Tandem [4+2]/[3+2] cycloadditions of nitroalkenes. 9. Synthesis of (-)-rosmarinecine

Article abstract of DOI:10.1021/ja961630x

(-)-Rosmarinecine (2) is the necine base portion of the pyrrolizidine alkaloid (-)-rosmarinine. (-)Rosmarinecine is a representative of the group of pyrrolizidines that show a cis relationship between adjacent stereocenters C(1), C(7), and C(7a), in addition to a highly oxygenated skeleton. (-)-Rosmarinecine (2) has been synthesized in eight steps and 14.8% overall yield, as an illustration of a general approach for the construction of pyrrolizidines having this stereochemical feature. The key step in the asymmetric synthesis is a Lewis acid-promoted, tandem inter-[4+2]/intra-[3+2] cycloaddition between a fumaroyloxy nitroalkene and a chiral vinyl ether.

Full text of DOI:10.1021/ja961630x

8266
J. Am. Chem. Soc. 1996, 118, 8266-8277
Tandem [4 + 2]/[3 + 2] Cycloadditions of Nitroalkenes. 9.
Synthesis of (-)-Rosmarinecine
Scott E. Denmark,* Atli Thorarensen, and Donald S. Middleton
Contribution from the Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
Urbana, Illinois 61801
ReceiVed May 15, 1996X
Abstract: (-)-Rosmarinecine (2) is the necine base portion of the pyrrolizidine alkaloid (-)-rosmarinine. (-)-
Rosmarinecine is a representative of the group of pyrrolizidines that show a cis relationship between adjacent
stereocenters C(1), C(7), and C(7a), in addition to a highly oxygenated skeleton. (-)-Rosmarinecine (2) has been
synthesized in eight steps and 14.8% overall yield, as an illustration of a general approach for the construction of
pyrrolizidines having this stereochemical feature. The key step in the asymmetric synthesis is a Lewis acid-promoted,
tandem inter-[4 + 2]/intra-[3 + 2] cycloaddition between a fumaroyloxy nitroalkene and a chiral vinyl ether.
Introduction and Background
Pyrrolizidine alkaloids have long attracted the interest of
synthetic organic chemists due to their diverse biological
properties and their structural complexity.1 Rosmarinine (1) was
isolated from S. rosmarinifolius Linn. (family Compositae) and
upon hydrolysis afforded the necine base (-)-rosmarinecine (2).2
Warren and co-workers3 determined the structure of (-)-
rosmarinecine by synthesis from retronecine (9), the structure
of which had already been determined by Adams and Hamlin.4
In addition, an X-ray crystal structure of rosmarinine (1) has
been reported for the purpose of examining the folding of the
macrolactone and the necine nucleus.5 The X-ray crystal
structure serves to establish independently the stereostructure
of (-)-rosmarinecine (2) with respect to the configurations at
C(1), C(6), C(7), and C(7a).
The necine portion of 1 has been found in other pyrrolizidine
alkaloids with different acid chains attached to the hydroxyl
groups: e.g., angularine (3), 12-O-acetylrosmarinine (4), neo-
rosmarinine (5), and petitianine (6) (Figure 1).12,13
Figure 1. Pyrrolizidine alkaloids that contain rosmarinecine.
triangularis,7 S. taiwanensis Hayata,8 S. pterophorus,9 S. hy-
grophilus,10 S. adnatus D.C.,11 S. angulatus L.,12 S. hadiensis
and S. syringifolius.13 In addition, rosmarinine, among other
alkaloids, has been isolated from butterflies in Southern
Australia of the Danaus plexippus L. and Danaus chrysippus
L species.9 It was demonstrated that the butterflies mainly
obtained rosmarinine by consumption of S.pterophorus. The
butterflies can store the alkaloids for extended period of time,
and it is speculated that the purpose is to make the insects
distasteful to predators. Finally, the biosynthesis of (-)-
rosmarinecine is now well understood.14,15
Rosmarinecine has since been isolated from various plants
in the Compositae family, including S. pleitocephalus,6 S.
X Abstract published in AdVance ACS Abstracts, August 1, 1996.
(1) (a) Leonard, N. J. In The Alkaloids; Manske, R. H. F., Holmes, H.
L., Eds.; Academic Press: New York, 1950; Vol. 1, Chapter 4. (b) Leonard,
N. J. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York,
1960; Vol. 6, Chapter 3. (c) Warren, F. L. Fortschr. Chem. Org. Naturst.
1955, 12, 198. (d) Warren, F. L. In The Alkaloids; Manske, R. H. F., Ed.;
Academic Press: New York, 1970; Vol. 12, Chapter 4. (e) Natural Occuring
Pyrrolizidine Alkaloids; Rizk, A-F. M., Ed.; CRC: Boston, 1991. (f) Bull,
L. B.; Culvenor, C. C. J.; Dick, A. T. The Pyrrolizidine Alkaloids; North-
Holland Publishing Co. Amsterdam, The Netherlands, 1968. (g) Pyrrolizi-
dine Alkaloids; Enviromental Health Organization: Geneva, Switzerland,
1988. (h) Mattocks, A. R. Chemistry and Toxicology of Pyrrolizidine
Alkaloids; Academic Press: New York, 1986. (i) Robins, D. J. Nat. Prod.
Rep. 1995, 12, 413. (j) Robins, D. J. Nat. Prod. Rep. 1994, 11, 613. (k)
Robins, D. J. Nat. Prod. Rep. 1993, 10, 487. (l) Robins, D. J. Nat. Prod.
Rep. 1992, 9, 313. (m) Robins, D. J. Nat. Prod. Rep. 1991, 8, 213. (n)
Robins, D. J. Nat. Prod. Rep. 1990, 7, 377. (o) Robins, D. J. Nat. Prod.
Rep. 1989, 6, 577. (p) Robins, D. J. Nat. Prod. Rep. 1989, 6, 221. (q) Robins,
D. J. Fortschr. Chem. Org. Naturst. 1982, 41, 116.
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L. J. Chem. Soc. 1965, 2370.
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Trans. 1 1991, 2003
S0002-7863(96)01630-7 CCC: $12.00 © 1996 American Chemical Society

Synthesis of (-)-Rosmarinecine
J. Am. Chem. Soc., Vol. 118, No. 35, 1996 8267
Scheme 1
Figure 2. Structure of several cis-substituted necines.
The simpler necines such as isoretronecanol have served as
common targets to demonstrate new synthetic methodology, as
witnessed by the myriad of synthetic approaches on record.1,16
(-)-Rosmarinecine, on the other hand, is structurally one of
the more complex necines bases, with four stereogenic centers
on the eight atoms that form the 1-azabicyclo[3.3.0]octane ring
system. It is, therefore, not very surprising that, prior to our
effort, there was only one synthesis of this natural product,
reported by Tatsuta et al., who prepared (-)-rosmarinecine in
17 steps from D-glucosamine.17
Scheme 2
mode on the same face of the nitronate dipole 13 to which the
tether is attached. This would give rise to a cis relationship
between the stereocenters at C(1) and C(7). Furthermore, the
stereocenter at C(7a) would be cis to those at C(1) and C(7)
and would establish the correct relative configuration between
C(1), C(7), and C(7a) for (-)-rosmarinecine. The configuration
at C(6) is established as a consequence of the dipolarophile
geometry, which in this case must be cis. Finally, the absolute
stereochemical outcome is established by the appropriate
combination of chiral auxiliary and Lewis acid for the inter-
molecular [4 +2] process to engender the correct configuration
at C(4) in the intermediate nitronate 13 (C(1) in (-)-rosmari-
necine). This center, in turn, will dictate the creation of all the
other required stereocenters in both a relative and an absolute
sense. Thus, the synthesis precursors simplify to the maleate-
derived â-acyloxy nitroalkene 12 and a nonracemic chiral vinyl
ether 11.
Synthesis Design
The asymmetric, tandem [4 + 2]/[3 + 2] nitroalkene
cycloaddition reaction has been explored extensively in recent
years.18,19 This transformation is ideally suited for the synthesis
of necine bases since the core pyrrolizidine skeleton arises from
hydrogenation of the bicyclic nitroso acetals, which are the end
products of the tandem cycloaddition. As an illustration of the
power of the asymmetric tandem [4 + 2]/[3 + 2] nitroalkene
cycloaddition reaction, we recently disclosed the synthesis of
(-)-hastanecine.20 This constituted the first example of the use
of nitroalkene cycloaddition chemistry in the synthesis of natural
products. Herein, we disclose a general approach to necines
which bear a cis relationship between any or all of the
stereocenters at C(1), C(7), and C(7a), as can be seen in
examples 2 and 7-10 (Figure 2).21
The retrosynthetic analysis for (-)-rosmarinecine is sum-
marized in Scheme 1. It was proposed that rosmarinecine could
be obtained from the corresponding R-hydroxy lactam 15 by
exhaustive reduction. The R-hydroxy lactam would arise from
hydrogenolytic cleavage of nitroso acetal 14, which itself
originates from a tandem inter-[4 + 2]/intra-[3 + 2] cycload-
dition of nitroalkene 12 and a chiral vinyl ether 11. The
geometrical constraints imposed by the tether require that the
intramolecular [3 + 2] cycloaddition must occur in an endo
This initial and highly direct approach had to be abandoned
due to the instability of the nitroalkene 12, which rapidly
isomerized to the fumarate isomer 16. After many unsuccessful
attempts to employ 12, it was recognized that 16 could also
serve as a suitable precursor for (-)-rosmarinecine (Scheme
2). This more tractable nitroalkene would lead to an R-hydroxy
lactam 17, by analogy to the maleate series, in a tandem [4 +
2]/[3 + 2] cycloaddition, followed by hydrogenolysis. Since
the two-dimensional stereochemistry of the fumarate will
translate into the incorrect configuration at C(6) in 17 for (-)-
rosmarinecine, an inversion at this center is necessitated. While
a strategic inelegance, the inversion of the hydroxyl at C(1)
should elongate the synthesis by only one or two steps, and
therefore, this would still constitute an efficient synthesis.
(15) (a) Robins, D. J. Chem. Soc. ReV. 1989, 18, 375. (b) Robins, D. J.
The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1995; Vol.
46, Chapter 1.
(16) (a) Ikeda, M.; Sato, T.; Ishibashi, H. Heterocycles 1988, 27, 1465.
(b) Dai, W.-M.; Nagao, Y. Heterocycles 1990, 30, 1231. (c) Wro´bel, J. T.
The Alkaloids: Brossi, A., Ed.; Academic Press: New York, 1985; Vol.
26, Chapter 7.
(17) Tatsuta, K.; Takahashi, H.; Amemiya, Y.; Kinoshita, M. J. Am.
Chem. Soc. 1983, 105, 4096.
Results and Discussion
(18) Denmark, S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137.
(19) (a) Denmark, S. E.; Moon, Y.-C.; Senanayake, C. B. W. J. Am.
Chem. Soc. 1990, 112, 311. (b) Denmark, S. E.; Senanayake, C. B. W.;
Ho, G. D. Tetrahedron 1990, 46, 4857. (c) Denmark, S. E.; Senanayake,
C. B. W. J. Org. Chem. 1993, 58, 1853. (d) Denmark, S. E.; Schnute, M.
E.; Senanayake, C. B. W. J. Org. Chem. 1993, 58, 1859. (e) Denmark, S.
E.; Schnute, M. E.; Marcin, L. R.; Thorarensen, A. J. Org. Chem. 1995,
60, 3205.
Use of Achiral Dienophiles. To evaluate the feasibility of
the approach outlined in Scheme 2, the nitroalkene 21 was
prepared by analogy with 2-(benzoyloxy)-1-nitroethene that was
used in the synthesis of (-)-hastanecine.20,22 The commercially
available ethyl ester 18 was easily converted to the acid chloride
(20) Denmark, S. E.; Thorarensen, A. J. Org. Chem. 1994, 59, 5672.
(21) Preliminary communication: Denmark, S. E.; Thorarensen, A.;
Middleton, D. S. J. Org. Chem. 1995, 60, 3574.
(22) Kraus, G. A.; Thurston, J.; Thomas, P. J.; Jacobson, R. A.; Su, Y.
Tetrahedron Lett. 1988, 29, 1879.

