Convergent and Biomimetic Enantioselective Total Synthesis of (-)-Communesin F

Article abstract of DOI:10.1021/jacs.6b04072

The first biomimetic enantioselective total synthesis of (-)-communesin F based on a late-stage heterodimerization and aminal exchange is described. Our synthesis features the expedient diazene-directed assembly of two advanced fragments to secure the con

Full text of DOI:10.1021/jacs.6b04072

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Article
Convergent and Biomimetic Enantioselective
Total Synthesis of (–)-Communesin F
Stephen P. Lathrop, Matthew Pompeo, Wen-Tau Timothy Chang, and Mohammad Movassaghi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b04072 • Publication Date (Web): 31 May 2016
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Journal of the American Chemical Society
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Convergent and Biomimetic Enantioselective Total Synthe-
sis of (–)-Communesin F
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Stephen P. Lathrop, Matthew Pompeo, Wen-Tau T. Chang, and Mohammad Movassaghi*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
Supporting Information Placeholder
Me
N1'
Me
O
H
O
H
ABSTRACT: The first biomimetic enantioselective total
synthesis of (–)-communesin F based on a late-stage het-
erodimerization and aminal exchange is described. Our
synthesis features the expedient diazene–directed assem-
bly of two advanced fragments to secure the congested
C3a–C3a' linkage in three steps, followed by a highly
efficient biogenetically inspired aminal reorganization to
access the heptacyclic communesin core in only two ad-
ditional steps. Enantioselective syntheses of the two
fragments were developed, with highlights including the
catalytic asymmetric halocyclization and diastereoselec-
tive oxyamination reactions of tryptamine derivatives, a
stereoselective sulfinimine allylation, and an efficient
cyclotryptamine–C3a-sulfamate synthesis by either a
new silver–promoted nucleophilic amination or a rhodi-
um–catalyzed C–H amination protocol. The versatile
synthesis of the fragments, their stereocontrolled assem-
bly, and the efficient aminal–exchange as supported by
in situ monitoring experiments, in addition to the final
stage N1'-acylation of the communesin core provide a
highly convergent synthesis of (–)-communesin F.
Me
H
Me
H
N
Me
Me
N
N
O
3a'
3a
NH
NH
N
Me
N
H
H
R
(–)-communesin F (1)
(–)-communesin A (2), R=Me
(–)-communesin E (3), R=H
Me
R
O
O
Me
Me
H
H
N
N
Me
Me
H
H
N
N
O
O
NH
NH
N
R
N
H
H
Me
(–)-communesin G (7), R=Et
(–)-communesin H (8), R=n-Pr
(–)-communesin B (4), R=Me
(–)-communesin C (5), R=H
(–)-communesin D (6), R=CHO
Figure 1. The Structure of Communesin Alkaloids
solution for this archetypical alkaloid. As an outgrowth
of our investigations in the area of calycanthaceous alka-
8,9
loids, we sought to develop a unified and convergent
approach to the communesin alkaloids. We drew inspi-
ration from a speculated biogenesis involving the stere-
ocontrolled oxidative union of two dissimilar tryptamine
Introduction. The communesin alkaloids are a family of
structurally complex natural products isolated from var-
ious marine and terrestrial Penicillium fungi, which have
been shown to possess insecticidal and antiproliferative
activities as well as significant cytotoxicity against lym-
phocytic leukemia.1,2 The core structures of these alka-
loids share a unique heptacyclic skeleton containing two
aminals and at least five stereogenic centers, of which
two are vicinal and quaternary (Figure 1). This exquisite
structural complexity coupled with an array of interest-
ing biological properties has prompted investigations
directed towards the chemical synthesis of these alka-
loids,2 culminating in innovative solutions for the total
synthesis of ( )-communesin F (1) by Qin,3 Weinreb,4
and Funk,5 in addition to a formal synthesis by Stoltz.6
To date, Ma’s total synthesis of (–)-communesin F (1)7
derivatives followed by reorganization of a C3a–C3a'
10,11,12,13
linked heterodimer,
reminiscent of the pathways
12,14,
leading to the related calycanthoids.
While our bio-
synthetic considerations were purely hypothetical at the
outset of this synthesis campaign, Houk, Garg, and Tang
15
have recently disclosed incisive biosynthetic and com-
putational studies that echo the key transformations de-
veloped in our synthesis. Herein, we present the shortest
enantioselective total chemical synthesis of (–)-
communesin F (1) with late-stage chemistry that fortui-
15b
tously parallels the latest insights and hypotheses con-
cerning the biogenesis of these alkaloids.
