A versatile enantioselective synthesis of azabicyclic ring systems: A concise total synthesis of (+)-grandisine D and unnatural analogues

Article abstract of DOI:10.1002/chem.201200629

Closing in on azacines: We have developed a new six step approach for the rapid and enantioselective synthesis of indolizidine, pyrrolo[1,2-a]azepine, and pyrrolo[1,2-a]azocine azabicyclic systems and their respective lactam congeners, which are found in a host of natural products as well as pharmaceutical preparations. This protocol enables a concise enantioselective total synthesis of (+)-grandisine D in 16.4 % overall yield from commercial materials (see scheme). Copyright

Full text of DOI:10.1002/chem.201200629

DOI: 10.1002/chem.201200629
A Versatile Enantioselective Synthesis of Azabicyclic Ring Systems: A
Concise Total Synthesis of (+)-Grandisine D and Unnatural Analogues
Olugbeminiyi O. Fadeyi,[b] Timothy J. Senter,[b] Kristopher N. Hahn,[b] and
Craig W. Lindsley*[a]
Azabicyclic ring skeletons are common structural subunits
present in numerous alkaloid natural products and serve as
important scaffolds in biologically active and pharmaceuti-
cally significant compounds.[1] Of particular interest in our
stemona alkaloid, stemonine (5),[3] and the manzamine alka-
loid, nakadomarin A (6),[4] to highlight but a few representa-
tive examples. Other related natural products contain the
corresponding lactam moiety, such as 7–9.[5–7] More recently,
these azabicyclic cores are key pharmacophores of high-
throughput screening (HTS) hits from our MLPCN probe
discovery efforts,[8] requiring robust methodology to rapidly
access the parent azabicyclic ring systems as well as flexibili-
ty to incorporate structural diversity for analogue synthe-
sis.[9]
laboratory (Figure 1), are the indolizidine 1, pyrroloACHTUNTRGNEUNG[1,2-
Many synthetic strategies have been developed for the
construction of azabicyclic ring systems,[10] such as 1 and 2,
including Staudinger-aza-Wittig approaches,[11] 7-exo-tet-
AHCTUNGTRENNUNG
cyclizations,[12] [4+2] and [2+2+2] cycloadditions,[13] ring-
closing metathesis (RCM) strategies,[14] nitrone rearrange-
ments[15] and intramolecular Schmidt rearrangements.[16]
General approaches for the synthesis of the pyrroloACHTUNGTRENNUNG[1,2-
a]azocine 3 system are rare and most lack stereocontrol.[10,17]
The majority of these were developed in the context of nat-
ural product target-oriented synthesis, and our laboratory
required a general synthetic strategy to access 1–3 with con-
siderable flexibility for both the synthesis of unnatural ana-
logues and the ease of scale-up. Here, we detail our contri-
butions to this dynamic field with the development of
a rapid, general protocol for the enantioselective construc-
tion of azabicyclic ring systems 1–3 and the application of
this new methodology to a concise total synthesis of
(+)-grandisine D, the formal total synthesis of (+)-grandisi-
ne B, and unnatural analogues.
Figure 1. Structures of indolizidine 1, pyrrolo
pyrrolo[1,2-a]azocine 3 alkaloid cores and natural products 4–9 that pos-
sess these azabicyclic ring systems.[1–7]
ACHTUNGTREN[NUNG 1,2-a]azepine 2, and
ACHTUNGTRENNUNG
a]azepine 2, and pyrrolo
[1,2-a]azocine 3 azabicyclic sys-
Our work was inspired by the chiral sulfinamide work of
Ellman and co-workers for the synthesis of chiral 2-substi-
tuted pyrrolidines (Scheme 1).[18] Addition of a Grignard re-
tems,[1] which are found in a number of natural products
such as the indolizidine alkaloid, serratezomine (4),[2] the
[a] Prof. C. W. Lindsley
Departments of Pharmacology & Chemistry
Vanderbilt Center for Neuroscience Drug Discovery
12415D MRBIV, Vanderbilt University Medical Center
Nashville, TN 37232 (USA)
Fax : (+) 615-345-6532
Scheme 1. Ellmanꢀs approach to the synthesis of chiral 2-substituted pyr-
rolidines. a) 95:5 TFA/H2O, 10 min, then Et3SiH.
