Application of diazene-directed fragment assembly to the total synthesis and stereochemical assignment of (+)-desmethyl-meso-chimonanthine and related heterodimeric alkaloids

Article abstract of DOI:10.1039/c3sc52451e

We describe the first application of our methodology for heterodimerization via diazene fragmentation towards the total synthesis of (-)-calycanthidine, meso-chimonanthine, and (+)-desmethyl-meso-chimonanthine. Our syntheses of these alkaloids feature an improved route to C3a-aminocyclotryptamines, an enhanced method for sulfamide synthesis and oxidation, in addition to a late-stage diversification leading to the first enantioselective total synthesis of (+)-desmethyl-meso-chimonanthine and its unambiguous stereochemical assignment. This versatile strategy for directed assembly of heterodimeric cyclotryptamine alkaloids has broad implications for the controlled synthesis of higher order derivatives with related substructures.

Full text of DOI:10.1039/c3sc52451e

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ARTICLE TYPE
Application of diazene-directed fragment assembly to the total synthesis
and stereochemical assignment of (+)-desmethyl-meso-chimonanthine
and related heterodimeric alkaloids
Stephen P. Lathrop and Mohammad Movassaghi*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
We describe the first application of our methodology for heterodimerization via diazene fragmentation
towards the total synthesis of (–)-calycanthidine, meso-chimonanthine, and (+)-desmethyl-meso-
chimonanthine.
Our syntheses of these alkaloids feature an improved route to C3a-
10 aminocyclotryptamines, an enhanced method for sulfamide synthesis and oxidation, in addition to a late-
stage diversification leading to the first enantioselective total synthesis of (+)-desmethyl-meso-
chimonanthine and its unambiguous stereochemical assignment. This versatile strategy for directed as-
sembly of heterodimeric cyclotryptamine alkaloids has broad implications for the controlled synthesis of
higher order derivatives with related substructures.
45
15 Introduction
Me
N
H
H
H
H
H
N
N
Alkaloids comprising multiple cyclotryptamine units adjoined at
C3a and C7 junctures constitute a large family of structurally
fascinating natural products, which display a wide range of bio-
logical activities1 and possess retrosynthetically challenging and
20 sterically crowded quaternary linkages. Moreover, in certain cas-
es the synthetic challenge is exacerbated by the heterodimeric
C3a–C3aʹ connectivity (Figure 1). Significant advances have
3a'
MeN
MeN
MeN
3a
NMe
NMe
NH
N
N
N
H
H
H
H
H
H
meso-chimonanthine (2)
(!)-calycanthidine (1)
(+)-desmethyl-meso-
chimonanthine (3, DMMC)
Me
N
H
2,3
4,5,6
Me
been made in the assembly of Csp2–Csp
,
Csp3–Csp
,
and N–
3
3
H
H
N
H
Me
N
N
NH
NMe
H
7
Csp linkages in cyclotryptamine based alkaloids. Recently, we
3
MeN
NH
25 reported a general strategy for the selective late stage C–C bond
construction at the C3a quaternary stereocenters of two dissimilar
cyclotryptamine subunits.5e Herein, we report the first application
of our diazene5e,8 based heterodimerization strategy for the total
synthesis of (–)-calycanthidine (1),9 meso-chimonanthine (2),10
30 and (+)-desmethyl-meso-chimonanthine (DMMC, 3), an alkaloid
with previously undefined stereochemistry.11 We sought a unified
approach for the selective synthesis of these three natural prod-
ucts as a critical demonstration of the broader applicability of our
diazene-based fragment-coupling chemistry for the synthesis of
35 more complex natural products such as (–)-idiospermuline (4)12
and (+)-caledonine (5).11 Our syntheses feature an improved route
to C3a-aminocyclotryptamines, an enhanced method for sulfa-
mide synthesis and oxidation, in addition to late-stage diversifica-
tion allowing access to both enantiomers of DMMC (3) from a
40 single heterodimeric intermediate, resulting in the first enantiose-
lective total synthesis of (+)-(3) and its unambiguous stereochem-
ical assignment.