The expectation that the biosynthesis of calycantha-
14
ceous family of alkaloids has relevance to the biogenesis
of the communesins stems from the structural similarity
of these alkaloids and their precursors (Scheme 1).
remains
the
only
enantioselective
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Page 2 of 9
Scheme 1. Comparison of the Bond Formations in the
Scheme 2. Biogenetically Inspired Retrosynthetic Analy-
1
2
3
4
5
6
7
8
Biogenesis of Structurally Related Dimeric Alkaloids
sis of (–)-Communesin F (1)
Ac
Me
N
N1'
CO2H
Me
Me
Me
N1–C8a'
and
N8'–C8a
H
H
Me
Me
1
N
H
1'
H
H 1
N
N
NHR
8a'
8a'
NH2
3a'
8a
3a'
8a
bond formation;
8'
NH
8'
N
3a
3a
N
H
NSO2Ph
–
acetylation
H
N
N
N
H
+
tryptamine (9), R=H
N-methyl tryptamine (10), R=Me L-tryptophan (11)
H
19
Me
Me
(–)-aurantioclavine (12)
(–)-communesin F (1)
biomimetic
homodimerization
heterodimerization
of 9 and 12
reorganization
9
of 10
Boc
H
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
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42
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44
45
46
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50
51
52
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56
57
58
59
60
Me
H
N
H
H
N
Me
Me
H
N
Boc
N
H
N
b
H
8a'
NSO2Ph
Me
8'
NSO2Ph
3a'
H
Me
3a'
N
MeHN
a
H
N
C3a–C3a'
MeN
N
3a'
path-b
8a'
3a'
3a'
3a
bond
formation
3a
8a
3a
CN
20
CN
a
3a
3a
N
NMe
N
8a
22
21
Me
Me
NHMe
b
N
N
H
NH2
N
H
13
14
15
Boc
N
directed coupling
Boc
H
path-a
NSO2Ph
3a'
Me
N
H
Me
Me
Me
Me
H
Boc
N
Boc
N
Me
H
N
N1'
H2N
+
H
H
H
NSO2Ph
3a'
H
Me
N
H
N
N
diazene
synthesis
MeN
3a'
N
N
NH2
8a
3a'
3a'
25
3a
3a
3a
N
CN
CN
3a
Me
3a
NH
NMe
N
N
HN
Me
23
24
Me
8
N
H
N
H
H
H
N1'-deacetyl N8-desmethyl
communesin F (18)
(+)-chimonanthine (16)
(–)-calycanthine (17)
Results and Discussion. As illustrated in our retrosyn-
thetic analysis of (–)-communesin F (1, Scheme 2), strict
adherence to the central paradigm in the biogenesis of
calycanthaceous alkaloids focused our design on the effi-
cient assembly and reorganization of a key heterodimeric
intermediate 20. Prompted by our strategy for directed
Woodward and Robinson independently proposed that
the biogenesis of the calycanthoids is predicated on the
oxidative homodimerization of N-methyl tryptamine
(10) to form indolenine dimers, such as 13, which can
give rise to five constitutional isomers upon reorganiza-
tion of the two aminal functional groupings.10–11 In the
illustrative case of indolenine dimer 13 (Scheme 1),
amine cyclization via path-a results in (+)-
chimonanthine (16), whereas an alternative cyclization
via path-b, perhaps through the intermediacy of hexacy-
cle 14, affords the isomeric alkaloid (–)-calycanthine
(17). Indeed, the equilibration of (+)-chimonanthine
(16) to (–)-calycanthine (17) under acidic aqueous con-
19
heterodimerization of cyclotryptamines, we envisioned
hexacycle 20 (Scheme 2) to serve as a surrogate for the
hypothetical biosynthetic intermediate 15 (Scheme 1).
We anticipated the N8'-sulfonamide would guide the
opening of the C8a'-aminal to present the C8a'-imine for
N1-addition. Furthermore, we projected the ionization
of the C8a-nitrile would offer the C8a-imininium ion
needed for aminal formation via N8'-addition. The chal-
lenging C3a–C3a' linkage of heterodimer 20 required a
directed and stereocontrolled union of a cyclotryptamine
fragment 21 and aurantioclavine derivative 22 to simul-
taneously secure the two critical quaternary stereocen-
ters. Our diazene-based strategy for directed complex
fragment assembly19 provided the essential framework to
explore this exciting and convergent approach to (–)-
communesin F (1). While we were confident the C8a'-
stereochemisry of the cyclotryptamine moiety would
guide the desired C3a'-stereochemical outcome in this
union, we were intrigued by the potential level of stereo-
chemical control expected at C3a during carbon–carbon
bond formation. We envisioned the synthesis of complex
heterodimeric diazene 23 from tricyclic amines 24 and
25 as tryptamine–surrogates necessary for securing the
C3a–C3a' linkage (Scheme 2).
16
8a,
ditions (16:17=15:85)
demonstrates the potential dy-
namic nature of these polycyclic structures. Anticipating
a related biogenesis for the communesins, we expected
the heterodimeric intermediate 15 to undergo a similar
dynamic reorganization to afford heptacycle 18. Con-
sistent with this hypothesis, an enzyme capable of the
oxidative coupling of tryptamines and Penicillium fungal
17,18
alkaloid (–)-aurantioclavine (12)
has been identified
that leads to the formation of the communesin core or an
isomeric heptacycle depending on the tryptamine. We
15b
began our studies with the recognition that successful
implementation of a biomimetic strategy for the efficient
synthesis of these alkaloids requires the directed and
stereocontrolled union of two dissimilar fragments fol-
lowed by selective reorganization of a C3a–C3a' linked
heterodimer to a single constitutional isomer consistent
with the communesin skeleton 18.