E-mail: craig.lindsley@vanderbilt.edu
[b] Dr. O. O. Fadeyi, T. J. Senter, K. N. Hahn
Department of Chemistry
Vanderbilt University
Nashville, TN 37232-6600 (USA)
agent 12 (with a latent aldehyde moiety) to a chiral aldimine
11 provides 13 in high yield and excellent diastereoselectiv-
ity. A one-pot deprotection/acetal hydrolysis facilitates an
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200629.
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Chem. Eur. J. 2012, 18, 5826 – 5831

COMMUNICATION
intramolecular reductive amination reaction to produce
chiral pyrrolidine 14 in high enantiomeric excess.[18] In our
hands,[19] the addition of organometallic reagents such as 12
to aldimines 11 always proceed with high diastereoselectiv-
ity, but the relative stereochemistry can be substrate-depen-
dent based on the ability of the dioxolane oxygens atoms to
coordinate the metal, thus the addition may proceed
through either a metal-chelated or non-metal-chelated tran-
sition state.[20,21]
diastereoselectivity and in 87% yield.[19,21] After column
chromatography, a single diastereomer of 20 resulted, which
was carried forward. Alkylation of the sulfinamide with allyl
bromide provided 21, which smoothly underwent an RCM
reaction with Grubbs II[22] to deliver 22 in good yield.[19] Hy-
drogenation to reduce the alkene, followed by a one-pot de-
protection/acetal hydrolysis/reductive amination sequence
produced the indolizidine alkaloid (+)-coniceine 1 with an
enantiomeric excess (ee) of more than 98%. This approach
for the synthesis of (+)-coniceine,[23] the simplest alkaloid
possessing the azabicyclic core 1, required only six steps and
proceeded in 43% overall yield.
Application of this approach for the enantioselective syn-
thesis of the pyrroloACTHNUTRGNE[NUG 1,2-a]azepine 2 proved more challeng-
ing. In this instance, we were unable to alkylate 20 with
a number of butenyl substrates (Cl, Br, I, OMs, OTS, and
OTf) in reasonable yield to
Based on the work of Ellman[18,20] and our experience,[19]
we envisioned a protocol involving either diastereoselective
Grignard or indium-mediated allylation of a chiral aldimine
substrate 15,[18–21] N-alkylation to afford 16, ring-closing
metathesis (RCM) to provide 17, and finally a one-pot de-
protection/acetal hydrolysis/reductive amination sequence to
afford enantiopure azabicyclic ring systems 1–3 (Scheme 2).
allow for the RCM to form the
seven-membered ring. There-
fore, we altered the approach
(Scheme 4). For the azabicyclic
core 2, commercially available
aldehyde 23 was converted into
the corresponding (R)-N-sulfi-
nyl aldimine 24 under Ti-
Scheme 2. Envisioned approach for the rapid, enantioselective synthesis of azabicylic ring systems 1–3.
AHCTUNRTGEG(NNNU OEt)4-mediated conditions in
In this sequence, the stoichiometric chiral auxiliary also
serves as a protecting group throughout the synthesis.
We began by applying the strategy outlined in Scheme 2
to the synthesis of the indolizidine core 1 (Scheme 3). The
commercially available aldehyde 18 was converted into the
corresponding (R)-N-sulfinyl aldimine 19 under standard
conditions[18–20] in 91% yield, followed by an indium-mediat-
ed allylation reaction that afforded 20 with greater than 15:1
Scheme 4. Synthesis of the pyrrolo
sulfinamide, Ti
ACHTUNGTRENUN[NG 1,2-a]azepine core 2. a) (R)-tert-butyl
(OEt)4, CH2Cl2, 95%; b) (2(À1,3-dioxan-2-yl)ethyl)magne-
G
sium bromide, THF, À458C, 88 % (>9:1 d.r.); c) LiHMDS, allyl bromide,
DMF, À208C to RT, 80%; d) Grubbs II (5 mol%), CH2Cl2, 408C, 1 h,
78%; e) H2, Pd/C; f) 1. TFA/H2O (95:5), RT, 5 min; 2. PS-BH
86% for two steps.
