢀ9ꢀBBN from
approaching the acetylenic moiety. Due to the less than satisfactory outcome of the key step,
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investigation of other haloborating agents was investigated. The order of reactivity of the
haloborating reagents commonly used is: BꢀIꢀ9ꢀBBN, BBr > BCl > BꢀBrꢀ9ꢀBBN. BꢀClꢀ9ꢀBBN.
3
3
Although BBr is equivalent in reactivity to BꢀIꢀ9ꢀBBN, the propensity of the N ꢀnitrogen in
3
b
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4
3a/b, to form stable borane complexes with smaller boranes as observed earlier in a similar
3
8
sarpagine framework and possibly altering the course of the reaction at the terminal alkyne,
rendered it unsuitable. The consistently poor yields obtained during this process led us to two
metal catalyzed approaches to achieve this critical conversion. The Pdꢀcatalyzed silastannation
reaction as well as the Moꢀcatalyzed hydrostannation were employed to this effect (Scheme 5).
Scheme 5. Functionalization of the acetylenic tetracyclic ketones 43a/b
The Moꢀcatalyzed hydrostannation process reported by Kazmaier et al. is a useful method
39
for the synthesis of αꢀvinyl stannanes. Secondary terminal propargylic systems are reported to
give higher αꢀselectivities with good to excellent yields under these conditions. The acetylene
system 43a on treatment with the catalyst Mo(CO) (CNtꢀBu) in the presence of Bu SnH in THF
3
3
3
at 60 °C gave a mixture of both the desired αꢀstannylated product 45a as well as the βꢀ
stannylated product 45a' in a 6 : 4 ratio in 60% yield (Scheme 5). The formation of the βꢀ
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5
5
5
6
stannylated alkenes 45a' suggested that the isonitrile ligands were not bulky enough to impart
regioselectivity in the system under study here. No further optimization was performed to
improve the selectivity in the process.
0
1
2
3
4
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7
8
9
0
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2
3
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1
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8
9
0
The first examples of the Pd catalyzed regioselective silastannation of alkynes was
4
0
41
reported by the groups of Mitchell and Chenard. Terminal acetylenes on treatment with
silylstannanes in the presence of catalytic amounts of tetrakis(triphenylphosphine)palladium
gave highly regioꢀ and stereoselective addition products (cis addition with tin always added to
4
2
the internal position). Tanner et al. reported the silastannation reaction of several secondary
terminal propargylic alcohols (protected and unprotected) with palladium dibenzylidene
chloroform adduct [Pd (dba) ·CHCl ] as the catalyst in combination with 1ꢀ2 equivalents of Ph P
2
3
3
3
per Pd., thereby improving the scope of this reaction. Both N ꢀH and N ꢀmethyl acetylenic
a
a
40
ketones 43a/b, when subjected to the conditions of the silastannation, underwent complete
conversion into the desired silastannanes 44a/b in 3.5 h (Scheme 5). The silastannane reagent,
trimethylsilyl triꢀnꢀbutylstannane (Bu SnSiMe ), was prepared on large scale, according to the
3
3
43
procedure of Rajanbabu et al. The syn addition of the silastannane reagent to the alkyne was
confirmed by Xꢀray analysis of 44b (Scheme 5). Although efforts were continued to improve the
haloboration approach; the poor selectivity obtained in the Moꢀcatalyzed hydrostannation
process necessitated the use of the lengthier silastannation method for the synthesis of vinyl
iodide 34a/b.
