Regio- and diastereocontrolled C-H insertion of chiral γ- and δ-lactam diazoacetates. Application to the asymmetric synthesis of (8S,8aS)-8-hydroxyindolizidine

Article abstract of DOI:10.1039/b606436a

γ- and δ-Lactam diazoacetates undergo efficient intramolecular C-H insertion catalyzed by Rh₂(MPPIM)₄ with excellent regioselectivity and cis-diastereoselectivity to provide synthetically useful bicyclic lactam lactones. The Royal So

Full text of DOI:10.1039/b606436a

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Regio- and diastereocontrolled C–H insertion of chiral c- and d-lactam
diazoacetates. Application to the asymmetric synthesis of (8S,8aS)-8-
hydroxyindolizidine{
Gao-jun Fan, Zhongyi Wang and Andrew G. H. Wee*
Received (in Bloomington, IN, USA) 5th May 2006, Accepted 27th June 2006
First published as an Advance Article on the web 2nd August 2006
DOI: 10.1039/b606436a
c- and d-Lactam diazoacetates undergo efficient intramolecular
C–H insertion catalyzed by Rh2(MPPIM)4 with excellent
regioselectivity and cis-diastereoselectivity to provide syntheti-
cally useful bicyclic lactam lactones.
The Rh(II)-catalyzed intramolecular carbon–hydrogen insertion
reaction continues to attract considerable attention due to the high
levels of regio-, chemo- and diastereoselectivity that can be
achieved.1 A decade ago, Doyle reported the intramolecular C–H
insertion reactions of chiral non-racemic alkyl substituted
cyclohexyl diazoacetates catalyzed by dirhodium(II) carbox-
amidates.2a The catalysts showed a matched/mismatched relation-
ship to the diazo substrates; Rh2(MEPY)4 and Rh2(MEOX)4
Scheme 1 Reagents and conditions: a. (i) TBDMSCl, imidazole, DMAP,
emerged as effective catalysts, which promoted highly regioselec-
DMF, 40 uC; (ii) BnBr, NaH, DMF; (iii) HCl, MeOH; 89%; b.
p-TSHACl, PhNMe2, iPr2NEt, CH2Cl2, 0 uC, 98%; c. Rh(II) cat.
(2 mol%), CH2Cl2, reflux (see Table 1 for details).
tive C–H insertion into equatorial secondary and tertiary C–H
bonds to give lactone products. The regioselectivity in
Rh2(MPPIM)4-catalyzed reactions, however, was found to be
substrate dependent.2 The regio- and diastereoselectivity of C–H
insertion in equivalent heterocyclic diazoacetates have not been
extensively examined. Previously, we showed the Rh(II)-carbox-
amidate-catalyzed C–H insertion of 3-(N-Cbz-pyrrolidinyl)diazo-
acetate did not exhibit a matched/mismatched relationship, and
also demonstrated the use of the method in the synthesis of
(2)-turneforcidine.3 In keeping with our ongoing interest in the
synthesis of piperidine- and pyrrolidine-containing alkaloids, we
needed access to functionalized piperidine and pyrrolidine building
blocks that would permit the facile assembly of a wide variety of
substituents and stereochemical diversity around the pyrrolidine
and piperidine framework. We investigated the rhodium(II)-
catalyzed diazo decomposition of c- and d-lactam diazoacetates
and, herein, report the results of our study.
optimal reaction conditions for C–H insertion reaction and to
determine product distribution.
In general, it was found that chiral Rh(II) catalysts were better
than achiral ones at promoting C–H insertion reaction (Table 1).
Carbon–hydrogen insertion was inefficient with Rh2(OAc)4 and
the less electrophilic Rh2(cap)4 as catalysts. The use of
Rh2(S-PTTL)4 led to a noticeable improvement on the yield
(28%) of 4, however, the yield of 4 was synthetically unacceptable.
We then turned our attention to three enantiomeric pairs of Rh(II)
carboxamidates and evaluated their efficiency in catalyzing the
C–H insertion reaction of (S)-3.