ACHTUNGTRENNUNG(OAc)3,
95% yield.[18–21] Following the Ellman protocol, addition of
Grignard reagent to 24 afforded the desired adduct 25 in
88% yield and with a diastereomer ratio (d.r.) of more than
9:1.[18–21] Alkylation of sulfinamide 25 with allyl bromide
provided 26 as a single diastereomer after column chroma-
tography in 80% yield (Scheme 4). Once again, an RCM re-
action with Grubbs II[22] delivered the seven-membered ring
27 in 78% yield. Hydrogenation to reduce the alkene, fol-
Scheme 3. Synthesis of (+)-coniceine (1), representing the basic indolizi-
dine core. a) (R)-tert-butyl sulfinamide, CuSO4, CH2Cl2, 91%; b) In0, allyl
bromide, satd aq. NaBr, RT, 16 h, 87% (>19:1 d.r.); c) LiHMDS, allyl
bromide, DMF, À208C to RT, 80%; d) Grubbs II (5 mol%), CH2Cl2,
408C, 1 h, 84%; e) H2, Pd/C; f) 1. TFA/H2O (95:5), RT, 45 min; 2. PS-
BH
ACHTUNGTRENNUNG(OAc)3, 81% for two steps. PS-BHACHTUNGTERN(NUGN OAc)3 =polymer-supported tria-
cetoxyborohydride; LiHMDS=lithium bis(trimethylsilyl)amide.
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5827

C. W. Lindsley et al.
lowed by a one-pot deprotection/acetal hydrolysis/reductive
amination sequence produced pyrrolo[1,2-a]azepine 2 in
AHCTUNGTRENNUNG
86% yield for the two steps and with >98% ee. This varia-
tion of the approach outlined in Scheme 1 for the synthesis
of 2 once again required only six steps and proceeded in
45% overall yield (Scheme 4).
For the more rarely described pyrroloACTHNUTRGNEUNG[1,2-a]azocine azabi-
cyclic system 3, the protocol employed for the synthesis of
the indolizidine core 1 (Scheme 3) proceeded smoothly. In
this case, alkylation of sulfinamide 20 with 5-bromo-1-pen-
tene provided 28, that smoothly underwent an RCM reac-
tion with Grubbs II[22] to deliver 29 in 70% yield for the two
steps (Scheme 5). Hydrogenation to reduce the alkene, fol-
Scheme 6. Synthesis of azabicyclic lactams 34–36. a) (S)-tert-butyl sulfina-
mide, CuSO4, CH2Cl2, 90%; b) In0, allyl bromide, satd aq. NaBr, RT,
16 h, 88% (>10:1 d.r.); c) 1. HCl, MeOH, RT; 2. Na2CO3, CH2Cl2, 97%;
d) 1. LiHMDS, allyl bromide, DMF, À208C to RT; 2. Grubbs II
(5 mol%), CH2Cl2, 408C, 1 h, 87% for two steps; e) 1. LiHMDS, butenyl
bromide, DMF, À208C to RT; 2. Grubbs II (5 mol%), CH2Cl2, 408C, 1 h,
86% for two steps; f) 1. LiHMDS, pentenyl bromide, DMF, À208C to
RT; 2. Grubbs II (5 mol%), CH2Cl2, 408C, 1 h, 73% for two steps.
Scheme 5. Synthesis of the pyrroloACTHNUTRGENUGN[1,2-a]azocine core 3. a) LiHMDS, 5-
bromo-1-pentene, DMF, À208C to RT, 85%; b) Grubbs II (5 mol%),
CH2Cl2, 408C, 1 h, 82%; c) H2, Pd/C; d) 1. TFA/H2O (95:5), RT, 45 min;
2. PS-BHACHTUNGTRENNUNG(OAc)3, 87% for two steps.
lowed by a one-pot deprotection/acetal hydrolysis/reductive
amination sequence produced pyrrolo[1,2-a]azocine 3 in
AHCTUNGTRENNUNG
87% yield for the two steps and with more than 98% ee.
