Tandem Inter [4 + 2]/Intra [3 + 2] Cycloadditions. 17. The Spiro Mode. Efficient and Highly Selective Synthesis of Azapropellanes

Article abstract of DOI:10.1021/jo9719057

A new variant of the tandem inter [4 + 2]/intra [3 + 2] nitroalkene cycloaddition has been developed. Intermolecular [4 + 2] cycloaddition of a 2-nitroalkene (bearing an unsaturated ester moiety, the dipolarophile) with a vinyl ether produces a cyclic nit

Full text of DOI:10.1021/jo9719057

1604
J . Org. Chem. 1998, 63, 1604-1618
Ta n d em In ter [4 + 2]/In tr a [3 + 2] Cycloa d d ition s. 17. Th e Sp ir o
Mod e. Efficien t a n d High ly Selective Syn th esis of Aza p r op ella n es
Scott E. Denmark* and Donald S. Middleton†
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801
Received October 15, 1997
A new variant of the tandem inter [4 + 2]/intra [3 + 2] nitroalkene cycloaddition has been developed.
Intermolecular [4 + 2] cycloaddition of a 2-nitroalkene (bearing an unsaturated ester moiety, the
dipolarophile) with a vinyl ether produces a cyclic nitronate substituted at C(3) wherein the only
stereogenic center is the anomeric carbon C(6). Since the dipolarophile is attached to a tether
extending from the C(3) of the nitronate (R-carbon of the nitroalkene), the intramolecular [3 + 2]
cycloaddition affords a spiro tricyclic nitroso acetal. The cycloaddition proceeds smoothly for three-
and four-atom tethers to afford five- and six-membered rings. Both E- and Z-unsaturated esters
serve well as dipolarophiles, but the E-isomers react more selectively. Hydrogenolysis of the nitroso
acetals affords the spiro tricyclic R-hydroxy lactams in good yield. Remarkably high levels of
asymmetric induction are observed with the use of a chiral vinyl ether derived from (1R,2S)-2-
phenylcyclohexanol. The origin of asymmetric induction is a combination of the established face
selectivity of the enol ether and the preference for a distal fold of the tether away from the
substituent on the anomeric carbon. The scope and limitations of this transformation and an
analysis of the origin of stereoselectivity are provided.
In tr od u ction
In recent years, the development and application of
tandem reactions has emerged as a powerful strategy for
increasing efficiency in organic synthesis.1 In our labo-
ratories, the tandem [4 + 2]/[3 + 2] cycloadditions of
nitroalkenes have proven extremely versatile for the
stereoselective construction of a diverse array of highly
functionalized polycyclic compounds.2 The structural
virtuosity of the tandem [4 + 2]/[3 + 2] cycloaddition
sequence derives from the number of permutations
possible for attachment of the various components (ni-
troalkene, dienophile, and dipolarophile).
F igu r e 1. Family of tandem [4 + 2]/[3 + 2] cycloadditions.
As for any tandem cycloaddition protocol, there are in
principle four different permutations that arise from the
pairwise combinations of inter- and intramolecularity for
each event, Figure 1. While all permutations have been
documented in our laboratories, our efforts have prima-
rily focused on the tandem inter [4 + 2]/intra [3 + 2]
variant. The overwhelming superiority of this process
is in large measure due to the existence of four distinct
subclasses of cycloadditions that encompass remarkable
structural diversity. These subclasses arise from the
various points of attachment of the dipolarophilic tether
to the intermediate nitronate as illustrated in Figure 2.
These can be seen to arise from two distinct types of
precursors: nitroso acetals A and B, which arise from
dipolarophile-tethered nitroalkenes, and nitroso acetals
C and D, which arise from dipolarophile tethered dieno-
philes.
Extensive investigations from these laboratories have
illustrated the scope and utility of the fused mode
cycloaddition for asymmetric synthesis of various nitrogen-
containing polycyclic compounds.2b-e Furthermore, re-
cent disclosures have demonstrated the potential for the
two variants of bridged mode process for the synthesis
of five- and six-membered carbocycles.2f,g In this report,
we disclose, in full, our studies on the scope and limita-
tions of the spiro mode cycloaddition between 2-nitroal-
kenes bearing dipolarophilic tethers at C(2) and (chiral)
vinyl ethers, Scheme 1.3
† Current address: Pfizer Limited, Sandwich, Kent CT 13 9NJ ,
England.
(1) (a) Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
(b) Ziegler, F. E. In Comprehensive Organic Synthesis, Combining C-C
π-Bonds; Paquette, L. A., Ed.; Pergamon Press: Oxford, 1991; Vol. 5;
Chapter 7.3. (c) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl.
1993, 32, 131. (d) Grigg, R., Ed. Cascade Reactions. Tetrahedron
Symposium in Print No. 62 1996, 52 (35).