2
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Scheme 3. Strategies for Synthesis of Tricycle 27
Scheme 4. Concise Synthesis of Sulfamate (+)-31a
1
2
3
4
5
6
7
8
F
F
S
F
S
O
O
O
O
SN1
amination
S
C–H
amination
Br
H
F
O
O
O
O
NH2
F
O
Br
HN
NBoc
NBoc
F
a
HN
3a'
3a'
NCbz
NBoc
N
N
H
H
C3a'–N
C3a'–N
63%
3a'
+
SO2Ph
SO2Ph
NCbz
NCbz
H
N
H
N
26
28
SO2Ph
H
SO2Ph
N
N
H
SO2Ph
27
SO2Ph
(+)-29, 96% ee
30
(+)-31
Our synthesis of (–)-communesin F (1) commenced
with the preparation of the two key tricyclic amines 24
and 25 required for the assembly of critical diazene 23
(Scheme 2). We pursued two approaches to the synthesis
of the C3a'-amino cyclotryptamine 25 and the corre-
sponding sulfamate 27 (Scheme 3). In the first approach,
motivated by efficient access to enantiomerically en-
9
aReagents and conditions: (a) AgSbF6, 2,6-di-tert-butyl-
4-methylpyridine, 2,6-difluorophenylsulfamate, CH2Cl2,
23 °C, 63%.
Scheme 5. Gram-scale Synthesis of Sulfamate (+)-27a
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
H
CO2Me
R
H
ArOSO2N
2'
c
b
20
a
3a'
3a'
NBoc
NBoc
NBoc
riched C3a'-halocyclotryptamine derivatives, we envi-
sioned a nucleophilic C3a'-amination (Scheme 4) remi-
niscent of our Friedel-Crafts strategy for C3a-
derivatization developed in the context of our
39%
69%
N
N
N
H
H
H
SO2Ph
SO2Ph
SO2Ph
(+)-27
(+)-32, R = Br
(+)-33, R = H
(+)-28
a
95%
21
naseseazine alkaloid total synthesis. Our second ap-
aReagents and conditions: (a) (Me3Si)3SiH, Et3B, air, 23
°C, >99:1 dr; (b) (i) KOH (aq.), MeOH, CH2Cl2, 23 °C,
(ii) N,N,N',N'-tetramethylchloroformamidinium hex-
afluorophosphate, thiopyridine N-oxide, 4-(N,N-
dimethylamino)pyridine, Et3N, THF; t-BuSH, hν, 23 °C;
(c) Rh2(esp)2, H2NSO3Ar, PhI(OAc)2, Ph(CH3)2CCO2H,
MgO, 5Å-MS, i-PrOAc, 23 °C; Ar=2,6-difluorobenzene.
22
proach to amine 25 relied on Du Bois amination of cy-
clotryptamine 28 to secure the sulfamate 27 (Scheme
19c
5).
Given the versatility of cyclotryptamine–sulfamates as
precursors to the corresponding mixed sulfamides,19c we
developed an efficient synthesis to access sulfamate (+)-
31 and related derivatives starting with C3a'-bromo-
cyclotryptamine (+)-29 (Scheme 4). Enantioselective
bromocyclization20a of Nβ-Cbz-N1-benzenesulfonyl-
tryptamine catalyzed by (S)-3,3′-bis(2,4,6-triisopropyl-
in 69% yield. Under optimal conditions, a Rh-catalyzed
C–H amination22 of cyclotryptamine (+)-28 afforded the
desired sulfamate (+)-27 in 39% yield after recrystalliza-
phenyl)-1,1′-binaphthyl-2,2′-diyl
hydrogenphosphate
24
(TRIP)20b afforded C3a'-bromocyclotryptamine (+)-29 in
tion. This three-step sequence efficiently generated
23
gram quantities of (+)-27 from the readily available
bromocyclotryptophan (+)-32 as an activated form of
C3a'-aminocyclotryptamine 25 (Scheme 2) that is ready
for coupling with tricyclic amine 24 for diazene synthe-
sis.
93% yield and 96% enantiomeric excess. Significantly,
21
electrophilic activation of the tricyclic bromide (+)-29
22
in the presence of 2,6-difluorophenylsulfamate provid-
ed the desired sulfamate (+)-31 in 63% yield (Scheme 4).
The use of 2,6-difluorophenylsulfamate as a nucleophile
to trap an intermediate C3a'-electrophile 30 provides a
new and expedient route for the directed synthesis of
complex diazenes.19c While this new single-step synthesis
of C3a'-sulfamates from the corresponding C3a'-
bromides offers a concise solution to the desired precur-
sors, its utility in conversion of the more acid sensitive
tert-butyl carbamate substrate 26 to sulfamate 27 gave
capricious and inferior outcomes (~50% yield).