Conversion of the silastannanes 44a/b to the respective vinyl iodides required two
additional steps. The first step of desilylation proved to be a challenging task. Vinyl silanes are
known to undergo desilylation under conditions of nucleophilic catalysis specifically wherein
ꢀ
good nucleophiles for silicon (i.e F or alkoxide) are employed. Conditions tend to be harsh or
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prolonged for efficient desilylation unless other factors come into play. Additionally, due to the
acid sensitive nature of the substrate, protodesilylation was not a feasible option. Desilylation of
44a/b with 1ꢀ1.5 eq. of TBAF in THF at room temperature resulted in yields consistently below
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
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54
55
56
57
58
59
60
1
0% due to very little conversion. Due to the absence of stabilizing groups in the silastannane
substrates 44a/b, it was felt the protodesilylation would require harsher conditions. A large
excess of TBAF·xH O (up to 25 eq at 70 °C for almost 20 h, 1.0 M solution in THF) was
2
required for complete consumption of 44a/b (Scheme 6). At best, only 65% conversion was
observed in both N ꢀH and N ꢀMe substrates. It was then decided to increase the nucleophilicity
a
a
of the fluoride ion by employing DMF as the solvent. A mixture of THF : DMF (3 : 2) improved
the rate and the yield of the reaction drastically. Upon further optimization, it was found that
performing the reaction in anhydrous DMF at 65 °C, with 13 (N ꢀH series) and 4 (N ꢀMe series)
a
a
equivalents of TBAF·xH O (solid), resulted in a much cleaner reaction with the desired vinyl
2
stannanes 45a/b obtained in 84% and 88% yield, respectively.
In order to obtain the iodoꢀolefins 34a/b, the next step was to subject the vinyl stannanes
45a/b to the conditions of halodestannation. Under the standard conditions for halodestannations,
very low yields of the desired iodoꢀolefins 34a/b were obtained. Addition of excess iodine or
performing the reaction at reflux (in CHCl with I /Nꢀiodosuccinimide) were detrimental to the
3
2
yield of the process. Although, complete conversion was achieved after performing the reaction
at 40 °C with 3.5 (for 45a) to 2 (for 45b) equivalents of iodine, the isolated yield of the process
was still low 35% (for 34a) and 50% (for 34b).
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Scheme 6. Synthesis of the vinyl iodides 34a/b via halodestannation
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
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9
0
Scheme 7. Haloboration of the acetylenic tetracyclic ketones 43a/b
Although the desired vinyl iodides 34a/b were synthesized via the silastannation
approach, effort were made to make this approach more efficient. The haloboranes BꢀIꢀ9ꢀBBN
and dicyclohexyliodoborane [IꢀB(Cy) ] have been employed for the synthesis of (Z)ꢀ
2
4
4
enolborinates exclusively from various ethyl ketones. IꢀB(Cy) is a highly stereoselective
2
4
5
46
reagent for executing enolboration of esters and tertiary amides. If all other parameters are
kept the same, the inability of BꢀIꢀ9ꢀBBN to drive the haloboration reaction to completion was
felt to be due to the rigid skeleton of the bicyclo ring of BꢀIꢀ9ꢀBBN as a major factor. In contrast,
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the two cyclohexyl rings of IꢀB(Cy) are conformationally more flexible and should be able to
2
adjust to the neighboring environment. This steric difference prompted the substitution of the Iꢀ
B(Cy) for the BꢀIꢀ9ꢀBBN in the haloboration sequence. Moreover, the regioselectivity of the
2
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process should remain unchanged on making this switch. After numerous trials, it was found that
addition of 2.5 eq of dicyclohexyliodoborane (1.0 M solution in hexanes) and subsequent
protonlysis with acetic acid provided the vinyl iodides 34a/b in 74% yield with complete
regioselectivity. This was a huge improvement over the previous haloboration method and also
provided a shorter and more efficient route to the core pentacyclic framework. To our
knowledge, this is also the first example of haloboration on terminal acetylenes using IꢀB(Cy) as
2
the haloborating reagent. The silastannation, protodesilylation and the halodestannation steps
could now be avoided and the acetylenic compounds 43a/b (individually) could now be
converted directly into the desired iodoꢀolefins in a single step in good yields.