(2) (a) Denmark, S. E.; Thorarensen, A. Chem. Rev. (Washington,
D.C.) 1996, 96, 137. (b) Denmark, S. E.; Thorarensen, A.; Middleton,
D. S. J . Am. Chem. Soc. 1996, 118, 8266. (c) Denmark, S. E.;
Thorarensen. A. J . Am. Chem. Soc. 1997, 119, 127. (d) Denmark, S.
E.; Hurd, A. R.; Sacha, H. J . J . Org. Chem. 1997, 62, 1668. (e)
Denmark, S. E.; Marcin, L. R. J . Org. Chem. 1997, 62, 1675. (f)
Denmark, S. E.; Guagnano, V.; Dixon, J . A.; Stolle, A. J . Org. Chem.
1997, 62, 4610. (g) Denmark, S. E.; Dixon, J . A. J . Org. Chem. 1997,
62, 7086.
(3) For preliminary reports see: (a) Denmark, S. E.; Senanayake,
C. B. W.; Schnute, M. E.; Moon, Y. C.; Ho, G. D.; Middleton, D. S.
Proceedings of the Fifth International Kyoto Conference on New Aspects
of Organic Chemistry; VCH Verlagsgesellschaft and Kodansha Ltd.:
Weinhein, 1992. (b) Denmark, S. E.; Schnute, M. E.; Thorarensen, A.;
Middleton, D. S.; Stolle, A. Pure Appl. Chem. 1994, 66, 2041.
S0022-3263(97)01905-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/14/1998

Tandem Inter [4 + 2]/Intra [3 + 2] Cycloadditions
J . Org. Chem., Vol. 63, No. 5, 1998 1605
Ch a r t 1
Sch em e 2
F igu r e 2. Subclasses of the inter [4 + 2]/intra [3 + 2]
cycloadditions.
Sch em e 1
cyclic and R-substituted nitroalkenes derived from simple
olefins.6 Reaction of the olefin with mercuric chloride or
mercuric perchlorate (1 equiv) and sodium nitrite (2
equiv) in water for 30 h affords nitromercurials that upon
treatment with aqueous hydroxide (2.5 N) or a tertiary
amine give the nitroalkenes.
The application of this nitromercuration-elimination
procedure to the preparation of the R-substituted ni-
troalkenes 1 and 2 required the synthesis of octa- and
nonadienoates with both E and Z geometries, Chart 1.
The preparation of both (E)- and (Z)-1,7-octadienoates
5 was achieved from 1-hydroxypyran. Treatment of the
latent aldehydes with (carbomethoxymethylene)triphen-
ylphosphorane afforded 7-hydroxyheptenoate (3) in 91%
yield as a 7/1 mixture of E and Z isomers. This mixture
of alcohols was then oxidized with PCC to the corre-
sponding aldehydes (E)-4 and (Z)-4, which were found
to be chromatographically separable. Conversion to the
dienoates (E)-5 and (Z)-5 was then accomplished in each
case by treatment with the ylide generated in situ from
methyl triphenylphosphonium bromide and n-butyllith-
ium, Scheme 2. The higher homologs (E)-9 and (Z)-9
were prepared as shown in Scheme 3. Ozonolysis of
cyclohexene provided monoprotected 1,6-dialdehyde 6 in
good yield, which was then converted to the terminal
olefin 7 via simple Wittig methylenation.7 The acetal
protecting group was then removed by treatment with
0.1 N HCl in THF to afford 6-heptenal (8) in 76% overall
yield from cyclohexene. Conversion to nonadienoates
(E)-9 and (Z)-9 was then achieved by Horner-Emmons
olefination with trimethyl phosphonoacetate.
This work addresses several topics related to the spiro-
mode tandem [4 + 2]/[3 + 2] cycloaddition process,
including the following: (1) the preparation of R-branched
nitroalkenes bearing an intramolecularly tethered dipo-
larophile, (2) the feasibility of employing such R-branched
nitroalkenes in tandem cycloaddition reactions, (3) the
effect of tether length and dipolarophile geometry on the
diastereoselectivity of the process, (4) the feasibility of
preparing spiro-fused R-hydroxy lactams from the nitroso
acetal products of the cycloaddition sequence, and (5) the
application of auxiliary-based asymmetric synthesis to
the preparation of enantiomerically enriched R-hydroxy
lactams.
Resu lts
Syn th esis of r-Br a n ch ed Nitr oa lk en es. The pro-
nounced reactivity of R-substituted nitroalkenes as Michael
acceptors dictated that formation of the nitro olefin
function constitute the final step in the preparation of
the nitro dienoate substrates (E)- and (Z)-1 and (E)- and
(Z)-2 required for this study, Chart 1. The added
complication of the intramolecularly tethered enoate
group precluded the use of nucleophile-based introduction
of the nitro olefin via Seebach’s NPP method.4 Instead,
we considered a two-step procedure involving nitromer-
curation5 and tertiary-amine-mediated elimination that
has been successfully applied to the synthesis of both
Reaction of methyl (E)-2,7-octadienoate ((E)-5) with
sodium nitrite (2 equiv) and mercuric perchlorate trihy-
drate (1 equiv) in water for 24 h afforded, after aqueous
workup, nitromercurial 10 as a viscous yellow oil. This
(4) Seebach, D.; Knochel, P. Helv. Chim. Acta 1984, 67, 261.
