5-(Methylthio)tetrazoles as versatile synthons in the stereoselective synthesis of polycyclic pyrazolines via photoinduced intramolecular nitrile imine-alkene 1,3-dipolar cycloaddition

Article abstract of DOI:10.1039/c4sc00107a

A key thioether substituent in readily accessible 2-alkyl-5-(methylthio) tetrazoles enables facile photoinduced denitrogenation and intramolecular nitrile imine 1,3-dipolar cycloaddition to afford a wide range of polycyclic pyrazoline products with excellent diastereoselectivity. The methylthio group red-shifts the UV absorbance of the tetrazole, obviating the requirement in all previous substrate systems for at least one aryl substituent, and can subsequently be converted into a variety of other functionalities. This synthetic platform has been applied to the concise total syntheses of the alkaloid natural products (±)-newbouldine and withasomnine. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4sc00107a

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5-(Methylthio)tetrazoles as versatile synthons in
the stereoselective synthesis of polycyclic
pyrazolines via photoinduced intramolecular nitrile
imine–alkene 1,3-dipolar cycloaddition†
Cite this: Chem. Sci., 2014, 5, 2407
a
ab
and David Y. Gin‡ab
*
*
Daniel Pla, Derek S. Tan
A
key thioether substituent in readily accessible 2-alkyl-5-(methylthio)tetrazoles enables facile
photoinduced denitrogenation and intramolecular nitrile imine 1,3-dipolar cycloaddition to afford a wide
range of polycyclic pyrazoline products with excellent diastereoselectivity. The methylthio group red-
shifts the UV absorbance of the tetrazole, obviating the requirement in all previous substrate systems for
at least one aryl substituent, and can subsequently be converted into a variety of other functionalities.
This synthetic platform has been applied to the concise total syntheses of the alkaloid natural products
(ꢀ)-newbouldine and withasomnine.
Received 10th January 2014
Accepted 10th March 2014
DOI: 10.1039/c4sc00107a
www.rsc.org/chemicalscience
address this signicant limitation in scope, we envisioned that
a C-heteroatom substituent might enable the use of non-aryl
Introduction
substituted tetrazoles in the photoinduced pathway by red-
shiing the absorbance of the substrate. We report herein
efficient, stereoselective, photoinduced, intramolecular dipolar
cycloadditions of readily accessible 2-alkyl-5-(methylthio)tetra-
zoles that afford a wide range of polycyclic pyrazolines. The
C-methylthio group is proposed to facilitate the initial photo-
denitrogenation step and also provides a versatile handle for
further functionalization, as demonstrated by application to the
total syntheses of the alkaloid natural products (ꢀ)-new-
bouldine and withasomnine.
Pyrazolines and pyrazoles have demonstrated a broad range of
biological activities, including antimicrobial, antiviral, anal-
gesic, anti-inammatory, anti-depressant, anticonvulsant, and
anticancer properties.1 1,3-Dipolar cycloaddition of nitrile
imines with alkenes and alkynes provides a powerful entry into
this class of structures, with concurrent formation of C–C and
C–N bonds (carboamination).2 In pioneering work on this
transformation, Huisgen demonstrated that the requisite nitrile
imines could be generated in situ by basic elimination of a-
halohydrazones3 or by thermal3a or photoinduced denitroge-
nation of tetrazoles.4 Subsequently, a variety of intramolecular
variants have been described to afford polycyclic products.5,6
More recently, Lin has reported photodenitrogenation under
milder conditions that are useful for biological applications
(‘photoclick’ reaction).7
Results and discussion
Synthesis of tetrazole substrates
Our general approach involves regioselective alkylation of
5-(methylthio)tetrazole at the 2 position, followed by photoin-
duced denitrogenation and intramolecular 1,3-dipolar cyclo-
addition (Fig. 1). Due to the tautomerism exhibited by tetrazoles
between their 1H and 2H forms, alkylation of 1 with alkyl
bromides afforded a 45 : 55 mixture of 1- and 2-alkylated
Notably, however, in all of these reactions, the nitrile imine
has at least one aryl substituent (N, C, or both); cycloaddition
reactions of non-aromatic nitrile imines have apparently not
been investigated previously,8 and it has been suggested that an
N-aryl substituent is absolutely required for reactivity in the
tetrazole photodenitrogenation route to nitrile imines.7c To
aMolecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer
Center, 1275 York Avenue, Box 422, New York, New York 10065, USA. E-mail:
tand@mskcc.org; daniel.pla@gmail.com
bTri-Institutional Research Program, Memorial Sloan-Kettering Cancer Center, 1275
York Avenue, Box 422, New York, New York 10065, USA
† Electronic supplementary information (ESI) available: Complete experimental
procedures and analytical data for all new compounds. See DOI:
10.1039/c4sc00107a
Fig. 1 General approach to photoinduced intramolecular dipolar
cycloaddition of 2-alkyl-5-(methylthio)tetrazoles (2) not requiring N-
or C-aryl substituents.