Scheme 6. Strategies for Synthesis of Tricycle 24
Br
Me
H
Me
Boc
N
t-Bu
NHBoc
3a
S
Br
stereoselective
oxyamination
stereoselective
allylation
N
NH2
O
8
N
3a
3a
8a
CN
O
8N
H
O
C3a–N
C3a–C
N
N
Boc
Me
34
35
24
With an expedient synthesis of sulfamate (+)-27
available, we turned our attention to the synthesis of the
tricyclic amine 24 (Scheme 6). While syntheses of au-
rantioclavine (12) have been reported,18 the synthesis of
a derivative needed to mimic fragment 22, necessary for
our biomimetic approach to (–)-communesin F (1), has
not been described. As a result, we sought to develop an
Our alternate approach for the synthesis of tert-butyl-
carbamate derivative 27 relied on the C–H amination
chemistry illustrated in Scheme 5. Mild reduction of
bromocyclotryptophan (+)-32 provided the desired
C3a'–H cyclotryptophan (+)-33 in 95% yield.23 Subse-
quent decarboxylation furnished cyclotryptamine (+)-28
3
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Scheme 7. Oxyamination Approach to Tricycle (+)-24a
Scheme 8. Sulfinimine Allylation Approach to Tricycle
1
2
3
4
5
6
7
8
(+)-24a
Me
Me
Me
Me
OH
OH
Br
NHBoc
NHBoc
X
NHBoc
t-Bu
10
t-Bu
t-Bu
9
p-Ns
N
a
b
Me
Me
H
H
8
N
S
Br
Br
Br
N
N
S
N S
3a
O
84%
68%
a
b
3a
O
O
O
8a
3a
3a
O
O
O
O
8N
Me
N
N
N
78%
79%
N
H
N
Boc
L
-Boc-Pro
L
-Boc-Pro
Me
Me
(+)-44, X = OH
(+)-45, X = NHBoc
(–)-34
(–)-36
(–)-37
(+)-43
(–)-42
c, 82%
Me
c,d 75%
Me
Me
Me
Me
Me
h
Me
f
Boc
N
Boc
N
Boc
N
9
d, 88%
OH
H
Me
Me
p-Ns
R
Me
Me
Me
Me
Me
Me
Me
Boc
N
H
9
BocN
N
N
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
NH2
N
t-Bu
t-Bu
t-Bu
H
3a
8a
9
H
H
O
O
52%
73%
N
S
CN
N
S
N
S
8
8
h
e
O
N
Me
N
Me
H
N
R
H
O
3a
O
O
O
O
90%
81%
N
N
N
(–)-40, R = p-Ns
(–)-41, R = H
(–)-38, R =
H
(+)-24
g
70%
e
83%
Me
Me
Me
(–)-39, R = CHO
(+)-48
(–)-47
Me
(–)-46
f, 60%
aReagents and conditions: (a) 1,1-dimethylallyl alcohol,
Pd(OAc)2, P(o-tol)3, Et3N, MeCN, 95 °C; (b) 3,3-
dimethyl-2-(p-nitrobenzenesulfonyl)-1,2-oxaziridine,
CuCl2, n-Bu4NCl, CHCl3, 21 °C, 89:11 dr; (c)
PdCl2(MeCN)2, MeCN, 82 °C; (d) (i) i-Bu2AlH, THF, 0
°C, (ii) 1,8-diazabicyclo[5.4.0]undec-7-ene, MeOH, 21
°C; (e) Ac2O, HCO2H, pyridine, CH2Cl2, 21 °C; (f)
NaBH4, TFA, THF, 0 °C; (g) PhSH, K2CO3, DMF, 50 °C;
(h) Me3SiCN, (F3C)2CHOH, H2O, 21 °C; p-Ns = para-
nitrobenzenesulfonyl.
Me
Me
Me
Boc
Boc
N
N
t-Bu
H
g
N
S
NH2
O
3a
64%
CN
CN
8a
N
N
Me
Me
(+)-49
(+)-24
aReagents and conditions: (a) allylMgBr, MgBr2, CH2Cl2,
–78 °C, >98:2 dr; (b) O3, MeOH, –78 °C; NaBH4, –78 →
23 °C; (c) o-NsNHBoc, diisopropyl azodicarboxylate,
polystyrene–PPh3, THF, 50 °C; PhSH, Cs2CO3, 50 °C; (d)
Me2C(OH)CH=CHSn(n-Bu)3, PdCl2(PPh3)2, PhMe,
THF, 110 °C; (e) PdCl2(MeCN)2, MeCN, 80 °C; (f) (i)
LiBH4, MeOH, THF, 0 → 23 °C; (ii) Me3SiCN,
(F3C)2CHOH, 0 °C; (g) HCl, dioxane, MeOH, 23 °C; (h)
enantioselective synthesis of a tricycle reminiscent of
alkaloid 12 that would allow for implementation of our
synthetic strategy (Scheme 2). The tricyclic aminonitrile
24 offered the necessary C3a-amine for diazene synthesis
and the C8a-aminonitrile to allow for mild generation of
the corresponding C8a-iminium ion needed for aminal
synthesis. We developed two strategies to access the key
intermediate 24 as illustrated in Scheme 6. The first
strategy involved tryptamine 34 as the substrate for the
Sc(OTf)3, F3CCH2OH, 23 °C; o-Ns
=
ortho-
nitrobenzenesulfonyl. ORTEP representation of amine
(+)-48: thermal ellipsoids drawn at 50% probability.23
by removal of the chiral auxiliary (88% yield) provided
the desired indoline (–)-38. The formylation of indoline
(–)-38 to give formamide (–)-39 (83% yield) followed by
mild reduction with sodium borohydride in the presence
of trifluoroacetic acid gave the desired N-methylindoline
25
application of Yoon’s oxyamination chemistry, while
the second strategy utilized tert-butyl sulfinimine 35 and
26
27
Ellman’s asymmetric allylation of such substrates.