Thus, from advanced intermediate 20, azabicyclic core 3
could be accessed in four steps and in 60% overall yield
(Scheme 5). Thus, this new methodology provided rapid,
high yielding access to enantiopure azabicyclic rings systems
1–3 from commercial reagents, and either enantiomer of 1–3
can be prepared by the use of either the (R)- or (S)-tert-
butyl sulfinamine.
Because many natural products, represented by 7–9, pos-
sess the azabicyclic cores 1–3 with a g-lactam moiety,[5–7] we
next applied our methodology to this molecular architecture.
Starting from commercial aldehyde 30, a highly convergent
approach to the lactam congeners of 1–3 was developed
(Scheme 6), in which 30 was first converted into the corre-
sponding (S)-N-sulfinyl aldimine 31 under standard condi-
tions in 90% yield.[18–21] An indium-mediated allylation re-
ing from 56–69% (Scheme 6). Importantly, the alkene can
either be reduced or used as a handle to install additional
functionality and chemical diversity.
Efforts now focused on the application of this methodolo-
gy towards targeted natural product total synthesis, with the
focus of determining if our streamlined approach for the
synthesis of azabicyclic ring systems would offer a tactical
advantage. After a perusal of the literature, we were attract-
ed to grandisines A–G (37–46), indolizidine alkaloids isolat-
ed by Carroll and co-workers from the leaves of the Austral-
ian rain-forest tree Elaeocarpus grandis (Figure 2).[24] These
alkaloids display selective human d-opioid receptor affinity.
Selective activation of the d-opioid receptor is an attractive
strategy for the development of new analgesics, thus grandi-
ACHTUNGTRENNUNGaction afforded 32 in 88% yield with more than 10:1 diaste-
reoselectivity, and, after column chromatography, a single
diastereomer.[19,21] A standard deprotection liberated the pri-
mary amine, which in the presence of sodium carbonate in-
duced cyclization to form key linchpin intermediate (S)-5-al-
lylpyrrolidin-2-one 33 in 97% yield. Allylation of lactam 33
and subsequent RCM with Grubbs II[22] provided indolizi-
none 34 in 87% yield for the two steps. Similarly, alkylation
of 33 with either butenyl bromide or pentenyl bromide, fol-
lowed by an RCM reaction with Grubbs II,[22] afforded aze-
pinone 35 or azocinone 36, respectively. Thus, azabicyclic
lactams 34–36 can be prepared in five steps from commer-
cial aldehyde 30, through linchpin 33, in overall yields rang-
Figure 2. Structures of the indolizidine alkaloids, the grandisines A–G
(37–43).
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Enantioselective Synthesis of Azabicyclic Ring Systems
COMMUNICATION
sines are potential potent analgesic agents.[25] To highlight
our new methodology, we elected to synthesize grandisine D
(41). Grandisine D (41) was previously synthesized by
Tamura and co-workers in 18 steps (12.5% overall yield)
employing a Brønsted acid-mediated Morita–Baylis–Hill-
man ring-closure reaction as the key step; however, two
steps suffered from poor stereocontrol.[26] Tamura was also
able to convert 41 into grandisine B (38) through a tandem
imination/amination reaction sequence.[26] Two years later,
Taylor and co-workers improved on the synthesis of 41, re-
quiring only 13 steps (10% overall yield) from commercial
starting materials, and featuring a new alkyne–acetal cycliza-
tion reaction.[27]
Our retrosynthesis led to the same key aldol chemistry as
that employed by Tamura and Taylor,[26,27] but a fundamen-
tally new approach to the indolizidine core (Scheme 7).[28]
Scheme 8. Synthesis of (+)-grandisine D (41). a) TBSCl, imidazole,
CH2Cl2, 95%; b) MnO2, CH2Cl2, 90%; c) (S)-tert-butyl sulfinamide,
Ti
G
mide, THF, À78 to À458C, 79% (>10:1 d.r.); e) LiHMDS, 3-buteynyl tri-
flate, HMPA/THF, À788C, 87%; f) Grubbs II (5 mol%), CH2Cl2, 408C,
1 h, 96%; g) TBAF, THF, 08C, 93%; h) MnO2, CH2Cl2, 100%; i) 1. 44,
nBu2BOTf, iPrNEt2, CH2Cl2, À788C to RT, 2. TFAA, DMSO, CH2Cl2,
Scheme 7. Retrosynthesis of grandisine D (41).