8268 J. Am. Chem. Soc., Vol. 118, No. 35, 1996
Denmark et al.
Scheme 3
Scheme 5
to be converted to 17 can be formulated. First, it is possible
that the lactone undergoes competitive reduction under the
hydrogenolysis conditions. Second, the shorter C-O bonds and
sp2-hybridized carbonyl group in the γ-lactone could be creating
strain in the tricyclic nitroso acetal. This strain may disfavor
recyclization after N-O bond cleavage, thus allowing unwanted
side reactions to occur preferentially. Third, unmasking the
aldehyde at C(6) may lead to â-elimination of the lactone
oxygen, also relieving ring strain. A potential solution to this
problem is to relieve the strain (and leaving group ability)
engendered by the carbonyl group in the five-membered ring
by changing the hybridization of C(3) in 22 from sp2 to sp3.
This could be accomplished by selectively reducing the carbonyl
function. Gratifyingly, treatment of the nitroso acetal 22 with
1 equiv of diisobutylaluminum hydride (DIBAL-H) at -78 °C
gave the lactol 25 in 55% yield (Scheme 5). Treatment of this
product with Raney nickel at 150 psi of hydrogen for 36 h gave
the R-hydroxy lactam 26 in 57% yield as a highly crystalline,
white solid after chromatography. Having thus established the
feasibility for the creation of a key intermediate in our planned
synthesis of (-)-rosmarinecine, we turned to the use of chiral
vinyl ethers.
Optimization of Reaction Parameters for the [4 + 2]/[3
+ 2] Cycloaddition. The tandem [4 + 2]/[3 + 2] cycloaddition
is the centerpiece in the planned synthesis of (-)-rosmarinecine.
In that reaction, all of the stereogenic centers are installed in
the correct relative and absolute sense, except that at C(6). To
assure both a high yielding and a highly selective sequence of
cycloadditions, we examined a number of permutations of Lewis
acids and chiral vinyl ethers. To maximize efficiency, the entire
synthesis was initially performed employing racemic auxiliaries.
Initial experiments employed MAPh and TiCl2(O-iPr)2 as the
Lewis acids. MAD was not considered due to its generally low
selectivity as the Lewis acid in tandem [4 + 2]/[3 + 2]
cycloadditions.18 The use of nitroalkene 21 and vinyl ether 27
(3 equiv) in reactions promoted by MAPh (3 equiv) led to a
93% yield of nitroso acetal 30 (Table 1). The use of less than
3 equiv of either the Lewis acid or the vinyl ether resulted in
low yields (Table 1, entries 1-3).
Scheme 4
19 (93%), which was subsequently treated with 2023 to afford
the nitroalkene 21 as a yellow solid in 90% yield (Scheme 3).
For orienting experiments, butyl vinyl ether was selected as
the test dienophile, in order to simplify product analysis by 1H
NMR spectroscopy. Addition of methylaluminum bis(2,6-di-
tert-butyl-4-methylphenoxide) (MAD)24 to a solution of ni-
troalkene 21 and butyl vinyl ether at -78 °C afforded the nitroso
acetal 22 in 59% yield as a 1.9:1 mixture of diastereomers, with
the endo diastereomer (R-anomer) predominating. Changing
the Lewis acid to methylaluminum bis(2,6-diphenylphenoxide)
(MAPh) gave 22 in 64% yield as a 1:1 mixture of diastereomers.
If TiCl2(O-iPr)2 was used as the Lewis acid, a single isomer of
22 was obtained. However, the yield was poor (28%), and the
reaction was found to give a number of byproducts that made
purification difficult.
With ready access to multigram quantities of 22, an extensive
study was then undertaken to establish the optimal conditions
for hydrogenolysis of the nitroso acetal 22 to R-hydroxy lactam
17 (Scheme 4). This study focused on four different catalysts
(PtO2, Raney nickel, Pd/C, and Pd(OH)2) in six different solvents
(methanol, 2-propanol, ethyl acetate, THF, toluene, and chlo-
roform) at three different pressures (1 atm, 100 psi, and 200
psi) for periods of time between 14 and 40 h. Disappointingly,
none of these conditions afforded the desired product 17. Either
decomposition to a number of unidentified byproducts occurred
or starting material was recovered. The inability to effect the
desired hydrogenolytic cleavage of 22 to 17 stands in sharp
contrast to the facile hydrolysis of nitroso acetals such as 23 to
the R-hydroxy lactam 24 (Scheme 4).
Although a high yield of the tandem cycloaddition product
could be obtained, the nitroso acetal 30 was produced as a 6.3:1
exo/endo mixture of diastereomers, (entry 1, Table 2). The use
of TiCl2(O-iPr)2 as the promoter improved the selectivity to 1:10
exo/endo, but this reaction was rather low yielding. More
importantly, the product isolated from this cycloaddition was
contaminated with unseparable impurities. We therefore turned
our attention to the vinyl ether (-)-28 derived from trans-2-
(1-methyl-1-phenylethyl)cyclohexanol with MAPh as the pro-
moter.25,26 The nitroso acetal 31 was isolated in excellent yield
The key structural difference between 22 and 23 is clearly
the lactone function, and several reasons for the failure of 22
(23) Babievskii, K. K.; Belikov, V. M.; Tikhohova, N. A. IzV. Akad.
Nauk SSSR, Ser. Kim. 1970, 5, 1161.
(24) (a) Maruoka, K.; Itoh, T.; Yamamoto, H. J. Am. Chem. Soc. 1985,
107, 4573. (b) Nonoshita, K.; Banno, H.; Maruoka, K.; Yamamoto, H. J.
Am. Chem. Soc. 1990, 112, 316. (c) Maruoka, K.; Ooi, T.; Yamamoto, H.
J. Am. Chem. Soc. 1990, 112, 9011. (d) Maruoka, K.; Itoh, T.; Shirasaka,
T.; Yamamoto, H. J. Am. Chem. Soc. 1988, 110, 310.
(25) (a) Comins, D. L.; Salvador, J. M. J. Org. Chem. 1993, 58, 4656.
(b) Comins, D. L.; Salvador, J. M. Tetrahedron Lett. 1993, 34, 801. (c)
Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1994, 35, 7343
(26) Denmark, S. E.; Thorarensen, A. J. Org. Chem. 1996, in press.

Synthesis of (-)-Rosmarinecine
J. Am. Chem. Soc., Vol. 118, No. 35, 1996 8269
1
Table 1. Cycloaddition with Vinyl Ether 27 Promoted by MAPh
Table 3. Selected H NMR Data of the Major Diasteromeric
Nitroso Acetals 30-32
entry
MAPh, equiv
27, equiv
yield,a %
entry
nitroso acetal
HC(6) ppm (J, Hz)
HC(2) ppm (J, Hz)
1
2
3
4
4.0
1.1
2.0
3.0
1.5
3
3
69
37
64
93
1
2
3
4
5
30a
30b
31a
32a
32b
a
a
5.25 (d, 3.7)
5.28 (d, 3.6)
5.20 (d, 3.6)
5.30 (d, 3.7)
5.30 (d, 3.9)
4.72 (t, 6.9)
4.64 (t, 7.1)
4.95 (dd, 2.2, 6.9)
3
a Yield after chromatographic purification.
a Obscured by ethyl ester signal.
Table 2. Cycloaddition with Vinyl Ethers 27-29
TiCl2(Oi-Pr)2 are generally endo selective, even with 29 as the
vinyl ether.19e
Configurational Assignment. In nitroso acetals of the
general structure 23, it had been observed that the relative
configuration of the anomeric center, C(6), with respect to the
ring junction carbon, C(4a), could be determined by analysis
of the splitting pattern of HC(6).28 In the cycloaddition
promoted by MAPh, the relationship should be trans if the exo
product were generated kinetically, and the anomeric proton
should be observed as a triplet. In contrast, with TiCl2(Oi-Pr)2
as the promoter, a cis relationship is dictated by the endo
approach of the vinyl ether in the [4 + 2] cycloaddition. In
this scenario, the anomeric proton should be observed as a
doublet of doublets. It is therefore interesting that the coupling
pattern of HC(6) in the nitroso acetals 30-32 displayed the same
behavior. The anomeric proton appeared as a triplet in the
nitroso acetal obtained from a MAPh-promoted reaction, sup-
porting a trans relationship to C(4a) (Table 3, entries 3 and 4).
On the other hand, the anomeric proton appeared as a doublet
of doublets when the cycloaddition was promoted by a titanium
Lewis acid, confirming a cis relationship between C(6) and
C(4a) (entry 5). Interestingly, the chemical shift of the anomeric
proton is also very sensitive to the auxiliary employed, while
all the other protons on the tricyclic ring system are only slightly
affected. The coupling pattern of the anomeric proton provided
a means to identify the different diastereomeric nitroso acetals
that were obtained in each cycloaddition. Armed with the
knowledge that 29 behaved in a predictable and selective fashion
with MAPh, it was easy to choose the appropriate configuration
of 2,2-diphenylcyclopentanol for the synthesis of natural (-)-
rosmarinecine.
diastereo-
selectivity, nitroso yield,
exo/endo
entry
R
auxiliary
promoter
MAPha
acetal
%
1
2
3
4
5
6
Et
Et
i-Pr
i-Pr
Et
27
27
28
28
29
29
6.3:1
30
30
31
31
32
32
93
57c
95
16
95
37c
TiCl2(Oi-Pr)2 1:10
MAPha
12.2:1d
TiCl2(Oi-Pr)2 6.6:4.1:1e
MAPha
41:1
TiCl2(Oi-Pr)2 >10:1b
Et
a All cycloadditions promoted by MAPh utilized 3 equiv of MAPh
and 3 equiv of vinyl ether. b Minor could not be detected due to
impurities. c Contaminated by an unknown impurity. d Minor assumed
to be the other exo diastereomer. e The major diastereomer was the
same as that from entry 3.
(95%) and with an improved exo/exo selectivity of 12.2:1. To
determine if the two diastereomeric nitroso acetals 31 belonged
to the same or opposite enantiomeric families, the mixture was
converted to an intermediate in the synthesis of (-)-rosmari-
necine.27 The enantiomeric purity for this intermediate (12.9:1
enantiomeric ratio by chiral HPLC analysis) was shown to
correspond well with the observed diasteromeric ratio of 12.2:
1. Thus, the two diasteromeric nitroso acetals 31 do, in fact,
belong to the opposite enantiomeric families. Unfortunately,
they could not be separated by chromatography or recrystalli-
zation; consequently, it was not possible to enrich the mixture.
The third vinyl ether to be examined was derived from (R)-
2,2-diphenylcyclopentanol 29.19e Cycloaddition of 21 and 29
promoted by MAPh afforded the nitroso acetal 32 in both
excellent yield (95%) and high diastereoselectivty (Table 2, entry
5). In repeated experiments, the diastereoselectivty was found
to be variable (41:1 to 20:1), probably due to unintentional
enrichment during chromatographic purification. The minor
diasteromer 32b was confirmed to be an endo-derived cycload-
duct, since it was formed preferentially from the cycloaddition
with TiCl2(Oi-Pr)2 as the promoter. Under these conditions,
mainly 32b was produced but in rather low yield (Table 2, entry
6). We have demonstrated that cycloadditions promoted by
Unmasking of the Nitroso Acetal. From our experience
with lactone 22, it was anticipated that reduction of the lactone
32 would be required to allow the ring closure to occur.29
Diisobutylaluminum hydride, which had been successfully
employed previously, afforded the lactol 33 in, at best, 38%
yield (Table 4).30 The transformation was complicated by the
competitive reduction of the ethyl ester, affording a mixture of
aldehyde 34a and alcohol 34b. Thus, a survey was undertaken
(28) Schnute, M. E. Ph.D. Thesis, University of Illinois at Urbana-
Champaign, Urbana, IL, 1995; pp 21-23.
(29) This was verified by the failure of 32 to undergo the desired
hydrogenolysis.
(30) (a) Hijfte, L. V.; Little, R. D.; Petersen, J. L.; Moeller, K. D. J.
Org. Chem. 1987, 52, 4647. (b) Ley, S. V.; Santafianos, D.; Blaney, W.
M.; Simmonds, M. S. J. Tetrahedron Lett. 1987, 28, 221. (c) Nakata, T.;
Saito, K.; Oishi, T. Tetrahedron Lett. 1986, 27, 6345. (d) Corey, E. J.;
Albonico, S. M.; Koelliker, U.; Schaaf, T. K.; Varma, R. K. J. Am. Chem.
Soc. 1971, 93, 1490. (e) Yoon, N. M.; Gyoung, Y. S. J. Org. Chem. 1985,
50, 2443. Review: (f) Winterfeldt, E. Synthesis 1975, 617.
(27) The enantiomeric ratio was determined on the 4-nitrobenzoate 50
by a sequence analogous to Scheme 11.