29
(–)-40 (73% yield). Exposure of sulfonamide (–)-40 to
The oxyamination25 route to aminonitrile 24 com-
thiophenol and potassium carbonate led to removal of
the para-nitrobenzenesulfonyl group and the isolation of
the stable oxazolidine (–)-41 in 70% yield. Given the
propensity of oxazolidine (–)-41 and aminonitrile (+)-24
toward elimination of the C3a-amino group under
strongly acidic or basic conditions, we developed mild
hydrolysis conditions to allow for cyanation of a transi-
ent C8a-hemiaminal leading to aminonitrile (+)-24 in
52% yield in addition to the C8a-epimer (26%). While
this approach provides flexibility for the late-stage intro-
duction of various N8-substituents and establishes the
C3a-configuration, the challenge in unraveling the oxa-
zolidine substructure prompted our investigation of an
menced with a Mizoroki-Heck reaction of bromoindole
23
(–)-34 with 1,1-dimethylallyl alcohol to provide allylic
alcohol (–)-36. Despite early reservations regarding pos-
sible competing C9-C10-oxyamination25b-f of vinyl indole
(–)-36 in place of the desired C3a-C8a-oxyamination, we
28
observed higher levels of diastereoselection for the oxy-
amination of the more advanced substrate (–)-36
(Scheme 7). The use of stoichiometric copper(II) chlo-
ride facilitated the reaction and gave oxazoline (–)-37 in
68% yield (89:11 dr). Treatment of alcohol (–)-37 with
bis(acetonitrile)dichloropalladium(II) in acetonitrile to
23
form the desired azepane (85% yield) followed
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Scheme 9. Directed Synthesis of Heterodimer (+)-51a
alternate route to aminonitrile (+)-24 (Scheme 6) involv-
ing C3a–C bond formation.
1
2
Boc
N
F
S
H
Me
H
Me
H
3
4
5
6
7
8
9
Our alternative synthesis of aminonitrile (+)-24 began
with the diastereoselective allylation26 of N8-methyl sul-
finimine (–)-42 (Scheme 8) to provide allyl oxindole (+)-
43 in 78% yield and with excellent diastereopurity after
trituration of the crude addition product with hexane
(>98:2 dr).23 In contrast to our first approach to ami-
nonitrile (+)-24, the placement of the chiral auxiliary on
the C3a-substituent enabled our use of the N8-methyl
variant of sulfinimine 35 (Scheme 6).23 Ozonolysis of
alkene (+)-43 followed by a reductive work-up afforded
the primary alcohol (+)-44 in 79% yield. The alcohol (+)-
44 was then converted to tert-butyl carbamate (+)-45 in
82% yield via a Mitsunobu displacement and subsequent
in situ desulfonylation. The allylic alcohol needed for
synthesis of the azepane substructure was introduced via
a Stille vinylation to furnish allylic alcohol (–)-46 in 88%
yield.30 A palladium-catalyzed allylic amination provided
azepane (–)-47 in 81% yield as a single diastereomer. The
stereochemistry at C3a and C9 of azepane (–)-47 was
confirmed unambiguously through analysis of the crystal
structure of the corresponding amine (+)-48 (Scheme 8).
We then focused on development of conditions for mild
and efficient conversion of oxindole (–)-47 to the desired
aminonitrile (+)-24. Partial reduction of oxindole (–)-47
with lithium borohydride afforded a mixture of C8a-
hemiaminal diastereomers that were too labile for isola-
tion. Direct treatment of the crude hemiaminal with tri-
Me
Me
a
Boc
N
Boc
N
NSO2Ph
O
S
O
O
3a'
F
O
O
N
HN
H
NH2
NH
+
3a'
80%
3a
NBoc
3a
CN
CN
8a
H
N
gram scale
N
N
SO2Ph
Me
Me
(+)-24
(+)-27
(+)-50
b, 57%
Boc
N
Boc
N
Me
H
Me
H
H
Me
Me
Boc
N
Boc
N
H
NSO2Ph
NSO2Ph
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
3a'
c
N
N
39%
3a
CN
CN
N
N
Me
Me
(+)-23
(+)-51
aReagents
and
conditions:
(a)
4-(N,N-
dimethylamino)pyridine, THF, 23 °C; (b) polystyrene–2-
t-butylimino-2-diethylamino-1,3-dimethyl-perhydro-
1,3,2-diazaphos-phorine, N-chloro-N-methylbenzamide,
MeOH, 23 °C; (c) hν (350 nm), 25 °C.
