Total syntheses of (+)-monomorine I and (-)-indolizidine 195B from sulfinimine-derived 3-oxo pyrrolidine 2-phosphonates

Article abstract of DOI:10.1016/j.tetlet.2010.10.076

Indolizidine alkaloids (+)-monomorine I (1) and (-)-indolizidine 195B (2), having cis and trans relationships of the C-3 and C-9 substituents, respectively, were prepared from the sulfinimine-derived chiral building blocks N-sulfinyl δ-amino β-ketophospho

Full text of DOI:10.1016/j.tetlet.2010.10.076

Tetrahedron Letters 52 (2011) 2054–2057
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Tetrahedron Letters
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Total syntheses of (+)-monomorine I and (ꢀ)-indolizidine 195B
from sulfinimine-derived 3-oxo pyrrolidine 2-phosphonates
⇑
Franklin A. Davis , Junyi Zhang, Yongzhong Wu
Department of Chemistry, Temple University, Philadelphia, PA 19122, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 25 October 2010
Indolizidine alkaloids (+)-monomorine I (1) and (ꢀ)-indolizidine 195B (2), having cis and trans relation-
ships of the C-3 and C-9 substituents, respectively, were prepared from the sulfinimine-derived chiral
building blocks N-sulfinyl d-amino b-ketophosphonate and 3-oxo pyrrolidine 2-phosphonate.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
have a trans relationship. While both these indolizidines have
been the subject of several asymmetric syntheses to the best of
Sulfinimine (N-sulfinyl imine)-derived chiral building blocks,
characterized as having one or more nitrogen stereocenters and
appropriate functional groups for further elaboration, have played
key roles in the asymmetric synthesis of stereochemically complex
nitrogen heterocycles (Fig. 1).1,2 Such building blocks are readily
prepared in one or two steps, in either enantiomeric form, by the
addition of enolate species to enantiopure sulfinimines.1–3 For
example, N-sulfinyl aziridine 2-carboxylates4 were introduced for
the synthesis of 2H-azirines 2-5 and 3-carboxylates6 including
our knowledge they have never been prepared from a common
intermediate.22,23 3-Oxo pyrrolidine 2-phosphonates available
from N-sulfinyl d-amino ketophosphonates,24 sulfinimine-derive
chiral building blocks, are common intermediates for the asym-
metric synthesis of functionalized cis- and trans-2,5-disubstituted
pyrrolidines.25 Using these building blocks we describe herein the
efficient asymmetric synthesis of the indolizidine alkaloids (+)-
monomorin I (1) and (ꢀ)-indolizidine 195B (2).
the marine alkaloid (R)-(ꢀ)-dysidazirine;5 N-sulfinyl
a-amino
2. 3-Oxo pyrrolidine 2-phosphonate
1,3-dithanes for the synthesis of pyrrolidines;7 N-sulfinyl d-amino
b-ketoesters were introduced for the synthesis of polysubstituted
piperidines, such as (ꢀ)-lasubine I8 and (ꢀ)-lasubine II;9 (ꢀ)-indo-
lizidines 223A10 and (ꢀ)-221T11 were prepared via an intramolec-
ular Mannich cyclization reaction with N-sulfinyl b-amino
ketones;12 N-sulfinyl 2,3-diamino esters13 were employed in the
synthesis of amino piperidines (+)-CP-99,99414 and (ꢀ)-epi-CP-
99,994,15 and the cytotoxic tetracyclic marine alkaloid (ꢀ)-agelast-
atin A.16 More recently, acyclic N-sulfinyl b-amino ketone ketals
were used to prepare substituted tropinones17 and homotropinon-
es,18 such as (ꢀ)-euphococcinine and (ꢀ)-adaline. (S)-(+) Cocaine
and novel C-1 cocaine analogs were also prepared using these
