Synthesis of functionalized octahydroindoles related to daphnyphyllum alkaloids

Article abstract of DOI:10.1055/s-0033-1340794

Functionalized octahydroindoles were synthesized from (±)-cyclohex- 2-en-1-ol as potential intermediates for convergent syntheses of several alkaloids from plants of the Daphnyphyllum genus. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1340794

LETTER
▌799
lSetyternthesis of Functionalized Octahydroindoles Related to Daphnyphyllum
Alkaloids
Synthesis of Functionalized Octahydroindoles
Stéphane Dorich, Juan R. Del Valle, Stephen Hanessian*
Department of Chemistry, Université de Montréal, Station Centre-Ville, C.P. 6128, Montreal, Quebec, H3C 3J7, Canada
Fax +1(514)3435728; E-mail: stephen.hanessian@umontreal.ca
Received: 16.12.2013; Accepted after revision: 16.01.2014
by various groups using diverse strategies.4 In a recent
synthesis of the tetracyclic core of daphniglaucin C,5 we
used 4-hydroxy-L-proline as a suitable chiron that was
manipulated to give an all-syn 3,4-disubstituted L-proline6
which was further elaborated to form the intended struc-
ture. We also investigated an alternative approach involv-
ing the elaboration of cyclohex-2-en-1-ol to give the 3-
methyloctahydroindoles. Here, we report some results
pertaining to the latter approach.
Abstract: Functionalized octahydroindoles were synthesized from
(±)-cyclohex-2-en-1-ol as potential intermediates for convergent
syntheses of several alkaloids from plants of the Daphnyphyllum
genus.
Key words: alkaloids, heterocycles, bicyclic compounds, natural
products, hydrogenation, diastereoselectivity
In recent decades, over two hundred structurally complex
natural products have been isolated from the plants of the
genus Daphnyphyllum.1 These alkaloids share highly con-
served polycyclic structures and stereochemistries. Sever-
al of them, such as the daphniglaucins A‒K,
daphnilactones A‒B, caldaphnine, and related com-
pounds, feature a substituted octahydroindole motif em-
bedded in various architecturally complex structures,
some examples of which are shown in Figure 1. The octa-
hydroindole motif is also found in the clinically relevant
angiotensin-converting enzyme inhibitor perindopril.2
The synthesis began with commercially available racemic
cyclohex-2-en-1-ol7 (4, Scheme 1). Epoxidation8 gave the
syn-epoxy alcohol 5, which was protected as its benzyl
ether 6. The epoxide underwent regioselective ring cleav-
age on treatment with trimethylsilyl triflate and 2,6-di-
methylpyridine,
followed
by
1,8-diazabicyclo-
[5.4.0]undec-7-ene, to give the allylic alcohol 7 in 87%
yield (two steps) after methanolysis of the intermediate
trimethylsilyl ether.9 Mitsunobu displacement10 with one
equivalent of 4-methyl-N-prop-2-yn-1-ylbenzenesulfon-
amide gave enyne 8 in 86% yield. The SN2′ addition by-
product was obtained as an inseparable mixture with 8
when excess alkyne was used. Next, we tried a number of
methods to convert enyne 8 into the intended octahydro-
indole, including zirconium-assisted cyclization11 or indi-
um-, ruthenium-, or palladium-catalyzed12–14 cyclizations.