À788C, 77%; j) 1. TFA/H2O (95:5), RT, 45 min; 2. PS-BH
47%. HMPA=hexamethylphosphoramide; TFAA=trifluoroacetic anhy-
dride, TBAF=tetrabutylammoniumfluoride.
Thus, 41 would be accessed by an aldol reaction between 8-
formylindolizidine 45 and known (S)-5-methylcyclohexa-
none 44.[29] 8-Formylindolizidine 45 would be prepared from
Grignard addition and RCM of (S)-sulfinyl aldimine 46.
Our synthetic study began with the synthesis of (S)-sulfi-
nyl aldimine 46 (Scheme 8). Starting from commercial diol
47, a mono-silyation and oxidation sequence, followed by
conversion into the corresponding (S)-N-sulfinyl aldimine 46
(+)-grandisine (41) also constitutes a formal total synthesis
of (À)-grandisine B (38).
To further highlight the power of this methodology for di-
versity-oriented synthesis, we applied it towards the synthe-
sis of an unnatural analogue of 41, in which the nitrogen
atom was moved from 4-position to the 9-position, resulting
in a fundamentally new molecular architecture. Starting
with (S)-N-sulfinyl aldimine 51 (the (S)-enantiomer of 19),
an indium-mediated allylation reaction afforded 52 (the
(S,S) enantiomer of (R,R)-20) in 87% yield with greater
than 19:1 diastereoselectivity, and, after column chromatog-
raphy, a single diastereomer (Scheme 9).[18–21] Diol 47 was
mono-protected as a TBS ether and the remaining hydroxyl
was converted into the corresponding allylic bromide 53 in
85% yield for the two steps. Allylation of 52 with 53 provid-
ed 54 in 90% yield, followed by an RCM reaction with
Grubbs II[22] afforded 54 in 81% yield for the two steps. De-
protection of the TBS ether and oxidation delivered key al-
dehyde 56, in 95% yield for the two steps. Once again, an
Evanꢀs aldol[30] employing boron-enolate methodology with
56 and enone 44,[29] followed by oxidation provided 57 in
67% yield. Finally, application of the one-pot deprotection/
acetal hydrolysis/reductive amination sequence produced
the unnatural analogue of (+)-grandisine D 58 in 49%
yield. The synthesis of 58 proceeded in 11 steps (the longest
linear sequence was 9 steps) from commercial materials in
17.8% overall yield (Scheme 9).
under TiACHTUNGTRENNUNG(OEt)4-mediated conditions proceeded in 74%
yield for the three steps.[18–21] Following the Ellman protocol,
addition of Grignard reagent to 46 afforded the desired
adduct 48 in 79% yield with >10:1 d.r..[18–21] Alkylation of
sulfinamide 48 with butenyl triflate provided 49 as a single
diastereomer after column chromatography in 87% yield
(Scheme 8). Again, an RCM reaction with Grubbs II[22] de-
livered the piperidine ring in 96% yield, followed by remov-
al of the TBS group and oxidation to key aldehyde 45 in
93% yield for the two steps. Next, an Evanꢀs aldol employ-
ing boron-enolate methodology[30] with 45 and enone 44,[29]
followed by oxidation provided 50 in 77% yield (Scheme 8).