building blocks.19
As previously reported for its enantiomer treatment of b-amino
ester (ꢀ)-3 with 5.0 of equiv of lithium dimethyl methylphospho-
nate at ꢀ78 °C afforded N-sulfinyl d-amino b-ketophosphonate
(ꢀ)-4 in 76% yield (Scheme 2).26 The N-sulfinyl group was replaced
with a Cbz group to give (+)-5 in excellent yield using equivalent
amounts of Et3N and DMAP. Interesting, catalytic DMAP gave (+)-
5 in only 30% yield. With NaH/4-acetamidobenzenesulfonyl azide
(4-ABSA) (+)-5 gave the stable
a-diazophosphonate (+)-6 in 85%
yield.25 Heating (+)-6 with 4 mol % Rh2(OAc)4 resulted in a diaste-
reoselective intramolecular metal carbenoide NH insertion reac-
tion affording 3-oxo pyrrolidine phosphonate (+)-7 in 81% yield
(Scheme 2).25
cis- and trans-2,5-disubstituted pyrrolidines are found in phar-
maceuticals, are constituents of numerous natural products, and
are important chiral ligands and auxiliaries for asymmetric
synthesis of indolizidine alkaloids (Scheme 1).20 For example in
(+)-monomorin 1 (1), isolated from Pharaoh’s ant Monomorium
pharaonis, the 3,9-pyrrolidine substituents have a cis relationship
(Scheme 1).21 In (ꢀ)-indolizidine 195B (2), isolated from the
Dendrobatidae neotropical poison frogs,20a these substituents
3. (+)-Monomorine I
Horner–Wadsworth–Emmons (HWE) olefination reaction of
(+)-7 with 4-oxopentanal using DBU/LiCl gave enone (+)-8 as a sin-
gle isomer.27,28 Hydrogenolysis of enone (+)-8 with 10% Pd–C/H2
(1 atm) for 72 h resulted in a remarkable five-step stereoselective
cascade reaction to give hydroxy indolizidine (+)-10 as a single
isomer in 55% yield. This noteworthy reaction includes deprotec-
tion of the pyrrolidine nitrogen, stereoselective reduction of the
olefin, the iminium ion, and the 3-oxo groups. While the sequence
⇑
Corresponding author. Tel.: +1 215 204 0477; fax: +1 215 204 0478.
E-mail address: fdavis@temple.edu (F.A. Davis).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.076

F. A. Davis et al. / Tetrahedron Letters 52 (2011) 2054–2057
2055
OH
O
H
N
Me
O
O
H
H
O
O
CO2Me
N
n-Bu
Me
n-Bu
P(OMe)2
O
N
N
DBU, LiCl
Cbz
(R)-(+)-8
Cbz
MeO
MeCN,rt, 16 h
(70%)
MeO
(-)-Lasubine I
(2S,5R)-(+)-7
(R)-(-)-dysidazirine
O
10% Pd-C,H2
MeOH, rt, 72 h
H
N
n-Bu
HO-
N
+
(55%)
Me
OMe
N
N
H
Ph
9
(-)-Indolizidine 223A
Me
OH
H 1) MsCl/Et3N
(+)-CP-99,994
H
2) t-BuOK, DMF
n-Bu
n-Bu
N
N
HO
N
O
Me
N
CO2Me
Me
Me
H
Br
(2 steps 51%)
NH
H
O
Ph
N
(3R,5S,9S)-(+)-11
(1S,3R,5S,9S)-(+)-10
H
H
N
O
O
(S)-(+)-Cocaine
H
N
(-)-Agelastatin A
10% Pd-C/H2
MeOH (65%)
n-Bu
Figure 1. Examples of sulfinimine-derived nitrogen heterocycles.
Me
(+)-monomorine I (1)
Scheme 3. Synthesis of (+)-monomorine I (1).
H
H
3
N
3
N
9
9
5
5
Me
Me
of these transformations is unknown, a reasonable intermediate
is indolizidine iminium ion 9 (Scheme 3). All that remains is to
remove the C-1 hydroxy group in (+)-10. This was readily
accomplished by transforming it into the mesylate with MsCl/
Et3N. The crude mesylate was dissolved in DMF and with one equiv
of t-BuOK indolizidine (+)-11 was obtained in 51% yield. Hydroge-
nation (10% Pd–C/H2, 1 atm) afforded (+)-monomorine I (1) in 65%
yield.22,25,27
(-)-Indolizidine 195B 2
(+)-Monomorin I 1
O
S
O
p-Tolyl
NH
O
O
R
P(OMe)2
O
N
P(OMe)2
R
Boc
δ-Amino β-ketophosphonate
3-Oxo pyrrolidine
2-phosphonate
4. (ꢀ)-Indolizidine 195B
Scheme 1. Retrosynthetic analysis of indolizidines (+)-1 and (ꢀ)-2.