Scheme 8. Synthesis of the Key Pentacyclic Ketones 22a/b
In keeping with the retrosynthetic analysis, the iodoꢀolefins 34a/b were subjected to the
conditions of the recently developed palladium catalyzed intramolecular cross coupling
4
7
reaction. The iodoꢀolefins 34a/b were stirred (individually) with Pd (dba) , DPEPhos and
2
3
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NaOtꢀBu in refluxing THF to provide the desired pentacyclic ketones 22a/b in 60ꢀ68% yield
(
Scheme 8). The key N ꢀH pentacyclic ketone 22a could now be used for both the synthesis of
a
the Cꢀ19 methyl substituted sarpagine and ajmaline alkaloids. The N ꢀMe intermediate 22b on
a
0
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9
0
the other hand, could now be employed for the synthesis of macroline and sarpagine alkaloids as
discussed earlier. The following sections detail the further functionalization of the ketones 22a/b,
toward achieving the synthesis of the target alkaloids.
Scheme 9. Synthesis of the Cꢀ20 primary alcohol 48
OMe
Ph P(Cl)CH OCH ,
tꢀBuOK, benzene,
H
N
3
2
3
2 N aq HCl, THF,
22a
rt, 13 h
55 °C, 6 h
N
H
H
4
H
6
H
H
H
ethylene glycol,
O
O
H
N
CHO
pTSA—H O,
2
N
benzene, DST,
reflux, 6 h, 90%
(over three steps)
N
N
H
H
H
H
H
H
4
7
3
5a
BH —DMS,
THF, rt, 2 h,
3
H
H
O
O
O
O
H
N
H
N
NaBO —4H O;
3
2
OH
N
Na CO , MeOH,
N
2
3
H
reflux, 5 h
H
H
H
H
H
OH
73% over two steps
H
36 (25)
48(1)
DST = DeanꢀStark trap
With the Cꢀ19 methyl pentacyclic ketone’s 22a/b now available in gram quantities; 22a
was subjected to a one carbon atom homologation process to provide the Cꢀ17 aldehyde in 35a.
Execution of a Wittig reaction, followed by acid hydrolysis of the corresponding two
stereoisomeric enol methyl ethers 46 afforded the thermodynamically stable αꢀaldehyde. The
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aldehyde at Cꢀ17 was located in the more stable configuration even with the presence of the Cꢀ19
methyl group in the βꢀposition. The aldehydic group in 35a was protected as the cyclic acetal 47
in 93% yield with 1,3ꢀdioxolane in the presence of para toluenesulfonic acid monohydrate
10
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13
14
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18
19
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48
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(
pTSA·H O) in refluxing benzene (Scheme 9). The hydroborationꢀoxidation sequence to
2
43
generate the desired primary alcohol 36, was achieved under kinetic control; 9 equivalents of
borane dimethylsulfide complex were added at room temperature in one portion to a solution of
the acetal 47 in THF, to minimize the Markovnikov alcohol 49 and to facilitate the formation of
the antiꢀMarkovnikov (kinetic) monol 36 (Scheme 9). The primary and tertiary alcohols existed
as N ꢀBH complexes (in the ratio of 25 : 1), because of the highly basic (highly exposed) nature
b
3
of the N ꢀnitrogen atom. The presence of the N ꢀborane complex was felt to be the reason for the
b
b
formation of a small amount of tertiary alcohol 48. Inverse addition of the acetal 47 to a solution
of borane dimethylsulfide complex in THF did not eliminate the formation of 48.
Decomplexation of the N ꢀborane complexes of 36 and 48 was achieved by stirring the mixture
b
with 5 eq. of Na CO in refluxing methanol for 5 h, after which the desired primary alcohol 36
2
3
along with tertiary alcohol 48 was obtained with the free nitrogen function in 88% yield. Clearly
the hydroboration of the C20ꢀC21 terminal olefin bond had taken place from the αꢀface and
supported its hindered nature from the βꢀface.