Finally, application of the one-pot deprotection/acetal hy-
drolysis/reductive amination sequence produced 41 in 47%
yield. Our synthetic 41 was in complete agreement with the
reported spectral and rotation data for the natural prod-
uct[24] as well as the previous synthetic efforts.[26,27] Thus, the
total synthesis of grandisine D (41), employing our azabicy-
clic methodology, required only 11 steps from commercial
starting materials in 16.4% overall yield and with excellent
stereocontrol throughout. Notably, based on the work of
both Tamura[26] and Taylor,[27] the total synthesis of
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C. W. Lindsley et al.
Keywords: alkaloids · enantioselectivity · grandisine D ·
lactams · synthetic methods · total synthesis
[1] a) J. P. Michael, Nat. Prod. Rep. 2005, 22, 603–626; b) A. Mitchen-
son, A. Nadin, J. Chem. Soc. Perkin Trans. 1 2000, 2862–2892; c) D.
OꢀHagan, Nat. Prod. Rep. 1997, 14, 637–651; d) K. Sakata, K. A.
Oki, C.-F. Chang, A. Sakurai, S. Tamura, S. Murakoshi, Agric. Biol.
Chem. 1978, 42, 457–465; e) H. Shinozaki, M. Ishida, Brain Res.
1985, 334, 33–39; f) R. A. Pilli, G. B. Rosso, M. D. C. F. De Oliveira,
Nat. Prod. Rep. 2000, 17, 117–127; g) R. A. Pilli, G. B. Rosso,
M. D. C. F. De Oliveira, Nat. Prod. Rep. 2010, 27, 1908–1937; h) C.
Seger, K. Mereiter, E. Kaltenegger, T. Pacher, H. Greger, O. Hofer,
Chem. Biodiversity 2004, 1, 265–279; i) H. Greger, J. Schinnerl, S.
Vajrodaya, L. Brecker, O. Hofer, J. Nat. Prod. 2009, 72, 1708–1711.
[2] H. Morita, M. Arisaka, J. Kobayashi, J. Org. Chem. 2000, 65, 6241–
6245.
[3] a) C. Zou, J. Li, H. Lei, H. Fu, W. Lin, J. Chin. Pharm. Sci. 2000, 9,
113–115; b) D. R. Williams, K. Shamim, R. Khalida, J. Reddy, G. S.
Amato, S. M. Shaw, Org. Lett. 2003, 5, 3361–3364.
[4] a) J. Kobayashi, D. Watanabe, N. Kawasaki, M. Tsuda, J. Org.
Chem. 1997, 62, 9236–9239; b) T. Nagatam, M. Nakgawa, A. Nishi-
da, J. Am. Chem. Soc. 2003, 125, 7484–7485; c) K. Ono, M. Nakaga-
wa, A. Nishida, Angew. Chem. Int. Ed. 2004, 43, 202–2023; d) P. Ja-
kubec, D. M. Cockfield, D. J. Dixon, J. Am. Chem. Soc. 2009, 13,
16632–16633; e) D. B. C. Martin, C. D. Vanderwal Angew. Chem.
2010, 122, 2893–2895; Angew. Chem. Int. Ed. 2010, 49, 2830–2832;
Angew. Chem. Int. Ed. 2010, 49, 2830–2832; f) M. G. Nilson, R. L.
Funk Org. Lett. 2010, 12, 4912–4915; g) B. Cheng, F. Wu, X. Yang,
Y. Zhou, X. Wan, H. Zhai Chem. Eur. J. 2011, 52, 6094–6097.
[5] a) S. R. Johns, J. A. Lamberton, A. A. Sioumis, Chem. Commun.
1968, 21, 1324–1325; b) S. R. Johns, J. A. Lamberton, A. A. Sioumis,
Aust. J. Chem. 1969, 22, 793–800.
Scheme 9. Synthesis of unnatural analogue (58). a) In0, allyl bromide,
satd aq. NaBr, RT, 16 h, 87% (>19:1 d.r.); b) LiHMDS, 53, DMF,
À208C to RT, 90%; c) Grubbs II (5 mol%), CH2Cl2, 408C, 1 h, 90%;
d) TBAF, THF, 08C, 95%; e) MnO2, CH2Cl2, 100%; f) 1. 44, nBu2BOTf,
iPrNEt2, CH2Cl2, À788C to RT; 2. TFAA, DMSO, CH2Cl2, À788C, 67%;
g) 1. TFA/H2O (95:5), RT, 45 min; 2. PS-BHACTHUNTRGNEU(GN OAc)3, DCE, 49%.