H
H
N
NMe
NMe
H
MeN
N
H
H
NH
NMe
N
N
N
H
H
H
Me
H
NMe
N
H
(!)-idiospermuline (4)
(+)-caledonine (5)
H
Figure 1. Representative cyclotryptamine based natural products.
biological activities, ranging from analgesic, antiviral, antifungal,
antibacterial to cytotoxicity against human cancer cell lines.11,13
50 (–)-Calycanthidine (1) was originally isolated in 1938 from Caly-
canthus floridus,9 with the structure being fully elucidated in
1962.14 Overman and co-workers’ concise enantioselective syn-
thesis of (–)-1 via diastereoselective dialkylation allowed for the
assignment of its absolute stereochemistry.2a,b Meso-
55 chimonanthine (2), originally isolated in 1961 from chimonathus
fragrans10a but not fully identified as a natural isolate until
1964,4d has been synthesized previously via the unselective oxi-
dative dimerization of tryptamine derivatives.2g,4a,c-f,m-o Overman
The dimeric, heterodimeric, and oligomeric cyclotryptamine
alkaloids have been found to possess an assortment of impressive
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and co-workers have reported the selective synthesis of meso-
chimonanthine (2) via a reductive dialkylation or a double Heck
thesis of amines 10–12.17 We envision that the optimization and
implementation of our planned strategy for the total synthesis of
cyclization to secure the vicinal quaternary stereocenters.4i,k,l (+)- 35 these heterodimeric cyclotryptamine natural products will serve
Desmethyl-meso-chimonanthine (3) was initially isolated in 1999
from the Rubiaceae Psychotria lyciiflora.11,15 However, the abso-
lute stereochemistry was not assigned in the isolation report.
as the foundation for further application to related complex natu-
ral products.
5
Synthesis of C3a-aminocyclotryptamines via catalytic inter-
molecular C–H amination
Retrosynthetic Analysis
40 Given the importance of the C3a-aminocyclotryptamines 10–12
to the success of our planned synthesis we sought improved
methods to access the desired amines.5e,18 With this in mind we
turned our attention to rhodium-catalyzed C–H amination for the
introduction of the required C3a-amine functional group. Based
45 on our previous success in selective benzylic bromination of
similar C3a–H cyclotryptamines,5a,e we hypothesized that the
benzylic C3a–H would serve as an ideal substrate for rhodium-
catalyzed C–H amination.19,20,21 Moreover, we believed that the
resulting sulfamate ester obtained from the C–H amination might
50 provide an opportunity for rapid synthesis of the desired mixed
sulfamides by removing the need to prepare the more sensitive
sulfamoyl chlorides22 used in our previous report.5e Indeed, as a
separate part of our studies directed at efficient synthesis of di-
azenes, 2-hydroxyphenyl23 and 4-nitrophenyl24 sulfamate esters
55 had proven effective coupling partners for entry to various sulfa-
mide derivatives.25 In order to test these hypotheses cyclotrypta-
mine (–)-14 was synthesized from the cyclotryptophan derivative
(+)-13 in 86% yield via hydrolysis of the ester, Barton ester for-
mation, and subsequent photodecarboxylation (Scheme 2a).26
A central objective of our retrosynthetic approach to (–)-
calycanthidine (1), meso-chimonanthine (2), (+)- and (–)-
10 desmethyl-meso-chimonanthine (DMMC, 3) was to establish a
general strategy reliant on the late-stage directed assembly of
versatile precursors with potential for application to more com-
plex cyclotryptamine containing alkaloids. We envisioned ac-
cessing these four alkaloids from only two heterodimers 6 and 7
15 that would in turn be prepared from enantiomerically enriched
C3a-aminocyclotryptamines 10–12 (Scheme 1). Whereas site
specific methyl amine synthesis on the “chiral”-heterodimer 6
would allow access to (–)-calycanthidine (1), a similar strategic
