An enantioselective total synthesis of (-)-stemoamide

Article abstract of DOI:10.1055/s-2004-822927

An enantioselective synthesis of (-)-stemoamide has been achieved in 14 steps starting from pyroglutamyl alcohol in ca. 7% overall yield. The key steps in the strategy are a conjugate addition of a vinyl copper reagent and a ring closing metathesis (RCM) reaction to form the seven-membered ring.

Full text of DOI:10.1055/s-2004-822927

LETTER
1211
An Enantioselective Total Synthesis of (–)-Stemoamide
Enantioselective Total
uSynthesis of
k
(
–)-Stemoa
m
u
ide nd P. Sibi,* Thangaiah Subramanian
Department of Chemistry, North Dakota State University, Fargo, ND 58105, USA
Fax +1(701)2311057; E-mail: Mukund.Sibi@ndsu.nodak.edu
Received 22 February 2004
ization of C-9 center using the precedence from Jacobi’s
work on stemoamide4b and C-10 methylation as described
previously by Narasaka and co-workers.4g The final lac-
tone ring would be constructed by iodolactonization of a
bicyclic lactam, installing the correct stereochemistry at
C-8. Other key steps in our strategy were the preparation
of a bicyclic lactam from 7 via a ring closing metathesis
(RCM) reaction. This precursor could be accessed
through a syn selective conjugate addition of a vinyl frag-
ment to 8. (S)-Pyroglutamic acid would serve as the initial
starting material similar to the several reported synthesis
of stemoamide.
Abstract: An enantioselective synthesis of (–)-stemoamide has
been achieved in 14 steps starting from pyroglutamyl alcohol in ca.
7% overall yield. The key steps in the strategy are a conjugate addi-
tion of a vinyl copper reagent and a ring closing metathesis (RCM)
reaction to form the seven-membered ring.
Key words: stemoamide, ring closing metathesis, conjugate addi-
tion, pyroglutamic acid
The stemona group of alkaloids has received considerable
attention from synthetic chemists in the past decade
(Figure 1).1 Root extracts from stemona species have been
used in traditional Chinese medicine to treat respiratory
disorders.2 Insecticidal, anti-feedant, and neuromuscular
activities of some members of the stemona group have
also been noted in the literature. Several groups have com-
pleted the synthesis of simple as well as more complex
members of the stemona group.3 A key feature of this
class of alkaloids is the 1-azabicyclo[5.3.0]decane core
(5) which is present in most members of this family. Five
enantioselective total syntheses of stemoamide have been
reported so far.4 In this work we report an enantioselective
synthesis of stemoamide that compares favorably in the
total number of steps and overall yield to those reported in
the literature.
O
Me
H
H
O
O
H
H
N
N
N
O
H
H
H
O
O
O
MeO
O
H
7
6
4 (–)-Stemoamide
O
O
HO2C
O
N
N
H
MeO
9 Pyroglutamic Acid
8
Scheme 1 Retrosynthetic analysis
Our strategy for the synthesis of stemoamide is outlined in
Scheme 1. Our plan involved the conversion of the key
tricyclic lactone 6 to the target which requires an epimer-
Our synthesis started from the inexpensive (S)-pyro-
glutamic acid 9 (Scheme 2). Esterification under standard
conditions gave the known methyl ester 10.5 Initially, we
attempted the alkylation of the lactam nitrogen of 10 with
bromobutene under a variety of conditions. Although the
alkylation was successful, extensive racemization of the
chiral center was observed. To reduce the acidity of the
methine hydrogen, the ester 10 was converted to the
known primary alcohol 11 using sodium borohydride.6
Protection of the primary alcohol as the TBS ether under
standard conditions gave the known compound 12.7
Alkylation of the imide using bromobutene gave 13 in
good yield.8 Deprotection of the TBS ether using TBAF
furnished the primary alcohol 14 in enantiomerically pure
form. Swern oxidation under carefully controlled condi-
tions gave the aldehyde which without purification was
subjected to Wittig reaction with the preformed ylide.9
The a,b-unsaturated ester 8 was obtained in good yield as
a single E-isomer.
O
H
Me
HO
O
N
O
O
H
O
N
O
O
O
H
1 Stemotinine
2 Tuberostemospirinone
O
1
H
O
9a
O
O
9
N
N
H
N
H
O
8
O
H
3 Stenine
5
4 Stemoamide
Figure 1 Stemona Alkaloids
SYNLETT 2004, No. 7, pp 1211–1214
0
3.
0
6.