8270 J. Am. Chem. Soc., Vol. 118, No. 35, 1996
Denmark et al.
Table 4. Survey of Reducing Agents for the Reduction of 32
Scheme 6
Scheme 7
mass recovery, %
lactol overreduction starting material
entry
reagent
DIBAL-H
Red-Al‚EtOH
LiAlH(Ot-Bu)3
Red-Al
Red-Al‚N-methyl
piperazine
L-Selectride
LS-Selectride
33
34
32
1a
2a
3b
4b
5b
38
18
26
33
22
82
58
0
24
trace
0
trace
29
0
85c
6a
7d
55
0
0
0
0
quantitative
a Isolated yield. b Ratios determined by H NMR. c Numerous side
products also observed. d No reduction product could be detected by
1H NMR.
1
employed to cleave ethyl or methyl esters and ethers, such as
potassium trimethylsilanolate,36 iodotrimethylsilane,37 lithium
ethane thiolate,38 dimethyl sulfide aluminum tribromide,39 and
sodium hydroxide in methanol.40 The only reaction that showed
even moderate success was the transesterification of 32 to a
methyl ester (36) in methanol promoted by CeCl3 or CoCl2
(Scheme 6).41
Increasing the bulk of the ester group proved to be a
successful strategy. Our initial approach was to use the
corresponding tert-butyl ester. From 18, the tert-butyl ester was
prepared in 90% yield by esterification with isobutylene
promoted by sulfuric acid (Scheme 7).42,43 Selective hydrolysis
of the ethyl ester with 1 equiv of LiOH in THF afforded the
acid 37 in 93% yield.44 The formation of the acid chloride from
37, and coupling with the potassium salt 20, afforded the
nitroalkene 38 in 48% yield.
with reagents capable of effecting the lactone-to-lactol conver-
sion:31 sodium bis(2-methoxyethoxy)aluminum hydride (Red-
Al),32 Red-Al‚EtOH,33 Red-Al‚amine,34 and lithium tris(tert-
butoxy)aluminum hydride (LiAlH(Ot-Bu)3).35 Red-Al reduction
of the lactone provided none of the desired product; instead,
both overreduction products 34a and 34b (29%) were obtained.
The ethanol-modified reagent afforded some of the desired
product 33 (24%), but the mass recovery was very poor. The
use of the N-methylpiperazine-modified Red-Al was ineffective.
More promising was the use of lithium tris(sec-butyl)borohy-
dride (L-Selectride), which afforded the desired lactol 33 in 55%
yield. These results were still rather unsatisfactory for such a
simple functional group transformation, and two separate
strategies were undertaken to differentiate these groups: (1)
hydrolysis of the ester to a carboxylic acid and (2) increasing
the size of the ester to disfavor sterically reduction.
(36) (a) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831.
(b) Baldwin, J. E.; Adlington, R. M.; Mitchell, M. B. J. Chem. Soc., Chem.
Commun. 1993, 1332.
(37) (a) Olah, G. A.; Narang, S. C.; Balaram Gupta, B. G.; Malhotra, R.
J. Org. Chem. 1979, 44, 1247. (b) Lott, R. S.; Chauhan, V. S.; Stammer,
C. H. J. Chem. Soc., Chem. Commun. 1979, 495. (c) Ho, T.-L.; Olah, G.
A. Angew. Chem., Int. Ed. Engl. 1976, 15, 774. (d) Jung, M. E.; Lyster, M.
A. J. Am. Chem. Soc. 1977, 99, 968. (e) Morita, T.; Okamoto, Y.; Sakurai,
H. J. Chem. Soc., Chem. Commun. 1978, 874.
(38) (a) Vaughan, W. R.; Baumann, J. B. J. Org. Chem. 1962, 27, 739.
(b) Feutrill, G. I.; Mirrington, R. N. Aust. J. Chem. 1972, 25, 1731. (c)
Kornblum, N.; Scott, A. J. Am. Chem. Soc. 1974, 96, 590. (d) Bartlett, P.
A.; Johnson, W. S. Tetrahedron Lett. 1970, 4459. For a review of
dealkylation methods, see: (e) McMurray, J. Org. React. 1976, 24, 187.
(39) (a) Node, M.; Nishide, K.; Sai, M.; Fuji, K.; Fujita, E. J. Org. Chem.
1981, 46, 1991. (b) Node, M.; Nishide, K.; Sai, M.; Fujita, E. Tetrahedron
Lett. 1978, 5211. (c) Williard, P. G.; Fryhle, C. B. Tetrahedron Lett. 1980,
21, 3731.
The simple hydrolysis of the ethyl ester 32 to the carboxylic
acid 35 was more difficult than expected. The nitroso acetal
32 was found to be extremely base sensitive, and, in most
instances, the free auxiliary was the only recovered material.
Also unsuccessful were various reagents that have been
(31) (a) Walker, E. R. H. Chem. Soc. ReV. 1976, 5, 23. (b) Brown, H.
C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567. (c) Barrett, A. G. M. In
ComprehensiVe Chemistry, Reductions; Fleming, I., Ed.; Pergamon Press:
Oxford 1991; Vol. 8, Chapter 1.10.
(32) (a) Doria, C.; Gaio, P.; Gandolfi, C. Tetrahedron Lett. 1972, 4307.
(b) Klo¨tzer, W.; Teitel, S.; Brossi, A. HelV. Chim. Acta 1971, 54, 2057. (c)
Disselnko¨tter, H.; Lieb, F.; Oediger, H.; Wendisch, D. Liebigs Ann. Chem.
1982, 150. (d) Hohlbrugger, R.; Klo¨tzer, W. Chem. Ber. 1979, 112, 849.
(33) (a) Hung, H.-K.; Lam, H.-Y.; Niemczura, W.; Wang, M.-C.; Wong,
C.-M. Can. J. Chem. 1978, 56, 638. (b) Tokoroyama, T.; Matsuo, K.;
Kotsuki, H.; Kanazawa, R. Tetrahedron 1980, 36, 3377.
(40) (a) Liu, H.-W.; Auchus, R.; Walsh, C. T. J. Am. Chem. Soc. 1984,
106, 5335. (b) Gawronski, J. K.; Reddy, S. M.; Walborsky, H. M. J. Am.
Chem. Soc. 1987, 109, 6726.
(34) (a) Bartsch, H.; Schwarz, O. J. Heterocycl. Chem. 1982, 19, 1189.
(b) Kanazawa, R.; Tokoroyama, T. Synthesis 1976, 526.
(35) (a) Girotra, N. N.; Wendler, N. L. Tetrahedron Lett. 1975, 227. (b)
Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R. J. Am. Chem. Soc. 1981, 103,
1222. (c) Tsuda, Y.; Yoshimoto, K.; Yamashita, T.; Kaneda, M. Chem.
Pharm. Bull. 1981, 29, 3238. (d) Cassidy, F.; Moore, R. W.; Wootton, G.;
Baggaley, K. H.; Geen, G. R.: Jennings, L. J. A.; Tyrrell, A. W. R.
Tertahedron Lett. 1981, 22, 253. (e) Stevens, R. V.; Vinogradoff, A. P. J.
Org. Chem. 1985, 50, 4056. (f) Skattebøl, L.; Stenstrøm, Y. Acta Chem.
Scand. B 1985, 39, 291.
(41) (a) Luche, J.-L.; Gemal, A. L. J. Chem. Soc., Chem. Commun. 1978,
976. (b) Gemal, A. L.; Luche, J.-L. J. Org. Chem. 1979, 44, 4187. For a
review of transesterification, see: (c) Otera, J. Chem. ReV. 1993, 93, 1449.
(42) Nelsen, S. F.; Gillespie, J. P. J. Org. Chem. 1975, 40, 2391.
(43) An alternative method for the preparation of this compound has
been reported: Neises, B.; Steglich, W. Org. Synth. 1985, 63, 183.
(44) Patel, D. V.; VanMiddlesworth, F.; Donaubauer, J.; Gannett, P.;
Sih, C. J. J. Am. Chem. Soc. 1986, 108, 4603.

