A facile synthesis of (-)- and (+)-Geissman-Waiss lactone via intramolecular Rh(II)-carbenoid mediated C-H insertion reaction: Synthesis of (1R,7R,8R)-turneforcidine

Article abstract of DOI:10.1016/S0040-4039(00)01664-6

The intramolecular C-H insertion reaction in chiral non-racemic diazoacetates (-)-6 and (+)-8 catalyzed by chiral Rh₂(MPPIM)₄ proceeded efficiently, with excellent regioselectivity and cis-diastereoselectivity, to give (-)- and (+)-G

Full text of DOI:10.1016/S0040-4039(00)01664-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9025–9029
A facile synthesis of (−)- and (+)-Geissman–Waiss lactone
via intramolecular Rh(II)-carbenoid mediated C–H insertion
reaction: synthesis of (1R,7R,8R)-turneforcidine
Andrew G. H. Wee*
Department of Chemistry, University of Regina, Regina, Saskatchewan, Canada S4S 0A2
Received 24 September 2000; accepted 26 September 2000
Abstract
The intramolecular C–H insertion reaction in chiral non-racemic diazoacetates (−)-6 and (+)-8 catalyzed
by chiral Rh2(MPPIM)4 proceeded efficiently, with excellent regioselectivity and cis-diastereoselectivity, to
give (−)- and (+)-Geissman–Waiss lactone, 4b, respectively. Bicyclic lactone (−)-4b was used in the
synthesis of the necine base (−)-turneforcidine 3. © 2000 Elsevier Science Ltd. All rights reserved.
Pyrrolizidine alkaloids belonging to the necine group are found in many plant families.1a Their
diverse structures and interesting biological activities1b have stimulated much interest in their
synthesis with most of the attention directed at the synthesis of the pyrrolizidine base. Recent
efforts have addressed the enantioselective construction of the pyrrolizidine moiety,2 wherein the
Geissman–Waiss lactone 4a3 and its N-protected derivatives, 4b,c, have proven to be versatile
building blocks (Scheme 1). Non-racemic 4a–c have been prepared, using routes of varying
lengths, from intermediates derived from: (1) the ‘chiral pool’;1b,f (2) kinetic resolution of
racemates,1b and (3) chiral auxiliary-based diastereoselective reactions.1b,g,h More direct routes to
non-racemic 4 would be invaluable in pyrrolizidine alkaloid synthesis and, to our knowledge,
only one such approach4 has been reported.
H
CH2OH
H
HO
1; α-H1, Platynecine
2; ∆1,2, Retronecine
3; β-H1, Turneforcidine
O
O
H
N
O
O
4
*
(R)-(-)-6 (Hα) or
(S)-(+)-8 (Hβ)
*
1
2
2
*
N2
N
Cbz
N
R
4 a; R = H; b; R = Cbz; c; R = t-Boc
Scheme 1.
* Fax: 306-585-4894; e-mail: andrew.wee@uregina.ca
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01664-6