(5) Bachman, G. B.; Whitehouse, M. L. J . Org. Chem. 1967, 32, 2303.
(6) Corey, E. J .; Estreicher, H. J . Am. Chem. Soc. 1978, 100, 6294.
(7) Claus, R. E.; Schreiber, S. L. Org. Synth. 1985, 64, 150.

1606 J . Org. Chem., Vol. 63, No. 5, 1998
Denmark and Middleton
Sch em e 5
Sch em e 3
F igu r e 3. Bulky monomeric aluminum Lewis acids.
enoate (E)-5 with phenylselenenyl bromide, silver nitrite,
and mercuric chloride in CH3CN/THF (1/1) at -78 °C for
85 min, afforded nitroselenide 12 in 32% yield (55% based
on recovered starting material), Scheme 5. The hydroxy
selenide, formed by nucleophilic attack of the ambident
nitrite anion, through oxygen, on the intermediate sele-
nonium ion, was also observed. Attempts to improve the
yield of 12 by modifying the reaction time and temper-
ature were unsuccessful. The attempted selenoxide
elimination of 12 using hydrogen peroxide was unsuc-
cessful. Other viable approaches exist to improve the
yield in the nitroalkene preparations; however, such
studies did not constitute the focal point of this work.
The nitromercuration-elimination strategy, although
proceeding in disappointing yield, was sufficiently concise
to allow adequate quantities of nitroalkenes to be syn-
thesized for the subsequent tandem cycloaddition studies,
and therefore, studies to optimize or improve the yields
were not pursued.
Sch em e 4
Ta n d em Cycloa d d ition Rea ction s w ith n -Bu tyl
Vin yl Eth er . For orienting experiments to establish the
ability of R-substituted nitroalkenes to engage in [4 + 2]
cycloaddition with n-butyl vinyl ether we first examined
the use of Ti(O-i-Pr)2Cl2. This Lewis acid has served
admirably in our previous studies of nitroalkene cycload-
ditions.9 Surprisingly, this Lewis acid failed to induce
cycloaddition of (E)-1 with n-butyl vinyl ether under
various combinations of time, temperature, stoichiome-
try, and addition order. In all instances (E)-1 was
recovered, albeit in modest yield (70%).
Our ongoing parallel investigations of fused and bridged
mode cycloadditions have established that the bulky,
aluminum-based Lewis acids methylaluminum bis(2,6-
di-tert-butyl-4-methylphenoxide) (MAD) and methylalu-
minum bis(2,6-diphenylphenoxide) (MAPh), Figure 3, are
excellent alternatives to TiCl2(Oi-Pr)2 for this process.10
Addition of in situ generated MAD to nitroalkene (E)-1
at -78 °C in CH2Cl2 followed by the addition of butyl
was immediately treated with triethylamine in CH2Cl2
to afford nitroalkene (E)-1 in 36% overall yield. By using
a similar two-step sequence, (Z)-5 was converted to
nitroalkene (Z)-1, via nitromercurial (Z)-10, Scheme 4,
albeit in poor yield.
Attempts to improve the disappointing overall yield for
these two sequences by changing reaction time, concen-
tration, and stoichiometry were all unsuccessful. Ni-
troalkenes (E)-2 and (Z)-2 were prepared by an analogous
procedure in 56% and 52% yield, respectively.
The generally modest overall yields for the nitromer-
curation-elimination protocol prompted a brief investi-
gation into alternative approaches to the synthesis of
these nitroalkenes. Tomoda has reported the synthesis
of 2-nitroalkyl phenylselenides and their subsequent
conversion to nitroalkenes.8 Thus, treatment of octadi-
(9) (a) Denmark, S. E.; Moon, Y. C.; Senanayake, C. B. W. J . Am.
Chem. Soc. 1990, 112, 311 and references therein. (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.
(10) (a) Denmark, S. E.; Schnute, M. E. J . Org. Chem. 1991, 56,
6738. (b) Denmark, S. E.; Schnute, M. E.; Senanayake, C. B. W. J .
Org. Chem. 1993, 58, 1859. (c) Denmark, S. E.; Schnute, M. E.; Marcin,
L. R.; Thorarensen, A. J . Org. Chem. 1995, 60, 3205. (d) Denmark, S.
E.; Thorarensen, A. J . Org. Chem. 1996, 61, 6727.
(8) Hayama, T.; Tomoda, S.; Takeuchi, Y.; Nomura, Y. Chem. Lett.