suffers from competitive arene-halogenation. After ex-
tensive experimentation, we discovered the unique abil-
ity of tertiary N-chloroamides to effect chemoselective
oxidation of sulfamide (+)-50 to the corresponding di-
azene (Scheme 9) without competitive arene-
halogenation. Exposure of sulfamide (+)-50 to N-chloro-
N-methylbenzamide (6 equiv) in conjunction with poly-
styrene-bound
2-tert-butylimino-2-diethylamino-1,3-
dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) in
31
methylsilyl cyanide in hexafluoroisopropanol furnished
methanol provided the desired diazene (+)-23 in 57%
32
35
the desired aminonitrile (+)-49 in 60% yield and the
yield. Photoexcitation and expulsion of dinitrogen from
23
easily separable minor C8a-epimer (30%). Methanolysis
a thin film of diazene (+)-23, followed by radical combi-
nation of the resulting cyclotryptamine 21 and azepane
22 (Scheme 2), afforded the desired heterodimer (+)-51
of the tert-butyl sulfinamide (+)-49 provided the desired
33
amino-azepane (+)-24 in 64% yield. The C8a-
36
aminonitrile proved to be an ideal trigger for late stage
in 39% yield as a single diastereomer. While the stereo-
34
hemiaminal formation while providing adequate stabil-
chemical outcome at C3a' of heterodimer (+)-51 is antic-
ipated,19 the remarkable diastereoselection at C3a is no-
table and likely due to the confluence of a rapid radical
combination step and the additional stereoinduction
ity for the implementation of an efficient fragment as-
sembly. We anticipate future adaptation of this robust
synthetic route to other N8-variants of azepane (+)-24
via judicious N8-substitution of sulfinimine 35.
23,37
imposed by the C8a-nitrile. Importantly, our diazene-
based strategy for directed complex fragment assembly
allowed for the stereoselective construction of the critical
C3a–C3a' linkage, securing the corresponding vicinal
quaternary stereocenters.
After developing versatile syntheses of both essential
fragments, we next examined the union of azepane (+)-
24 and cyclotryptamine (+)-27 to introduce the critical
C3a–C3a' bond. Dissolution of the two fragments in tet-
rahydrofuran
in
the
presence
of
4-(N,N-
With the successful union of the tricyclic–azepane
and the cyclotryptamine fragments at hand, we turned
our attention to the development of a biogenetically in-
spired aminal reorganization of heterodimer (+)-51 to
access the heptacyclic communesin core. Informed by
experience in rearrangement of the calycanthaceous
dimethylamino)pyridine afforded sulfamide (+)-50 in
23
80% yield on gram-scale (Scheme 9). Consistent with
our prior observation, the oxidation of sterically shielded
sulfamides containing electron-rich arenes, such as the
N-methyl aniline substructure of sulfamide (+)-50,
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Page 6 of 9
38
excellent solvent for this transformation, likely due to
Scheme 10. Synthesis of (–)-Communesin F (1) via a
Biogenetically Inspired Final Stage Reorganizationa
1
2
3
4
5
6
7
8
its ability to stabilize reactive intermediates as the corre-
sponding O-alkyl-hemiaminals. Although intermediate
Boc
H
1
23
Me
H
Me
H
H
52 could be observed by in situ H NMR spectroscopy,
H
N
N
Me
8'
Me
Boc
H
1'
1'
NSO2Ph
8a'
NSO2Ph
8a'
N
N
this compound did not show sufficient stability for isola-
tion. We suspect this may be due to the sensitive nature
of the C8a'-aminal of heptacycle 52, which upon reversi-
ble opening to the C8a'-imine increases the lability of the
C3a–C3a' bond. As a testimony to the sensitivity of the
C3a–C3a' linkage of heterodimer (+)-20, simple heating
of a derivative (C8a-OMe instead of C8a-CN) in acetoni-
1
1
3a'
3a'
a
3a
3a
8a
67%
CN
CN
8a
N
N
Me
Me
(+)-51
(+)-20
9
b, 82%
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
1'
H
Me
Me
H
N1'
N
8a'
H
Me
Me
H
H
1N
1N
8a'
N1–C8a'
and
39
trile-d3 at 80 °C predominantly led to fragmentation.
Indeed, treatment of the basic solution of heptacycle 52
with pyridinium p-toluenesulfonate to quench the alkox-
ides, followed by addition of acetic anhydride afforded
8'
N8'–C8a
bond formation
8a
8a
NSO2Ph
NSO2Ph
–
N
N
H
+
Me
Me
52
19
23
the N1'-acetyl derivative (–)-53 in 82% overall yield. A
Me
N1'
Me
final-step unveiling of the N8'-amine was accomplished
by treatment of (–)-53 with sodium amalgam to provide
(–)-communesin F (1) in 83% yield. All 1H and 13C NMR
data as well as optical rotation (observed [α]D24 = –249, c
O
H
O
H
Me
H
Me
H
N
Me
Me
N
N
c
83%
8'
20
NSO2Ph
NH
= 0.13, CHCl3; literature [α]D = –264, c = 0.34,
N
N
H
H
,
1c 23
CHCl3), for our synthetic (–)-communesin F (1) were
Me
(–)-53
Me
(–)-communesin F (1)
in agreement with literature data.
aReagents and conditions: (a) Sc(OTf)3, F3CCH2OH, 23
°C; (b) t-BuOLi, MeOH, 50 °C; dry PPTS, Ac2O, 23 °C;
(c) Na(Hg), NaH2PO4, THF, MeOH, 23 °C.