With Rh2(5S-MEPY)4, a modest yield (45%) of 4 was obtained
and the outcome was encouraging. However, the enantiomeric
Rh2(5R-MEPY)4 gave a significantly lower yield of 4 (14%). In all
the cases (entries 1–5) studied thus far, the regioisomer 5 was not
d-Lactam diazoacetate (S)-3 was readily obtained (Scheme 1)
from the known4 (S)-5-hydroxy-2-piperidinone (1) via hydroxyl
group protection (TBDMSCl) and N-benzylation. O-Desilylation
(HCl, MeOH) then afforded the alcohol 25 {[a]D22 216.7u (c 3.30,
CHCl3), 89% over three steps}. Treatment of 2 with p-TSHACl6
Table 1 Rh(II)-catalyzed reaction of (S)-3a
Entry Rh2L4
4 (%) 5 (%) 6 (%) (E : Z)b 7 (%)
25
1
2
3
4
5
6
7
8
9
a
Rh2(OAc)4
Rh2(cap)4
6
11
28
45
14
44
16
0
0
0
0
0
0
23
0
72
b
14 (1 : 1)
64 (1 : 3)
11 (1 : 3)
28 (1 : 3)
12 (1 : 3)
28 (1 : 3)
0
21
23
0
13
3
9
12
3
gave an excellent yield (98%) of (S)-3 {[a]D +25.0u (c 5.90,
CHCl3)}.
Rh2(S-PTTL)4
Rh2(5S-MEPY)4
Rh2(5R-MEPY)4
Rh2(4S-MEOX)4
Rh2(4R-MEOX)4
The diazoacetate (S)-3 was evaluated against achiral and chiral
Rh(II) carboxylate and carboxamidate catalysts to delineate
Department of Chemistry and Biochemistry, University of Regina,
Regina, Saskatchewan, S4S 0A2, Canada.
E-mail: Andrew.Wee@uregina.ca; Fax: (1) 306-337-2409;
Tel: (1) 306-585-4767
{ Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b606436a
Rh2(4S-MPPIM)4 87
Rh2(4R-MPPIM)4 14
0
0
10
Product yields are isolated yields. Ratio of E : Z isomers was
based on the integration of the singlets due to the olefinic hydrogens
centered at d 6.12 (Z) and d 6.64 (E).
3732 | Chem. Commun., 2006, 3732–3734
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detected. The results from the reactions catalyzed by the Rh2(4S/
R-MEOX)4 and Rh2(4S/R-MPPIM)4 were especially interesting
and displayed important differences from those obtained from
Rh2(S-PTTL)4 and Rh2(5R/S-MEPY)4. Although the result
obtained for Rh2(4S-MEOX)4 mirrored that for Rh2(5S-
MEPY)4 (see entries 4 and 6), the reaction catalyzed by
Rh2(4R-MEOX)4 gave a 1 : 1.4 ratio of 4 : 5 in a combined
yield of 39% (entry 7). The use of the hindered Rh2(4S-MPPIM)4
resulted in the highest yield (87%) of 4, whereas with
Rh2(4R-MPPIM)4, the regiosomer 5 was formed as the major
product (72%). The C–H insertion reaction proceeded with
excellent regioselectivity and cis-diastereoselectivity, which was
confirmed by NOESY1D. Neither the trans-fused c- nor
spirocyclic b-lactones were detected, in contrast to the results
from Rh2(MPPIM)4-catalyzed intramolecular C–H insertion
reaction of cyclohexyl diazoacetates.2a
Scheme 3 Reagents and conditions: a. (i) TBDMSCl, imidazole, DMAP,
DMF, 40 uC; (ii) BnBr, BuLi, DMF, THF, 215 uC; (iii) HCl, MeOH;
82%; b. p-TSHACl, PhNMe2, iPr2NEt, DCM, 0 uC, 98%; c. Rh cat.
(2 mol%), CH2Cl2 or 1,2-dichloroethane, reflux (see Table 2 for details).