1982, 1109 and references therein.

Tandem Inter [4 + 2]/Intra [3 + 2] Cycloadditions
J . Org. Chem., Vol. 63, No. 5, 1998 1607
Sch em e 6
Sch em e 9
Sch em e 7
Sch em e 10
Sch em e 8
as an inseparable 10/1 mixture of diastereomers with the
distal isomer 18a predominating, Scheme 8.
Nitroalkenes (E)-2 and (Z)-2 were similarly converted
to nitroso acetals 20 and 22, respectively, with an erosion
of diastereoselectivity relative to their respective lower
homologs, Schemes 9 and 10.
Intermediate nitronate 19, in contrast to the lower
homolog 15, did not undergo the intramolecular [3 + 2]
cycloaddition at room temperature and could be readily
isolated. Interestingly, nitronate 21 required prolonged
heating (230 min) in toluene at 100 °C to achieve
complete conversion to the nitroso acetals 22a and 22b.
Diastereomeric ratios in all cases were established by
integration of the diagnostic anomeric protons.
In view of the difficulties encountered in preparing
nitroalkene substrate (Z)-1 and more importantly the
relatively poor diastereoselectivity (compared to (E)-1)
observed in the cycloaddition leading to 18, further
studies on this substrate in the tandem cycloaddition
were not undertaken.
Hyd r ogen olytic Clea va ge of Nitr oso Aceta ls: P r e-
p a r a tion of r-Hyd r oxy La cta m s. The conversion of
nitroso acetals 16, 20, and 22 to their respective R-hy-
droxy lactams 23, 24, and 25 was accomplished using our
standard hydrogenolysis reaction, Scheme 11.
The diastereomeric mixture of nitroso acetals 16 was
treated with a catalytic amount of Raney nickel in
methanol under 1 atm of hydrogen for 37.5 h to afford
the R-hydroxy lactam 23 as a single isomer. Conducting
the hydrogenolysis reaction at 1 atm, the reaction was
found to be somewhat capricious depending upon sub-
strate. This problem of irreproducibility was solved,
vinyl ether afforded 13 and 14 in 26% and 13% yield,
respectively, but with no cycloaddition products, Scheme
6. These unwanted products arose from Michael addition
of the aluminum phenoxide to the reactive acceptor
double bonds in (E)-1. This problem could be overcome
by simply having the dienophile present as the Lewis acid
was added to the nitroalkene.
Thus, addition of MAD (3 equiv) to a solution of
nitroalkene and n-butyl vinyl ether (6 equiv) at -78 °C
resulted in the complete consumption of starting ni-
troalkene and the formation of the more polar nitronate
product 15. Intramolecular [3 + 2] cycloaddition of the
crude nitronate 15 (isolated after aqueous extraction to
remove aluminum salts) was facilitated by warming in
toluene at 75 °C for 85 min. The nitroso acetal 16 was
isolated as an inseparable 35/1 mixture of diastereomers
with the distal isomer 16a predominating, Scheme 7. The
assignment of relative configuration was made by anal-
ogy to the nonracemic series, vide infra.
Treatment of the nitroalkene (Z)-1 with MAD (3 equiv)
in the presence of n-butyl vinyl ether gave, after workup
and warming in toluene, nitroso acetal 18 in 62% yield

1608 J . Org. Chem., Vol. 63, No. 5, 1998
Denmark and Middleton
Sch em e 12
Sch em e 11
however, by conducting the reaction at 160 psi, to furnish
the R-hydroxy lactams 24 and 25, both as single isomers,
in 75% and 76% yield, respectively.
Ra d ica l Deoxygen a tion of r-Hyd r oxy La cta m s.
We assumed that the isomeric R-hydroxy lactams 24 and
25 differed only at the hydroxyl bearing center. This
would be a simple consequence of the different dipolaro-
phile geometries in (E)-2 and (Z)-2 if both substrates
underwent [3 + 2] cycloaddition via the same (exo-fold)
transition structure. To establish this (and thereby
establish the identity of reaction pathways), the hydroxyl
groups were removed from 24 and 25.
Sch em e 13
Thus, alcohols 24 and 25 were converted to their
corresponding xanthates 26 and 27 by reaction with 1,1′-
(thiocarbonyl)diimidazole in boiling CH2Cl2, Scheme 12.
Slow addition of a benzene solution of Bu3SnH and AIBN
over 4 h to a refluxing solution of 26 in benzene yielded
tricyclic lactam 28 in 85% yield. Similarly, deoxygen-
ation of light sensitive 27 using Bu3SnH and AIBN in
refluxing benzene yielded a tricyclic lactam 28 identical
with that prepared from 26.
The observation that both 26 and 27 ultimately yield
the identical tricyclic lactam after radical deoxygenation
establishes that a single (exo) (vide infra) folding orienta-
tion of the dipolarophile tether occurs in the [3 + 2]
cycloaddition independent of double bond geometry.