‡ Deceased, March 22, 2011.
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products.9 In contrast, Mitsunobu alkylation with alcohols membered rings in 3c and 3f (entries 2–6). The inaccessibility of
proceeded with high regioselectivity for the desired 2-alkylated 3c and 3f and decreased yields of 3d and 3e appeared to be due
tetrazoles 2.10
to competing quasi-dimerization side reactions.11 Along similar
lines, Padwa has reported that attempted 3- and 4-membered
ring forming photoinduced cycloadditions with the corre-
sponding 5-phenyltetrazole substrates result only in polymeric
byproducts.6i
Initial studies of photoinduced intramolecular cycloaddition
We rst investigated photoinduced denitrogenation and intra-
molecular cycloaddition of 2a (Table 1). Although initial studies
with a low-wattage Pen-Ray mercury lamp (5.5 W, 254 nm)
appeared promising, low yields (<40% conversion, NMR) of 3a
were obtained even with extended reaction times (entries 1 and
2). In contrast, signicantly higher yields were obtained upon
irradiation for 5 h in a photoreactor (10 ꢁ 7.2 W low-pressure
mercury lamps, 254 nm) (entry 3). Despite incomplete conver-
sion under these conditions, longer irradiation times (8 h) did
not result in improved yields (entry 4), and extended irradiation
for 16 h led to complete S-demethylation to afford only thio-
pyrazolidinone byproduct 4a (entry 5). Freeze–pump–thaw
degassing of reactions had little inuence on yield, and the
reaction could be carried out conveniently under Ar or air
atmosphere with similar efficiencies (entries 6 and 7), while
reactions in other solvents resulted in slightly decreased yields
(entries 8 and 9). Overall, reaction in CH3CN under Ar atmo-
sphere at rt for 5 h proved optimal, allowing consumption of
z65–70% of the starting material with little or no S-demethy-
lation to afford the highest overall yield of 3a (entry 6).
Both E and Z-disubstituted olens in 2g and 2h were effective
dipolarophiles, forming 3g and 3h, respectively (entries 7 and
8). While the incomplete diastereoselectivity in 3g can be
attributed to the presence of a small amount of the Z-isomer in
the starting material 2g, the incomplete diastereoselectivity in
3h appears to be due to in situ photoinduced olen isomeriza-
tion of the substrate 2h during the reaction (vide infra).11
A
vinylcyclopropane dipolarophile in 2i also reacted effectively to
form the intact cyclopropane-substituted pyrazoline 3i (entry 9),
consistent with a concerted reaction mechanism.12 1,1-Disub-
stituted and 1,2,2-trisubstituted olens in 2j and 2k were also
accommodated to form, respectively, 3j having a methyl
substituent at the bridgehead carbon and 3k having a gem-
dimethyl group on the pyrazoline ring (entries 10 and 11). A
styrene dipolarophile in 2l provided the corresponding pyr-
azoloisoindole tricycle 3l (entry 12).