48
With the all important primary alcohol 36 in hand, the next step was oxidation to obtain
the βꢀaldehyde followed by epimerization. The basicity of the N ꢀnitrogen function in the
b
sarpagine framework and the electron rich character of the indole nucleus (especially with the
indole N ꢀH function), contributed in making the oxidation of the primary alcohol in 36 more
a
problematic. Swern oxidation gave a complex mixture of products whereas DessꢀMartin
periodinane (DMP) oxidation led to aldehyde N ꢀoxide formation and some over oxidized
b
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byproduct as identified by mass spectrometry. Because of the susceptibility of the N ꢀnitrogen
b
atom in the monol 36 to over oxidation, attention focused on the much milder CoreyꢀKim
oxidation. During initial attempts, the addition of the alcohol 36 in CH Cl at room temperature
2
2
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to 5 equivalents of the CoreyꢀKim salt at –78 °C, generated a small amount of the aldehyde Nbꢀ
oxide (not shown). Reduction of the equivalents of the CoreyꢀKim reagent from 5 to 3.5,
accompanied by addition of the cooled solution (–78 °C) of 36 in CH Cl to the reagent at –78 °C
2
2
resulted in a much cleaner reaction and completely eliminated formation of any over oxidized
byproduct. The reaction mixture was then treated with 16 eq. of triethylamine and allowed to stir
Scheme 10. Completion of the total synthesis of 1 and 2
H
O
NCS/DMS, CH Cl ,
2
2
H
N
5
°C to 10 °C;
O
0.5 h, cool to 78 °C;
NaBH4, EtOH
36
N
Et N, warm to rt,
3
0
°C ꢀ rt, 94%
H
H
H
3
h, 67%
4
9
CHO
H
O
H
H
H
N
CHO
1.38 N aq HCl,
O
N
acetone/H O,
2
N
N
H
70 °C, 96%
H
H
H
H
H
50
OH
1
OH
H
H
NaBH4,
EtOH
OH
N
H
94%
N
H
H
2
OH
1
at –78 °C for 1 h and at rt for 1 h. Since an epimeric mixture of aldehydes were obtained ( H
NMR spectrum), it was decided to carry out complete epimerization in the same reaction vessel
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by allowing the reaction mixture to stir at rt for an additional 2 h. Column chromatography
purification of the crude furnished the α ꢀaldehyde 49 as a colorless oil (Scheme 10).
Reduction of the stable αꢀaldehyde 49 with NaBH in ethanol for 3 h at room temperature
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
furnished the αꢀalcohol 50 in 95% yield (Scheme 10). This was followed by hydrolysis of the
acetal group in 50 under acidic conditions (1.38 N aqueous HCl) in refluxing acetone to provide
19(S),20(R)ꢀdihydroperaksineꢀ17ꢀal 1 in 96% yield. A modified workup which took advantage of
the basicity of the N ꢀnitrogen function was sufficient to remove all the hydrocarbon impurities
b
1
13
and the product 1 thus obtained required no further purification. The signals in the H and C
3
NMR spectra of 1 were in excellent agreement with the literature values. The 19(S),20(R)ꢀ
dihydroperaksineꢀ17ꢀal (1) was then further subjected to reduction with NaBH to complete the
4
first total synthesis of 19(S),20(R)ꢀdihydroperaksine 2 (Scheme 10). The synthetic 1 and 2 were
also identical on TLC including a mixed TLC sample to the sample of natural 19(S),20(R)ꢀ
dihydroperaksineꢀ17ꢀal (1) and natural 19(S),20(R)ꢀdihydroperaksine (2) kindly supplied by
4
9
Professor Joachim Stöckigt.
To effect the formation of the hemiacetal ring in peraksine (6), the monol 36 was heated
1
to reflux for 24 h in THF in the presence of 10 eq. of 1 N aq HCl. Examination of the H NMR
spectrum of the crude material after 24 h indicated the formation of the hemiacetal ring but the
cyclic acetal ring had opened only half way to give an ether linkage (see 51) as a single
diastereomer (Scheme 11). To overcome this problem the reaction was also carried out in THF :
H O (1:1), but this also resulted in the formation of ether 51 after 1 day at reflux. The continued
2
heating of ether 51 with an additional 10 eq of 1 N aqueous HCL for 4 days resulted in the
formation of a trace amount of 6.