introduction of methyl units onto “meso”-heterodimer 7 would
20 readily afford meso-chimonanthine (2) as well as both enantio-
mers of DMMC (3). The vicinal quaternary stereocenters bearing
the C3a–C3aʹ linkage of the key heterodimers 6 and 7 would be
secured from diazenes 8 and 9, respectively, via implementation
of our diazene-directed heterodimerization strategy using C3a-
25 aminocyclotryptamines 10–12.5e,16 Owing to our knowledge of
the relatively weak nature of the benzylic C3a–H bond of related
cyclotryptamines,1c,5a,e we saw an opportunity for examination of
the latest advances in intermolecular C–H amination for the syn
60
With cyclotryptamine (–)-14 in hand we were poised to exam-
ine the desired C–H amination. Utilizing the latest conditions
and reagents generously provided to us by Du Bois and cowork-
Me
H
H
H
H
H
N
N
N
MeN
MeN
R1N
ers for selective intermolecular tertiary C–H amination19 we
,27
were able to obtain the desired arylsulfamate ester (–)-15 in 53%
NMe
NMe
NR2
65 yield. Interestingly, we observed the undesired C–H amination at
C2 to be the major byproduct of the rhodium catalyzed C–H ami-
nation reaction (10–15%).28,29 We postulate that the increased
steric demands of the C3a–H cyclotryptamine (–)-14 lead to the
observed competitive C2 amination.30 Hydrolysis of the sulfamate
70 ester (–)-15 efficiently gave the desired C3a amine (–)-16 in 91%
N
N
N
H
H
H
H
H
H
R1 = Me, R2 = H; (+)-DMMC (3)
R1 = H, R2 = Me; (!)-DMMC (3)
meso-chimonanthine (2)
(!)-calycanthidine (1)
site-specific
methylamine synthesis
R3
N
R5
N
H
R1N
H
"meso"
core
MeO2CN
yield.
The
differentially
functionalized
C3a-
aminocyclotryptamine (–)-20 was synthesized in an analogous
fashion from the tricycle (–)-17 in 38% yield over 4 steps
(Scheme 2b).31 We subsequently discovered that the desired
75 amine (+)-24 could be directly obtained from the corresponding
cyclotryptamine in a two-step sequence without purification of
the sulfamate ester. In the event, rhodium-catalyzed C–H amina-
tion of cyclotryptamine (+)-22 followed by treatment of the crude
sulfamate ester 23 with pyridine in acetonitrile–water mixture at
80 70 ºC directly afforded the C3a-aminocyclotryptamine (+)-24 in
46% yield over two-steps (Scheme 2c).
"chiral"
core
NCO2Me
NCO2Me
N
N
H
H
R4
R4
6
7
heterodimerization
via diazene
fragmentation
R3
N
R5
N
H
H
R1N
MeO2CN
N
N
N
N
NCO2Me
NCO2Me
N
N
H
The application of selective C–H amination allows for direct
access to the desired C3a-aminocyclotrytamine in only two steps
from the corresponding C3a–H cyclotryptamines, eliminates the
85 need for preparation of azides, and precludes the requirement for
prior activation as the benzylic bromide.5e Furthermore, access to
sulfamate ester (–)-19 has allowed examination of its use as a
coupling partner in place of our previously utilized sulfamoyl
chlorides for the synthesis of mixed sulfamides (vide infra).
H
R4
R4
8
9
directed diazene
synthesis
H2N
H2N
H2N
NR1
NCO2Me
NCO2Me
N
N
H
H
N
H
R4
R5
R3
10
11
12
30 Scheme 1. Retrosynthetic analysis of (–)-calycanthidine (1), meso-
chimonanthine (2), (+)- and (–)-desmethyl-meso-chimonanthine (3,
DMMC).
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a.
desired product while requiring fewer equivalents of both base
and oxidant. Notably, more electrophilic chlorinating agent 1,3-
dichloro-5,5-dimethylhydantoin (DCDMH) proved ideal. Under
our new and optimized conditions, treatment of sulfamide (–)-25
45 with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 5 equiv) and
DCDMH (2.5 equiv) in methanol provided the diazene (–)-26 in
92% isolated yield. Most likely, the alcoholic solvent increases
the rate of proton transfer, leading to an increase in the rate of
oxidation of the sulfamide nitrogen and therefore decreases the
50 undesired consumption of the oxidant by the amine base.