In the end, we used radical enyne cyclization under stan-
dard conditions [tributylstannane, 2,2′-azobis(isobutyro-
nitrile)]15 to obtain the octahydroindole 9 in 83% yield
after protolysis of the intermediate vinyl stannane. This
method proved to be reproducible and could be performed
on a gram scale.16 The structure and relative stereochem-
istry of 9 were confirmed by X-ray crystal structure anal-
ysis.16
CO2Me
OH
Me
O
O
Me
N
O
H
N
O
H
H
daphniglaucin C (1)
daphnilactone B (2)
Me
OH
Me
N
H
caldaphnine (3)
At this stage, we attempted to hydrogenate the exocyclic
methylene group under standard conditions to convert it
into a methyl group at the 3-position. We had hoped that
the shape of the bicyclic ring would force the hydrogena-
tion to occur from the convex pro-S face to give the de-
sired S-diastereoisomer, as found in daphnyphyllum
alkaloids (Figure 1). Unfortunately, when we used palla-
dium(II) hydroxide/carbon under one atmosphere of hy-
Figure 1 Selected alkaloids that feature substituted octahydroindole
motifs, isolated from plants of the Daphnyphyllum genus
Although the biosynthesis of the daphnyphyllum alka-
loids has been studied,3 the absolute stereochemistry of
some members is not unequivocally known. It is possible
that the methyl group is derived from mevalonic acid
[(3R)-3,5-dihydroxy-3-methylpentanoic acid]. Approach- drogen in methanol, in ethyl acetate, or in a 1:1 mixture of
the two solvents, hydrogenation with concomitant hydro-
genolysis of the benzyloxy group gave the desired S-dia-
stereoisomer as the minor component of an inseparable
1:3.5 mixture with the corresponding all-syn R-isomer,
formed through hydrogenation from the concave face (Ta-
ble 1, entries 1‒3). Oxidation of the secondary alcohol
es to the synthesis of these alkaloids have been addressed
SYNLETT 2014, 25, 0799–0804
Advanced online publication: 24.02.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340794; Art ID: ST-2013-S1144-L
© Georg Thieme Verlag Stuttgart · New York

800
S. Dorich et al.
LETTER
Table 1 Hydrogenation of Intermediate 9 Giving Ketone 10 as the
Major Diastereoisomer
NaH, BnBr
DMF, 93%
MCPBA
O
O
CH2Cl2, 75%
Me
Me
H
H
H
OH
OBn
OH
( )-4
1. conditions
5
6
+
N
N
N
2. DMP, CH2Cl2
83%, 2 steps
NHTs
H
OBn
H
H
1. TMSOTf, 2,6-lutidine
Ts
Ts
Ts
O
O
then, DBU
9
10
11
X-ray
OH
DIAD, Ph3P
PhH, 86%
2. K2CO3, MeOH
87%, 2 steps
OBn
Entry
Conditionsa
10/11
7
H
1. Bu3SnH, AIBN
PhMe, reflux
1
2
3
4
5
6
7
Pd(OH)2/C, H2, MeOH, 16 h
Pd(OH)2/C, H2, EtOAc, 16 h
3.5:1
3.5:1
3.5:1
3.5:1
2:1b
2:1b
–
3
3a
7a
7
N
N
2. TsOH, CH2Cl2
83%
H
OBn
Ts
OBn Ts
Pd(OH)2/C, H2, EtOAc–MeOH (1:1), 16 h
Pd/C, H2, EtOAc–MeOH (1:1), 16 h
[Ir(COD)(PCy3)(py)]PF6, H2, CH2Cl2, 3 d
RhCl(PPh3)3, H2, CH2Cl2, 3 d
8
9
X-ray
Scheme 1 Synthesis of the octahydroindole intermediate 9
NBSHc, toluene, 3 d
groups in the S- and R-products gave ketones 10 and 11,
respectively, which were subjected to X-ray crystal struc-
ture analysis. It became clear that the concave shape of the
octahydroindole 9 actually forces the N-tosyl protecting
group to point toward the convex face of the product (see
the X-ray crystal structure of 9).16 As a result, hydrogena-
tion occurs from the least-hindered concave face. Never-
theless, we tested various hydrogenation conditions in an
attempt to reverse the diastereoselectivity. Unfortunately,
neither palladium/carbon (entry 4) nor Crabtree’s catalyst
(entry 5) nor Wilkinson’s catalyst (entry 6) allowed the
formation of the desired diastereoisomer 11 as the major
product. Furthermore, the use of 2-nitrobenzenesulfono-
hydrazine,17 a known hydrogen source, led to recovery of
9 (entry 7).
a All reactions were carried out at r.t.
b Without hydrogenolysis of the benzyl ether.
c NBSH = 2-nitrobenzenesulfonohydrazine.