We next investigated branched substrates to assess the
inuence of various substituents on reaction efficiency and
diastereoselectivity (Table 3). Introduction of a methyl substit-
uent a to the tetrazole in 2m favored formation of 3m having a
syn relationship between the methyl group and the bridgehead
proton in good diastereoselectivity (entry 1). 1,1-Disubstituted
and 1,2,2-trisubstituted olens were again well-tolerated in 3n
and 3o of this series (entries 2 and 3). In contrast, incorporation
of a methyl substituent b to the tetrazole in 2p favored the anti
product 3p (entry 4), with the methyl substituent presumably
adopting an equatorial orientation on the otherwise sterically
congested concave face of the ring system.11 When the methyl
substituent was shied g to the tetrazole in 2q, the diastereo-
preference reverted back to the syn product 3q (entry 5).
Introduction of a cyclic constraint between the g- and d-
carbons in 2r afforded the spirotricycle 3r as a single dia-
stereomer (entry 6), consistent with the diastereopreference
observed above for 3q (entry 5). Meanwhile, installation of a
cyclic constraint between the a- and b-carbons in 2s led to the
fused tricycle 3s with somewhat decreased diastereoselectivity
(entry 7), as might be expected based on the opposing diastereo-
preferences above for 3n and 3p (entries 2 and 4). Moving to six-
membered ring closures, high diastereoselectivity was achieved
with cyclic constraints bridging the b- and g-positions in
reactions of 2t, 2u, and 2v to form 3t, 3u, and 3v, respectively
(entries 8–10). Notably, the tertiary amine functionality was
well-tolerated, providing access to pharmaceutically relevant
piperidine and indole motifs.
Scope of photoinduced intramolecular cycloaddition
With these results in hand, we evaluated the effectiveness of
this reaction across a wider range of substrates, synthesized via
Mitsunobu alkylation with the corresponding alcohols.11
Replacement of the 5-methylthio group with a 5-benzylthio
group in 5 provided benzylthiopyrazoline 6 in similar yield
(Table 2, entry 1). The reaction also accommodated formation of
3-, 6-, and 7-membered rings in 3b, 3d, and 3e, but not of 4- or 8-
Table 1 Optimization of photoactivated intramolecular cycloaddition
of 3aa
Entry
Methoda
Solvent
Conditionsb
t (h)
Yieldc 3a (%)
1
2
3
4
5
6
7
8
9
A
A
B
B
B
B
B
B
B
CD3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
MeOH
Air, rt
Ar, rt
Ar (FPT), rt
Ar (FPT), rt
Ar (FPT), rt
Ar, rt
Air, rt
Ar, rt
Ar, rt
16
5
5
8
16
5
5
5
5
24
40
57
59
31 [4a]
64
60
51
55
Next, we investigated substrates having various alternative
dipolarophiles (Table 4). An allyl ether in 2w was accommo-
dated readily to form pyrazolomorpholine 3w (entry 1). Mean-
while, reaction of vinyl ether 2x afforded pyrazole derivative 7,
presumably via initial formation of the corresponding
pyrazolooxazolidine 3x (not shown) followed by aromatization
Acetone
a
Method A: Pen-Ray 5.5 W 254 nm lamp; method B: Luzchem 10 ꢁ 7.2
b
W 254 nm photoreactor. FPT ¼ freeze–pump–thaw degassed three
times. c Isolated yields; majority of mass balance is 2a.
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Table 2 Photoactivated intramolecular cycloadditions of substrates with varied ring sizes and alkene substitutiona,b
Entry
Substrate
Yield (%)
5: 73
Product
Yield (%)
6: 65
1
2
2b: 56
3b: 68
3
4
2c: 77
2d: 79
3c: 0c
3d: 56c
5
6
2e: 77
3e: 35c
2f: 77
3f: 0c
7
8
2g: 75 (96 : 4 E/Z)
3g: 64d (19 : 1 dr)
3h: 62d (19 : 1 dr)
2h: 81 (>99 : 1
Z/E)
2i: 72 (94 : 6)
Z/E
9
3i: 61d (18 : 2 dr)
10
11
2j: 76
3j: 70
2k: 77
3k: 67
12
2l: 65
3l: 70
a
b
hn (254 nm, Luzchem 10 ꢁ 7.2 W lamp photoreactor), CH3CN, Ar, rt, 5 h. Relative stereochemistries determined by NOESY analysis.11
c
Remainder quasi-dimeric products, see Fig. SI4. d Isolated yield of inseparable mixture of diastereomers.