Asym m et r ic Syn t h esis of r-H yd r oxy La ct a m s.
Ta n d em Cycloa d d ition s Usin g a Non r a cem ic Vin yl
Eth er . The unexpectedly high diastereoselectivities
observed for the tandem cycloaddition reaction with
n-butyl vinyl ether, particularly for nitrodienoates (E)-1
and (E)-2, made the possibility of auxiliary-controlled
asymmetric synthesis an attractive avenue for investiga-
tion, Scheme 13.
Unlike the fused-mode tandem cycloadditions, the
spiro-mode creates only a single stereogenic center in the
[4 + 2] process, that at the anomeric position. Since this
center is ultimately destroyed in the hydrogenolysis, the
stereoinduction (relative to this center) in the [3 + 2]
cycloaddition creates all of the centers that persist. Thus,
successful enantioselective synthesis of R-hydroxy lac-
tams using this approach depended critically on achiev-
ing the following: (1) highly diastereofacial reaction of
the chiral vinyl ether in the initial [4 + 2] cycloaddition
to create the anomeric center with high selectivity and
(2) selective alkoxy-controlled distal side approach of the
dipolarophile to the nitronate in the [3 + 2] step.
To test the viability of this approach, we chose (-)-
(1R,2S)-2-phenylcyclohexanol as the chiral auxiliary. The
corresponding vinyl ether (-)-29 has been employed with
good success in all modes of tandem-cycloaddition and
has served admirably in a number of total synthesis
efforts.2c,d,10b While it is not, in fact, the optimal auxiliary
for the MAD- or MAPh-promoted cycloadditions used
herein,10d it is easily accessible11 and allows us to evaluate
proof of principle.
Addition of MAD (3.0 equiv) to a solution of nitroalkene
(E)-1 and chiral vinyl ether (-)-29 (3.0 equiv) in CH2Cl2
at -78 °C provided an approximately 1/1 mixture of
diastereomeric nitronate 30, which after aqueous workup
and warming in toluene at 75 °C for 60 min, afforded
(11) Schwartz, A.; Madan, P.; Whitesell, J . K.; Lawrence, R. M. Org.
Synth. 1990, 69, 1.

Tandem Inter [4 + 2]/Intra [3 + 2] Cycloadditions
J . Org. Chem., Vol. 63, No. 5, 1998 1609
Sch em e 14
Sch em e 16
Sch em e 15
Sch em e 17
1
nitroso acetal 31 in 81% yield. The H NMR spectrum
of this material showed two major products in ap-
proximately equal amounts. Hydrogenolytic cleavage of
this nitroso acetal mixture was performed as described
above to afford R-hydroxy lactam 23 along with the
recovered auxiliary, Scheme 14. The enantiomeric excess
of the hydroxy lactam was established by conversion to
the 3,5-dinitrophenyl carbamate derivative 32 using 3,5-
dinitrobenzoyl azide in refluxing toluene, Scheme 15.
Comparison of the chiral stationary phase HPLC12 traces
of this derivative with those of racemic carbamate
(()-32, prepared from (()-23, established the enantio-
meric excess as 2%.
Similarly, addition of MAPh (2.8 equiv) to a solution
of nitroalkene (E)-2 and vinyl ether (-)-29 (3.0 equiv) in
CH2Cl2 at -78 °C afforded nitroso acetal 33 in 95% yield.
1
The H NMR spectrum of this material showed it to be
an approximately 20/1 mixture of diastereomers. Hy-
drogenolysis afforded hydroxy lactam (-)-24 in 75% yield
together with the recovered alcohol (-)-2-phenylcyclo-
hexanol, again in very high yield. Transformation to the
carbamate derivative (-)-34 and chiral HPLC analysis
(with comparison to the racemic carbamate derivative
prepared independently from (()-24) showed it to be 89%
enantiomerically enriched in the more strongly retained
enantiomer, Scheme 17.
Deter m in a tion of Absolu te Con figu r a tion . The
absolute configurations of R-hydroxy lactams (-)-23 and
(-)-24 were established by using two empirical tech-
niques; chemical shift nonequivalence and chiral HPLC
elution order. The (S)-O-methylmandelate esters of
racemic R-hydroxy lactams 23 and 24 were readily
prepared by the method of Trost,13 and the diastereomers
were easily separated, Schemes 18 and 19.
A spectacular improvement in stereoselectivity was
observed for the tandem process upon changing the Lewis
acid from MAD to MAPh. Thus, addition of MAPh (3.0
equiv) to a solution of (E)-1 and vinyl ether (-)-29 in CH2-
Cl2 at -78 °C gave, after workup and warming in toluene,
1
nitroso acetal 31 in 98% yield. The H NMR spectrum
of this highly crystalline solid showed it to be an
approximately 19.5/1 mixture of diastereomers. Hydro-
genolytic cleavage to the hydroxy lactam (Raney nickel,
methanol, 160 psi) afforded (-)-23 in 78% yield along
with an almost quantitative recovery of (-)-2-phenyl-
cyclohexanol. Conversion to the carbamate derivative 32
as above (71% yield) and chiral HPLC analysis revealed
an enantiomeric enrichment of 83% in the more strongly
retained enantiomer, Scheme 16.