Table 2 Rh(II)-catalyzed reaction of (S)-15
To confirm the above outcome, the enantiomeric diazoacetate
(R)-9 was synthesized (Scheme 2). (S)-Alcohol 2 was transformed
to its enantiomer 8 {[a]D22 +17.4u (c 3.30, CHCl3)}, via Mitsunobu
inversion7 (ClCH2CO2H, DEAD, Ph3P) and subsequent base
hydrolysis. Alcohol 8 was treated with p-TSHACl6 to give the
Entry Rh2L4
Solvent 16 (%) 17 (%) 18 (%) (E : Z)b
1
2
3
4
5
6
a
Rh2(4S-MEOX)4 CH2Cl2 17
Rh2(4R-MEOX)4 CH2Cl2
Rh2(4S-MPPIM)4 CH2Cl2 51
Rh2(4R-MPPIM)4 CH2Cl2
Rh2(4S-MPPIM)4 DCEa 70
Rh2(4R-MPPIM)4 DCE
21
13
28
37
11
19
20 (1 : 11)
11 (1 : 33)
20 (2.4 : 1)
30 (1.5 : 1)
7 (only E)
0
0
0
25
desired diazoacetate (R)-9 {[a]D 222.0u (c 5.90, CHCl3)}. The
0
Rh2(4R-MPPIM)4-catalyzed reaction of (R)-9 gave a high yield
(85%) of bicyclic lactam lactone 10, but with Rh2(4S-MPPIM)4,
the major product obtained was the regioisomer 11 (68%).
These results show that the optimal catalyst for achieving
high regioselectivity in the formation of bicyclic lactam lactone is
the use of Rh2(MPPIM)4 as catalyst; (S)-3/Rh2(4S-MPPIM)4 and
(R)-9/Rh2(4R-MPPIM)4 represent the matched pairs for highly
regioselective C–H insertion reaction.
b
DCE 5 1,2-dichloroethane. Ratio of E : Z isomers was based on
the integration of the singlets due to the olefinic hydrogens centered
at d 6.23 (Z) and d 6.77 (E).
conducted in refluxing 1,2-dichloroethane, whereas the corre-
sponding R-catalysts failed to give any C–H insertion products.
Further, unlike (S)-3, the R-catalysts did not lead to C3–H
insertion to form the corresponding regioisomer of 16. Neither
trans-16 nor the spirocyclic b-lactone was detected.
Next, the efficiency and regioselectivity of the C–H insertion
reaction of the c-lactam diazoacetate 15 were studied. Compound
15 was synthesized (Scheme 3) from commercially available (S)-4-
hydroxy-2-pyrrolidinone (13)8 in the manner described for
compound (S)-3.
Using the Rh2(4S- or 4R-MPPIM)4-catalyzed reaction of (S)-3
as an example, we envisioned the formation of 4 and 5 to proceed
via the rapidly interconverting reactive conformers9,10 A, A9, B and
B9 depicted in Fig. 1. In conformers
A and A9, the
On the basis of the results obtained for (S)-3, we chose Rh2(4S/
4R-MEOX)4 and Rh2(4S/4R-MPPIM)4 as catalysts. The results in
Table 2 clearly show that reaction temperature has a definite
influence on the efficiency of the reaction. In refluxing CH2Cl2,
which was found to be effective for (S)-3, poor to moderate yields
of the C–H insertion product 16 were obtained (entries 1, 3).
Gratifyingly, a significantly higher yield (70%) of 16 was realized
when the Rh2(4S-MPPIM)4-catalyzed reaction of (S)-15 was
Rh(II)-carbenoid moiety is oriented in the pseudoaxial and
pseudoequatorial positions, respectively. Lactone 4 is formed
Scheme 2 Reagents and conditions: a. (i) ClCH2CO2H, Ph3P, DEAD,
CH2Cl2; (ii) K2CO3, MeOH; 70%; b. p-TSHACl, PhNMe2, iPr2NEt,
CH2Cl2, 0 uC, 98%; c. Rh2(4R-MPPIM)4 (2 mol%), CH2Cl2, reflux, 10
(85%), 11 (0%), 12 (4%); Rh2(4S-MPPIM)4 (2 mol%), CH2Cl2, reflux, 10
(17%), 11 (67%), 12 (14%).
Fig. 1 Reactive conformer models for reaction of (S)-3.
Chem. Commun., 2006, 3732–3734 | 3733
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mixture of Z/E diastereomers. N-Debenzylation14 of 20 was
followed by hydrolysis of the enol ether unit and NaBH4 reduction
to provide the primary alcohol 21 in an overall yield of 76%.