Initially, we sought to exploit the solvent-cage effect we ob-
served previously by conducting the photolysis of unsymmetrical
diazene (–)-26 in tert-butanol.5e However, diazene (–)-26 was
found to be sparingly soluble in tert-butanol. Therefore, we ex-
55 plored conducting the photolysis in the solid state with the hope
of increasing the localization effect and favoring the heterodimer-
ization33 while being cognizant that an increase in the formation
of disproportionation products was concievable.33a,b We found
that photolysis of the diazene (–)-26 as a thin film in the absence
60 of solvent afforded the “chiral” heterodimer (–)-27 in 67% yield
with minimal formation of disproportionation products and the
absence of related cross-over products.
Applying a similar strategy we were able to access the desired
“meso” heterodimer (+)-30. Treatment of the sulfamate ester (–)-
65 19 with triethylamine in the presence of tricyclic amine (+)-24
afforded the new mixed sulfamide (+)-28 in 88% yield. Subse-
quent oxidation under our newly optimized conditions for diazene
formation provided the unsymmetrical diazene (+)-29 in 86%
yield. Photolysis of (+)-29 as a thin film selectively provided the
70 “meso“ heterodimer (+)-30 in 63% yield without any detectable
cross-over products. Importantly, the application of our diazene
based strategy for heterodimer assembly has allowed the rapid
and selective synthesis of two strategically functional heterodi-
mers [(–)-27 and (+)-30] for selective late stage methylamine
75 synthesis, from two distinct amines [(–)-16 and (+)-24] and a
single versatile sulfamate ester (19).
H
R
H
ArO3SN
H2N
b
c
2
3a
NCO2Me
NCO2Me
NCO2Me
53%
91%
N
N
N
H
H
H
Boc
Boc
Boc
(!)-16
(+)-13, R = CO2Me
(!)-14, R = H
(!)-15
Ar = 2,6-F2-C6H3
a
86%
b.
H
R
H
ArO3SN
H2N
b
c
NCO2Me
48%
NCO2Me
NCO2Me
90%
N
N
N
H
H
H
SO2C6H4-p-tBu
SO2C6H4-p-tBu
SO2C6H4-p-tBu
(!)-20
(!)-17, R = CO2Me
(!)-18, R = H
(!)-19
d
88%
c.
H
R
ArO3SN
H2N
H
c
b
NTroc
NTroc
NTroc
46%
(2-steps)
N
N
N
H
H
H
SO2Ph
SO2Ph
SO2Ph
(+)-24
(+)-21, R = CO2Me
(+)-22, R = H
23
e
79%
Scheme 2. C–H Amination, synthesis of amines (–)-16, (–)-20 and (+)-
24. Conditions: (a) i) 5 N KOH (aq), MeOH, 23 ºC; ii) TCFH, thi-
opyridine N-oxide, DMAP, Et3N, THF, then t-BuSH, hν, 23 ºC, 86%; (b)
5 Rh2(esp)2, H2NSO3Ar, PhI(OAc)2, Ph(CH3)2CCO2H, MgO, 5 Å MS, i-
PrOAc, 23 ºC, for 14→15, 53%, 18→19, 48%; (c) pyridine, MeCN, H2O,
70 ºC, for 15→16, 91%, 19→20, 90%, 22→24, 46% (2 steps); (d) i) 5 N
KOH (aq), MeOH, 23 ºC; ii) (COCl)2, DMF, CH2Cl2, 23 ºC; iii)
(Me3Si)3SiH, AIBN, PhMe, 80 ºC, 88%; (e) i) Me3SnOH, DCE, 80 ºC; ii)
10 TCFH, thiopyridine N-oxide, DMAP, Et3N, THF, then t-BuSH, hν, 23 ºC
(79%, 2 steps); DMF = dimethylformamide, AIBN = azobisisobutyroni-
trile, TCFH = N,N,Nʹ,Nʹ-tetramethylchloroformamidinium hexafluoro-
phosphate, DMAP = 4-(dimethylamino)pyridine, THF = tetrahydrofuran,
DCE = 1,2-dichloroethane.
15 Sulfamide formation, oxidation and diazene fragmentation
With the desired amines in hand we were ready to access the
heterodimers (–)-27 and (+)-30 via directed sulfamide formation,
mild oxidation, and localized diazene fragmentation (Scheme 3).