9026
Herein we report the realization of the Rh(II)-carbenoid mediated transformation 6 (or
8)“4b. Carbon–hydrogen insertion was found to proceed with excellent regioselectivity, occur-
ring only at C-2, even though a second (C-4) potential site for insertion was present. In addition,
the reaction proceeded with high diastereoselectivity to provide only the cis-bicyclic lactone
product. This method was used in the facile construction of both (−)- and (+)-4b.1b (−)-4b was
employed in the synthesis of (−)-turneforcidine 3.
Our initial studies used diazoacetate (R)-(−)-6, which was readily prepared via acylation of the
known5a (R)-(−)-N-benzyloxycarbonyl-3-hydroxypyrrolidine (5)5b with a-(p-toluenesulfonyl-
hydrazone)acetyl chloride6a under Corey–Myers conditions.6b Compound 6 was then exposed to
achiral and chiral Rh(II) catalysts and the results are summarized in the Table 1.
Table 1
Dirhodium(II)-catalyzed reaction of (R)-6a
H
O
O
O
O
O
O
O
O
O
O
O
4
N2
2
Rh2L4
N
N
Cbz
N2
O
H
N
Cbz
N
or Rh2L*4
N
Cbz
Cbz
Cbz
N
7 a; Z-isomer Cbz
b; E-isomer
(S)-8
(+)-4b
(R)-6
(-)-4b
Entry
Catalyst
Yieldb
(−)-4bc
7 (a:b)c,d
1
2
3
4
5
6
Rh2(OAc)4
14
5
15
54
78
25
78
72
72
86
100
74
22 (1:2)
28 (1:3)
28 (1:4)
10e (1:4)
0
Rh2(4R-MEPY)4
Rh2(4R-MEOX)4
Rh2(4S-MEOX)4
Rh2(4R-MPPIM)4
Rh2(4S-MPPIM)4
26 (1:1.3)
a Reactions ran in dry Cl(CH2)2Cl (0.03 M), 2 mol% catalyst, 60°C, addition of (R)-6 over 2 h (syringe pump),
under Ar.
b Total combined yield of 4b and 7a,b.
c Relative yields determined for the mixture of closely moving products, obtained after filtration (SiO2, 1:1
hexanes:EtOAc), by 1H NMR analysis: relative yields were based on the integration of the a-CH2 signals (l 2.64–2.93)
in the g-lactone moiety of 4b, the singlet at l 6.25 of 7a, and the singlet at l 6.85 of 7b.
d Ratio of 7a:7b is based on the integration of olefinic protons.
e The remaining 4% is due to the ether product (l 4.25, s, CH2O) formed from insertion reaction of water and two
molecules of metallocarbenoid intermediate.
The widely used Rh2(OAc)4 gave the desired (−)-4b albeit in poor yield (entry 1, Table 1).
However, it was found that C–H insertion had occurred with excellent regioselectivity (at C-2)
and cis-diastereoselectivity. Surprisingly, the use of Rh2(Cap)4, a catalyst shown to be effective
for C–H insertion,7 did not afford (−)-4b and only dimers 7a,b (Z:E=3:1, 36%) were produced.
From these initial results, it is apparent that olefin formation via dimerization is a significant
competitive pathway in this system. To improve on the yield of (−)-4b, as well as to suppress
dimer formation, diazoacetate 6 was evaluated against three enantiomeric sets of chiral catalysts,
Rh2(MEPY)4,7 Rh2(MEOX)4,8 and Rh2(MPPIM)4.9
With the chiral catalysts, it was found that the C–H insertion reaction again proceeded with
high regio- and diastereoselectivity to give (−)-4b. The preference for metallocarbenoid insertion
into the C2ꢀH bond is likely due to activation of this sigma bond by the adjacent carbamoyl