with N-prop-2-yn-1-ylmethanesulfonamide gave amine
14 in 78% yield, with none of the SN2′ byproduct (Scheme
3). The free radical-mediated enyne cyclization of 14 then
gave octahydroindole 15 in 80% yield after protolysis of
the vinyl stannane. Hydrogenation of 15 with Pearlman’s
catalyst under one atmosphere of hydrogen followed by
oxidation of the secondary alcohol group gave ketones 16
and 17 in a 2.4:1 ratio. The relative stereochemistry of ke-
tone 17 (and, hence, of ketone 16) was ascertained by X-
ray crystal structure analysis.16
We reasoned that the bulky benzyl ether might have
caused the undesired diastereoselectivity by sterically
forcing the N-tosyl group to adopt the unfavorable inver-
tomer. We therefore cleaved the benzyl ether with boron
tribromide under standard conditions to give the alcohol
12 in 83% yield (Scheme 2). However, hydrogenation
again eventually gave the undesired R-diastereoisomer 10
as the major product, this time in a 2:1 ratio with the S-iso-
mer 11. Oxidation of alcohol 12 to the corresponding ke-
tone 13 and subsequent hydrogenation also gave the
undesired R-diastereoisomer as the major product, albeit
in an improved ratio of 1.4:1. When we used Wilkinson’s
catalyst or Crabtree’s catalyst for the hydrogenation of ke-
tone 13, we obtained diastereoisomers 10 and 11 in a 1:1
ratio.
H
H
H
BBr3, CHCl3
83%
DMP, CH2Cl2
82%
N
N
N
H
OBn
H
H
Ts
Ts
Ts
OH
12
O
13
9
1. H2, Pd(OH)2/C
EtOAc, quant.
2.(COCl)2, Et3N, DMSO
CH2Cl2, 80%, 2 steps
(10/11 = 2:1)
H2, Pd(OH)2/C
EtOAc, quant.
(10/11 = 1.4:1)
Me
Me
H
H
We rationalized that it might be possible to reverse the
trend in diastereoselectivity by using a different N-pro-
tecting group. We rationalized that the use of a protective
group smaller than N-tosyl would reduce steric hindrance
on the convex face of the bicyclic intermediate, permitting
the hydrogenation to proceed in the desired manner. To
this end, the Mitsunobu displacement reaction of enol 7
+
N
N
H
H
Ts
Ts
O
O
10
11
Scheme 2 Attempts to improve the diastereoselectivity of the hydro-
genation at C‒3
Synlett 2014, 25, 799–804
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Functionalized Octahydroindoles
801
regioselectively functionalizing ketone 11 at C-6.20 We
conjectured that simple treatment of 11 with a base and
subsequent trapping of the enolate with an electrophile
might permit functionalization as a step toward advanced
tricyclic and tetracyclic intermediates. However, our pre-
liminary attempts using various bases and Mander’s
reagent21 gave complex mixtures of regioisomers, diaste-
reoisomers, and enol tautomers. To simplify the analysis
of the products, we treated the ketone with lithium hexa-
methyldisilazide in tetrahydrofuran, and quenched the re-
sulting enolate with tert-butyl(dimethyl)silyl triflate to
give the silyl enol ethers 21 and 22 in a 2:1 ratio (Scheme
5). We observed no significant improvement when we
used a reverse-addition protocol. The use of lithium hexa-
methyldisilazide in other solvents (diethyl ether, toluene,
tetrahydropyran/hexamethylphosphoramide) and the use
of alternative bases (sodium or potassium hexamethyldi-
silazide or lithium diisopropylamide) also failed to give
any marked improvement.
1. Bu3SnH, AIBN
PhMe, reflux
NHMs
OH
DIAD, Ph3P
PhH, 78%
N
2. TsOH, CH2Cl2
80%, 2 steps
OBn
OBn Ms
7
14
Me
Me
H
H
H
1. H2, Pd(OH)2/C
EtOAc–MeOH
+
2. (COCl)2, Et3N
DMSO, CH2Cl2
82%, 2 steps
N
H
N
N
H
H
Ms
Ms
Ms
OBn
O
O
16
17
X-ray
15
(2.4:1)
Scheme 3 Formation and hydrogenation of the octahydroindole in-
termediate 15
To assess the effect of the size of the N-protecting group
on the outcome of the hydrogenation reaction in more de-
tail, we synthesized the smaller N-acetyl intermediate.