In summary, we have developed a novel six step approach
for the rapid and enantioselective synthesis of indolizidine
1, pyrroloACHTUNGTRENNUNG[1,2-a]azepine 2, and pyrroloACHUTNGTREN[NNGU 1,2-a]azocine 3 azabi-
[6] W. Lin, R. Xu, Q. Zhong, Huaxue Xuebao 1991, 38, 927–931.
[7] a) E. Valencia, V. Fajardo, A. J. Freyer, M. Shamma, Tetrahedron
Lett. 1985, 26, 993–996; b) F. G. Fang, G. B. Feigelson, S. J. Dani-
shefsky, Tetrahedron Lett. 1989, 30, 2743–2746.
cyclic systems and their respective lactam congeners 34–36,
that are found in a host of natural products as well as phar-
maceutical preparations. The methodology described herein
allows the preparation of either enantiomer, based on the
stereochemistry of the tert-butyl sulfinamide employed and
the nature of the transition state of the organometallic used
in the initial allylation. To highlight this technology in natu-
ral product total synthesis, (+)-grandisine D (41) was pre-
pared in 11 synthetic steps and in 16.4% overall yield, a no-
table advance over the two previous syntheses, and also con-
stitutes a formal total synthesis of (À)-grandisine B (38).
This methodology also lent itself to the rapid synthesis of an
unnatural analogue 58, expanding the utility of the method-
ology for diversity-oriented synthesis. Further refinements,
applications to the related pyrrolizidine alkaloids and bio-
logical investigations are in progress and will be reported in
due course.
[8] For information on the MLPCN and the Vanderbilt Center, please
see:
http://www.mc.vanderbilt.edu/centers/mlpcn/index.html
or
http://mli.nih.gov/mli/mlpcn/
[9] J. P. Kennedy, L. Williams, T. M. Bridges, R. N. Daniels, C. D.
Weaver, C. W. Lindsley, J. Comb. Chem. 2008, 10, 345–354.
[10] For reviews on the synthesis of azabicyclic ring systems, see: a) J. P.
Michael, Beilstein J. Org. Chem. 2007, 3, 27; b) D. M. Hodgson,
L. H. Winning, Org. Biomol. Chem. 2007, 5, 3071–3082; c) B. B.
Toure, D. G. Hall, Chem. Rev. 2009, 109, 4439–4486; d) J. P. Mi-
chael, Nat. Prod. Rep. 2008, 25, 139–165; e) D. Enders, T. Thiebes,
Pure Appl. Chem. 2001, 73, 573–578; f) R. A. Pili, G. B. Rosso, F.
De Oliviera, M. da Conceicao, Nat. Prod. Rep. 2011, 27, 1908–1937;
g) R. Aibes, M. Figueredo, Eur. J. Org. Chem. 2009, 15, 2421–2435;
h) S. K. Khim, A. G. Schultz, J. Org. Chem. 2004, 69, 7734–7736.
[11] a) D. R. Williams, D. L. Brown, J. W. Benbow, J. Am. Chem. Soc.
1989, 111, 1923–1925; b) D. R. Williams, M. G. Fromhold, J. D.
Early, Org. Lett. 2001, 3, 2712–2724; c) D. R. Williams,
K,
Shamim, J. P. Reddy, G. S. Amato, S. M. Shaw, Org. Lett. 2003, 5,
3361–3364.
[12] Y. Kohno, K. Narasaka, Bull. Chem. Soc. Jpn. 1996, 69, 2063–2070.
[13] a) P. A. Jacobi, K. Lee, J. Am. Chem. Soc. 1997, 119, 3409–3410;
b) P. A. Jacobi, K. Lee, J. Am. Chem. Soc. 2000, 122, 4295–4303;
c) R. T. Yu, T. Rovis, J. Am. Chem. Soc. 2006, 128, 12370–12371.