via elimination across the hemiaminal moiety (entry 2).11 Enol photochemical reaction conditions, which was observed in the
ethers with the oxygen positioned at the distal end of the double remaining starting materials aer the 5 h reaction time (2aa <
bond were also accommodated effectively in 2y, 2z, 2aa, and 2bb 1 : 99 / 36 : 64 E/Z at 65% conversion; 2bb > 99 : 1 / 92 : 8 E/Z
to form 3y, 3z, 3aa, and 3bb, respectively (entries 3–6). The at 56% conversion).11 These ratios, combined with the observed
incomplete diastereoselectivity of these reactions is attributed diastereomeric ratios of the products, suggest that the Z-olen
to olen isomerization in the substrates under the substrate 2aa reacts faster than the E-olen substrate 2bb.
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Table 3 Photoactivated intramolecular cycloadditions of substrates with substituted linkersa,b
Yield
Entry
1
Substrate
(%)
Product
Yield (%)
3m: 76c
(17 : 3 dr)
2m: 83
3n: 72c
(18 : 2 dr)
2
3
2n: 72
2o: 88
3o: 75c
(16 : 4 dr)
3p: 72c
(16 : 4 dr)
4
5
2p: 78
2q: 75
3q: 61d
(16 : 4 dr)
3q0: 15d
3r: 77d
(>20 : 1
dr)
6
7
2r: 77
2s: 70
3s: 69d
(15 : 5 dr)
3s0: 27d
3t: 63d
(>20 : 1
dr)
8
9
2t: 71
2u: 39
3u: 61d
(19 : 1 dr)
3v: 42c
(18 : 2 dr)
10
2v: 76
a
c
hn (254 nm, Luzchem 10 ꢁ 7.2 W lamp photoreactor), CH3CN, Ar, rt, 5 h. b Relative stereochemistries determined by NOESY analysis.11 Isolated
yield of inseparable mixture of diastereomers. d Isolated yield of individual diastereomer shown.
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Table 4 Photoactivated intramolecular cycloadditions of substrates with alternative dipolarophiles and tetrazole C5-substituentsa,b
Entry
Substrate
Yield (%)
Product
Yield (%)
1
2w: 81
3w: 70
2
3
2x: 78
7: 72
2y: 86c (95 : 5
Z/E)
3y: 70 f (18 : 2 dr)
2z: 85c (97 : 3
E/Z)
4
5
3z: 66 f (15 : 5 dr)
3aa: 62g (18 : 2 dr)
2aa: 94d (>99 : 1)
Z/E
2bb: 86d (>99 : 1)
E/Z
6
7
3bb: 43g (17 : 3 dr)
2cc: 84
8: 19h
8
2dd: 71e
9: 0i
9
2ee: 72
11: 66
10: 0 j
12: 0k
10
11
12
a
13: 45
15: 91
14: 68
16: 89
c
hn (254 nm, Luzchem 10 ꢁ 7.2 W lamp photoreactor), CH3CN, Ar, rt, 5 h. b Relative stereochemistry determined by NOESY analysis.11 Based on
d
theoretical maximum yield from 37 : 63 Z/E ratio of alcohol precursor. Based on theoretical maximum yield from 50 : 50 Z/E ratio of alcohol
precursor. e Two-step yield from 4-hydroxybutyraldehyde dimethyl acetal precursor aer acetal deprotection (LiBF4, 2% H2O in CH3CN, rt, 20 h).
f
g
h
Isolated yield of inseparable mixture of diastereomers. Isolated yield of major diastereomer. Remainder unreacted starting material (major)
i
j
k
and additional unidentied byproducts. Complex mixture recovered. Quasi-dimer recovered.11 Unreacted starting material recovered aer 5
and 10 h irradiation.