Tosylation of 21 and cyclization of the primary tosylate (NaH)
yielded the bicyclic lactam 22a (95%). MOM ether deprotection of
22a gave 22b;13e subsequent reduction of the lactam carbonyl
group (BH3?SMe2) afforded, initially, a very stable, non-polar 23 :
borane complex as a white solid.15 The volatile indolizidine 23 was
obtained only after refluxing the 23 : borane complex in 95%
ethanol for 24 h. Compound 23 was purified (Dowex 50x2-400, H+
form) and characterized as its hydrochloride salt.
In summary, we have shown that the Rh2(MPPIM)4-catalyzed
C–H insertion reaction of c- and d-lactam diazoacetates proceeded
efficiently with excellent regioselectivity and cis-diastereoselectivity.
Regioselectivity in the d-lactam diazoacetate is dependent on the
chirality of the Rh(II) catalyst. Reactive conformer models are
proposed to explain product formation from (S)-3. The synthetic
utility of the bicyclic lactam lactones is demonstrated by the
concise asymmetric synthesis of 23 from 4 (9 steps, 34% overall
yield). Applications to other alkaloid targets are in progress.
We thank the Natural Sciences and Engineering Research
Council, Canada and the University of Regina for financial
support.
Scheme 4 Reagents and conditions: a. Red-Al, THF–PhMe, 278 uC,
94%; b. (i) Ph3PLCHOMe, THF, 240 uC, 74%, (ii) MOMCl, cat. Bu4NI,
i-Pr2NEt. 89%; c. (i) Na, liq. NH3; NH4Cl. quant., (ii) 1 M aq. HCl then
NaBH4, 76%; d. (i) TsCl, Et3N, cat. DMAP, 91%, (ii) NaH, 95%; e. (i) 1 M
aq. HCl, MeOH. 95%, (ii) BH3?SMe2, THF; then EtOH, reflux, 88%.
preferentially through metallocarbenoid insertion into C–Ha (A)
as the Rh(II)-carbene and C–Ha s-bond are aligned parallel to
each other and the insertion is also facilitated by the greater
nucleophilicity of the s-bond (early TS) due to the activating
influence of the amide nitrogen atom.11 Insertion of the
Rh(II)-carbenoid into C–Hb (A) is prevented from occurring
because the C–Hb s-bond and the Rh(II)-carbenoid bond cannot
adopt the proper alignment. Conformer A9 is destabilized by steric
interaction of the pseudoaxial C–Hc and C–Hd with the ligand
wall/N–C(O)(CH2)2Ph of the Rh(II) catalyst. Thus, regioisomer 5
is not formed.
Notes and references
1 C. A. Merlic and A. L. Zechman, Synthesis, 2003, 1137.
2 (a) M. P. Doyle, A. V. Kalinin and D. G. Ene, J. Am. Chem. Soc., 1996,
118, 8837; (b) M. P. Doyle, J. P. Morgan, J. C. Fettinger, P. Y. Zavalij,
J. T. Colyer, D. J. Timmons and M. D. Carducci, J. Org. Chem., 2005,
70, 5291 and references cited.
In the mismatched Rh2(4R-MPPIM)4-catalyzed reaction, con-
former B is destabilized by the interaction of C–Ha and C–Hb
with the ligand wall/N–C(O)(CH2)2Ph. However, because C–Ha is
activated by the amide nitrogen, its interaction with the vacant
p-orbital of the Rh(II)-carbenoid carbon can occur at a greater
distance (early TS) resulting in the formation of the minor product
4. With B9, the Rh(II)-carbenoid bond and the C–Hc bond are
properly aligned and C–H insertion leads to the regioisomer 5 as
the major product. Insertion into C–Hd, as with C–Hb in A, is
unattainable for geometric reasons.