[14] a) R. Alibes, M. Figueredo, J. Org. Chem. 2009, 74, 2421–2435; b) S.
Torssell, E. Wanngren, P. Somafi, J. Org. Chem. 2007, 72, 4246–
4249; c) M. P. Sibi, T. Subramanian, Synlett 2004, 1211–1214;
d) H. F. Olivo, R. Tovar-Miranda, E. Barragan, J. Org. Chem. 2006,
71, 3287–3290; e) A. T. Hoye, P. Wipf, Org. Lett. 2011, 13, 2634–
2637.
Acknowledgements
The authors acknowledge the Vanderbilt Department of Pharmacology,
VUMC and the NIH for funding our research, and in particular the
MLPCN (U54MH084659) for the Vanderbilt Specialized Chemistry
Center.
[15] P. Cid, M. Closa, P. De March, M. Figueredo, J. Font, E. Sanfeliu, A.
Soria, Eur. J. Org. Chem. 2004, 4215–4233.
5830
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 5826 – 5831

Enantioselective Synthesis of Azabicyclic Ring Systems
COMMUNICATION
[16] A. Kapat, E. Nyfeler, G. T. Giuffredi, J. Renaud, J. Am. Chem. Soc.
2009, 131, 17746–17747.
[17] Y. Zeng, B. T. Smith, J. Hershberger, J. Aubeꢀ, J. Org. Chem. 2003,
68, 8065–8067.
[24] a) A. R. Carroll, G. Arumugan, R. J. Quinn, G. Guymer, P. Grim-
shaw, J. Org. Chem. 2005, 70, 1889–1892; b) P. L. Katavic, D. A.
Venables, P. I. Forster, G. Guymer, A. R. Carroll, J. Nat. Prod. 2006,
69, 1295–1299.
[25] A. A. Pradham, K. Befort, C. Nozaki, C. Gaveriaux-Ruff, B. L. Bri-
gitte, Trends Pharm. Sci. 2011, 32, 581–590.
[26] a) H. Kurasaki, I. Okamoto, N. Morita, O. Tamura, Org. Lett. 2009,
11, 1179–1181; b) H. Kurasaki, I. Okamoto, N. Morita, O. Tamura,
Chem. Eur. J. 2009, 15, 12754–12763.
[27] J. D. Cuthbertson, A. A. Godfrey, R. J. K. Taylor, Org. Lett. 2011,
13, 3976–3979.
[28] See the Supporting Information for full details.
[29] A. Carlone, M. Margio, C. North, A. Landa, K. A. Jorgensen, Chem.
Commun. 2006, 4928–4930.
[18] a) K. M. Brinner, J. A. Ellman, Org. Biomol. Chem. 2005, 3, 2109–
2113; b) D. A. Coogan, J. A. Ellman, J. Am. Chem. Soc. 1999, 121,
269–270; c) T. P. Tang, J. A. Ellman, J. Org. Chem. 2002, 67, 7819–
7832.
[19] M. L. Schulte, C. W. Lindsley, Org. Lett. 2011, 13, 5684–5687.
[20] D. A. Coogan, G. Liu, J. A. Ellman, Tetrahedron 1999, 55, 8883–
8904.
[21] X.-W. Sun, M. Liu, M.-H. Xu, G.-Q. Lin, Org. Lett. 2008, 10, 1259–
1262.
[22] K. M. Kuhn, T. M. Champange, S. H. Hong, W.-H. Wei, A. Nickel,
C. W. Lee, S. C. Virgil, R. H. Grubbs, R. L. Pederson, Org. Lett.
2010, 12, 984–987.
[30] a) D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981, 103,
2127–2129; b) D. A. Evans, J. V. Nelson, T. R. Taber, Top. Stereo-
chem. 1982, 13, 1–115.
[23] H. Yoda, H. Katoh, Y. Ujihara, K. Takabe, Tetrahedron Lett. 2001,
42, 2509–2512.
Received: February 24, 2012
Published online: March 30, 2012
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