Reaction with an alkyne dipolarophile in 2cc proved slug-
It was of particular interest to note that replacement of the
gish, providing a low yield of the pyrazole 8 (entry 7).6a,b,i 5-methylthio group with a simple 5-methyl substituent in
Attempted hetero-dipolar cycloaddition with an aldehyde3a in tetrazole 11 rendered the substrate unreactive to photo-
2dd to form oxadiazole 9 afforded only a complex mixture while denitrogenation, and only unreacted starting material was
attempted use of a nitrile dipolarophile3a in 2ee to form 1,2,4- recovered upon irradiation (entry 10). However, the corre-
triazole 10 yielded only an unidentied byproduct, possibly an sponding 5-(carboethoxy)tetrazole 13 did undergo effective
unsymmetrical quasi-dimer (MS, NMR) (entries 8 and 9).
photodenitrogenation and dipolar cycloaddition to afford
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Fig. 2 UV absorbance spectra of 5-(methylthio)tetrazole 2a (3254
¼
2520 Mꢂ1 cmꢂ1), 5-(benzylthio)tetrazole 5 (3254 ¼ 3080 Mꢂ1 cmꢂ1), 5-
methyltetrazole 11 (3254 ¼ 4.89 Mꢂ1 cmꢂ1), 5-(carboethoxy)tetrazole 13
Fig. 3 Downstream transformations of pyrazoline 3a. (DDQ ¼ 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone; 3-Me-Sal ¼ 3-methyl.)
(3254 ¼ 72.6 Mꢂ1 cmꢂ1), and 5-phenyltetrazole 15 (3254 ¼ 8670 Mꢂ1
cmꢂ1) at 1.25 mM concentration in EtOH.
3
254
values were calculated
11
based on spectra for which 0.1 < A254 < 3.0, the linear range of the
instrument.11
Liebskind–Srogl cross-coupling14 of the thioimidate with phe-
nylboronic acid also provided phenyl-substituted pyrazoline 16.
While such aryl-substituted scaffolds could, of course, be
synthesized directly by photoinduced cycloaddition of appro-
priate 2-alkyl-5-aryltetrazoles (e.g., 15 / 16, Table 4, entry 12),
the commercial availability of a wide range of boronic acids
makes this alternative, divergent approach highly attractive.
The thioimidate moiety could also be hydrolyzed efficiently to
the cyclic hydrazide 17. Such pyrazolidinones can undergo N–N-
bond cleavage to prepare b-homoproline amide derivatives,15
for use in b-peptides.16 A novel desulfurizative reduction of 3a in
the presence of AgOTf also provided direct entry to the corre-
sponding pyrazolidine 18.
pyrazoline ester 14 (entry 11). Similarly, the 5-phenyltetrazole 15
was efficiently converted to phenylpyrazoline 16 (entry 12), as
reported previously by Padwa.6i
UV absorbance of 5-substituted tetrazoles
These last results highlight the importance of the 5-methylthio
group in enabling the initial photodenitrogenation reaction,
and suggest that the previous restriction of this reaction to aryl-
substituted tetrazoles is due, at least in the case of photo-
activated reactions, to the need for substrate absorbance in the
medium-wave UV domain. Thus, we analyzed UV spectra of 5-
(methylthio)tetrazole 2a, 5-(benzylthio)tetrazole 5, 5-methylte-
trazole 11, 5-(carboethoxy)tetrazole 13, and 5-phenyltetrazole 15
(Fig. 2). The 5-thiotetrazoles 2a and 5 absorbed strongly at 254
nm, nearly as well as the 5-phenyltetrazole 15. In contrast, the 5-
methyltetrazole 11 absorbed very weakly at this wavelength.