Our synthesis of (ꢀ)-indolizidine 195B (2) begins with common
intermediate (RS,R)-(ꢀ)-4 (Scheme 4). The N-sulfinyl group was
O
S
O
S
p-Tolyl
NH
O
p-Tolyl
NH
O
O
1) TFA/MeOH
O
CH3P(O)(OMe)2
2) (Boc)2O, Et3N
P(OMe)2
S
Boc
n-Bu
OMe
(RS,R)-(-)-3
n-Bu
DMAP
p-Tolyl
NH
O
O
NH
O
O
n-BuLi, -78 o
(76%)
C
P(OMe)2
P(OMe)2
(RS,R)-(-)-4
n-Bu
n-Bu
(83%)
(RS,R)-(-)-4
(R)-(+)-12
1) TFA/MeOH
2) CbzCl/Et3N
DMAP
1) NaH
Boc
1) NaH
Cbz
NH
O
O
2) 4-ABSA
NH
O
O
2) 4-ABSA
4 mol% Rh2(OAc)4
DCM (79%)
P(OMe)2
P(OMe)2
n-Bu
n-Bu
THF, 1 h (85%)
THF, 1 h (83%)
(90%)
N2
35 o
C
(R)-(+)-5
(R)-(+)-13
O
CO2Me
CHO
Cbz
4 mol% Rh2(OAc)4
O
O
NH
O
O
15
P(OMe)2
n-Bu
P(OMe)2
O
N
CO2Me
DCM, 35 oC, 5 h
(81%)
n-Bu
Cbz
n-Bu
P(OMe)2
n-Bu
N
N
DBU, LiCl
MeCN, rt, 16 h
(73%)
Boc
Boc
N2
O
(2S,5R)-(+)-7
(R)-(+)-6
(2S,5S)-(+)-14
(R)-(+)-16
Scheme 2. Synthesis of 3-oxo pyrrolidine 2-phosphonate (+)-7.
Scheme 4. Synthesis of enone (+)-16.

2056
F. A. Davis et al. / Tetrahedron Letters 52 (2011) 2054–2057
O
OH
CeCl3•NaBH4
CO2Me
CO2Me
MeOH, 0 oC
n-Bu
N
n-Bu
N
Boc
Boc
(R)-(+)-16
17
TFA-NaBH3CN
OH
I2, imidazole, Ph3P
DCM, -45 oC
(61% 2 steps)
CO2Me
n-Bu
N
PhMe, 100 oC, (55%)
Boc
(2R,3S,5R)-(-)-18
O
HCl•NHMe(OMe)
OMe
CO2Me
n-Bu
N
N
n-Bu
N
n-BuLi, THF, -78 oC
(78%)
Boc
Boc
Me
(2R,5R)-(-)-20
(2R,5R)-(-)-19
1) HCl
2) Pd-C, H2
O
10 equiv MeMgBr
n-Bu
Me
H
N
Et2O, -78 oC
(85%)
Boc
MeOH (75%)
(2R,5R)-(-)-21
3
N
9
5
HCl
Me
(-)-Indolizidine 195B 2
Scheme 5. Synthesis of (ꢀ)-indolizidine 195B (2).
replaced with an N-Boc group and was transformed into 3-oxo pyr-
rolidine 2-phosphonate (2R,5S)-(+)-14 as previously described
(Scheme 4).24 The HWE reaction was accomplished with 4-oxobut-
anoate (15) in acetonitrile for 16 h to give enone (+)-16 in 73%
yield.
achieved from sulfinimine-derived common intermediates N-sulfi-
nyl d-amino-b-ketophosphonate (ꢀ)-4 and 3-oxopyrrolidine phos-
phonates (+)-7 and (+)-14. A novel five-step cascade reaction
initiated by hydrogenolysis of enone (+)-8 was used to generate
the core indolizidine ring system in (+)-1. The trans ring juncture
in (ꢀ)-2 was achieved via a hydroxy directed reduction of the pyr-
rolidine exocyclic double bond in allylic 17.