Conclusion. A highly convergent enantioselective total
synthesis of (–)-communesin F (1) with late-stage chem-
istry that parallels the latest insights15 and hypotheses
concerning the biogenesis of these alkaloids is described.
Our expedient synthesis involves the union of fragments
(+)-24 and (+)-27 to provide complex sulfamide (+)-50
on gram-scale. This advanced intermediate is converted
to alkaloid (–)-1 in only five additional steps (Schemes 9
and 10) which include the application of our diazene–
directed fragment assembly strategy to secure the con-
gested C3a–C3a' linkage, and a guided biomimetic rear-
rangement to selectively provide the heptacyclic core of
these alkaloids. Highlights of our synthesis include an
efficient cyclotryptamine–C3a-sulfamate synthesis by
either a new silver–promoted nucleophilic amination or
rhodium–catalyzed C–H amination protocol, application
of catalytic asymmetric halocyclization and diastereose-
lective oxyamination reactions in complex settings, a
stereoselective sulfinimine allylation, and efficient as-
sembly and utility of a richly functional diazene for com-
plex fragment coupling. The successful implementation
of this synthetic strategy and the versatile synthesis of the
fragments, along with a final stage acylation of the com-
munesin core provide a foundation for a unified synthet-
ic route to access structurally related complex alkaloids
and derivatives.
8,14
alkaloids, we recognized the significance in the judi-
cious choice of reaction conditions for the planned trans-
formation due to the sensitive nature of the C3a–C3a'
linkage. Furthermore, we anticipated that an appropriate
sequence of amine unveiling would maximize efficiency
for the desired aminal exchange. We projected that un-
veiling the N1- and N1'-amines of heterodimer (+)-51
would allow opening of the C8a' aminal with the ben-
zenesulfonamide as the leaving group, thus allowing rap-
id trapping of the C8a'-imine of intermediate 19 en route
to heptacycle 52. Treatment of heterodimer (+)-51 with
scandium trifluoromethanesulfonate in trifluoroethanol
provided the desired heterodimer (+)-20 by selective
removal of the tert-butyl carbamates while preserving the
sensitive C8a-aminonitrile (Scheme 10). The electron-
withdrawing N8'-sulfonamide enabled our examination
of basic conditions to selectively open the cyclotrypta-
mine substructure. In the event, treatment of heterodi-
mer (+)-20 with lithium tert-butoxide in methanol pro-
vided clean and complete conversion to the desired hep-
tacyclic structure 52 within 1 h at 50° C as observed by
1
in situ H-NMR spectroscopy.23 Significantly, only the
desired heptacycle 52 was formed in preference to other
15b
constitutional isomers. Methanol was found to be an
6
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ASSOCIATED CONTENT
1
Vogt, F.; May, J. A.; Krishnan, S.; Gatti, M.; Virgil, S. C.; Stoltz, B.
2
3
4
5
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8
9
M. J. Org. Chem. 2015, 80, 528.
Supporting Information
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13226. For enantioselective syntheses of (–)-1 and (–)-2, see (b) Zuo,
Z.; Ma, D. Angew. Chem. Int. Ed. 2011, 50, 12008.
The Supporting Information is available free of charge
on the ACS Publications website. Experimental proce-
dures, spectroscopic data, crystal structure of (+)-48
(CIF), and copies of NMR spectra (PDF).
(8) (a) Movassaghi, M; Schmidt, M. A. Angew. Chem. Int. Ed.
2007, 46, 3725. (b) Schmidt, M. A.; Movassaghi, M. Synlett 2008, 3,
313.
(9) Kim, J.; Movassaghi, M. Acc. Chem. Res. 2015, 48, 1159.
(10) Woodward, R. B.; Yang, N. C.; Katz, T. J.; Clark, V. M.;
Harley-Mason, J.; Ingleby, R. F. J.; Sheppard, N. Proc. Chem. Soc.
1960, 76.
AUTHOR INFORMATION
10
11
12
13
14
15
16
17
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19
20
21
22
23
24
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26
27
28
29
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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
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60
(11) Robinson, R.; Teuber, H. J. Chem. Ind. 1954, 27, 783.