Birch reduction18 of tosylate 9 with lithium in ammonia19
gave the free amino alcohol 18 in 90% yield (Scheme 4).
Acetylation under standard conditions followed by hydro-
genation with Pearlman’s catalyst still led to the (3R)-oc-
tahydroindole intermediate 20 as the major product, in a
1.5:1 ratio. The diastereoisomeric ratio was calculated by
integrating the 1H NMR spectrum and by comparison with
spectra of products obtained by the Birch reduction of the
known intermediate 19 (see Table 1).16 Finally, we exam-
ined the direct hydrogenation of the free amino alcohol 18
under previously reported conditions. Only then did we
obtain the desired S-diastereoisomer 11 as the major prod-
uct (dr = 1:5) in 63% yield over three steps from 18 after
reinstallation of the N-tosyl group.
Me
Me
Me
H
H
H
bases
solvents
7a
+
6
7
TBSOTf
N
N
N
H
OTBS
H
Ts
Ts
Ts
O
OTBS
11
21
22
(2:1, inseparable)
Me
Me
H
H
Me2NNH2
AcOH (cat.)
3 Å MS, MeOH
84%
N
N
H
H
Ts
Ts
O
Me
N
N
11
23
Me
Scheme 5 Formation of the silyl enol ethers 21 and 22 and hydra-
zone 23
1. H2, Pd(OH)2/C
EtOAc–MeOH
(R/S = 1:5)
H
Me
H
H
(S)
Li, NH3
90%
In an attempt to improve the regioselectivity of the func-
tionalization at C‒6, we prepared the hydrazone 23 in
85% yield under standard conditions22 and then we sub-
jected it to the same conditions as those used for ketone 11
(see above). However, no alkylation was observed when
hydrazone 23 was treated with lithium hexamethyldisil-
azide, lithium diisopropylamide, or sec-butyllithium in
the presence of Mander’s reagent, iodomethane, or
3-phenylpropanal.
N
2. TsCl, Et3N,
DMAP, CH2Cl2
3. DMP, CH2Cl2
63% (3 steps)
N
N
H
H
Ts
H
H
OBn
Ts
OH
18
O
9
11
1. Ac2O, DMAP, py, CH2Cl2
then K2CO3, MeOH
2. H2, Pd(OH)2/C, EtOAc–MeOH
72%, 2 steps (R/S = 1.5:1)
1. Li, NH3
Me
H
Me
2. Ac2O, DMAP
CH2Cl2, py
H
H
We then reasoned that ketone 11 had a propensity to un-
dergo undesired deprotonation at the C-7a ring-junction
position, and that treatment with a base should be avoided
to permit regioselective functionalization at C-6. With this
in mind, we attempted to convert ketone 11 into enone 24,
which might, in turn, serve as a Baylis–Hillman precursor
for regioselective functionalization at C-6.
The use of 2-iodobenzoic acid (IBX)23 in dimethyl sulfox-
ide, alone or mixed with toluene, led to no reaction after
several days, even when five equivalents of IBX were
used (Table 2, entries 1 and 2). When dimethyl sulfoxide–
benzene was used as a solvent combination, slow overox-
(R)
(R)
3. K2CO3, MeOH
45% (3 steps)
N
N
H
Ts
Ac
OH
OH
20
19
(R/S = 3.5:1)
Scheme 4 Preparation and hydrogenation of amino alcohol 18
In proceeding with syntheses of high-valued octahydroin-
dole intermediates as precursors of a range of daphny-
phyllum alkaloids, our next challenge was that of
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 799–804

802
S. Dorich et al.
LETTER
Table 2 Attempted Preparations of Enone 24
Me
Me
Me
H
H
conditions
+
N
N
N
H
H
Ts
Ts
Ts
O
O
OH
25
11
24
Entry
Conditions
Yield (%) of 24
Yield (%) of 25
1
2
3
4
5
6
7
8
IBXa (5 equiv), DMSO–toluene (2:1), 75 °C
IBX (5 equiv), DMSO, 105 °C
no conversion
no conversion
IBX (5 equiv), DMSO–benzene (2:1), 75 °C
IBX (5 equiv), DMSO–C6F6 (2:1), 75 °C
[PhSe(O)]2O (3 equiv), THF, 65 °C
trace
38
–
25
15
trace
12
[PhSe(O)]2O(1.1 equiv), toluene, 110 °C
[PhSe(O)]2O (5 equiv), toluene, 85 °C
PhSeCl (1.1 equiv), EtOAc, then py–H2O2
29
13
–
45
34
a IBX = 2-iodobenzoic acid.