Synthesis of (-)-Rosmarinecine
J. Am. Chem. Soc., Vol. 118, No. 35, 1996 8271
Table 5. Reductions of 39 with Various Hydride Reagents
Scheme 8
mass recovery, %a
side product
lactol
starting material
entry
reagent
40
34
41
39
1
2
3
DIBAL-H
LiAlH(Ot-Bu)3
L-Selectride
31
65
86
14
33
0
0
21
0
0
a Isolated yield after chromatography.
Scheme 9
The nitroalkene 38 was then combined in a cycloaddition
with vinyl ether 29 promoted by MAPh. The desired nitroso
acetal 39 was isolated in 93% yield as a 19:1 mixture of exo/
endo diastereomers. The nitroso acetal could be enriched by a
simple recrystallization from ethanol to a 31:1 exo/endo
diastereomeric mixture. Surprisingly, DIBAL-H was still a
rather nonselective reducing agent, affording only 31% yield
of the desired lactol 40 with considerable reduction of the tert-
butyl ester to 34 (Table 5). Lithium tris(tert-butoxy)aluminum
hydride (2 equiv) afforded the desired lactol 40 in 65% yield,
along with the unwanted diol 41 in 21% yield. However, when
L-Selectride was employed as the reducing agent, the lactol 40
was isolated cleanly in 86% yield, with no overreduction
detected.
The nitroalkene 44 was then transformed into the correspond-
ing nitroso acetal 45 by a tandem cycloaddition with 29 in
excellent yield. The reduction of the lactone to the lactol 46
was consistently achieved in greater than 90% yield with
L-Selectride, with no evidence of overreduction. Moreover,
subjecting the lactol 46 to the hydrogenolytic conditions with
Raney nickel gratifyingly afforded the desired product 26 in
59% yield.
To optimize the yield of 26, a survey of hydrogen pressure
was undertaken. In this system, higher pressures afforded lower
yields, though little difference was observed between 14.6 and
160 psi. In some instances, a very small amount of overre-
duction was detected wherein the lactol had been reduced to a
diol (47). The optimum conditions employed 160 psi of
hydrogen pressure for 48 h. In addition, following removal of
the catalyst, the filtrate was heated at 60 °C for 1 h to ensure
complete ring closure to the lactam.
Correction of the Configuration at C(6). The lactam 26
possessed all of the correct structural features of (-)-rosmari-
necine. However, to convert the lactam to (-)-rosmarinecine,
inversion of the configuration at C(1) (which becomes C(6) of
(-)-rosmarinecine) was required (Scheme 9). In addition, it
remained to reveal the free amino triol by reduction of the lactam
and the lactol.
The free hydroxyl at C(1) makes the Mitsunobu reaction the
perfect choice to correct the configuration of C(1).47 In addition,
the resulting ester could be deprotected under the same reducing
conditions in which the amino triol would be revealed. Initial
attempts to selectively invert the stereocenter at C(1) in the
presence of the free lactol in 26 were foiled. The only isolated
product (54%) contained one benzoate group; unfortunately, it
was as a result of an inversion of the lactol, not the C(1)
hydroxyl. The selective protection of the lactol as a methyl
Subjecting of lactol 40 to the standard hydrogenolysis
conditions, employing Raney nickel as the catalyst, afforded
none of the desired product 26 after workup. The isolated
product was very polar, as judged by TLC analysis, and seemed
1
to include the tert-butyl ester by H NMR spectroscopy. It
appeared that the initial stages of the hydrogenolysis had been
successful, but the final lactamization required to give the
desired product did not occur. All attempts to cyclize the
suspected intermediate failed. Apparently, the tert-butyl group
was too bulky to allow the pyrrolidine to attack the carbonyl
group in the strained bicyclic framework. We thus elected to
test the corresponding isopropyl ester in the hope that it would
serve effectively in both stages of the unmasking processes.
The requisite nitroalkene 44 was easily prepared from maleic
anhydride (Scheme 8). Reaction of maleic anhydride with
potassium isopropoxide, according to the procedure of Veibel
and Pedersen, afforded the potassium maleate salt 42 in excellent
yield (91%).45 Treatment of 42 with (COCl)2/DMF as before
resulted in the formation of the desired acid chloride 43 (66%).46
The attendant isomerization of the double bond was assured by
the 15.4 Hz vicinal coupling constant, which is in good
agreement with that observed in the nitroalkenes derived from
18. The acid chloride 43 was coupled with 20 to afford the
target nitroalkene 44 in 69% yield.
(45) Veibel, S.; Pedersen, C. Acta Chem. Scand. 1955, 9, 1674.
(46) For alternative methods for the preparation of the acid chloride,
see: (a) Oiwa, M.; Matsumoto, A. Jpn. Kokai Tokkyo Koho JP 62 45,561,
1987; Chem. Abstr. 1987, 107, 176634b. Several methods exist for the
preparation of the monoisopropyl fumaric acid, as an example: (b) Zecher,
W.; Merten, R. Eur. Pat. Appl. EP 69926 A1, 1983. (c) Gordinskii, B. Y.;
Shimanskii, V. M.; Vishnyakova, R. S. Zh. Prikl. Kim. 1967, 40, 1881. (d)
Ushakov, S. N.; Nikolaev, A. F.; Toroptseva, A. M.; Trizno, M. S. Zh.
Prikl. Kim. 1959, 32, 667.
(47) Review of the Mitsunobu reaction: Hughes, D. L. Org. React. 1992,
42, 335.

8272 J. Am. Chem. Soc., Vol. 118, No. 35, 1996
Denmark et al.
Scheme 10
Scheme 11
Figure 3. Hydrolysis of 50 as a function of TFA concentration.
Scheme 12
Scheme 13
acetal was easily accomplished (MeOH/pTsOH/HC(OMe)3/
reflux) to afford 48 in 74-84% yield as a single anomer, as
1
judged by H NMR spectrocopy (Scheme 10). If the reaction
was carried out for a shorter time, or at room temperature, a
mixture of anomeric methyl acetals was obtained.48 The
assignment of configuration of the acetal is made on the
assumption of thermodynamic control; the most stable methyl
acetal should be of the R configuration due to steric interaction
on the concave side of the tricyclic structure. In addition, the
acetal proton appeared as a singlet, indicating a trans relationship
between HC(7) and HC(7a). The minor anomer appeared at
5.14 ppm as a doublet (J ) 5.6 Hz), indicating a cis relationship
between HC(7) and HC(7a).
The configuration at C(1) was now easily corrected under
standard Mitsunobu reaction conditions utilizing benzoic acid
as the nucleophile. The product 49 was isolated in 73% yield
(Scheme 11). Recent reports have demonstrated that more
acidic nucleophiles, such as 4-nitrobenzoic acid, afforded higher
yield in reactions with sterically hindered alcohols.49 This
simple modification dramatically improved the yield in the
inversion with 48, affording the inverted lactam 50 in 94% yield.
The only complication in this reaction was the similar polarity
of the substitution product and the byproduct triphenylphosphine
oxide, requiring multiple purifications by silica gel chromatog-
raphy to obtain 50 cleanly.
As confirmation that the methyl acetal 48 had, indeed,
undergone invertive substitution and was not simply acylated
in the Mitsunobu reaction, the R-hydroxy lactam 48 was treated
with 4-nitrobenzoyl chloride to obtain the 4-nitrobenzoate 51
in 79% yield (Scheme 11). Comparison of the 1H NMR spectra
of the two esters confirmed that the Mitsunobu reaction had
occurred with inversion. The 1H NMR spectrum of lactam 50
has a singlet at 5.40 ppm, indicating a trans relationship between
HC(7a) and HC(1), while the lactam 51 displayed a doublet at
6.06 ppm (J ) 8.5 Hz), indicating a cis relationship between
HC(7a) and HC(1).
Synthesis of Rosmarinecine. The final production of amino
triol 2 by deprotection of the 4-nitrobenzoate and reduction of
the lactam lactol required that the methyl acetal first be cleaved.
Simple hydrolysis with 1 N HCl provided the desired product
in very low yield, and iodotrimethylsilane37 or boron trifluoride
etherate/tetrabutyl ammonium iodide50 afforded no reaction at
all. More promising results were obtained with the use of
trifluoroacetic acid (TFA), which provided the desired product
51 in variable yield.51 Since the reaction appeared to be very
sluggish, the TFA concentration was optimized in a series of
1H NMR experiments. The approximate half-life of the
hydrolysis was determined at three different acid concentra-
tions: 80%, 90%, and 95% TFA. All the reactions were
performed at room temperature in TFA-d, diluted with D2O to
the appropriate concentration. As can be seen in Figure 312,
all of the reactions displayed pseudo-first-order kinetics. The
80% TFA reaction was very slow, with a t1/2 of 14.5 h. Under
these reaction conditions, only a trace amount of byproducts
was generated, even after a long reaction time. The use of 95%
TFA increased the rate dramatically (t1/2 ) 3.1 h) and afforded
a more tolerable reaction time. Unfortunately, under these
strongly acidic conditions, a large number of byproducts were
1
observed in the H NMR spectrum. The 90% TFA solution
(48) The production of a single anomer or a high anomeric ratio was
important to achieve good yield in the subsequent reaction, as the minor
component could never be isolated after workup (vide infra).
(49) Dodge, J. A.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994, 59,
234.
provided an excellent balance between rate and selectivity, with
(50) Mandal, A. K.; Soni, N. R.; Ratnam, K. R. Synthesis 1985, 274.
(51) Nakajima, N.; Uoto, K.; Yonemitsu, O.; Hata, T. Chem. Pharm.
Bull. 1991, 39, 64.

Synthesis of (-)-Rosmarinecine
J. Am. Chem. Soc., Vol. 118, No. 35, 1996 8273
1
Figure 4. (a) 13C NMR and (b) H NMR spectra of i, ii, and rosmarinecine 2 after silica gel chromatography.
Scheme 14
a t1/2 of 4.8 h and a byproduct profile similar to that obtained
with the 80% TFA reaction.
hydrolysis by comparision of the 1H and 13C NMR spectra; thus,
the assignment of the lactol structure as 52 was secured.
The final transformation involved an exhaustive reduction
of the lactam, ester, and latent lactol carbonyl groups. In our
(-)-hastanecine synthesis, a similar reduction with lithium
aluminum hydride revealed the desired amino diol. To complete
the synthesis of (-)-rosmarinecine, the 4-nitrobenzoate 52 was
treated with lithium aluminum hydride to afford compound i in
66-84% yield after silica gel chromatography (Scheme 13).
The isolation, purification, and identification of 52 proved
to be challenging. The 1H NMR spectra of the lactol 52 usually
contained broad peaks with little fine structure, regardless of
the solvent employed. Therefore, to ensure that our assignment
of the lactol structure was correct, 52 was methylated with
iodomethane and silver oxide (Scheme 12). The methyl acetal
50 was isolated in 53% yield, along with 28% of recovered 52.
The product isolated was the same methyl acetal 50 used in the
1
The H and 13C NMR spectra of i differed significantly from