2
0
0
4
Advanced online publication: 10.05.2004
DOI: 10.1055/s-2004-822927; Art ID: S01504ST
© Georg Thieme Verlag Stuttgart · New York

1212
M. P. Sibi, T. Subramanian
LETTER
NaBH4
O
O
SOCl2
MeOH
O
H
O
O
O
MgBr
N
H
O
N
H
N
H
N
MeO
O
N
HO
MeO
HO
H
H
CuBr·DMS,
LiBr, –78 °C
81%
O
MeO
10
9
11
8
7
NaH
TBSCl
92%
O
O
N
H
N
TBSO
4-Bromo- TBSO
1-butene
O
Grubbs II (6 mol%)
H
N
H
1 N NaOH, MeOH
83%
O
CH2Cl2, reflux
95%
80%
12
13
MeO
15
O
H
O
O
H
N
H
N
1. Swern Oxd.
5% NaHCO3, I2
91%
O
O
TBAF
95%
N
N
H
I
O
HO
MeO
O
2.
O
O
HO
H
Ph3P
8
14
OMe
17
16
73%, two steps
O
H
Scheme 2 Synthesis of the conjugate addition precursor 8
Bu3SnH, AIBN,
toluene
N
H
O
O
H
70%
Highly syn stereoselective conjugate addition of copper
reagents to g-amino alkenoates have been reported in the
literature.10 This is in contrast to the high anti selectivity
observed in conjugate additions to g-alkoxy alkenoates.11
With the intermediate 8 in hand, the introduction of the
key vinyl group was undertaken (Scheme 3). Conjugate
addition with the copper reagent derived from vinyl mag-
nesium bromide and copper bromide gave 7 in excellent
yield and as a single syn diastereomer.12 The origins of the
stereoselectivity with the g-amino alkenoates are not com-
pletely apparent at the present time. However, re face ad-
dition in a Felkin–Anh model accounts for the observed
syn selectivity for 7. It should be noted that the configura-
tion at the newly formed chiral center (C-9) is opposite to
that of the target stemoamide.13 The formation of seven-
membered rings using RCM has been well established in
the literature.14 Ring closure of 7 using either Grubbs I or
II catalyst gave the bicyclic lactam 15 in high yield. Hy-
drolysis of the ester gave the acid 16. Iodolactonization
under standard conditions produced the tricyclic lactone
17 in excellent yield. A detailed NMR structure analysis
of 17 clearly established the relative stereochemistry at
the four contiguous chiral centers. Thus the lactonization
allows for the installation of the proper stereochemistry at
C-8. Reduction of the iodolactone under radical condi-
tions gave 6 in good yield over two steps.15
6
Scheme 3 Synthesis of key tricyclic lactam 6
lactone 204a with the proper configuration at C-9.4b Meth-
ylation of lactone 20 using a slight modification of the
previously reported conditions of Narasaka4g gave ste-
moamide in 70% yield. The spectral and analytical char-
acteristics of 4 were identical to those reported in the
literature for (–)-stemoamide.18 The overall yield of ste-
moamide is ca. 7% starting from pyroglutamyl alcohol 11.
The present synthesis compares favorably in yield and
number of steps to those reported in the literature.4
PhSe
O
O
H
O
H
N
LiHMDS, PhSeBr
81%
N
H
H
O
O
O
H
H
18
6
O
O
H
H
2O2
N
N
NiCl2
H
H
O
O
76%
NaBH4
78%
O
O
H
H
19
20
H3C
O
N
H
H
LiHMDS, THF
The next key step was epimerization of the stereocenter at
C-9 (Scheme 4) by a three step protocol. Jacobi in his ex-
cellent work on the synthesis of stemoamide has shown
that it is possible to obtain correct stereochemistry at C-9
by a stereoselective reduction.4b This is based on confor-
mational analysis of the tricyclic core of the stemoam-
ide.16 Phenylselenation of 6 was achieved by treating it
H
MeI
O
O
70%
4 (–)-Stemoamide
Scheme 4 Completion of the synthesis of (–)-stemoamide
with LiHMDS followed by the addition of phenylselenyl In conclusion we have developed an efficient synthesis of
bromide furnishing 18 in good yield.17 Installation of the
stemoamide, which highlights the use of stereoselective
C9-C10 double bond was accomplished by selenoxide
elimination providing 19 in good overall yield over two
steps. The crucial reduction was accomplished using nick-
el chloride and sodium borohydride furnishing the known
conjugate addition and ring closing metathesis as the key
steps. The synthesis of other members of the stemona
alkaloid family is underway in our laboratory.
Synlett 2004, No. 7, 1211–1214 © Thieme Stuttgart · New York

LETTER
Enantioselective Total Synthesis of (–)-Stemoamide
1213
1011. (e) Jako, I.; Uiber, P.; Mann, A.; Wermuth, C. G.;
Boulanger, T.; Norberg, B.; Evrard, G.; Durant, F. J. Org.