idation occurred exclusively, leading to low yields of phe- rect bromo enal25 or enaminone26 formation. However, no
nol 25 (entry 3). However, when a combination of conversion was observed in either case. We therefore at-
dimethyl sulfoxide and hexafluorobenzene was used at tempted to α-halogenate the ketone 11 with molecular
75 °C, the enone 24 was formed regioselectively in 38% bromine in chloroform (Table 3, entry 1).27 To our delight,
yield after three days, together with phenol 25 (15% yield; the bromo ketone 26 was obtained exclusively as the sole
entry 4). As an alternative, we attempted selenium-medi- regioisomer and diastereoisomer. However, on a gram
ated oxidations24 of ketone 11 with 1,3-diphenyldi- scale, yields varied between 51% and 92%.28 Note that the
selenoxane 1,3-dioxide (entries 5‒7); the best results were phenol 25 was again isolated in a minor but significant
obtained by using 1.1 equiv of the reagent in toluene, yield (5–33%). The formation of this byproduct can be ex-
which gave the enone 24 in only 29% yield, along with the plained in terms of sequential dehydrogenation and bro-
phenol 25 (12%). When we attempted stepwise oxidation mination of 26.29 When an excess of N-bromosuccinimide
with benzeneselenenyl chloride and hydrogen peroxide, was used in the presence of 4-toluenesulfonic acid in ace-
the phenol 25 was obtained exclusively in 34% yield (en- tonitrile, ketone 11 was slowly but selectively converted
try 8).
into bromo ketone 26 (entry 3). Eventually, by using N-
bromosuccinimide (6.0 equiv) in acetic acid at 60 °C, we
obtained 26 in 96% yield after three days (entry 4).
Several other methods were tried in the attempt to func-
tionalize ketone 11 at C-6 without using a base, such as di-
Table 3 Diastereoselective and Regioselective Bromination of Ketone 11
Me
Me
Me
H
H
conditions
+
N
N
N
Br
H
H
Ts
Ts
Ts
O
O
OH
25
11
26
Entry
Conditions
Yield (%) of 26
Yield (%) of 25
1
2
3
4
Br2 (1.0 equiv), CHCl3, 0 °C
Br2 (1.0 equiv), MeCN, 0 °C to r.t.
51–92
48a
5–33
13
–
NBS (10 equiv), TsOH (3.0 equiv), MeCN, r.t.
NBS (6 equiv), AcOH, 60 °C
48a
96
–
a 30–35% of the starting material was also recovered.
Synlett 2014, 25, 799–804
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Functionalized Octahydroindoles
803
We conjectured that, with the bromine atom in place, the 7). Furthermore, treatment of bromo ketone 26 with tetra-
C-6 enolate might be formed regioselectively under basic butylammonium acetate gave keto acetate 30 in 63%
conditions. Elegant work by de Meijere30 had previously yield; the structure of this product was confirmed compar-
shown that bromoenol triflates can be formed in good ing its 1H NMR spectrum to those of the acetylated acyl-
yields, and coupled chemoselectively under Stille cou- oins. The ease of displacement at C-6 was also illustrated
pling conditions. We therefore attempted the preparation by treatment of bromo ketone 26 with tetrabutylammoni-
of bromoenol triflate 27 by treating bromo ketone 26 with um bromide in toluene at room temperature for sixteen
lithium hexamethyldisilazide in tetrahydrofuran, with hours to give a 1:1.5 mixture of 26 and its C-6 epimer.