8274 J. Am. Chem. Soc., Vol. 118, No. 35, 1996
Denmark et al.
1
Table 6. Selected H NMR Data for Nitroso Acetals 45a,b
satisfying 64% yield with a small amount of an overreduced
lactol. The chiral auxiliary (R)-2,2-diphenylcyclopentanol was
recovered in 98% yield after the hydrogenation. Protection of
the lactol (+)-26 as its methyl acetal (+)-49 (73%), followed
by inversion at C(2) by a Mitsunobu reaction utilizing 4-ni-
trobenzoic acid as the nucleophile, afforded the 4-nitrobenzoate
(+)-50 (94%), which was determined to be 97.3% by chiral
HPLC. The deprotection of (+)-50 was accomplished with 90%
trifluoroacetic acid, to afford the lactol (+)-52 in 87% yield.
Reduction of lactol (+)-52 with Red-Al in THF at reflux
afforded, after extensive chromatographic purification on both
silica gel and basic alumina, a white solid, which was recrystal-
lized from acetone/pentane to afford (-)-rosmarinecine (2) as
an analytically pure, white solid in 66% yield. The physical
properties matched those of the reported values: mp 169-170
nitroso acetal
HC(6) ppm (J, Hz)
HC(7b) ppm (J, Hz)
(-)-45a
(+)-45b
4.63 (t, 7,2)
4.95 (dd, 2.2, 6.8)
4.39 (dd, 6.6, 8.6)
4.26 (dd, 6.4, 8.6)
those reported for natural (-)-rosmarinecine.52 In only one
instance under these reaction conditions was (-)-rosmarinecine
isolated from 52 (45%). Employing Red-Al instead as the
reducing agent with 52 afforded an 82% yield of yet another
amino triol ii, which differed from both rosmarinecine and i.
Still more surprising was the fact that LiAlH4 reduction of the
benzoate lactol 53 (prepared by TFA hydrolysis of 49) produced
2 in moderate yield (69%) after silica gel chromatography. The
dissimilarity of the NMR spectra of i, ii, and 2 is easily seen,
as depicted in Figure 4.
°C, [R]21 -117.6° (EtOH, c ) 0.96), lit.52 mp 170-172 °C,
D
[R]23D -119.1° (EtOH, c ) 0.94); lit.10 mp 171-172 °C, [R]25
D
-118.5 °; lit.12 mp 171-172 °C, [R]25 -116.5° (EtOH, c )
D
0.01); lit.17 [R]21 -121° (EtOH, c ) 0.01). Importantly, the
D
1H NMR and 13C NMR data of the synthetic product are nearly
identical to those of the natural compound (mp 168-170 °C,
[R]21 -119.8° (EtOH, c ) 1.01)) obtained by hydrolysis of
D
rosmarinine (see supporting information).
Conclusion. The synthesis of (-)-rosmarinecine was ac-
complished in eight steps and 14.8% overall yield from the
fumaroyl acid chloride 43. All the stereocenters were installed
in a single transformation with high selectivity, which demon-
strates the utility of the tandem [4 + 2]/[3 + 2] cycloaddition
strategy and serves to illustrates the predictive power of the
various stereochemical features of the reaction sequence. Since
(-)-rosmarinecine is among the more complex necine bases
containing an all-cis relationship, this synthesis demonstates the
generality of the tandem [4 + 2]/[3 + 2] cycloaddition chemistry
for the synthesis of this class of compounds.
This unanticipated outcome caused considerable consterna-
tion. The gross similarity of the NMR spectra of i, ii, and 2
suggested that epimeric forms of the desired product were being
generated.1,53 Some of these possibilities could be eliminated,
and we eventually realized that the anomalies in the spectra
were caused by variable concentrations of hydrates or N-
complexes of rosmarinecine itself. This was proven by ad-
ditional purification of each of the three substances i, ii, and 2
on basic alumina to afford the same compound, which in each
instance possessed the same 1H and 13C NMR spectra as those
reported for natural (-)-rosmarinecine.52
Total Synthesis of (-)-Rosmarinecine: Summary. The
synthesis of enantiomerically pure (-)-rosmarinecine employing
the optically active vinyl ether 29 is detailed in Scheme 14,
where the yields refer to homogenous, analytically pure material.
The requisite nitroalkene 44 was subjected to the tandem [4 +
2]/[3 + 2] cycloaddition sequence, utilizing MAPh as the Lewis
acid promoter and (-)-29. Reaction of the nitroalkene with 3
equiv of the chiral vinyl ether in the presence of 3 equiv of
MAPh afforded the nitroso acetal 45 in 94% yield. The nitroso
acetal 45 was isolated as a 25:1 exo/endo mixture of diastere-
omers that could not be enriched by recrystallization. The
diastereomers 45a,b were, therefore, separated by silica gel
chromatography. The chromatographic fractions containing the
desired product (-)-45a were concentrated in two separate
portions. The composition of the major portion (74%) was
determined by 1H NMR spectroscopy to be approximatly 95:1
exo/endo mixture of diastereomers, and the minor portion
consisted of a 6.3:1 exo/endo mixture. The stereochemical
assignment of the diastereomers was based, 1H NMR: the
anomeric proton in the exo diastereomer (-)-45a appears as a
triplet, while the same proton in the endo diastereomer (+)-
45b appears as a doublet of doublets (Table 6).
Experimental Section
General Experimental. See supporting information for details.
(E)-4-Chloro-4-oxo-2-butenoic Acid 1-Methylethyl Ester (43). In
a three-neck, 500 mL, round-bottom flask fitted with a Schlenk filtration
tube was placed the potassium isopropoxy maleate 42 (15.0 g, 76.5
mmol) in CH2Cl2 (120 mL). To the solution was added oxalyl chloride
(16.7 mL, 191 mmol, 2.49 equiv), followed by dimethylformamide (0.90
mL, 11.6 mmol, 0.15 equiv), whereupon massive evolution of gas was
observed. The resulting solution was stirred at room temperature in
an aluminum foil-covered flask for 22 h. Pentane (210 mL) was added,
and the precipitated salts were filtered off and washed with pentane
(30 mL). The filtrate was concentrated in vacuo, and the black residue
was filtered again and fractionally distilled to afford 8.90 g (66%) of
1
43 as a clear, colorless oil: bp 44-45 °C (0.8 Torr); H NMR (400
MHz, CDCl3) δ 6.97 (d, J ) 15.4 Hz, 1H), 6.92 (d, J ) 15.4 Hz, 1H),
5.12 (septet, J ) 6.3 Hz, 1H, HC(5)), 1.30 (d, J ) 6.1 Hz, 6H, HC(6));
13C NMR (100 MHz, CDCl3) δ 165.42 (C(1)), 163.22 (C(4)), 138.49
(C(3)), 136.44 (C(2)), 69.92 (C(5)), 21.62 (C(6)); IR (neat) ν 2985
(m), 2940 (w), 1766 (s), 1726 (s), 1376 (m), 1352 (m), 1337 (m), 1303
(s), 1278 (s), 1262 (s), 1239 (m), 1184 (s), 1146 (m), 1104 (s), 1024
(s), 984 (s), 972 (s), 907 (m); MS (70 eV) mz (relative intensity) 176
(M+, 1), 141 (27), 135 (14), 119 (17), 118 (10), 117 (54), 99 (40), 91
(19), 89 (62), 85 (10), 83 (16), 82 (26), 59 (31), 55 (29), 54 (36), 53
(16), 43 (100), 42 (86). Anal. Calcd for C7H9ClO3 (176.59): C, 47.60;
H, 5.13. Found: C, 47.45; H, 5.17.
The lactone was then reduced with L-Selectride to afford the
lactol (-)-46 in excellent yield (91%). The lactol (-)-46 was
then submitted to the standard hydrogenation conditions to
afford the tricyclic R-hydroxy lactam-lactol (+)-26 in a
(E)-[(2-(Nitroethenyl)oxy]-4-oxo-2-butenoic Acid 1-Methylethyl
Ester (44). To a slurry of potassium nitroacetaldehyde 20 (2.20 g,
17.3 mmol) in nitromethane (32 mL) at -6 °C was added rapidly a
solution of 43 (3.09 g, 17.3 mmol, 1.0 equiv) in CH2Cl2 (12 mL). The
mixture was allowed to stir for 45 min at -6 °C. During this time,
the color changed to light brown, with precipitation of a white solid.
Dichloromethane (250 mL) was then added, and the resulting suspension
was filtered through Whatman No.1 filter paper. The filtrate was
(52) Denholm, A. A. Ph.D. Thesis, University of Glasgow, 1990. We
gratefully acknowledge professor David J. Robins for the copies of this
experimental procedure.
(53) We are not aware of a report in the open literature discussing this
phenomena, but considering the enormous numbers of papers in this field,
a report could have been unintentionally missed.