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2
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2
3
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3
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3
4
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4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
Scheme 11. Completion of the total synthesis of peraksine (6)
H
H
N
H
1
N aq HCl
10 eq)
THF, reflux,
1 N aq HCl
O
(
(additional 10 eq)
36
OH
6
O
continued reflux
for 4 days
N
1
d
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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9
0
1
2
3
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6
7
8
9
0
H
H
H
H
5
1
OMe
H
pTSA—H O, MeOH,
H
N
2
CHCl , reflux, 6 h, 93%;
OMe
19
OH
1 N aq HCl,
THF, reflux,
d, 52%
3
46a
BH —DMS, THF, rt, 2 h,
3
N
1
NaBO —4H O; Na CO ,
3
2
2
3
H
H
H
MeOH, reflux, 5 h, 35%
H
52
H
H
H
N
OH
O
N
H
H
H
H
6
Because of the resistance of the ethereal linkage in 51 to hydrolysis due to reversible
formation of the 1,3ꢀdioxolane ring, the cyclic acetal was converted into the dimethoxy acetal.
The dimethoxy acetal group was not as stable as the 1,3ꢀdioxolane group to the hydroboration
reaction conditions and resulted in only 35% yield of the desired monol 52. The monol 52 when
subjected to reflux in acidic conditions effected the hemicacetal ring formation and thus provided
peraksine 6 as an epimeric mixture at Cꢀ17 in 52% yield (Scheme 11) analogous to Arthur et.
9
b
al.
Studies directed toward the total synthesis of macrosalhine chloride (5) as well as the
partial total synthesis of talcarpine (26).
With the successful synthesis of the Cꢀ19 methyl functionalized sarpagine alkaloids 1
and 2 in the N ꢀH series, synthesis of the hemiacetal alkaloid (in the N ꢀmethyl series)
a
a
macrosalhine chloride 5, was next attempted. Macrosalhine 5 was isolated from the stem bark of
Alstonia macrophylla WALL. by Schmid et. al. in small amounts as the chloride or the
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thiocyanate salt. The structure of this alkaloid was determined on the basis of NMR, and by Xꢀ
8
ray analysis of its bromide salt. With the key pentacyclic template 31b in hand, attention was
focused on the synthesis of the hemiacetal ring formation in 5. It was decided to first reduce the
aldehyde at Cꢀ16 into an alcohol, protect it with a suitable acidꢀlabile group, and then
functionalize the terminal olefin to the least stable βꢀaldehyde by a hydroborationꢀoxidation
sequence. Cyclization of this βꢀaldehyde with the protected primary alcohol under acidic
conditions would then enable the hemiacetal ring formation in 5.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 12. Synthesis of Cꢀ20 primary alcohol 54
Ph P(Cl)CH OCH ,
tꢀBuOK, benzene,
H
3
2
3
H
N
CHO
rt, 13 h;
22b
2
N aq HCl,
THF, 55 °C,
h, 90%
N
Me
H
H
6
35b
ORTEP view of the
crystal structure of 35b
H
BH —DMS,
THF, rt, 2 h,
3
H
N
OTIPS
NaBH , EtOH,
4
0 °C ꢀ rt, 90%
NaBO —4H O;
3
2
N
TIPSOTf,
Na CO ,
2 3
Me
H
2,6ꢀlutidine,
H
MeOH, reflux, 5 h
CH Cl , rt, 95%
81% over two steps
2
2
53
H
H
H
H
N
H
N
H
N
OTIPS
OH
OTIPS
OH
N
N
N
Me
Me
Me
H
H
H
H
H
H
H
OH
H
54 (71%)
55 (3%)
56
(7%)
The pentacyclic ketone 22b was thus converted to the aldehyde 35b by a Wittigꢀ
hydrolysis sequence. The αꢀposition of the aldehyde at C16 was confirmed by Xꢀray analysis
(
Scheme 12). Reduction of 35b with NaBH afforded the alcohol (95%), which was then
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1
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2
2
2
2
2
2
2
2
2
3
3
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3
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4
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5
5
5
5
5
5
5
5
5
5
6
protected as its silyl ether to give 53. Hydroboration of the terminal olefin in 53 provided the
desired monol 54, accompanied by the expected tertiary alcohol 55 and the unusual
protodeboronation byproduct 56 (Scheme 12).