For both hydroxy lactams, the more polar diastereomer
(i.e., 35b and 36b ) displayed an upfield shift for the
(12) (a) Pirkle, W. H.; Mahler, G.; Hyun, M. H. J . Liq. Chromatogr.
1986, 9, 443. (b) Pirkle, W. H.; Pochapsky, T. C.; Burke, J . A.; Deming,
K. C. In Chiral Separations; Stevenson, D., Wilson, I. D., Eds;
Plenum: New York, 1988; p 23. (c) Pirkle, W. H.; Pochapsky, T. C.
Chem. Rev. 1989, 89, 347.
(13) Trost, B. M.; Belletire, J . L.; Godleski, S.; McDougal, P. G.;
Balkovec, J . M.; Baldwin, J . J .; Christy, M. E.; Ponticello, G. S.; Varga,
S. L.; Springer, J . P. J Org. Chem. 1986, 51, 2370.

1610 J . Org. Chem., Vol. 63, No. 5, 1998
Denmark and Middleton
Sch em e 20
Sch em e 18
Discu ssion
P r ep a r a tion of 2-Nitr oa lk en es. Several problems
became apparent with this nitromercuration strategy.
First, incomplete conversion of the starting dienoates 5
and 9 to the intermediate nitromercurial was encoun-
tered. This may be a consequence of the insolubility of
the nitromercurial causing entrainment of the starting
material in the heterogeneous mixture. Unreacted start-
ing material was recovered in all cases (ca. 10%) after
chromatography. The addition of an organic solvent was
not deemed suitable since it is known to retard the rate
of nitromercuration.5 Second, the nitromercuration step
was found to give the products derived from both Mark-
ovnikov and anti-Markovnikov addition, thus necessitat-
ing a chromatographic separation after conversion to the
nitroalkene. Third, base-mediated intramolecular (or
intermolecular) Michael-addition to the R,â-unsaturated
ester by the R-nitro anion competes with the desired
elimination. The higher yields for the nonadienoate
products (E)-2 and (Z)-2 relative to their octadienoate
analogues (E)-1 and (Z)-1 may be ascribed, at least in
part, to a reduction in the likelihood of the (proposed)
intramolecular Michael addition upon increasing the
chain length. The improvement in yield upon lengthen-
ing the methylene tether from three to four units is
particularly apparent for the preparation of (Z)-1 (4%
yield) and (Z)-2 (52%).
Ta n d em Cycloa d d ition s. Our previous experience
with 2,2-disubstituted 1-nitroalkenes14 showed that the
rate of the [4 + 2] cycloaddition is severely retarded by
bulky substituents on the nitroalkene. Accordingly, we
expected that substrates 1 and 2 should react rapidly.
We were surprised, therefore, that the mild Lewis acid
Ti(i-OPr)2Cl2 failed to induce reaction. Indeed, recent
studies in these laboratories with nitroethylene have
shown that aluminum and tin-based Lewis acids are the
most effective for promoting [4 + 2] cycloaddition.15
Presumably, this is related to the low Lewis basicity of
unsubstituted nitroalkenes, which gives rise to a low
equilibrium concentration of the reactive complex.16
Accordingly, the [4 + 2] cycloaddition of 1 and 2 with
both butyl vinyl ether and (-)-29 proceeded readily at
Sch em e 19
proton at HC(9a) and HC(10a), respectively, relative to
their less polar diastereomeric partner. Examination of
an “extended Newman projection” for these diastereo-
mers shows that a shielding of HC(9a) and HC(10a), in
23 and 24, respectively, by the phenyl ring is expected
in the isomer with the 1R-configuration.
Treatment of enantiomerically enriched R-hydroxy
lactams (-)-23 and (-)-24 with (S)-O-methylmandaloyl
chloride and pyridine in CH2Cl2 afforded, by TLC and
1H NMR comparison with authentic samples, esters 35a
and 35b respectively, Scheme 20.
On the basis of this analysis, the enantiomerically
enriched R-hydroxy lactams (-)-23 and (-)-24 obtained
from the cycloaddition using MAPh and (-)-2-phenyl-
cyclohexyl vinyl ether were assigned as possessing the
(1S,6aS,9aS) and (1S,6aS,10aS) configurations, respec-
tively. These assignments were corroborated by the
observed chiral HPLC elution order for these compounds
relative to their minor enantiomers. A large body of
empirical data, recently supported by modeling, shows
that, generally, the S-enantiomer is more strongly
retained.12b,c
(14) (a) Denmark, S. E.; Marcin, L. R. J . Org. Chem. 1993, 58, 3857.