Synthesis of (-)-Rosmarinecine
J. Am. Chem. Soc., Vol. 118, No. 35, 1996 8275
concentrated by rotary evaporation, and the remaining nitromethane
was removed under high vacuum with a water bath at room temperature
to give 3.77 g of the crude nitroalkene. The crude product was
recrystallized from hexane/Et2O 10:1 (118 mL) with hot gravity
filtration to afford 2.80 g (69%) of 44 as yellow, crystalline solid: mp
67-68 °C (hexane/Et2O); 1H NMR (400 MHz, CDCl3) δ 8.90 (d, J )
11.0 Hz, 1H, HC(2)), 7.37 (d, J ) 11.2 Hz, 1H, HC(1)), 7.07 (d, J )
15.6 Hz, 1H, HC(5)), 6.92 (d, J ) 15.9 Hz, 1H, HC(6)), 5.14 (septet,
J ) 6.3 Hz, 1H, HC(9)), 1.32 (d, J ) 6.4 Hz, 6H, HC(10)); 13C NMR
(100 MHz, CDCl3) δ 163.23 (C(7)), 160.07 (C(4)), 147.40 (C(2)),
138.87 (C(5)), 130.30 (C(1)), 129.16 (C(6)), 69.80 (C(9)), 21.59 (C(10));
IR (KBr) ν 3131 (m), 3081 (m), 2981 (m), 1744 (s), 1711 (s), 1671
(m), 1648 (w), 1532 (m), 1373 (m), 1362 (m), 1340 (w), 1315 (m),
1283 (w), 1189 (m), 1147 (w), 1109 (w), 1007 (w), 945 (w); MS(CI,
CH4) m/z (relative intensity) 230 (M+ + H, 2), 159 (12), 142 (9), 141
(100), 117 (6), 99 (9). Anal. Calcd for C9H11NO6 (229.18): C, 47.16;
H, 4.83; N, 6.11. Found: C, 47.17; H, 4.84; N, 6.12.
Calcd for C28H31NO7 (493.55): C, 68.13; H, 6.33; N, 2.83. Found:
C, 68.28; H, 6.42; N, 3.01.
For (+)-45b: mp 80-84 °C (hexane/EtOAc); 1H NMR (400 MHz,
CDCl3) δ 7.27-7.09 (m, 10H), 5.28 (d, J ) 3.9 Hz, 1H, HC(2)), 5.10
(septet, J ) 6.3 Hz, 1H, HC(9)), 4.95 (dd, J ) 2.2, 6.8 Hz, 1H, HC-
(6)), 4.79 (ddd, J ) 3.0, 6.0, 9.3 Hz, 1H, HC(4a)), 4.72 (d, J ) 5.4
Hz, 1H, HC(1′)), 4.26 (dd, J ) 6.4, 8.6 Hz, 1H, HC(7b)), 3.93 (dd, J
) 3.7, 8.6 Hz, 1H, HC(2a)), 2.63-2.55 (m, 1H, HC(3′)), 2.26-2.13
(m, 2H, HC(3′ and 5′)), 1.94-1.86 (m, 1H, HC(5′)), 1.84-1.72 (m,
2H, HC(5 and 4′)), 1.50 (ddd, J ) 3.1, 6.9, 16.0 Hz, 1H, HC(5)), 1.37-
1.25 (m, 1H, HC(4′)), 1.31 (d, J ) 6.1, 3H, HC(10)), 1.30 (d, J ) 6.1
Hz, 3H, HC(10)); 13C NMR (100 MHz, CDCl3) δ 173.72 (C(3)), 166.88
(C(8)), 146.04 (C), 145.25 (C), 128.42 (CH), 128.12 (CH), 127.61 (CH),
126.88 (CH), 125.90 (CH), 125.54 (CH), 101.07 (C(6)), 87.40 (C(1′)),
84.48 (C(2)), 74.54 (C(4a)), 72.56 (C(7b)), 70.54 (C(9)), 60.25 (C(2′)),
49.46 (C(2a)), 34.78 (C(3′)), 32.33 (C(5′)), 29.85 (C(5)), 21.60 (C(10)),
21.56 (C(10)), 20.39 (C(4′)); IR (KBr) ν 3056 (w), 3023 (w), 2979
(m), 2878 (w), 1781 (s), 1741 (s), 1494 (w), 1447 (w), 1386 (w), 1375
(m), 1359 (m), 1346 (w), 1297 (s), 1288 (m), 1238 (s), 1209 (m), 1180
(s), 1154 (s), 1105 (s), 1082 (m), 1072 (m), 1046 (m), 1012 (m), 919
(m); MS (FAB) m/z (relative intensity) 494 (M+ + H, 4) 307 (31),
289 (14), 258 (10), 237 (12), 221 (43), 155 (27), 154 (100), 139 (13),
138 (29), 137 (55), 136 (62), 123 (10), 119 (10), 116 (20), 106 (17);
[R]21D +12.9° (CHCl3, c ) 0.54); TLC Rf ) 0.45 (hexane/EtOAc 1:1).
Anal. Calcd for C28H31NO7 (493.55): C, 68.13; H, 6.33; N, 2.83.
Found: C, 68.12; H, 6.32; N, 2.99.
(2R,2aS,4aR,6S,7bR)- and (2S,2aR4aS,6S,7bS)-6-[(1R)-(2-Diphen-
ylcyclopentyl)oxy]-3-oxooctahydro-1,4,7-trioxa-7a-azabicyclopent-
[cd]indene-2-carboxylic Acid 1-Methylethyl Ester (45). To a solution
of 2,6-diphenylphenol (8.202 g, 33.30 mmol, 6.0 equiv) in CH2Cl2 (61
mL) was added trimethylaluminum (2.0 M in toluene, 8.3 mL, 17 mmol,
3.0 equiv). Gas evolution was observed, and the resulting light yellow
solution was stirred at room temperature for 40 min.
To a solution of 44 (1.272 g, 5.550 mmol) in CH2Cl2 (22 mL) at
-75 °C was added a solution of (R)-2,2-diphenylcyclopentoxyethene
((-)-29)19e (4.402 g, 16.65 mmol, 3.0 equiv) in CH2Cl2 (13 mL). MAPh
was added slowly to the resulting mixture over 36 min, keeping the
internal temperature below -70 °C. During the addition, the solution
changed color from light yellow to deep, dark brown. The brown
solution was stirred for additional 1.5 h and then was quenched with
MeOH (15.6 mL), poured into CH2Cl2 (1 L), and washed with water
(2 × 0.6 L). The aqueous phases were back-extracted with CH2Cl2 (2
× 0.5 L), and the combined organic extracts were dried (Na2SO4),
filtered through Celite, and concentrated in vacuo. The crude product
was purified by silica gel (330 g) column chromatography, eluting with
hexane/EtOAc (1:0 (0.9 L), 30:1 (0.9 L), 8:1 (0.9 L), 4:1 (1.8 L), 2:1
(0.9 L), 1:1 (0.9 L), 0:1(0.9 L)). The first fractions contained 2,6-
diphenylphenol, which was recrystallized from hexane (300 mL) to
afford 7.00 g (85%) of recovered phenol. The chromatographic
fractions containing the desired product were concentrated in two
separate portions. The major portion afforded 2.051 g (74.7%) of a
white foam, the composition of which was determined by 1H NMR to
be a 95:1 exo/endo mixture of diastereomers ((-)-45a/(+)-45b). The
minor portion afforded 0.574 g (20.9%) as a white foam, which
consisted of a 6.3:1 exo/endo mixture. An analytically pure sample of
the endo diastereomer (+)-45b was obtained by radial chromatography
(1 mm silica plate), eluting with hexane/EtOAc (4:1, 2:1, 1:1).
(2R,2aS,4aR,6S,7bR)-6-[(1R)-(2-Diphenylcyclopentyl)oxy]-3-hy-
droxyoctahydro-1,4,7-trioxa-7a-azabicyclopent[cd]indene-2-carbox-
ylic Acid 1-Methylethyl Ester ((-)-(46)). To a solution of (-)-45a
(1.965 g, 3.981 mmol) in THF (71 mL) at -74 °C was added dropwise
lithium tri(sec-butyl)borohydride (0.95 M in THF, 4.20 mL, 3.98 mmol,
1.0 equiv) over 5 min. The resulting solution was stirred for 1 h and
then quenched with a solution of aqueous phosphate buffer (pH 6.9)/
glycerol (1:1, 70 mL). The mixture was immediately poured into
CH2Cl2 (0.5 L) and then washed with water (150 mL) and brine (2 ×
150 mL) and back-extracted with CH2Cl2 (2 × 150 mL). The combined
organic extracts were dried (Na2SO4), filtered, and concentrated in
vacuo. The crude product was purified by silica gel column chroma-
tography, eluting with hexane/EtOAc (8:1, 4:1, 2:1, 1:1, 0:1) to afford
1.810 g (91.8%) of (-)-46 as a white foam: mp 82-88 °C; 1H NMR
(400 MHz, CDCl3) δ 7.25-7.09 (m, 10H), 5.49 (s, 0.88H, HC(3R)),
5.41 (dd, J ) 6.8, 12.7 Hz, 0.12H, HC(3â)), 5.21 (d, J ) 3.4 Hz, 0.12H,
HC(2â)), 5.11 (septet, J ) 6.3 Hz, 1H, HC(9)), 4.96 (d, J ) 6.6 Hz,
0.88H, HC(2R)), 4.74-4.73 (m, 1.12H, HC(1′ and 6â)), 4.63 (t, J )
7.1 Hz, 0.88H, HC(6R)), 4.52-4.49 (m, 0.88H, HC(4aR)), 4.46 (d, J
) 13.0 Hz, 0.12H, OH(â)), 4.33 (dd, J ) 6.0, 8.9 Hz, 1.12H, HC(7b
and 4aâ)), 3.56 (ddd, J ) 3.4, 6.9, 8.5 Hz, 0.12H, HC(2aâ)), 3.28 (ddd,
J ) 1.5, 5.3, 9.0 Hz, 0.88H, HC(2aR)), 3.04 (d, J ) 2.6 Hz, 0.88H,
OH(R)), 2.64-2.56 (m, 1H, HC(3′)), 2.30-2.20 (m, 2H, HC(3′ and
5′)), 2.16-2.10 (m, 1H, HC(5′)), 1.85-1.80 (m, 2H, HC(4′ and 5)),
1.69 (ddd, J ) 3.4, 7.4, 15.3 Hz, 1H, HC(5)), 1.46-1.36 (m, 1H,
HC(4′)), 1.28 (d, J ) 6.2 Hz, 5.3H, HC(10R)), 1.27 (d, J ) 6.3 Hz,
0.7H, HC(10â)); 13C NMR (100 MHz, CDCl3) 164.46 (C(8â)), 168.19
(C(8R)), δ 146.43 (C(R)), 146.22 (C(â)), 145.39 (C(R)), 145.22 (C(â)),
128.42 (CH(R)), 128.28 (CH(â)), 128.15 (CH(â)), 128.07 (CH(R)),
127.63 (CH(â)), 127.52 (CH(R)), 126.91 (CH(R)), 126.80 (CH(â)),
125.89 (CH(â)), 125.80 (CH(R)), 125.57 (CH(â)), 125.48 (CH(R)),
102.00 (C(3R)), 100.53 (C(6â)), 99.38 (C(6R)), 98.34 (C(3â)), 86.20
(C(1′â)), 85.51 (C(1′R)), 84.24 (C(2R)), 83.85 (C(2â)), 78.22 (C(7bâ)),
77.53 (C(7bR)), 73.16 (C(4aR)), 73.03 (C(4aâ)), 69.97 (C(9â)), 69.80
(C(9R)), 60.05 (C(2′)), 58.57 (C(2aR)), 53.63 (C(2aâ)), 35.10 (C(3′R)),
35.05 (C(3′â)), 31.74 (C(5′R)), 31.67 (C(5′â)), 29.48 (C(5â)), 28.05
(C(5R)), 21.60 (C(10)), 20.41 (C(4′)); IR (KBr) ν 3441 (w, br), 3022
(w), 2978 (m), 2946 (m), 2874 (m), 1736 (s), 1494 (m), 1446 (m),
1384 (m), 1376 (m), 1322 (m), 1286 (m), 1267 (m), 1241 (m), 1218
(m), 1198 (m), 1147 (m), 1106 (s), 1073 (s), 1064 (s), 1036 (s), 1019
(m), 974 (m), 949 (m), 926 (m); MS (FAB) m/z (relative intensity)
496 (M+ + H, 10), 309 (13), 276 (11), 222 (19), 221 (100), 186 (11),
155 (57), 154 (14), 153 (18), 152 (27), 144 (14), 143 (15), 137 (10),
134 (43), 120 (15), 118 (88), 117 (45), 102 (42); [R]21D -42.1° (CHCl3,
For (-)-45a: mp 81-85 °C; 1H NMR (400 MHz, CDCl3) δ 7.25-
7.09 (m, 10H), 5.25 (d, J ) 3.6 Hz, 1H, HC(2)), 5.09 (septet, J ) 6.3
Hz, 1H, HC(9)), 4.79 (ddd, J ) 2.2, 3.6, 6.4 Hz, 1H, HC(4a)), 4.72 (d,
J ) 4.1 Hz, 1H, HC(1′)), 4.63 (t, J ) 7.2 Hz, 1H, HC(6)), 4.39 (dd, J
) 6.6, 8.6 Hz, 1H, HC(7b)), 3.90 (dd, J ) 3.4, 8.3 Hz, 1H, HC(2a)),
2.64-2.56 (m, 1H, HC(3′)), 2.30-2.26 (m, 2H, HC(5′ and 3′)), 2.14-
2.06 (m, 1H, HC(5′)), 1.89-1.85 (m, 2H, HC(5 and 4′)), 1.54 (ddd, J
) 2.0, 7.2, 13.5 Hz, 1H, HC(5)), 1.45-1.38 (m, 1H, HC(4′)), 1.30 (d,
J ) 6.1 Hz, 3H, HC(10)), 1.29 (d, J ) 6.4 Hz, 3H, HC(10)); 13C NMR
(100 MHz, CDCl3) δ 173.81 (C(3)), 166.97 (C(8)), 146.13 (C), 145.25
(C), 128.31 (CH), 128.16 (CH), 127.65 (CH), 126.82 (CH), 125.92
(CH), 125.59 (CH), 99.55 (C(6)), 86.05 (C(1′)), 84.84 (C(2)), 74.04
(C(7b)), 73.98 (C(4a)), 70.60 (C(9)), 60.09 (C(2′)), 49.13 (C(2a)), 35.01
(C(3′)), 31.72 (C(5′)), 28.30 (C(5)), 21.59 (C(10)), 21.55 (C(10)), 20.44
(C(4′)); IR (KBr) ν 3056 (w), 3023 (w), 2979 (m), 2876 (w), 1783 (s),
1740 (s), 1494 (m), 1447 (m), 1385 (m), 1375 (m), 1356 (m), 1287
(s), 1237 (s), 1205 (m), 1176 (s), 1147 (m), 1106 (s), 1067 (s), 1049
(s), 1032 (m), 1012 (m), 932 (m), 914 (s); MS (FAB) m/z (relative
intensity) 532 (M+ + K, 2), 494 (M+ + H, 4), 309 (15), 274 (17), 223
(100), 221 (100), 155 (60), 154 (17), 153 (21), 152 (10), 149 (10), 143
(12), 137 (11), 135 (48), 120 (16), 118 (99), 117 (37), 102 (49); [R]21
D
-80.1° (CHCl3, c ) 1.00); TLC Rf ) 0.45 (hexane/EtOAc 1:1). Anal.