This is consistent with the hypothesis that the phenyl and thi-
omethyl substituents facilitate the initial photodenitrogenation
reaction by increasing the UV absorbance of the substrates at
254 nm. Notably, however, 5-(carboethoxy)tetrazole 13 absorbed
relatively weakly at this wavelength, despite its effectiveness in
the photoinduced cycloaddition reaction (Table 4, entry 11).
Thus, these tetrazole substituents may also play a role in
increasing substrate reactivity by electronic stabilization of the
corresponding nitrile imine intermediates.13
Total synthesis of (ꢀ)-newbouline and withasomnine
To demonstrate further the utility of photoinduced nitrile imine
cycloadditions of 2-alkyl-5-(methylthio)tetrazoles, we applied
this synthetic platform to the total syntheses of (ꢀ)-new-
bouldine (19) and withasomnine (20, Fig. 4). This family of
pyrrolopyrazole alkaloids was isolated from plant sources17,18
that are used in traditional medicines for a wide range of
indications.19 Several syntheses of the achiral pyrazole congener
withasomnine have been reported, most of which start from a
pyrazole or pyrrolidine scaffold with cyclization of a sidechain
to install the second ring.20,21 In contrast, the rst synthesis of
Further functionalization of pyrazoline scaffolds
The (methylthio)pyrazoline products of these photoinduced
cycloaddition reactions proved to be versatile scaffolds that
underwent a variety of downstream transformations (Fig. 3).
Oxidation of 3a with DDQ under microwave irradiation
provided rapid, efficient access to the corresponding pyrazole
8,6i which could not be accessed efficiently by direct cycloaddi-
Fig. 4 Structures of the newbouldine and withasomnine alkaloid
tion of alkyne 2cc above (Table 4, entry 7). Palladium-catalyzed families and retrosynthetic disconnections.
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above (Table 1, entries 7, 8, and Table 4, entries 5, 6), this dia-
stereomeric mixture is attributed to in situ olen isomerization
of the substrate under the photochemical reaction conditions,
which was observed in the remaining starting material 22 aer 8
h reaction time (97 : 3 / 95 : 5 E/Z). Similarly, photoinduced
cycloaddition of the corresponding Z-olen substrate Z-22
afforded a mixture of the corresponding anti-3,4 pyrrolopyr-
azoline anti-23 and syn-23, with olen isomerization observed
in the remaining starting materials (Fig. 6).11
Attempts to desulfurize syn-23 directly to newbouline using
Raney Ni and Raney Cu resulted in decomposition and recovery
of unreacted starting material, respectively. Desulfurization of
the model substrate 3a was also attempted under a variety of
conditions and resulted in either no reaction (Al$Hg; NiB; H2,
Pd(OH)2/C; LiAlH4; Raney Cu; Et3SiH, Pd/C; Bu3SnH,
CuBr$SMe2, Pd(PPh3)4) or decomposition (BH3$THF; LiBHEt3).
However, a two-step procedure involving initial hydrolysis of
syn-23 to pyrazolidinone 24 followed by selective hydrazide-to-
hydrazone reduction with Schwartz's reagent24 afforded
(ꢀ)-newbouldine (19) in ve steps and 40% overall yield from
acid 21.
In initial efforts to access withasomnine (20), an analogous
alkynyl tetrazole substrate 27 underwent sluggish photoinduced
cycloaddition to pyrrolopyrazole 25 in 22% yield (Fig. 5),
consistent with the reduced reactivity observed above for alkyne
substrate 2cc (Table 4, entry 7). In contrast, the same pyrazole 25
could be accessed more efficiently by DDQ oxidation6i of the
alkene-derived pyrazoline syn-23. Subsequent desulfurization
with Raney Ni provided withasomnine (20) in ve steps and 51%
overall yield from acid 21.