subsequent trapping by triflic anhydride (Scheme 6). We
obtained a low yield that was not improved by changing
the solvent to diethyl ether, toluene, or tetrahydrofuran–
hexamethylphosphoramide (10:1) or by forming the eno-
late with potassium hexamethyldisilazide, sodium hexa-
methyldisilazide, or lithium diisopropylamide in
Encouraged by the reactivity of the bromo ketone 26 in
the formation of 28 and 30, and by the ready epimeriza-
tion at C-6, we attempted to use this as a strategy to form
a C‒C bond and, in further elaborations, to give azabicy-
clic compounds. However, when we treated bromo ketone
26 with potassium cyanide in tetrahydrofuran–metha-
tetrahydrofuran. However, when we switched to the
nol,33 attack took place at the C-7 carbonyl position to
Comins reagent, a 24% yield of 27 was obtained.31 We
give epoxide 32 in 87% yield; the structure of this product
speculate that the enolate is insufficiently reactive and
was confirmed by X-ray crystal structure analysis
that, in the basic medium, the water used for quenching
(Scheme 8).16,34,35
the reaction rapidly engages in an SN2 displacement at
C-6 to form the acyloin byproduct 28 in 30–60% yield
(Scheme 6).
Me
Me
H
H
KCN
6
7
THF–MeOH
87%
N
Me
Ts
Me
Me
N
Br
H
H
H
H
LHMDS
Comins' reagent
O
H
CN
H
Ts
Ts
O
H
+
6
26
32
X-ray
THF, –78 °C
N
N
N
Br
Br
HO
H
Ts
Ts
(C-3 epimer)
O
OTf
O
26
27 (24%)
X-ray
(C-3 epimer)
28: (6S)-up (30–60%)
Scheme 8 Unexpected regioselectivity for the cyanide displacement
reaction of bromo ketone 26
X-ray (C-3 epimer)
29: (6R)-down (0–30%)
In conclusion, a variety of octahydroindole compounds
were prepared as potential synthetic precursors to several
natural products isolated from plants of the genus
Daphnyphyllum (Figure 1). The reactivities of the func-
tionalized octahydroindole intermediates described in this
paper are subject to interesting topological effects that
Scheme 6 Formation of the acyloins 28 and 29 in preference to bro-
moenol triflate 27
When the reaction mixture was subsequently stirred for
four hours or more, the (6S)-acyloin 28 epimerized to a
1:1 mixture with (6R)-isomer 29 without transposition of
the ketone. The structures of 27 and 28 were confirmed by
X-ray diffraction analysis.16,32
dictate
the
stereochemical
outcomes
of
diastereoselective and regioselective transformations.
Further studies in this series of stereochemically distinct
and enantiopure azabicylic compounds are in progress
and will be reported in due course.
To explore the reactivity of 26 further, we acetylated ac-
yloins 28 and 29 separately under standard conditions to
give the corresponding keto acetates 30 and 31 (Scheme
Acknowledgment
Me
Me
H
H
We acknowledge financial support from NSERC, and from FQRNT
for a fellowship to S.D. We thank the CFI for a departmental grant.
Special thanks are due to Benoît Deschênes-Simard for the X-ray
diffraction analyses.
Bu4NOAc
PhMe, r.t.
63%
N
N
Br
AcO
H
H
Ts
Ts
O
O
26
30
1H NMR comparison
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SupInpfioomgrattr
o
nSupprigI
o
tnnofrmat
Me
Me
Me
H
H
H
Ac2O, py
CH2Cl2
+
References and Notes
0 °C to r.t.
72%
N
N
N
HO
AcO
AcO
H
H
H
(1) Kobayashi, J.; Kubota, T. Nat. Prod. Rep. 2009, 26, 936; and
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Volland, J. P. Drug Des. Discovery 1992, 9, 11.
Ts
Ts
Ts
O
O
O
28: (6S)-up
29: (6R)-down
30
31
Scheme 7 Formation of the acetylated acyloins 30 and 31
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 799–804

804
S. Dorich et al.
LETTER
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(35) Crystallographic data for compounds 9, 11, 17, 27, 28, and
32 have been deposited with the accession numbers CCDC
968290, 968291, 968292, 968293, 968294, and 968295,
respectively, and can be obtained free of charge from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk; Web site:
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Synlett 2014, 25, 799–804
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