(12) Wigley, L. J.; Mantle, P. G.; Perry, D. A. Phytochemistry
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2003, 44, 1203. (b) May, J. A.; Stoltz, B. M. Tetrahedron 2006, 62,
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M. The Alkaloids: Chemistry and Pharmacology; Brossi, A.; Ed.;
Academic Press: New York, 1989; Vol. 34, pp 1–75. (c) Crich, D.;
Banerjee, A. Acc. Chem. Res. 2007, 40, 151. (d) Steven, A.; Overman,
L. E. Angew. Chem. Int. Ed. 2007, 46, 5488. (e) Xu, J.-B.; Cheng, K.-
J. Molecules 2015, 20, 6715.
(15) (a) Lin, H.-C.; Chiou, G.; Chooi, Y.-H.; McMahon, T. C.;
Xu, W.; Garg, N. K.; Tang, Y. Angew. Chem. Int. Ed. 2015, 54, 3004.
(b) Lin, H.-C.; McMahon, T. C.; Patel, A.; Corsello, M.; Simon, A.;
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Soc. 2016, 138, 4002.
Corresponding Author
movassag@mit.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful for financial support from NIH-NIGMS
(GM089732) and NSF (CHE1212527). S. P. L. acknowl-
edges a Ruth L. Kirschstein NRSA postdoctoral fellow-
ship (F32GM097776). M. P. thanks the Natural Sciences
and Engineering Research Council of Canada (NSERC)
for a PGS D3 Scholarship. We thank Dr. Peter Müller,
Dr. Justin Kim, and Mr. Brandon M. Nelson for X-ray
crystal structure analysis of (+)-48, and thank Ms. Petra
Lindovska, Dr. François Brucelle, and Mr. Jonathan V.
Truong for helpful discussions.
(16) (a) Hendrickson, J. B., Göschke, R.; Rees, R. Tetrahedron
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(28) For comparison, the oxyamination of the corresponding L-
(3,5-di-tert-butylphenylcarbamoyl)-Pro derivatives of substrates (–)-
34 and (–)-36 gave the desired product in 27% (53:47 dr) and 79%
(73:27 dr) yield, respectively.
(29) Methylation of indoline (–)-38 with Meerwein’s reagent or
its reductive amination with formalin and NaBH3CN resulted in the
desired N-methylindoline (–)-40 in 15% and 21% yield, respectively.
(30) Likely due to the greater steric constraints imposed by the
fully substituted tetrahedral C3a in bromide (+)-45, related Heck
protocols described in prior syntheses of alkaloid 1 were unsuccess-
ful.
(31) Herzon, S. B.; Myers, A. G. J. Am. Chem. Soc. 2005, 127,
5342.
(32) The C8a-configuration of the major diastereomer was deter-
mined by nOe analysis of a derivative.
(33) Exposure of the C8a-epimer to the same conditions resulted
in only 22% yield of the desired epimeric aminonitrile.
(34) For representative examples of related use of aminonitriles in
synthesis, see: (a) Overman, L. E.; Jacobsen, E. J. Tetrahedron Lett.
1982, 23, 2741. (b) Ksander, G.; Bold, G.; Lattmann, R.; Lehmann,
C.; Fruh, T.; Xiang, Y.-B.; Inomata, K.; Buser, H. P.; Schreiber, J.;
Zass, E.; Eschenmoser, A. Helv. Chim. Acta 1987, 70, 1115. (c) Stork,
G. S. Pure Appl. Chem. 1989, 61, 439. (d) Corey, E. J.; Gin, D. Y.;
Kania, R. S. J. Am. Chem. Soc. 1996, 118, 9202. (e) Myers, A. G.;
Kung D. W. J. Am. Chem. Soc. 1999, 121, 10828.
(35) Use of N-chlorosuccinimide (6 equiv) as the oxidant in con-
junction with N,N-dimethylaniline (1 equiv) as electrophilic chlorine
scavenger gave only 37% yield of diazene (+)-23, in addition to re-
covered (+)-50 (17%), and a tricyclic cyanoindole side product (25%)
arising from E2-elimination of C3a-sulfamide.
(36) The formation of the tricyclic cyanoindole (~47%) and a
C3a'-H cyclotryptamine 28 (~51%) as disproportionation products is
reflective of the significant steric barrier for C3a–C3a' bond formation
and competitive C8a-H abstraction.
(37) Calculations suggest the C8a-CN provides 3.8 kcal/mol pref-
erence for the desired C3a stereochemical outcome.
(38) Use of tetrahydrofuran-d8 as solvent led to a less efficient
aminal reorganization and afforded product (–)-53 in 52% yield.
(39) Experiment conducted over 13 h in the absence of acid or
base promoter. We reason that reversible C8a-iminium ion formation
8
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(9 cm x 3-1/2 cm)
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9
Boc
N
H
Me
8a'
ArO
NSO2Ph
O
H
3a'
Boc
N
O
S
Me
H
Me
H
H
N
H
N
Me
Me
Boc
O
Boc
N
8a'
NSO2Ph
8a'
Me
H
N
N
Me
3a'
hetero-
aminal
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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44
45
46
47
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50
51
52
53
54
55
56
57
58
59
60
+
3a'
dimerization
3 steps
exchange
3a
3a
8a
NH2
NH
CN
3 steps
8a
3a
8a
N
N
H
CN
Me
Me
N
(–)-communesin F
Me
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