Chem. 1991, 56, 5729. (f) Hanessian, S.; Sumi, K. Synthesis
1991, 1083. (g) Hanessian, S.; Demont, E.; van Otterlo, W.
A. L. Tetrahedron Lett. 2000, 41, 4999. (h) Hanessian, S.;
Wang, W.; Gai, Y. Tetrahedron Lett. 1996, 37, 7477.
(i) Paz, M. M.; Sardina, F. J. J. Org. Chem. 1993, 58, 6990.
(11) For examples of highly diastereoselective conjugate
additions of copper reagents to g-substituted alkenoates and
discussions on stereoselectivity in these reactions see:
(a) Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.;
Kitahara, H. J. Am. Chem. Soc. 1992, 114, 7652. (b) Roush,
W. R.; Lesur, B. M. Tetrahedron Lett. 1983, 24, 2231.
(c) Roush, W. R.; Michaelides, M. R.; Tai, D. F.; Lesur, B.
M.; Chong, W. K. M.; Harris, D. J. J. Am. Chem. Soc. 1989,
111, 2984.
(12) Procedure for Conjugate Addition: Lithium bromide
(2.59 g, 30.1 mmol, 6 equiv) and CuBr·DMS (3.059 g, 15.0
mmol) were placed in a dry round bottomed flask. THF (35
mL) was added to the solids and the reaction mixture was
cooled to –78 °C. Vinyl magnesium bromide (30 mL, 0.977
molar solution in THF, 6 equiv) was added dropwise. After
stirring for 30 min at the same temperature, ester 8 (1.1072
g, 5 mmol) in THF (10 mL) was added dropwise and the
resultant solution was stirred at the same temperature for 10
min and at –40 °C for 50 min. The reaction was quenched
with NH4Cl solution and extracted with Et2O repeatedly.
The combined extracts were washed with brine, dried over
Na2SO4 and concentrated under reduced pressure. The
concentrated residue was purified by silica gel column
chromatography using EtOAc and hexane (EtOAc–hexane,
1:1) to give the ester 7 (1.02 g, 81%). 1H NMR (500 MHz,
CDCl3): d = 1.69–1.76 (m, 1 H), 1.95–2.04 (m, 1 H), 2.25–
2.39 (m, 4 H), 2.29 (d, J = 7.0 Hz, 2 H), 2.93 (m, 1 H), 3.05–
3.11 (m, 1 H), 3.66 (s, 3 H), 3.75–3.84 (m, 2 H), 5.04 (d, J =
10.0 Hz, 1 H), 5.08 (d, J = 17.5 Hz, 1 H), 5.18 (dd, J = 13.5,
3 Hz, 2 H), 5.73 (m, 2 H). 13C NMR (125 MHz, CDCl3): d =
19.5, 30.4, 31.7, 32.4, 39.9, 41.3, 52.1, 60.0, 117.3, 117.9,
135.3, 136.7, 172.7, 175.6. IR (neat): 1733, 1674 cm–1.
[a]D25 +17.3 (c = 1.0, MeOH). HRMS: m/z calcd for
C14H21NO3Na+: 274.1413; found: 274.1410. The
Acknowledgment
We thank the NSF and NIH for support of our research programs.
We also express our gratitude to Dr. N. Prabagaran for valuable
experimental assistance.
References
(1) (a) Pilli, R. A.; Ferreira de Olivera, M. C. Nat. Prod. Rep.
2000, 17, 117. (b) Lin, W.-H.; Ye, Y.; Xu, R.-S. J. Nat.
Prod. 1992, 55, 571.
(2) (a) Qin, G. W.; Xu, R. S. Med. Res. Rev. 1998, 18, 375.
(b) Ye, Y.; Qin, G.-W.; Xu, R.-S. Phytochemistry 1994, 37,
1201. (c) Ye, Y.; Qin, G.-W.; Xu, R.-S. Phytochemistry
1994, 37, 1205. (d) Ye, Y.; Qin, G.-W.; Xu, R.-S. J. Nat.
Prod. 1994, 57, 655. (e) Brem, B.; Seger, C.; Pacher, P.;
Hofer, O.; Vajrodaya, S.; Greger, H. J. Agric. Food Chem.
2002, 50, 6383.
(3) (a) Tuberostemonine: Wipf, P.; Rector, S. R.; Takahashi, H.
J. Am. Chem. Soc. 2002, 124, 14848. (b) For stenine see the
following: Morimoto, Y.; Iwahashi, M.; Nishida, K.;
Hayashi, Y.; Shirahama, H. Angew. Chem., Int. Ed. Engl.