In our previous report, we carried out sulfamide formation by
20 first selectively converting one of the amines to the sulfamoyl
chloride followed by treatment with the other amine to afford the
desired mixed sulfamide.5e We hypothesized that arylsulfamate (–
)-19, the direct product of C–H amination, could be utilized in
place of the sulfamoyl chloride. We were delighted to find that
25 exposure of sulfamate ester (–)-19 to amine (–)-16 in the presence
of triethylamine in tetrahydrofuran afforded the desired sulfamide
(–)-25 in 85% yield. Notably, only a slight excess (1.2 equiv) of
sulfamate (–)-19 is required to efficiently obtain the desired
product despite the severe steric constraints inherent in these
30 systems. This represents a significant streamlining of sulfamide
synthesis as the heterodimeric sulfamide can now be directly
generated from the C–H amination product without need for for-
mation of the more sensitive sulfamoyl chloride. We expect that
this process should provide a general route to a wide range of
35 sulfamide derivatives and the corresponding diazenes.
Total syntheses of (–)-calycanthidine (1), meso-chimonanthine
(2), (+)- and (–)-desmethyl-meso-chimonanthine (3).
With access to both desired heterodimers we were poised to ac-
80 cess (–)-calycanthidine (1, Scheme 4) via selective functionaliza-
tion of “chiral” heterodimer (–)-27. Treatment of heterodimer 27
with trifluoroacetic acid selectively removed the tert-butyl car-
bamate (90% yield), allowing the ensuing reductive methylation
of the resultant indoline (–)-31 to afford the desired N-methyl
85 indoline (–)-32 in 90% yield. Exposure of (–)-32 to sodium
amalgam in methanol, followed by reduction of the methylcar-
bamate functional groupings of indoline (–)-33 provided synthet-
ic (–)-calycanthidine (1) in 65% yield over the final two steps.
All 1H and 13C NMR data as well as the optical rotation (observed
90 [α]24 = –289.6, c = 1.54, MeOH; literature [α]20 = –285.1, c =
D
D
1.992, MeOH) for synthetic (–)-1 were in agreement with litera-
Next, oxidation of sulfamide (–)-25 to the diazene was re-
quired.32 Our previous conditions for oxidation necessitated a
large excess of oxidant and base to ensure complete conversion to
the desired diazene.5e Upon further optimization of the reaction
40 conditions we found that protic solvents gave high yields of the
ture data.2a,b, 9
95
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SO2Ph
N
H2N
Boc
N
H2N
H
H
F
NTroc
NCO2Me
TrocN
MeO2CN
N
N
H
H
O
O
O
O
O
O
HN
HN
F
O
SO2Ph
HN
S
HN
Boc
a
S
S
(+)-24
(!)-16
b
HN
85%
88%
NCO2Me
NCO2Me
NCO2Me
N
N
N
H
H
H
SO2C6H4-p-tBu
SO2C6H4-p-tBu
SO2C6H4-p-tBu
(+)-28
(!)-25
(!)-19
heterodimeric
"chiral" core
heterodimeric
"meso" core
c
92%
c
86%
SO2Ph
H
N
Boc
H
N
SO2Ph
Boc
MeO2CN
TrocN
H
H
N
N
d
d
N
N
MeO2CN
TrocN
N
N
63%
67%
NCO2Me
NCO2Me
NCO2Me
NCO2Me
N
N
N
N
H
H
H
H
SO2C6H4-p-tBu
SO2C6H4-p-tBu
SO2C6H4-p-tBu
SO2C6H4-p-tBu
(!)-26
(!)-27
(+)-30
(+)-29
Scheme 3. Synthesis of heterodimers (–)-27 and (+)-30 via diazene fragmentation. Conditions: (a) Et3N, (–)-16, THF, 23 ºC, 85%; (b) Et3N, (+)-24,
THF, 23 ºC, 88%; (c) 1,3-dichloro-5,5-dimethylhydantoin, DBU, MeOH, 23 ºC, for 25→26, 92%, 28→29, 86%; (d) hν (380 nm), 23 ºC, for 26→27, 67%,
29→30, 63%; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
Me
R
related reorganized natural products in the chiral chimonanthine
series,4k,5a,35 we investigated the rearrangement of meso-
30 chimonanthine (2) to the corresponding meso-calycanthine (36,
Scheme 5). In the event, the acid mediated rearrangement of me-
so-chimonanthine (2) was explored by heating a solution of 2 in
deuterium oxide and acetic acid-d6 to 95 ºC and the progress
H
H
N
N
MeO2CN
MeO2CN
b
90%
NCO2Me
NCO2Me
N
H
N
H
SO2C6H4-p-tBu
SO2C6H4-p-tBu
(!)-32
1
monitored by in situ H NMR.36 After 24 h, >90% consumption
(!)-27, R = Boc
(!)-31, R = H
a
c
92%
90%
35 of meso-chimonanthine was observed, affording a mixture of
meso-calycanthine (36) as well as products related to fragmenta-
tion of the fragile C3a-C3aʹ bond. Subsequent basic work-up and
purification by flash column chromatography provided meso-
calycanthine (36) in 36% yield. Resubmission of isolated meso-
40 calycanthine (36) to the acidic conditions resulted in no change,
suggesting that in contrast to the equilibrium observed between
chimonanthine and calycanthine (15:85),5a the thermodynamic
equilibrium between 2 and 36 strongly favors meso-calycanthine
(36).