To produce (ꢀ)-indolizidine 195B (2) using a strategy similar to
that employed for (+)-monomorine I (1) requires that (+)-16 be
transformed into a pyrrolidine where the 2,5-substituents are trans
to one another. This can be accomplished via a hydroxy directed
reduction of the pyrrolidine exocycle double bond in (+)-16 using
the methodology developed earlier in our laboratories.25 Luche
reduction of (+)-16 with CeCl3ꢁ7H2O/NaBH4 in MeOH at 0 °C for
20 min gave the crude alcohol 17 which could not be isolated be-
cause of its instability (Scheme 5). For this reason 17 was immedi-
ately taken onto the next step following workup (extracted into
EtOAc and drying over Na2SO4). In DCM crude 17 was treated with
1.5 equiv of NaBH3CN at rt, cooled to ꢀ45 °C and 1.5 equiv of TFA
was added to give hydroxy pyrrolidine (ꢀ)-18 in 61% yield as a sin-
gle isomer for the two steps. The 3-hydroxy group was removed (I2,
Ph3P, heat) to give alkene (ꢀ)-19 and the ester was converted into
the Weinreb amide by reaction with 8 equiv of lithium N,O-dim-
ethylhydroxyamine at ꢀ78 °C (Scheme 5). Next the Weinreb amide
was treated with 10 equiv of MeMgBr in ether at ꢀ78 °C to give ke-
tone (ꢀ)-21 in excellent yield. The ketone was treated with HCl–
dioxane followed by hydrogenolysis, 10% Pd–C, H2 (1 atm) for 2 h
affording (ꢀ)-indolizidine 195B (2) as the hydrochloride in 75%
yield (Scheme 5).23d,29
Acknowledgment
This work was supported by grants from the National Institute
of General Medicinal Sciences (GM57878 and GM51982).
References and notes
1. For a review see: Davis, F. A. J. Org. Chem. 2006, 71, 8993.
2. Davis, F. A.; Chao, B.; Andemichael, Y. W.; Mohanty, P. K.; Fang, T.; Burns, D. M.;
Rao, A.; Szewczyk, J. M. Heteroatom Chem. 2002, 13, 486.
3. (a) For reviews on the chemistry of sulfinimines see: Ref. 1; (b) Morton, D.;
Stockman, R. A. Tetrahedron 2006, 62, 8869; (c) Senanayake, C. H.;
Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou, I. Aldrichim. Acta 2005, 38, 93;
(d) Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003.
4. Aziridine 2-carboxylates: (a) Davis, F. A.; Liang, C.-H.; Liu, H. J. Org. Chem. 1997,
62, 3796; (b) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang, Y. J. Org.
Chem. 1999, 64, 7559; (c) Davis, F. A.; Zhang, Y.; Rao, A.; Zhang, Z. Tetrahedron
2001, 57, 6345; (d) Davis, F. A.; Deng, J.; Zhang, Y.; Haltiwanger, R. C.
Tetrahedron 2002, 58, 7135.
5. Davis, F. A.; Liu, H.; Liang, C.-H.; Reddy, G. V.; Zhang, Y.; Fang, T.; Titus, D. D. J.
Org. Chem. 1999, 64, 8929.
6. Davis, F. A.; Deng, J. Org. Lett. 2007, 9, 1707.
7. (a) Davis, F. A.; Ramachandar, T.; Liu, H. Org. Lett. 2004, 6, 3393; (b) Davis, F. A.;
Ramanchandar, T.; Chai, J.; Skucas, E. Tetrahedron Lett. 2006, 47, 2743.
8. Davis, F. A.; Rao, A.; Carroll, P. J. Org. Lett. 2003, 5, 3855.
In summary, new syntheses of the indolizidine alkaloids (+)-
monomorine
I
(1) and (ꢀ)-indolizidine 195B (2) have been

F. A. Davis et al. / Tetrahedron Letters 52 (2011) 2054–2057
2057
9. Davis, F. A.; Chao, B. Org. Lett. 2000, 2, 2623.
22. (+)- and (ꢀ)-Monomorine I: for leading references see: Toyooka, N.; Zhou, D.;
Nemoto, H. J. Org. Chem. 2008, 73, 4575.
23. (ꢀ)-Indolizidine 195B: (a) Angle, S. R.; Kim, M. J. Org. Chem. 2007, 72, 8791; (b)
Celimene, C.; Dhimane, H.; Lhomment, G. Tetrahedron 1998, 54, 10457; (c)
Machinaga, N.; Kibayashi, C. J. Org. Chem. 1992, 57, 5178; (d) Royer, J.; Husson,
H.-P. J. Org. Chem. 1985, 50, 670.