1996, 35, 904. (c) Morimoto, Y.; Iwahashi, M.; Kinoshita,
T.; Nishida, K. Chem.–Eur. J. 2001, 7, 4107. (d) Wipf, P.;
Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117,
11106. (e) Golden, J. E.; Aube, J. Angew. Chem. Int. Ed.
2002, 41, 4316. (f) Chen, C. Y.; Hart, D. J. J. Org. Chem.
1993, 58, 3840. (g) Ginn, J. D.; Padwa, A. Org. Lett. 2002,
4, 1515. For other stemona alkaloids see the following: (h)
Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett.
2001, 3, 2721. (i) Kende, A. S.; Martin Hernando, J. I.;
Milbank, J. B. J. Tetrahedron 2002, 58, 61. (j)Martin, S. F.;
Barr, K. J.; Smith, D. W.; Bur, S. K. J. Am. Chem. Soc. 1999,
121, 6990.
(4) Enantioselective synthesis: (a) Gurjar, M. K.; Reddy, D. S.
Tetrahedron Lett. 2002, 43, 295. (b) Jacobi, P. A.; Lee, K. J.
Am. Chem. Soc. 2000, 122, 4295. (c) Kinoshita, A.; Mori,
M. Heterocycles 1997, 46, 287. (d) Kinoshita, A.; Mori, M.
J. Org. Chem. 1996, 61, 8356. (e) Williams, D. R.; Reddy,
J. P.; Amato, G. S. Tetrahedron Lett. 1994, 35, 6417. For
racemic synthesis see the following: (f) Jacobi, P. A.; Lee,
K. J. Am. Chem. Soc. 1997, 119, 3409. (g) Kohno, Y.;
Narasaka, K. Bull. Chem. Soc. Jpn. 1996, 69, 2063.
(5) Ester 10 is commercially available.
(6) Acevedo, C. M.; Kogut, E. F.; Lipton, M. A. Tetrahedron
2001, 57, 6353. The alcohol is also commercially available.
(7) (a) Ref. 6. (b) Frieman, B. A.; Bock, C. W.; Bhat, K. L.
Heterocycles 2001, 55, 2099.
(8) For an example of alkylation of protected pyroglutamyl
alcohol see: Sato, Y.; Saito, N.; Mori, M. Tetrahedron 1998,
54, 1153; also see refs. 4b, 4d.
(9) For stereoselective olefination of prolinal derivatives see:
(a) Langois, N.; Radom, M.-O. Tetrahedron Lett. 1998, 39,
857. (b) Mulzer, J.; Shanyoor, M. Tetrahedron Lett. 1993,
34, 6545. (c) Moriwake, T.; Hamano, S.; Miki, D.; Saito, S.;
Torii, S. Chem. Lett. 1986, 815. (d) Clark, J. S.; Hodgson, P.
B.; Goldsmith, M. D.; Blake, A. J.; Cooke, P. A.; Street, L.
J. J. Chem. Soc., Perkin Trans. 1 2001, 3325. (e) Lee, E.;
Li, K. S.; Lim, J. Tetrahedron Lett. 1996, 37, 1445.
(10) For conjugate addition to g-amino alkenoates with varied
levels of syn selectivity see: (a) Moriwake, T.; Hamano, S.;
Saito, S. Heterocycles 1988, 27, 1135. (b) Le Coz, S.;
Mann, A.; Thareau, F.; Taddei, M. Heterocycles 1993, 36,
2073. (c) Reetz, M. T.; Röhrig, D. Angew. Chem., Int. Ed.
Engl. 1989, 28, 1706. (d) Jako, I.; Uiber, P.; Mann, A.;
Taddei, M.; Wermuth, C. G. Tetrahedron Lett. 1990, 31,
stereochemistry at C-9 was unambiguously established at a
later stage (compounds 15 and 17).
(13) Interestingly, conjugate addition to the corresponding Z-
ester gave a 2:1 mixture of diastereomers with 7 as the major
product (data not shown).
(14) (a) For recent reviews on ring-closing metathesis see: Trnka,
T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(b) Also see: Fürstner, A. Angew. Chem. Int. Ed. 2000, 39,
3012. For the formation of 7-membered azacycles using
RCM see the following: (c) Turling, C. A.; Holmes, A. B.;
Markwell, R. E.; Pearson, N. D. J. Chem. Soc., Perkin Trans.
1 1999, 1695. (d) Barrett, A. G. M.; Ahmed, M.; Baker, S.