Me
Me
H
N
H
N
MeO2CN
MeN
d
71%
NCO2Me
NMe
N
H
N
H
H
H
(!)-33
(!)-calycanthidine (1)
5
Scheme 4 Total synthesis of (–)-calycanthidine (1). Conditions: (a)
CH2Cl2, TFA, 90%; (b) formalin, NaBH3CN, AcOH, MeCN, 23 ºC, 90%;
(c) Na(Hg), NaH2PO4, MeOH, 23 ºC, 92%; (d) Red-Al, PhMe, 110 ºC,
71%; TFA
10 methoxyethoxy)aluminium hydride.
45
We next turned our focus to the synthesis and assignment of
absolute stereochemistry of (+)-DMMC (3) from the same versa-
tile “meso” heterodimer (+)-30. Our ability to unequivocally
assign the absolute stereochemistry of (+)-DMMC (3) centered
on our capacity to access both enantiomers of this previously
=
trifluoroacetic acid, Red-Al
=
sodium bis(2-
Having successfully employed “chiral” heterodimer (–)-27 en
route to (–)-calycanthidine (1) we hoped to exploit a similar strat-
egy utilizing the “meso” heterodimer (+)-30 for the synthesis of
meso-chimonanthine (2, Scheme 5) in addition to (+)-DMMC (3)
15 and (–)-DMMC (3). While attempts to reduce both carbamate
functional groupings of heterodimer (+)-30 to the corresponding
methyl amines resulted in removal of the trichloroethyl carba-
mate, treatment of heterodimer (+)-30 with lithium triethyl-
borohydride led exclusively to the formation of ethyl carbamate
20 (+)-34 in 84% yield.34 Although unexpected, the formation of
intermediate (+)-34 proved critically beneficial as it permitted
selective removal of the arenesulfonyl groups to afford the free
indoline (–)-35 in 80% yield. A final reduction of the two car-
bamate functional groupings selectively gave meso-
50 unassigned natural alkaloid. We found exposure of heterodimer
(+)-30 to sodium amalgam in methanol resulted in removal of the
trichloroethyl carbamate along with the sulfonyl groups in a sin-
gle step to afford triamine (–)-37 in 68% yield (Scheme 5). Sub-
sequent reduction of the methyl carbamate with Red-Al afforded
1
55 the desired methyl amine 3 in 91% yield. All H and 13C NMR
data for synthetic 3 were identical in all respects to the literature
values for (+)-DMMC (3).11 However, the observed optical rota-
tion of our synthetic 3 was opposite in sign to that of the natural
product (observed [α]24 = –1.8, c = 0.20, EtOH; literature [α]25
D
D
60 = +0.5, c = 1, EtOH)11 and therefore we assigned the depicted
structure as (–)-DMMC (3). Importantly, careful and repeated
analysis of the same sample over 2 h indicated a steady decrease
in the magnitude of the observed rotation with eventual inversion
1
25 chimonanthine (2) in 91% yield. All H and 13C NMR data for
1
of the sign. Both H NMR and TLC analysis of the sample indi-
our synthetic 2 were identical in all respects to the literature val-
ues for meso-chimonanthine (2).4 Intrigued by the presence of
65 cated minor decomposition (<5%) of the natural product during
this process, which is likely responsible for the gradual drift of
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DOI: 10.1039/C3SC52451E
the optical rotation value.37 We hypothesize that this observed
consistent with that reported in the literature (observed [α]24
=
D
variation in optical rotation over time is responsible for the dis- 35 +2.7, c = 0.13 EtOH). Importantly, the same observations regard-
crepancy in the absolute value of the optical rotation of our sam-
ple and that of the natural isolate.11 Nevertheless, we are fully
confident in the high quality of our sample, its optical rotation,
and its absolute stereochemistry as depicted in Scheme 5.