0
1
2
3
4
5
6
7
8
9
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2
3
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5
6
7
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9
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3
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6
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8
9
0
Scheme 13. CoreyꢀKim oxidation
Due to the susceptibility of the more basic N ꢀnitrogen to form Nꢀoxides, as observed in
b
the N ꢀH series, it was decided to employ the milder CoreyꢀKim oxidation to carry out the
a
oxidation, although it was felt some of the more stable αꢀaldehyde 57b might form in this
process. The oxidation was carried out under identical conditions developed in the N ꢀH series
a
and resulted in a mixture of aldehydes 57a/b (reaction mixture was not allowed to warm to rt
1
after addition of Et N). The ratio of the two aldehydes as determined by H NMR was 4 : 1 in
3
favor of the βꢀaldehyde 57a. The mixture of aldehydes 57a/b was then heated at reflux under
mild acidic conditions to attempt formation of the cyclic hemiacetal. However, upon stirring in
acidic media, complete epimerization to the αꢀaldehyde accompanied by desilyation of the TIPS
ether was observed (Scheme 13). Reduction of the equivalents of Et N from 16 to 3 failed to
3
improve the outcome of the process. Thus the inability to prevent the formation of the αꢀ
aldehyde in the CoreyꢀKim oxidation was detrimental to the hemiacetal ring formation.
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Scheme 14. DMP Oxidation and Acid Mediated Hemiacetal Ring Formation
H
H
H
N
H
N
OTIPS
OH
OTIPS
DMP, CH Cl ,
2
2
O
N
0 C ꢀ rt,
3 h, 67%
N
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CHO
Me
H
H
H
H
H
H
54
59
MeI, THF,
0 C, overnight, 99%
1 N aq HCl,
THF, reflux,
2
h, 75%
H
H
H
N
H
OTIPS
OH
I
O
O
N
OH
N
Me
N
Me
H
H
H
H
H
61
H
60
H
reduction,
quaternization
H
H
DMP, DCM
OTIPS
CHO
I
5
N
N
Me
H
H
6
2
H
As performed in the N ꢀH series, the DessꢀMartin periodinane (DMP) oxidation was next
a
attempted. As expected, the Nꢀoxide of the desired βꢀaldehyde 59 was obtained as the only
stereoisomer (Scheme 14), in spite of efforts to prevent over oxidation by either using fewer
equivalents of DMP or performing the reaction at lower temperature. Attempts at using TFA
(
equivalents varied from 1.5 to 1.1 eq.) in the above case (to protonate the N ꢀnitrogen) or
b
IBX/DMSO to carry out the oxidation also gave similar results along with recovered starting
material 52. Since macrosalhine chloride 5 is a quaternary salt, the N nitrogen in amine 54 was
b
quaternized with excess methyl iodide to give salt 61. However, oxidation of alcohol 61 with
DMP resulted in a complex mixture with no evidence of aldehyde formation. In all the above
processes strict anhydrous conditions were maintained.
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5
5
5
5
5
5
5
5
5
6
Since the βꢀaldehyde 59 was obtained as the sole product during the above oxidation
process, it was decided to first attempt the hemiacetal ring formation and then perform a
reduction of the Nꢀoxide to complete the synthesis of 5. Thus refluxing the aldehyde 59 in 1 N
aqueous HCl for 24 h, furnished the cyclic hemiacetal 60. At this point with only limited material
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
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9
0
left in hand, efforts to reduce the Nꢀoxide with Zn/AcOH failed to produce the free N ꢀnitrogen.
b
Further work toward attempting this key step this is necessary to complete the total synthesis of
5
.