10. Davis, F. A.; Yang, B. J. Am. Chem. Soc. 2005, 127, 8398.
11. Davis, F. A.; Song, M.; Qiu, H.; Chai, J. Org. Biomol. Chem. 2009, 7, 5067.
12. (a) Davis, F. A.; Nolt, M. B.; Wu, Y.; Prasad, K. R.; Li, D.; Yang, B.; Bowen, K.; Lee,
S. H.; Eardley, J. H. J. Org. Chem. 2005, 70, 2184; (b) Davis, F. A.; Song, M. Org.
Lett. 2007, 9, 2413.
13. Davis, F. A.; Deng, J. Org. Lett. 2004, 6, 2789.
24. Davis, F. A.; Wu, Y.; Xu, H.; Zhang, J. Org. Lett. 2004, 6, 4523.
25. Davis, F. A.; Zhang, J.; Qiu, H.; Wu, Y. Org. Lett. 2008, 10, 1433.
26. Davis, F. A.; Wu, Y. Org. Lett. 2004, 6, 1269.
14. Davis, F. A.; Zhang, Y.; Li, D. Tetrahedron Lett. 2007, 48, 7838.
15. Davis, F. A.; Zhang, Y. Tetrahedron Lett. 2009, 50, 5205.
16. (a) Davis, F. A.; Deng, J. Org. Lett. 2005, 7, 621; (b) Davis, F. A.; Zhang, J.; Ahang,
Y.; Qiu, H. Synth. Commun. 2009, 39, 1914.
17. Davis, F. A.; Theddu, N.; Gaspari, P. M. Org. Lett. 2009, 11, 1647.
18. Davis, F. A.; Edupuganti, R. Org. Lett. 2010, 12, 848.
19. Davis, F. A.; Theddu, N.; Edupuganti, R. Org. Lett. 2010, 12, 4118.
20. (a) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556; (b)
O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435. and references cited therein; (c)
Leclercq, S.; Braekman, J. C.; Daloze, D.; Pasteels, J. M. Prog. Chem. Org. Nat. Prod.
2000, 79, 115; (d) Daly, J. W.; Garraffo, H. M.; Spende, T. F. In Alkaloids: Chemical
and Biological Perspectives; Pelletier, S. W., Ed.; Pergamon: New York, 1999; Vol.
13,. Chapter 1.
27. Synthesis of (+)-monomorine I (1): (ꢀ)-3 clear oil, ½a D20
ꢀ88.7 (c 1.1, CHCl3);
ꢂ
(RS,R)-(ꢀ)-4 clear oil, ½a D20
ꢂ
ꢀ69.7 (c 1.4, CHCl3); (R)-(+)-5, clear oil, ½a D20
ꢂ
+31.3 (c
1.2, CHCl3); (R)-(+)-6 clear oil, ½a D20
ꢂ
+10.2 (c 0.5, CHCl3); (2S,5R)-(+)-7, clear oil,
½
a 2D0
ꢂ
+42.0 (c 1.1, CHCl3); (R)-(+)-8, clear oil, ½ ꢂ +12.4 (c 0.5, CHCl3);
a 2D0
(1S,3R,5S,9S)-(+)-10, clear oil, ½a D20
ꢂ
+33.4 (c 0.6, CHCl3); (3R,5S,9S)-(+)-11, clear
oil, ½a 2D0
ꢂ
+41.3 (c 0.4, CHCl3); (+)-1, clear oil, ½a D20
ꢂ
+33.7 (c 1.2, hexane).
28. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masaune, S.; Roush, W.
R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
29. Synthesis of (ꢀ)-indolizidine (2): (2S,5R)-(+)-14, see Ref. 24; (R)-(+)-16, clear
oil, ½a 2D0
ꢂ
+13.8 (c 0.5, CHCl3); (2R,3S,5R)-(ꢀ)-18, clear oil, ½a D20
ꢀ12.4 (c 0.5,
ꢂ
CHCl3); (2R,3S,5R)-(ꢀ)-19, clear oil, ½a D20
ꢀ207.2 (c 0.42, CHCl3); (2R,5R)-(ꢀ)-
ꢂ
21. Ritter, F. J.; Rotgans, I. E. M.; Tulman, E.; Verwiel, P. E.; Stein, F. Experientia 1973,
29, 530.
20, clear oil, ½a D20
ꢂ
ꢀ151.6 (c 0.38, CHCl3); (2R,5R)-(ꢀ)-21, clear oil, ½a D20
ꢀ155.7
ꢂ
(c 0.31, CHCl3); (ꢀ)-2, ½a D20
ꢀ64.4 (c 0.49, MeOH).
ꢂ