SO2Ph
ing the critical purity of the sample in optical activity determina-
tion were observed once again. Having accessed both enantio-
mers of the natural product from known chiral feedstock we can
confidently assign the absolute configuration of (+)- and (–)-
40 desmethyl-meso-chimonanthine (3) as shown in Scheme 5.38
5
H
H
H
N
H
H
N
N
e
f
TrocN
HN
HN
Conclusions
68%
91%
NCO2Me
NCO2Me
NMe
Application of our diazene based method for heterodimerization
has allowed the total syntheses of (–)-calycanthidine (1), meso-
chimonanthine (2), (+)- and (–)-desmethyl-meso-chimonanthine
45 (3). Our synthetic route takes advantage of the inherent sym-
metry found in this group of natural products and allows us to
selectively access these four unique compounds from only two
distinct heterodimers (27 and 30), two unique amines (16 and 24)
and the sulfamate (19). Furthermore, access to (+)- and (–)-
50 desmethyl-meso-chimonanthine (3) has allowed for its unambig-
uous stereochemical assignment. The successful implementation
of our diazene-based heterodimerization for the synthesis of the
three heterodimeric cyclotryptamine alkaloids will serve as the
foundation for further application to the controlled synthesis of
55 more complex cyclotryptamine-containing natural products such
as (–)-idiospermuline (4) and (+)-caledonine (5).
N
H
N
N
H
H
SO2C6H4-p-tBu
H
H
(+)-30
(!)-37
(!)-DMMC (3)
g
a
84%
83%
SO2Ph
N
SO2Ph
N
SO2Ph
N
H
H
MeN
H
HN
EtO2CN
h
85%
NCO2Me
NCO2Me
NCO2Me
N
N
H
N
H
H
SO2C6H4-p-tBu
SO2C6H4-p-tBu
SO2C6H4-p-tBu
(+)-34
(!)-38
(!)-39
i
83%
b
80%
H
N
H
H
H
H
H
N
N
MeN
EtO2CN
MeN
j
50%
NCO2Me
NCO2Me
NH
N
H
N
N
H
H
H
H
H
(!)-40
(!)-35
(+)-DMMC (3)
Acknowledgements
c
91%
H
We acknowledge financial support by NIH-NIGMS
(GM089732). S. P. L. is grateful to the a NIH for a Ruth L.
60 Kirschstein NRSA postdoctoral fellowship (F32GM097776). We
acknowledge the NSF under CCI Center for selective C–H func-
tionalization (CHE-1205646) for support related to C–H amina-
tion chemistry. We are grateful for advice, catalysts, and reagents
provided by professors J. Du Bois, H. M. L. Davies, H. Lebel,
65 and J. L. Roizen.
H
N
MeN
H
N
MeN
d
N
36%
H
NMe
NMe
N
H
H
meso-chimonanthine (2)
meso-calycanthine (36)