Scheme 15. Formal total synthesis of talcarpine
Although the CoreyꢀKim oxidation could not be utilized for the synthesis of 5, it
provided a much milder method for the synthesis of the epimeric aldehydes 57a/b (Scheme 13)
and then to the thermodynamically stable αꢀaldehyde 57b (Scheme 15) in a one pot process.
Further quaternization of the N ꢀnitrogen atom in 57b with excess MeI provided salt 63 which
b
when subjected to a retro Michael reaction provided the macroline framework in olefin 64
(Scheme 15). Desilylation of the TIPS group in olefin 64 to the free alcohol would generate the
allꢀimportant macroline equivalent 32a (Figure 4b), which was the intermediate involved in the
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50
partial synthesis of talcarpine 25 by Sakai et. al. This resulted in the formal total synthesis of 25
here. The macroline intermediate 64 would also serve as the precursor for the potential synthesis
of the macroline related alkaloids 26, 29 and 30. Additionally 32b, with the 10ꢀmethoxy
equivalent of 32a and the northern hemisphere of the Alstonia bisindoles (+)ꢀangusticraline, (+)ꢀ
alstocraline and (+)ꢀfoliacraline (Figure 4A) could be synthesized from 5ꢀmethoxyꢀDꢀtryptophan
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
1
ethyl ester via the route developed here.
CONCLUSION
The first enantiospecific, stereospecific total synthesis of 19(S),20(R)ꢀdihydroperaksine (1),
1
9(S),20(R)ꢀdihydroperaksineꢀ17ꢀal (2) and peraksine (6) has been accomplished. A
stereospecific approach towards the synthesis of macrosalhine chloride (5) was also developed.
Commercially available Dꢀ(+)ꢀtryptophan has served both as the chiral auxiliary and the starting
material. Moreover, this is the first synthesis which sets the stereochemistry of the methyl group
at Cꢀ19 in a stereospecific fashion. The acetylenic moiety 43a/b was modified to the key vinyl
iodide 34a/b by silylꢀstannation and haloboration approaches. Initial attempts at haloboration
were accompanied by inconsistent reproducibility, purification problems and very low yield,
which were circumvented by modification of the reaction conditions and the use of a superior
haloborating agent (dicyclohexyliodoborane). It is important to point out that the palladium
catalyzed αꢀvinylation has been extended to the Cꢀ19 chiral methyl series which make it a
process of more general applicability. The key N ꢀH pentacyclic ketone 22a could now be used
a
for the synthesis of the Cꢀ19 methyl substituted ajmaline alkaloids 10, 11, 14ꢀ17 and a route
amenable to the synthesis of macroline–related alkaloids 27ꢀ31 is now possible due to the
efficient synthesis of the advanced intermediate 64 via a general strategy for the synthesis of Cꢀ
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5
5
5
6
1
9 methyl substituted indole alkaloids. This process provides a general entry; it is felt, into a
whole series of biosynthetically important monoterpene Cꢀ19 substituted indole alkaloids.
EXPERIMENTAL SECTION
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0
The experimental details for the synthesis of alkaloids 1, 2 and compounds 22a, 34a, 36, 41, 42a,
43a, 47, 49 and 50 are contained in the SI of reference 24a
. For general experimental
considerations see SI.
Lipase catalyzed kinetic resolution of 4ꢀtriisopropylsilylꢀ3ꢀbutynꢀ2ꢀol (37). A 5 L round
bottom flask, which had been flame dried, was equipped with an overhead mechanical stirrer and
was charged with 69.0 g of ground activated 4Å molecular sieves and 50 g (0.5 mass equiv) of
the lipase (crude) Amano AK20. To this were added 4 L of distilled hexanes, 158.2 g (1.83
mmol) of vinyl acetate (dried over MgSO ) and the racemic alcohol 37 (104 g, 0.46 mol). This
4
suspension was stirred at 25 °C for 5 days, after which analysis by NMR spectroscopy indicated
5
0% conversion to the Rꢀacetate 38. The solution was filtered and concentrated under reduced
pressure, and the crude product purified by column chromatography (silica gel) with 2ꢀ10%
EtOAc/hexanes as the eluant to afford the Rꢀacetate 38 (63.0 g, 45.8%) and the Sꢀalcohol 39
(46.0 g, 44%).