Fig. 5 Total synthesis of newbouldine and withasomnine via photo-
induced intramolecular nitrile imine cycloaddition of 2-alkyl-5-
(methylthio)tetrazole E-22.
the pyrazoline congener (ꢂ)-newbouldine was reported only
recently by Trauner, using reductive cyclization of a nitroalkyl-
substituted pyrrolidine and conrming the racemic nature of
this natural product.22
Thus, we synthesized the tetrazole substrate E-22 by LiAlH4
reduction of acid 21 (ref. 23) followed by Mitsunobu reaction of
the resulting alcohol with 5-(methylthio)tetrazole (1) (Fig. 5).10
Photoinduced intramolecular nitrile imine cycloaddition of E-
22 proceeded efficiently to the pyrrolopyrazoline syn-23, albeit
requiring an extended 16 h reaction time for consumption of all
starting material. The crude product was obtained in 18 : 2 dr
and the major diasteromer syn-23 was isolated in 73% yield. As
Conclusions
Nitrile imine cycloadditions were rst described by Huisgen
over 50 years ago3,4 and provide rapid access to functionalized
pyrazoline scaffolds found in diverse biologically active mole-
cules. However, to date, these reactions have apparently been
restricted in scope to nitrile imines having at least one aryl
substituent, regardless of whether the nitrile imines are
generated photochemically or thermally from tetrazoles, or via
basic elimination of a-halohydrazones. Thus, these aryl
substituents may play a role in stabilizing the reactive nitrile
imine intermediates to decrease kinetic barriers and/or avoid
undesired rearrangement side reactions.13 In the case of
photoinduced reactions involving initial denitrogenation of
tetrazoles, UV analysis of substrates having differential reac-
tivities herein (Fig. 2) suggests an additional role of such aryl
substituents in facilitating the initial photodenitrogenation
step by increasing the UV254 absorbance of the substrates.
Importantly, we have found that introduction of a heteroatom
substituent allows tetrazole photodenitrogenation and intra-
molecular nitrile imine cycloaddition to proceed under mild
conditions. The reaction tolerates a wide range of substituent
patterns and is diastereoselective, although photochemical
olen isomerization can be limiting for certain substrates.
Further, this versatile 5-methylthio group can subsequently be
converted to a variety of other functionalities. Indeed, the utility
Fig. 6 Photoinduced intramolecular cycloaddition of Z-olefin Z-22
results in a mixture of anti-23 and syn-23 with E/Z isomerization of
remaining starting material (Z/E-22).
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of this 5-(methylthio)tetrazole platform has been demonstrated
by application to the concise total syntheses of the pyrrolopyr-
azole alkaloids (ꢀ)-newbouline and withasomnine. The nding
that the photoinduced cycloaddition can also be potentiated by
other, non-aryl substituents such as esters (Table 4, entry 11)
opens the door to investigation of other such substituents in the
future.
A. Locatelli and G. Zecchi, J. Heterocycl. Chem., 1976, 13,
657–659; (f) L. Garanti, A. Sala and G. Zecchi, J. Org. Chem.,
1977, 42, 1389–1392; (g) H. Meier, H. Heimgartner and
H. Schmid, Helv. Chim. Acta, 1977, 60, 1087–1090; (h)
H. Meier and H. Heimgartner, Helv. Chim. Acta, 1977, 60,
3035–3038; (i) A. Padwa, S. Nahm and E. Sato, J. Org.
Chem., 1978, 43, 1664–1671; (j) E. Sato, Y. Kanaoka and
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Acknowledgements
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Dedicated to the memory of our esteemed colleague and
mentor, Prof. David Y. Gin (1967–2011). We thank Dr William
Walkowicz (MSKCC) for assistance with UV spectra and Dr
George Sukenick, Dr Hui Liu, Hui Fang, and Dr Sylvia Rusli
(MSKCC Analytical Core Facility) for expert NMR and mass
spectral support. Financial support from the NIH (GM067659 to
D. Y. G.) and an European Commission Marie Curie Interna-
tional Outgoing Fellowship under the 7th Framework Pro-
gramme (FP7-PEOPLE-2009-IOF-253205 to D. P.) is gratefully
acknowledged.
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