9027
nitrogen atom.10 The yield of (−)-4b was found to vary with the type and configuration of the
catalyst employed. Dimer formation was still observed. Rh2(4S-MEPY)4 was found to be
inefficient as a catalyst and gave the lowest yield (3.6%) of (−)-4b (entry 2).11 Among the chiral
catalysts examined, Rh2(4R-MPPIM)4 emerged as the best catalyst for the C–H insertion
reaction (entry 5), which afforded (−)-4b {[h]2D5.2 −115.5° (c 1.12, CHCl3), lit.4 [h]D26 −122.3 (c 4.7,
CHCl3)}as the exclusive product and in excellent yield (78%). Dimer formation was completely
suppressed in this case. This result can be contrasted to the lower yield (19%) obtained with the
S-enantiomer (entry 6). Interestingly, Rh2(4S-MEOX)4 gave a good yield (46%) of (−)-4b,
whereas the R-enantiomer gave a lower yield (11%) of (−)-4b (entries 5 and 6).
Doyle and co-workers9,12 have shown that C–H insertion reactions of select chiral non-
racemic diazoacetates that are configurationally matched with chiral Rh(II) carboximidates
exhibit high regio- and diastereoselectivity. That is, for a given non-racemic diazoacetate, a
R-configurated catalyst promotes the preferential formation of one regio- and diastereomer and
the S-configurated catalyst favours another regio- and diastereomer. In contrast, our results do
not indicate that a matched/mismatched relationship is occurring in the reaction between (R)-6
and the chiral Rh(II) catalysts used in this study since only cis-4b was formed in all cases
examined. Furthermore, Rh2(4R-MPPIM)4 and Rh2(4S-MEOX)4 efficiently catalyzed the for-
mation of (−)-4b from (R)-6.
Encouraged by the outcome from the reaction of Rh2(4R-MPPIM)4, we prepared7 the
(S)-diazoacetate 8 (vide supra, Table 1) from the known13 (S)-(+)-N-benzyloxycarbonyl-3-
hydroxypyrrolidine. Treatment of (S)-8 with Rh2(4S-MPPIM)4 led to a high yield (76%) of the
enantiomeric Geissman–Waiss lactone, (+)-4b; [h]2D6.8 +123° (c 1.14, CHCl3), lit.4 [h]D24 122.9° (c
1.14, CHCl3)] and no dimer products were detected.
Equipped with a facile method for the synthesis of either (−)- or (+)-4b, and to demonstrate
the synthetic utility of this method, we turned our attention to the synthesis of (−)-turnefor-
cidine, (−)-3, from (−)-4b (Scheme 2).
O
OTBDPS
OTBDPS
OR
O
OH
RO
OR
H
N
b
c
e
OH
R
N
Cbz
N
N
Cbz
2
Cbz
(-)-4b, R = H
12, R = TBDPS
(-)-3, R = H
10
a; R = H
11
a
f
d
b; R = Ms
9, R = CH2CH=CH2
Scheme 2. (a) LiHMDS, THF, HMPA (1 equiv.), −78°C; then allyl bromide, HMPA (1 equiv.), −78°C (1 h) to −45°C
(30 min), 57%; (b) NaBH4, 95% EtOH, rt, 24 h, 86%; (c) (i) TBDPSCl, imidazole, DMF, rt, (ii) 20 mol% OsO4, 3
equiv. NaIO4, Et2O–H2O, then NaBH4, 95% EtOH, 73% (two steps); (d) MsCl, Et3N, cat. DIPEA, CH2Cl2, 0°C,
88%; (e) 10% Pd/C, cyclohexene, MeOH, reflux, then K2CO3, reflux, 92%; (f) Bu4NF, THF, rt; 68%
(−)-Turneforcidine is a naturally occurring necine base found in pyrrolizidine alkaloids
typified by cropodine, retusine1a and the recently isolated racemozine.14 Two routes15a,b leading
to ( )-turneforcidine have been reported and, surprisingly, only two reports15c,d have described
the enantioselective synthesis of (−)-turneforcidine. In the latter two enantioselective routes both
of the starting compounds were derived from pyrrolizidine alkaloids.
The synthesis began with the allylation (57%) of the lactone moiety in (−)-4b, which would
provide the requisite side-chain to be used for the construction of the second ring. Reduction15a
of the g-lactone moiety in 9 was accomplished using four equivalents of NaBH4 which led to a
high yield of the diol 10. Subsequent silylation of the diol 10 with t-butylchlorodiphenylsilane,

9028
followed by oxidative cleavage16 of the double-bond yielded the corresponding aldehyde, which
was immediately reduced with NaBH4 to give the primary alcohol 11a. Mesylation of 11a,
followed by catalytic transfer hydrogenolysis17 of the N-Cbz protecting group in 11b and
base-mediated intramolecular alkylation provided an excellent yield of the pyrrolizidine bis-silyl
ether, 12 {[h]2D7.7 −7.6° (c 1.05, CHCl3)}. Interestingly, attempted hydrogenolysis of the N-Cbz
group over 10% Pd/C using either 1 atm. (balloon) or 35 psi of hydrogen pressure only returned
unreacted 11b. Desilylation of 12 with TBAF gave the very polar (−)-3 {[h]2D6 −13.9° (c 0.36,
MeOH). Lit.15c [h]2D3 −12° (c 0.82, MeOH), lit.15d [h]2D3 −12.5° (c 1.3, MeOH)} in 68% yield.
1
Synthetic (−)-3 showed H and 13C NMR data that are in accord with those reported.15
In conclusion, the enantiomeric pair of N-Cbz protected Geissman–Waiss lactone, (−)- and
(+)-4b, is readily prepared via the Rh2[4(R or S)-MPPIM]4 catalyzed reaction of the enan-
tiomeric diazoacetates (R)-6 or (S)-8. (−)-Turneforcidine was prepared in an overall yield of
20% starting from (−)-4b. Further work using this Rh(II)-carbenoid approach in the synthesis of
naturally occurring saturated N-heterocycles is in progress and will be reported in the future.
Acknowledgements
Financial support from NSERC, Canada and the University of Regina is gratefully acknow-
ledged. I would like to thank Michael Doyle, University of Arizona, for his hospitality during
my sabbatical and for stimulating discussions as well as making laboratory resources available
to me which made this work possible. Thanks also go to the Doyle group members for making
my laboratory excursions enjoyable.
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9029
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