1
Rꢀacetate 38: R 0.59 (silica gel, EtOAc/hexanes, 1:7); H NMR (400 MHz, CDCl ) δ 5.49 (q,
f
3
1
H, J = 6.8 Hz), 2.10 (s, 3H), 1.51 (d, 3H, J = 6.8 Hz), 1.09 (s, 21H). The % ee of the Rꢀacetate
1
38 was determined as 95%, by Eu(hcf) aided H NMR analysis. The acetate was not subjected to
3
any further characterization and was used in the next step as is.
1
Sꢀalcohol 39: R 0.33 (silica gel, EtOAc/hexanes, 1:7); H NMR (300 MHz, CDCl ) δ 4.54 (q,
f
3
1
1H, J = 6.6 Hz), 1.91 (s, 1H), 1.47 (d, 3H, J = 6.6 Hz), 1.07 (s, 21H) [ H NMR was identical to
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+
that reported for Rꢀalcohol 40 herein]; HRMS (APCIꢀTOF) m/z: [M+H] Calcd for C H OSi
1
3
27
227.1826, Found 227.1828.
This material was employed directly in the next step without any further characterization.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hydrolysis of the Rꢀacetate 38 to the R-alcohol 40. The Rꢀacetate 38 (10 g) was dissolved in a
saturated solution (100 mL) of K CO in MeOH : H O (15:1). The solution, which resulted, was
2
3
2
stirred at rt for 2 h until the disappearance of the starting material 38 as monitored by TLC (silica
gel). The solvent was then removed under reduced pressure and the mixture, which resulted, was
extracted with ether. The organic layer was separated and dried over anhydrous Na SO , and
2
4
concentrated to give the Rꢀalcohol 40 as a clear oil (8.1 g, 96%). Rf 0.33 (silica gel,
2
0
1
EtOAc/hexanes, 1 : 7); [α] + 23.38° (c 2.01 CHCl ); H NMR (400 MHz, CDCl ) δ 4.56 (q,
D
3
3
1
3
1
H, J = 6.4 Hz), 2.06 (br s, 1H), 1.49 (d, 3H, J = 6.4 Hz), 1.09 (s, 21H); C NMR (75 MHz,
+
CDCl ) δ 109.8, 84.4, 58.8, 24.6, 18.6, 11.1; HRMS (APCIꢀTOF) m/z: [M+H] Calcd for
3
C H OSi 227.1826, Found 227.1826.
13
27
Mitsunobu inversion of the Sꢀalcohol 39 to the Rꢀalcohol 40. To a stirred solution of Sꢀalcohol
9 (28.0 g, 0.124 mol) in dry THF (2.1 L) at rt was added triphenylphosphine (64.85 g, 0.247
3
mol) and benzoic acid (30.2 g, 0.247 mol). The mixture, which resulted, was then cooled to 0 °C
and to it was added diethyl azodicarboxylate (41 g, 0.235 mol). The reaction mixture was
allowed to warm to rt and stirred for an additional 2.5 h. The solution was then concentrated and
the residue was dissolved in ethyl acetate and filtered through a pad of celite topped with silica
gel. The filtrate was concentrated and the residue was dissolved in a solution of MeOH (200
mL), THF (70 mL), H O (70 mL) and 15 g NaOH. This mixture was stirred for 2 h and the
2
solvents were removed under reduced pressure. The aq residue was extracted with diethyl ether
(
3 x 100 mL). The combined organic extracts were dried over Na SO , filtered and concentrated
2 4
2
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