8276 J. Am. Chem. Soc., Vol. 118, No. 35, 1996
Denmark et al.
c ) 0.90); TLC Rf ) 0.40 (hexane/EtOAc 1:1). Anal. Calcd for C28H33-
NO7 (495.57): C, 67.86; H, 6.71; N, 2.82. Found: C, 67.80; H, 6.86;
N, 3.18.
CDCl3) δ 177.41 (C(2)), 105.57 (C(7)), 81.31 (C(5a)), 71.41 (C(1)),
66.56 (C(7b)), 54.84 (C(8)), 51.26 (C(7a)), 42.53 (C(4)), 29.50 (C(5));
IR (KBr) ν 3355 (s), 2989 (m), 2972 (m), 2953 (m), 1702 (s), 1477
(m), 1432 (m), 1320 (m), 1306 (m), 1279 (m), 1233 (m), 1197 (m),
1162 (m), 1129 (s), 1106 (s), 1079 (m), 1069 (m), 1032 (m), 1006 (s),
964 (m), 926 (m); MS m/z (relative intensity) (70 eV) 199 (M+, 15),
168 (25), 167 (46), 142 (58), 140 (42), 139 (15), 138 (25), 122 (19),
112 (18), 111 (27), 110 (79), 100 (11), 98 (15), 96 (23), 95 (100), 94
(12), 87 (25), 86 (10), 84 (19), 83 (67), 82 (24), 71 (20), 70 (12), 69
(15), 68 (38), 67 (24), 57 (12), 56 (14), 55 (31), 54 (11), 53 (13), 45
(1R,5aS,7S,7aR,7bR)-1,7-Dihydroxy-6-oxaoctahydro-2H-cyclopenta-
[gh]pyrrolizin-2-one ((+)-(26)) and (1R,6S,6aR,7S)-1,6-Dihydroxy-
7-(hydroxymethyl)hexahydro-1H-pyrrolizin-2-one (47). To a solu-
tion of (-)-46 (1.783 g, 3.598 mmol) in methanol (100 mL) was added
a catalytic amount of methanol-washed (6 × 80 mL) W-2 Raney nickel.
The suspension was stirred at room temperature in a 300 mL flask
inside a steel autoclave for 48 h under 160 psi atmosphere of H2. The
catalyst was filtered off through Celite and washed with methanol (200
mL), and the solution was stirred at 65 °C for 1 h and then concentrated
in vacuo. The residue was separated by silica gel column chromatog-
raphy, eluting with CHCl3/MeOH (1:0, 99:1, 19:1, 9:1, 6:1, 4:1, 2:1)
into three fractions. The first fraction contained a mixture of (+)-26
and (R)-2,2-diphenylcyclopentanol. The second portion contained 0.406
g of pure (+)-26, and the third fraction contained 0.040 g of a mixture
of (+)-26 and 47. The first fraction was repurified by silica gel column
chromatography, eluting with CHCl3/MeOH (1:0, 99:1, 19:1, 9:1, 4:1,
2:1) to afford 0.836 g (98% recovery) of (1R)-2,2-diphenylcyclopentanol
and 0.037 g of (+)-26. The pure fractions of R-hydroxy lactam (+)-
26 were combined and recrystallized from pentane/CHCl3/MeOH to
give 0.428 g of (+)-26 (64%) as a white amorphous solid. The third
fraction was repurified by basic alumina (activity II) column chroma-
tography, eluting with CHCl3/MeOH (19:1, 6:1, 4:1, 2:1 followed by
CHCl3/MeOH/NH4OH 10:5:1), to afford 0.029 g of an 8:1 mixture (as
(15), 43 (17), 42 (20), 41 (49); [R]21 +186.4° (CHCl3, c ) 0.69);
D
TLC Rf ) 0.45 (CHCl3/MeOH 9:1). Anal. Calcd for C9H13NO4
(199.20): C, 54.26; H, 6.58; N, 7.03. Found: C, 54.15; H, 6.67; N,
7.01.
(1S,5aS,7S,7aR,7bR)-7-Methoxy-1-[(4-nitrobenzoyl)oxy]-6-oxaoc-
tahydro-2H-cyclopenta[gh]pyrrolizin-2-one ((+)-(50)). To a solution
of (+)-48 (0.158 g, 0.793 mmol) and triphenylphosphine (0.312 g, 1.190
mmol, 1.5 equiv) in THF (7.6 mL) was added rapidly a solution of
4-nitrobenzoic acid (0.199 g, 1.190 mmol, 1.5 equiv) and diethyl
azodicarboxylate (DEAD, 0.187 mL, 1.190 mmol, 1.5 equiv) in THF
(2.1 mL). The resulting yellow solution was stirred in an aluminum
foil-covered flask for 21.5 h and then poured into CH2Cl2 (100 mL).
The organic layer was washed with saturated aqueous NaHCO3 solution
(2 × 30 mL) and brine (30 mL) and then was dried (Na2SO4), filtered,
and concentrated in vacuo. The crude product was then purified by
silica gel column chromatography, eluting with hexane/EtOAc (6:1,
4:1, 2:1, 1:1, 1:2, 1:4, 1:0) to afford 0.398 g of (+)-50, which was
further purified by silica gel column chromatography, eluting CHCl3/
MeOH (1:0, 99:1, 19:1, 9:1). The product was then recrystallized from
acetone/Et2O/pentane to give 0.280 g (94%) of (+)-50 as a yellow solid.
The 4-nitrobenzoate (+)-50 was determined to be of 97.3% ee by chiral
1
determined by H NMR) of 47 and (+)-26.
For (+)-26: mp (sealed tube) 153 °C dec (pentane/CHCl3/MeOH);
1H NMR (400 MHz, CD3OD) δ 5.61 (s, 1H, HC(7)), 4.76 (d, J ) 8.1
Hz, 1H, HC(1)), 4.71 (t, J ) 3.7 Hz, 1H, HC(5a)), 4.19 (dd, J ) 3.1,
5.5 Hz, 1H, HC(7b)), 3.80 (ddd, J ) 6.8, 8.9, 11.6 Hz, 1H, HC(4)),
3.08-3.01 (m, 2H, HC(7a and 4)), 2.21-2.03 (m, 2H, HC(5)); 13C
NMR (100 MHz, CD3OD) δ 178.90 (C(2)), 100.12 (C(7)), 82.80
(C(5a)), 72.66 (C(1)), 67.65 (C(7b)), 54.12 (C(7a)), 43.31 (C(4)), 30.36
(C(5)); IR (KBr) ν 3385 (s), 3279 (m), 3178 (s), 3008 (w), 2994 (m),
2967 (m), 2936 (m), 2900 (m), 1678 (s), 1481 (m), 1443 (s), 1360
(m), 1338 (m), 1323 (m), 1308 (m), 1281 (m), 1231 (m), 1221 (m),
1203 (m), 1127 (s), 1091 (m), 1075 (s), 1031 (m), 983 (m), 968 (m),
949 (m), 924 (m), 917 (m); MS (70 eV) m/z (relative intensity) 185
(M+, 16), 168 (48), 167 (18), 141 (22), 140 (19), 139 (14), 138 (20),
128 (16), 123 (13), 122 (31), 112 (11), 111 (57), 110 (70), 96 (37), 95
(59), 86 (10), 85 (16), 84 (43), 83 (100), 82 (25), 73 (29), 70 (19), 69
(17), 68 (33), 67 (30), 58 (10), 57 (30), 56 (19), 55 (45), 54 (16), 53
1
HPLC analysis: mp 124-126 °C (acetone/Et2O/pentane); H NMR
(400 MHz, CDCl3) δ 8.30 (dd, J ) 1.9, 7.1 Hz, 2H), 8.24 (dd, J )
2.0, 6.9 Hz, 2H), 5.40 (s, 1H, HC(1)), 5.12 (s, 1H, HC(7)), 4.66-4.64
(m, 1H, HC(5a)), 4.50 (dd, J ) 3.4, 5.9 Hz, 1H, HC(7b)), 4.08 (ddd,
J ) 6.1, 8.1, 12.0, Hz, 1H, HC(4)), 3.37 (s, 3H, HC(6′)), 3.22 (ddd, J
) 6.8, 8.9, 12.1 Hz, 1H, HC(4)), 2.89 (d, J ) 6.1 Hz, 1H, HC(7a)),
2.33-2.28 (m, 2H, HC(5)); 13C NMR (100 MHz, CDCl3) δ 171.68
(C(2)), 163.93 (C(1′)), 150.78 (C(5′)), 134.27 (C(2′)), 131.03 (C(3′)),
123.61 (C(4′)), 109.19 (C(7)), 80.79 (C(5a)), 78.40 (C(1)), 69.06
(C(7b)), 54.68 (C(6′)), 51.32 (C(7a)), 43.93 (C(4)), 31.42 (C(5)); IR
(KBr) ν 3069 (w), 2960 (w), 1742 (s), 1727 (m), 1701 (s), 1607 (m),
1530 (s), 1443 (w), 1402 (m), 1385 (w), 1361 (m), 1350 (m), 1296
(m), 1272 (s), 1259 (s), 1242 (m), 1217 (m), 1200 (m), 1097 (s), 1083
(s), 1052 (s), 1013 (s), 997 (m), 960 (w); MS (FAB) m/z (relative
(16), 45 (10), 44 (11), 43 (21), 42 (32); [R]21 +130.9° (MeOH, c )
D
0.61); TLC Rf ) 0.20 (CHCl3/MeOH 9:1). Anal. Calcd for C8H11NO4
(185.17): C, 51.89; H, 5.99; N, 7.56. Found: C, 51.88; H, 5.96; N,
7.39.
intensity) 349 (M+
+ H, 2), 307 (44), 289 (18), 155 (27), 154 (100),
139 (12), 138 (32), 137 (60), 136 (61), 123 (10), 106 (15); [R]21D +37.1°
(CHCl3, c ) 0.49); TLC Rf ) 0.18 (hexane/EtOAc 1:1); HPLC (Daicel,
Chiralcel OJ cellulose tris(4-methylbenzoate) (25 cm × 4.6 mm),
hexane/EtOH 70:30, 0.9 mL/min) tR (1S,5aR,7S,7aR,7bR)-(+)-50, 20.0
min (98.6%), tR (1R,5aS,7R,7aS,7bS)-(-)-50, 26.2 min (1.3%). Anal.
Calcd for C16H16N2O7 (348.31): C, 55.17; H, 4.62; N, 8.04, Found:
C, 55.06; H, 4.50; N, 7.91.
For 47: 1H NMR (400 MHz, CD3OD) δ 4.42 (d, J ) 7.6 Hz, 1H,
HC(1)), 4.27 (t, J ) 2.8 Hz, 1H, HC(6)), 3.91 (dd, J ) 5.9, 11.2 Hz,
1H, HC(8)), 3.80-3.72 (m, 2H, HC(8 and 6a)), 3.61-3.54 (m, 1H,
HC(4)), 3.17 (dd, J ) 10.0, 11.0 Hz, 1H, HC(4)), 2.91-2.83 (m, 1H,
HC(7)), 2.25-2.14 (m, 1H, HC(5)), 2.09-2.03 (m, 1H, HC(5)); 13C
NMR (100 MHz, CD3OD) δ 177.46 (C(2)), 73.76 (CH), 69.33 (CH),
66.69 (C(6a)), 58.09 (C(8)), 44.22 (C(7)), 40.68 (C(4)), 36.54 (C(5)).
(1R,5aS,7S,7aR,7bR) 1-Hydroxy-7-methoxy-6-oxaoctahydro-2H-
cyclopenta[gh]pyrrolizin-2-one ((+)-(48)). To a solution of (+)-26
(0.213 g, 1.150 mmol) and p-toluenesulfonic acid (0.060 g, 0.345 mmol,
0.33 equiv) in MeOH (90 mL) was added trimethyl orthoformate (13
mL). The resulting solution was heated at reflux for 5 h and then cooled
to room temperature and quenched with poly(vinylpyridine) (0.085 g).
The suspension was filtered, and the filtrate was concentrated in vacuo.
The resulting crude product was purified by basic alumina (activity II)
column chromatography eluting with hexane/EtOAc (1:1, 0:1) followed
by CHCl3/MeOH (19:1, 9:1, 6:1, 2:1), to afford 0.185 g of (+)-48.
The methyl acetal was recrystallized from acetone/Et2O/pentane to
provide 0.169 g (73%) of (+)-48 as a white amorphous solid: mp 159-
(1S,5aS,7aR,7bR)-7-Hydroxy-1-[(4-nitrobenzoyl)oxy]-6-oxaoc-
tahydro-2H-cyclopenta[gh]pyrrolizin-2-one ((+)-(52)). A solution
of (+)-50 (0.330 g, 0.947 mmol) in 90% aqueous trifluoroacetic acid
(TFA) (16.8 mL) was stirred at room temperature for 20 h. The solution
was then concentrated under high vacuum to ca. 3 mL and then was
repeatedly diluted with benzene (25 mL) and concentrated in vacuo.
The crude product was then purified by silica gel column chromatog-
raphy, eluting with hexane/EtOAc (4:1, 2:1, 1:1, 1:2, then acetone), to
afford 0.308 g of (+)-52. The lactol was recrystallized from acetone/
Et2O/pentane to give 0.275 g (87%) of (+)-52 as a white amorphous
1
solid: mp (sealed tube) 145 °C dec (acetone/Et2O/pentane); H NMR
(400 MHz, THF-d8, major only) δ 8.34-8.30 (m, 2H), 8.26-8.23 (m,
2H), 5.69 (d, J ) 3.2 Hz, 1H), 5.51 (d, J ) 4.0 Hz, 1H), 5.34 (s, 1H,
OH), 4.70 (t, J ) 4.2 Hz, 1H, HC(5a)), 4.48 (dd, J ) 3.4, 5.9 Hz, 1H,
HC(7b)), 3.90 (ddd, J ) 5.4, 9.3, 12.0 Hz, 1H, HC(4)), 3.09 (ddd, J )
5.4, 10.0, 11.7 Hz, 1H, HC(4)), 2.82 (d, J ) 5.8 Hz, 1H, HC(7a)),
2.24 (ddd, J ) 5.1, 10.0, 19.2 Hz, 1H, HC(5)), 2.14-2.07 (m, 1H,
HC(5)); 13C NMR (100 MHz, THF-d8, major only) δ 172.35 (C(2)),
164.57 (C(1′)), 151.87 (C(5′)), 135.85 (C(2′)), 131.72 (C(3′)), 124.36
1
160 °C (acetone/Et2O/pentane); H NMR (400 MHz, CDCl3) δ 5.26
(s, 1H, HC(7)), 4.71 (dd, J ) 1.9, 8.3 Hz, 1H, HC(1)), 4.61 (t, J ) 3.6
Hz, 1H, HC(5a)), 4.12 (dd, J ) 3.1, 5.5 Hz, 1H, HC(7b)), 4.08 (d, J
) 3.0 Hz, 1H, OH), 3.92 (ddd, J ) 7.0, 8.8, 11.7 Hz, 1H, HC(4)),
3.31 (s, 3H, HC(8)), 3.13 (dd, J ) 5.8, 8.2 Hz, 1H, HC(7a)), 3.08-
3.02 (m, 1H, HC(4)), 2.22-2.07 (m, 2H, HC(2)); 13C NMR (100 MHz,