3 A. G. H. Wee, J. Org. Chem., 2001, 66, 8513.
4 R. K. Olsen, K. L. Bhat, R. B. Wardle, W. J. Hennen and G. Kini,
J. Org. Chem., 1985, 50, 896.
5 Racemic 2: C. Herdeis, Arch. Pharm., 1983, 316, 719.
6 (a) H. O. House and C. J. Blankley, J. Org. Chem., 1968, 33, 53; (b)
E. J. Corey and A. G. Myers, Tetrahedron Lett., 1984, 25, 3559.
7 Review: D. L. Hughes, Org. React., 1983, 29, 1.
8 Purchased from Aldrich; can also be prepared: T. H. Park, S. Paik and
S. H. Lee, Bull. Korean Chem. Soc., 2003, 24, 1227.
9 (a) The minimum energy conformation about the Rh(II)-carbene carbon
bond is based on: M. P. Doyle, W. R. Winchester, J. A. A. Hoorn,
V. Lynch, S. H. Simonsen and R. Ghosh, J. Am. Chem. Soc., 1993, 115,
9968; (b) AM1 calculations (PC Spartan Pro, v.6.0.6) were performed on
the d-lactams with a pseudoaxial and pseudoequatorial diazoacetyl unit:
DHf (axial) 5 231.822 kcal/mol, DHf (equatorial) 5 232.164 kcal/mol.
10 Trajectory for C–H insertion, see: (a) D. F. Taber, K. K. You and
A. L. Rheingold, J. Am. Chem. Soc., 1996, 118, 547; (b) M. P. Doyle,
L. J. Westrum, W. N. E. Wolthius, M. M. See, W. P. Boone, V. Bagheri
and M. M. Pearson, J. Am. Chem. Soc., 1993, 115, 958; (c)
E. Nakamura, N. Yoshikai and M. Yamanaka, J. Am. Chem. Soc.,
2002, 124, 7181; (d) N. Yoshikai and E. Nakamura, Adv. Synth. Catal.,
2003, 345, 1159.
For (S)-15, the absence of the regioisomer of 16 suggests that the
C3–H bond in 15 is deactivated towards metallocarbenoid
insertion by the amide carbonyl group. This outcome taken
together with that obtained in the Rh2(4R-MPPIM)4-catalyzed
reaction of (S)-3 to form 5 indicated that C–H bonds located a to
an amide carbonyl group are deactivated towards
Rh(II)-carbenoid insertion; b-C–H bonds are not deactivated.12
To demonstrate the utility of the bicyclic lactam lactone
products, the enantioselective synthesis of (8S,8aS)-8-hydroxyoc-
tahydroindolizidine13 (23) starting from 4 was conducted. Several
syntheses13a–d of (¡)-23 have been described; only one asymmetric
synthesis of (8S,8aS)-23, which was obtained in 13 steps and 17%
overall yield from a chiral non-racemic 4-formyl-b-lactam inter-
mediate,13e was reported. Our building block 4 already has the
correct configurations at the two stereocentres and seven of the
eight carbons of the carbon framework in 23.
11 A. G. H. Wee and S. C. Duncan, J. Org. Chem., 2005, 70, 8372.
12 For the deactivation of a- and b-C–H bonds in esters, see: G. Stork and
K. Nakatani, Tetrahedron Lett., 1988, 29, 2283.
13 Racemic synthesis: (a) D. H. R. Barton, M. M. M. A. Pereia and
D. K. Taylor, Tetrahedron Lett., 1994, 35, 9157; (b) C. P. Rader,
R. L. Young, Jr. and H. S. Aaron, J. Org. Chem., 1965, 30, 1536; (c)
T. J. Bond, R. Jenkins, A. C. Ridley and P. C. Taylor, J. Chem. Soc.,
Perkin Trans. 1, 1993, 2241; (d) T. Shono, Y. Matsumura, K. Tsubata,
K. Inoue and R. Nishida, Chem. Lett., 1983, 21. Asymmetric synthesis;
(e) H. K. Lee, J. S. Chun and C. S. Pak, J. Org. Chem., 2003, 68, 2471.
14 A. J. Birch, Pure Appl. Chem., 1996, 68, 553.
The synthesis began with the chemoselective reduction of 4 with
Red-Al1, which gave an excellent yield of the bicyclic lactam lactol
19 (Scheme 4). Wittig olefination (Ph3PLCHOMe) followed by
MOM protection of the secondary alcohol gave the ether 20 as a
15 In ref. 13e, 23 was obtained as a white solid; we think that the product
isolated is in fact the 23 : borane complex. IR nmax (B–H): 2367 and 2320
cm21; 1H NMR of 23 : borane complex is identical to that reported.
3734 | Chem. Commun., 2006, 3732–3734
This journal is ß The Royal Society of Chemistry 2006