(b) Denmark, S. E.; Schnute, M. E. J . Org. Chem. 1994, 59, 4576. (c)
Denmark, S. E.; Marcin, L. R. J . Org. Chem. 1995, 60, 3221.
(15) Denmark, S. E.; Hurd, A. R. Manuscript submitted.
(16) Denmark, S. E.; Kesler, B. S.; Moon, Y.-C. J . Org. Chem. 1992,
57, 4912.

Tandem Inter [4 + 2]/Intra [3 + 2] Cycloadditions
J . Org. Chem., Vol. 63, No. 5, 1998 1611
Sch em e 21
F igu r e 4. Steric interactions for (Z)- and (E)-enoates in a
proximal folding alignment.
Sch em e 22
-78 °C with MAD and MAPh. The intermediate nitron-
ates were not characterized as they underwent cycload-
dition at room temperature or on warming in toluene.
The overall chemical yield for this sequence was good
(62-84%).
For the three-methylene-tethered precursors (E)-1 and
(Z)-1, the spirocyclic nitroso acetals 16 and 18 were
formed with surprisingly high diastereoselectivities (dis-
tal/proximal, 35/1 and 10/1, respectively). The origin of
the diastereoselectivity in this variant of the tandem inter
[4 + 2]/intra [3 + 2] is fundamentally different from
either the fused or the bridged modes and merits careful
analysis. In the spiro-mode, the [4 + 2]-cycloaddition
creates a single, new stereogenic center at the anomeric
position (C(6)). Thus, unlike the fused mode or bridged
mode, the dipolarophilic tether is not automatically
predisposed to fold on one side or the other of the
nitronate. Rather, the facial selectivity of the folding of
the chain is solely controlled by the disposition of the
substituent (butoxy group) on the anomeric center. The
preferred pathway is that in which the dipolarophile
tether approaches that face of the nitronate ring in the
half-space opposite the butoxy group, Scheme 21.
The initial [4 + 2] cycloaddition between the nitroal-
kene and butyl vinyl ether results in the formation of
nitronate 15 with a single stereogenic center at the
anomeric position. Folding of the dipolarophile tether
can then occur in an exo or endo fashion to either the
proximal or the distal face of the nitronate ring. Exo
folding is a significantly lower energy process, since the
tether is attached to an sp2 center. Endo folding is
mechanically very difficult and would lead to a trans-
fused 3.3.0 system. Should the dipolarophile tether fold
to the proximal face of the nitronate, a significant
unfavorable steric interaction results between the ester
linkage on the tether and the butoxy group. However,
folding of the dipolarophile tether to the distal face of
the nitronate, opposite the butoxy group, alleviates this
steric interaction and ultimately results in the formation
of the major nitroso acetal 16a . This also explains the
observation that the (Z)-enoates display lower diastereo-
selectivities than their (E)-analogues. For the (Z)-enoate,
proximal orientation of the dipolarophile tether positions
the ester group on the same face but away from the
butoxy substituent, Figure 4. This reduced steric inter-
action makes a proximal orientation of the (Z)-enoate less
disfavored than the same orientation for the (E)-analogue
resulting in reduced facial selectivity and, therefore,
lower diastereoselectivity.
The reduced diastereoselectivities for both (E)- and (Z)-
nonadienoate substrates 2 relative to their respective
lower homologs 1 (21/1 vs 35/1 and 3.5/1 vs 10/1) may be
rationalized by the increased geometrical freedom at-
tendant with increasing the length of the dipolarophile
tether from three to four methylene units. This increased
flexibility permits the enoate tether to more readily adopt
an alignment that allows for effective orbital overlap but
reduces unfavorable steric interactions. This ability to
minimize these steric interactions, the origin of the
diastereoselectivity, results in poorer distal/proximal face
differentiation relative to the three methylene tether
analogs and hence lower stereoselectivities.
The formation of the R-hydroxy lactam from the nitroso
acetal is believed to proceed through a number of discrete
intermediates. A plausible sequence of events for this
transformation is shown in Scheme 22. Hydrogenolytic
N-O bond cleavage of 16a would form hemiacetal i,
which upon loss of butanol would give amino aldehyde
ii. Intramolecular imine formation iii and subsequent
reduction would give amine iv, which upon lactamization
yields R-hydroxy lactam product 23. The R-hydroxy

1612 J . Org. Chem., Vol. 63, No. 5, 1998
Denmark and Middleton
Sch em e 23
With the knowledge that to obtain the observed con-
figuration in the R-hydroxy lactam products it is neces-
sary to access the si-face of the vinyl ether (Scheme 23),
four possible limiting transition-state complexes may be
proposed to account for the observed configuration of the
product nitroso acetal. These molecular “aggregations”
are constructed by pairwise combinations of two vinyl
ether conformations and exo or endo orientation of the
auxiliary relative to the nitroalkene. For clarity, the
bulky monomeric aluminum Lewis acid has been omitted,
Scheme 24.