Scheme 5. Total synthesis of meso-chimonanthine (2) and (+)- and (–)-
desmethyl-meso-chimonanthine (DMMC, 3). Conditions: (a) LiEt3BH,
10 THF, 65 ºC, 84%; (b) Na(Hg), NaH2PO4, MeOH, 23 ºC, 80%; (c) Red-Al,
PhMe, 110 ºC, 91%; (d) D2O, CD3CO2D, 95 ºC, 24 h, 36%; (e) Na(Hg),
NaH2PO4, MeOH, 23 ºC, 68%; (f) Red-Al, PhMe, 110 ºC, 91%; (g) Zn,
AcOH, MeOH, 23 ºC, 83%; (h) formalin, NaCNBH3, AcOH, MeCN, 23
ºC, 85%; (i) Na(Hg), NaH2PO4, MeOH, 23 ºC, 83%; (j) 5 N NaOH (aq),
15 MeOH, 65 ºC, 50%.
Notes and references
Massachusetts Institute of Technology, Department of Chemistry, Cam-
bridge, Massachusetts 02139, USA; E-mail: movassag@mit.edu
† Electronic Supplementary Information (ESI) available: Details for all
70 biological assays as well as experimental procedures, spectroscopic data,
and copies of 1H, 13C, and 19F NMR spectra. See DOI: 10.1039/b000000x/
To further clarify the absolute stereochemistry of (+)- and (–)-
DMMC (3), and to confirm our observations regarding sample
sensitivity as described above, we sought to access (+)-DMMC
(3) by exploiting the versatility of the “meso” heterodimer (+)-30
20 (Scheme 5). Enantioselective total synthesis of both (+)- and (–)-
DMMC (3) from heterodimer (+)-30, would allow unambiguous
confirmation of the absolute stereochemistry of DMMC (3) and
also highlight the utility of heterodimer (+)-30 as a synthetic in-
termediate for preparation of these cyclotryptamine alkaloids.
25 Selective trichloroethyl carbamate removal with zinc in a mixture
of acetic acid and methanol provided the free amine (–)-38 in
83% yield. Subsequent reductive methylation with formalin and
sodium cyanoborohydride (85% yield), followed by removal of
the arenesulfonyl groupings to afford the free indoline (–)-40
30 (83% yield) and hydrolysis of the methyl carbamate provided the
1
2
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36 The acid-mediated rearrangement of meso-chimonanthine under
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37 Although the specific decomposition products could not be fully
identified, mass spectral analysis indicated the presence of oxindole
related byproducts.
38 Attempts at the acid-mediated rearrangement of both (–)-
calycanthidine (1) and (+)-DMMC (3) led to exclusive fragmentation
of the C3a-C3aʹ bond as evidenced by the isolation of N-
methyltryptamine. A similar result has been observed in the attempt-
ed acid-mediated rearrangement of (±)-folicanthine, see ref 4h.
24 (a) J. Charalambous, M. J. Frazer and W. Gerrard, J. Chem. Soc.,
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25 In preliminary studies we found 4-nitrophenyl sulfamate esters to be
competent coupling partners with our tricyclic amines. However,
synthesis of the 4-nitrophenyl sulfamate ester from the tricyclic
amine is complicated by undesired homodimeric sulfamide for-
mation; see ref. 24.
26 (a) D. H. R. Barton, H. A. Dowlatshahi, W. B. Motherwell and D.
Villemin, J. Chem. Soc., Chem. Commun., 1980, 732; (b) D. H. R.
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27 J. L. Roizen, D. N. Zalatan and J. Du Bois, Angew. Chem. Int. Ed.,
2013, Early View, DOI: 10.1002/anie.201304238.
28 For examples of the unexpected intramolecular Rh-catalyzed C–H
amination of secondary C–H bonds next to nitrogen, see (a) S.
Toumieux, P. Comapin, O. R. Martin and M. Selkti, Org. Lett., 2006,
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Ameriks, Chem. Eur. J., 2011, 17, 7890.
29 See the ESI for details.
30 In the intramolecular Rh-catalyzed C–H amination, secondary ethere-
al C–H bonds react preferentially over both secondary benzylic and
tertiary C–H bonds, see ref 19g.
31 tert-Butylbenzenesulfonyl protective group was utilized to increase
solubility of tricycle (–)-18 in isopropyl acetate, the optimal solvent
for the rhodium-catalyzed C–H amination.
32 For key references on oxidation of sulfamides, see: (a) R. Ohme and
E. Schmitz, Angew. Chem., Int. Ed., 1965, 4, 433; (b) F. Golzke, G.
A. Oberlinner and C. Rüchardt, Nouv. J. Chim., 1977, 1, 169; (c) H.-
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