Synthesis of (-)-Rosmarinecine
J. Am. Chem. Soc., Vol. 118, No. 35, 1996 8277
(C(4′)), 104.00 (C(7)), 81.62 (C(5a)), 79.49 (C(1)), 69.98 (C(7b)), 53.08
(C(7a)), 44.37 (C(4)), 30.08 (C(5)); IR (KBr) ν 3354 (m, br) 2940 (m),
1745 (s), 1702 (s), 1611 (m), 1535 (m), 1438 (m), 1412 (m), 1362
(m), 1347 (s), 1319 (m), 1301 (m), 1268 (s), 1204 (m), 1118 (s), 1100
(m), 1086 (m), 1053 (m), 1041 (m), 1015 (m), 1008 (m), 997 (m); MS
(FAB) m/z (relative intensity) 335 (M+ + H, 4), 309 (11), 155 (63),
154 (20), 153 (27), 152 (41), 149 (13), 137 (14), 135 (59), 121 (17),
temperature, diluted with EtOH (50 mL), and concentrated in vacuo.
The solid residue was triturated with boiling EtOH (2 × 25 mL), and
the extracts were filtered and concentrated in vacuo. The crude product
was purified by silica gel chromatography, eluting with CHCl3/MeOH/
NH4OH (10:5:1), to give 81 mg of a yellow oil. The silica gel column
was prepared with a large Celite plug (half the height of the silica gel)
at the bottom of the column. The oil required further purification by
chromatography on basic alumina (activity II) (CHCl3/MeOH 6:1, 4:1,
2:1, followed by CHCl3/MeOH/NH4OH 10:5:1), to give 61 mg of white
solid, which was recrystallized from acetone/pentane to give 50 mg
(58%) of (-)-rosmarinecine as a highly crystalline, slightly yellow-
white solid: mp (sealed tube) 168-170 °C (acetone/pentane); 1H NMR
(400 MHz, CD3OD) δ 4.37 (ddd, J ) 7.8, 7.8, 9.6 Hz, 1H, HC(6)),
4.23-4.21 (m, 1H, HC(1)), 4.02 (dd, J ) 6.8, 11.0 Hz, 1H, HC(8)),
3.90 (dd, J ) 3.7, 11.0 Hz, 1H, HC(8)), 3.35 (dd, J ) 2.8, 8.2 Hz, 1H,
HC(7a)), 3.18 (ddd, J ) 1.5, 8.1, 9.7 Hz, 1H, HC(3)), 2.99 (dd, J )
8.0, 11.0 Hz, 1H, HC(5)), 2.89 (dd, J ) 7.3, 11.2 Hz, 1H, HC(5)),
2.76 (ddd, J ) 7.0, 10.0, 11.5 Hz, 1H, HC(3)), 2.31-2.24 (m, 1H,
HC(7)), 1.88-1.75 (m, 2H, HC(2)); 13C NMR (100 MHz, CD3OD) δ
72.56 (C(7a)), 72.41 (C(1)), 70.96 (C(6)), 64.64 (C(5)), 59.63 (C(8)),
55.21 (C(3)), 51.71 (C(7)), 36.24 (C(2)); IR (KBr) ν 3337 (s, br), 2971
(s), 2965 (s), 2935 (s), 2910 (s), 2895 (s), 2878 (m), 2859 (m), 2758
(m), 2654 (m), 2643 (m), 1479 (w), 1469 (m), 1458 (m), 1444 (m),
1437 (m), 1379 (w), 1359 (m), 1321 (w), 1241 (w), 1206 (w), 1165
(m), 1139 (w), 1096 (s), 1063 (s), 1051 (s), 1034 (s), 1002 (s), 973
(w); MS (70 eV) 173 m/z (relative intensity) (M+, 11), 129 (35), 99
118 (100); [R]21 +16.2° (THF, c ) 0.48); TLC Rf ) 0.14 (hexane/
D
EtOAc 1:2). Anal. Calcd for C15H14N2O7 (334.28): C, 53.89; H, 4.22;
N, 8.38. Found: C, 53.80; H, 4.20; N, 8.38.
Synthetic (-)-Rosmarinecine (2). To a solution of (+)-52 (0.203
g, 0.607 mmol) in THF (40 mL) was added Red-Al (1.24 M in THF,
5.8 mL, 7.2 mmol, 12 equiv). The clear solution was stirred at room
temperature for 0.5 h, during which time the solution changed color
from to yellow to red. The resulting solution was then heated at reflux
for 3 h, during which time the color changed from purple to black-
yellow. The mixture was cooled to room temperature and quenched
with water (0.68 mL), 2 N NaOH (0.60 mL), and water (1.36 mL),
and then it was diluted with THF (30 mL) and stirred for 5 min. The
resulting solution was concentrated to ca. 5 mL, and the crude product
was purified by silica gel chromatography, eluting with (CHCl3/MeOH/
NH4OH 10:5:1). The silica gel column was prepared with a large Celite
plug (half the height of the silica gel) at the bottom of the column, to
give 93 mg of a white-yellow solid. The solid required further
purification by chromatography on basic alumina (activity II) eluting
with CHCl3/MeOH (6:1, 4:1, 2:1, followed by CHCl3/MeOH/NH4OH
10:5:1), to give 81 mg of a white solid, which was recrystallized from
acetone/pentane to provide 69 mg (66%) of (-)-rosmarinecine as a
highly crystalline, white solid: mp (sealed tube) 169-170 °C (acetone/
pentane); 1H NMR (400 MHz, CD3OD) δ 4.37 (ddd, J ) 7.7, 7.7, 9.7
Hz, 1H, HC(6)), 4.23-4.22 (m, 1H, HC(1)), 4.02 (dd, J ) 6.8, 11.0
Hz, 1H, HC(8)), 3.90 (dd, J ) 3.7, 11.0 Hz, 1H, HC(8)), 3.37 (dd, J
) 3.0, 8.1 Hz, 1H, HC(7a)), 3.19 (ddd, J ) 1.7, 8.1, 9.8 Hz, 1H, HC(3)),
2.99 (dd, J ) 8.1, 11.0 Hz, 1H, HC(5)), 2.90 (dd, J ) 7.3, 11.2 Hz,
1H, HC(5)), 2.77 (ddd, J ) 6.8, 10.0, 11.4 Hz, 1H, HC(3)), 2.31-2.24
(m, 1H, HC(7)), 1.89-1.76 (m, 2H, HC(2)); 13C NMR (100 MHz,
CD3OD) δ 72.59 (C(7a)), 72.38 (C(1)), 70.96 (C(6)), 64.61 (C(5)), 59.63
(C(8)), 55.21 (C(3)), 51.70 (C(7)), 36.24 (C(2)); IR (KBr) ν 3296 (s,
br), 2971 (s), 2934 (s), 2895 (s), 2877 (s), 2859 (s), 1479 (m), 1470
(m), 1458 (m), 1434 (m), 1358 (w), 1323 (m), 1310 (w), 1241 (w),
1166 (m), 1139 (m), 1099 (s), 1087 (s), 1063 (s), 1051 (m), 1034 (m),
1013 (m), 1002 (s), 986 (w); MS (70 eV) m/z (relative intensity) 173
(M+, 10), 129 (34), 99 (13), 98 (100), 82 (16), 68 (11); [R]21D -117.6°
(EtOH, c ) 0.96); TLC Rf ) 0.23 (CHCl3/MeOH/NH4OH 10:5:1); Anal.
Calcd for C8H15NO3 (173.21): C, 55.47; H, 8.72; N, 8.09. Found: C,
55.36; H, 8.82; N, 8.07.
(13), 98 (100), 82 (17), 68 (10); [R]21 -119.8° (EtOH, c ) 1.01);
D
TLC Rf ) 0.22 (CHCl3/MeOH/NH4OH 10:5:1). Anal. Calcd for
C8H15NO3 (173.21): C, 55.47; H, 8.72; N, 8.09. Found: C, 55.44; H,
8.91; N, 8.01.
Acknowledgment. This work is dedicated to pyrrolizidine
pioneer and gracious colleague Nelson J. Leonard on the
occasion of his 80th birthday. We are grateful to the National
Institutes of Health (GM-30938) for financial support. We also
thank Dr. Feng Lin of the University of Illinois NMR Facility
for technical assistance. Professors David J. Robins (University
of Glasgow) and Siegfried E. Drewes (University of Natal) are
greatly acknowledged for the gift of natural rosmarinine. A.T.
thanks the University of Illinois for a Graduate Fellowship.
Supporting Information Available: Experimental and
spectroscopic data for 19, 21, 22, 25, 26, 30, 31, 32, 37, 38,
1
39, 50, and 51, along with H NMR, 13C NMR, IR, and MS
spectra of natural and synthetic (-)-rosmarinecine (30 pages).
See any current masthead page for ordering and Internet access
instructions.
Natural (-)-Rosmarinecine (2). A solution of rosmarinine (1)
(0.177 g, 0.50 mmol) in 1 N aqueous NaOH (3.8 mL) was heated at
reflux for 3 h. The resulting yellow solution was cooled to room
JA961630X