P.; Baugh, S. P. D.; Braddock, D. C.; Procopiou, P. A.;
White, A. J. P.; Williams, D. J. J. Org. Chem. 2000, 65,
3716. (e) Martin, S. F.; Chen, H.-J.; Courtney, A. K.; Liao,
Y.; Pätzel, M.; Ramser, M. N.; Wagman, A. S. Tetrahedron
1996, 52, 7251. (f) Colombo, L.; Di Giacomo, M.; Vinci,
V.; Colombo, M.; Manzoni, L.; Scolastico, C. Tetrahedron
2003, 59, 4501. (g) Vo-Thanh, G.; Boucard, V.; Sauriat-
Dorizon, H.; Guibe, F. Synlett 2001, 37. (h) Lim, S. H.; Ma,
S.; Beak, P. J. Org. Chem. 2001, 66, 9056. (i) Beal, L. M.;
Liu, B.; Chu, W.; Moeller, K. D. Tetrahedron 2000, 56,
10113. (j) Hoffmann, T.; Lanig, H.; Waibel, R.; Gmeiner, P.
Angew. Chem. Int. Ed. 2001, 40, 3361. (k) Grossmith, C.
E.; Senia, F.; Wagner, J. Synlett 1999, 1660.
Synlett 2004, No. 7, 1211–1214 © Thieme Stuttgart · New York

1214
M. P. Sibi, T. Subramanian
LETTER
(15) Preparation of the Tricyclic Lactam 6: The iodolactone 17
(0.748 g, 2.2 mmol) was dissolved in degassed toluene (75
mL) in a two-neck round-bottomed flask fitted with a reflux
condenser and a rubber septum. Tributyltin hydride (0.722
mL, 2.68 mmol) was added and the reaction heated to 80 °C.
A solution of AIBN (60 mg) in toluene (5 mL) was added to
the reaction mixture four times with the interval of 1 h. The
resultant solution was refluxed for 10 h. The solvent was
removed and the residue was chromatographed over silica
gel to give 6 as a highly viscous liquid that solidified upon
cooling (0.321 g, 70%); mp 42–43 °C. 1H NMR (500 MHz,
CDCl3): d = 1.51–1.60 (m, 2 H), 1.70 (q, J = 10.5 Hz, 1 H),
1.83–1.85 (m, 1 H), 2.02–2.08 (m, 1 H), 2.36–2.41 (m, 4 H),
2.47–2.53 (m, 1 H), 2.60–2.70 (m, 1 H), 2.76–2.87 (m, 1 H),
4.0 (dt, J = 6.0, 10.5 Hz, 1 H), 4.11–4.14 (m, 1 H), 4.27 (dt,
J = 3.0, 10.5 Hz, 1 H). 13C NMR (125 MHz, CDCl3): d =
22.9, 25.7, 30.8, 31.2, 34.8, 40.4, 45.1, 56.3, 80.0, 174.3,
174.9. [a]D25 –91.9 (c = 1.0, CHCl3). HRMS: m/z calcd for
C11H15NO3Na: 232.0944; found: 232.0940.
(16) Also see ref. 4c for a similar reduction and establishment of
stereocenter at C-9 and C-10.
(17) Lactone 6 could also be methylated to provide C-9, C-10
diepi stemoamide (data not shown).
(18) Mp: 185–186 °C. 1H NMR (500 MHz, CDCl3): d = 1.31 (d,
J = 6.9 Hz, 3 H), 1.50–1.58 (m, 2 H), 1.72 (quint, J = 10.7
Hz, 1 H), 1.85–1.90 (m, 1 H), 2.0–2.10 (m, 1 H), 2.38–2.45
(m, 4 H), 2.60 (dq, J = 6.9, 12.5 Hz, 1 H), 2.65 (dd, J = 12.3,
14.1 Hz, 1 H), 3.99 (dt, J = 10.8, 6.3 Hz, 1 H), 4.16 (m, 1 H),
4.20 (dt, J = 3.1, 10.3 Hz, 1 H). 13C NMR (125 MHz,
CDCl3): d = 14.1, 22.5, 25.6, 30.5, 34.8, 37.3, 40.2, 52.7,
55.8, 77.6, 174.0, 177.3. IR (neat): 1768, 1681 cm–1. [a]D
25
–191.6 (c = 0.5, MeOH). {Lit. [a]D25 –183.5 (c = 1.36,
MeOH);4b [a]D30 –219.3 (c = 0.5, MeOH);4d [a]D –181.6
(c = 0.89, MeOH)}.4e HRMS: m/z calcd for C12H17NO3Na+:
246.1100: found: 246.1099.
Synlett 2004, No. 7, 1211–1214 © Thieme Stuttgart · New York