An endo orientation of vinyl ether (-)-29 in the s-cis
conformation v clearly places the phenyl ring directly
between the vinyl ether and the diene, preventing reac-
tion between the [2π]-system of the vinyl ether and the
nitroalkene. A similar analysis for the s-cis conformation
in the exo-mode vii again places the phenyl ring between
the vinyl ether si-face and the nitroalkene. On the other
hand, the s-trans conformation of the vinyl ether, in
either the endo or exo mode (vi and viii respectively),
places the phenyl ring away from the reacting vinyl ether
si-face and the nitroalkene, making either of these
pathways viable; both ultimately leading to the same
product.
Thus, on the basis of this analysis, the [4 + 2]
cycloaddition reaction, which leads to the S-configuration
at the anomeric center, proceeds through either the
s-trans-exo viii or the s-trans-endo vi orientation. It is
impossible to unambiguously distinguish between these
two pathways using this steric model alone. However,
previous studies carried out in these laboratories have
established the high exo-preference of MAPh, relative to
MAD, in tandem [4 + 2]/[3 + 2] cycloaddition reactions
using â-substituted nitroalkenes.
lactams formed were all colorless highly crystalline solids
that were found to be stable indefinitely when stored in
the freezer. The observation that mixtures of nitroso
acetals give a single R-hydroxy lactam product indicates
that the nitroso acetals generated in the tandem cycload-
dition differ stereochemically only at the anomeric center
(which, of course, is destroyed in the hydrogenolysis step).
Or igin of Ster eoselectivity in th e Asym m etr ic
Ta n d em Cycloa d d ition . With the knowledge of the
absolute configuration of the R-hydroxy lactams (-)-23
and (-)-24 it is possible to infer the configuration of the
anomeric center in the nitroso acetal from which it was
created and from this identify which face of the vinyl
ether is involved in the initial [4 + 2] cycloaddition
reaction. This stereochemical “lineage” is shown in
Scheme 23. The 1S-configuration at the secondary
hydroxyl center in the R-hydroxy lactam products must
necessarily derive from the nitroso acetal bearing the
S-configuration at the anomeric center. Modeling shows
that this configuration originates from a si-face attack
on (-)-(1R,2S)-trans-2-phenylcyclohexyl vinyl ether (-)-
29 in the [4 + 2] cycloaddition step.
MM2 energy-minimized ground-state structures for the
s-cis and s-trans conformations of (-)-29 shows that in
the s-cis conformation the phenyl ring shields the si-face
of the vinyl ether; the re-face being exposed. In contrast,
the s-trans conformation effectively shields the re-face;
the si-face being readily accessible. Interestingly, MM2
calculations show that the two limiting conformations
have almost identical energies in the ground state (s-cis
14.16 kcal/mol, s-trans 14.66 kcal/mol).
A similar exo preference may be reasonably expected
with MAPh employing an R-substituted nitroalkene, and
thus, by analogy with these previous studies, the initial
[4 + 2] in the asymmetric spiro-mode tandem cycload-
dition may be reasonably assumed to proceed through
the s-trans-exo orientation viii. As pictorially repre-
sented in Scheme 25, this creates the anomeric center
with the S-configuration.
In an analogous fashion to the racemic variant dis-
cussed earlier, the [3 + 2] cycloaddition can then occur
Sch em e 24

Tandem Inter [4 + 2]/Intra [3 + 2] Cycloadditions
J . Org. Chem., Vol. 63, No. 5, 1998 1613
for (-)-29 with this Lewis acid.10a,b With MAPh, the
chiral vinyl ether (-)-29 reacts in a highly exo-selective
fashion via the s-trans conformation, thus exposing the
si-face of the vinyl ether for cycloaddition. With MAD,
on the other hand, (-)-29 exhibits poor exo/endo and
diastereofacial selectivity. In the exo-mode, the s-cis
conformation of the vinyl ether is accessed, exposing the
re-face of the vinyl ether (leading to the R-configuration
at the anomeric center). In the endo-mode, the s-trans
conformation of the vinyl ether is accessed, exposing the
si-face of the vinyl ether (leading to the S-configuration
at the anomeric center). This facial selectivity, which
leads to enantiomorphic anomeric centers, explains the
formation of racemic R-hydroxy lactam with MAD. The
isolation of 30 from these reactions as a 1/1 mixture of
diastereomers confirms the poor facial selectivity of the
[4 + 2] event.
Sch em e 25
Sch em e 26
Con clu sion
The spiro mode variant of the tandem inter [4 +
2]/intra [3 + 2] cycloaddition has been documented.
2-Nitroalkenes bearing unsaturated esters with three
and four methylene tethers underwent tandem cycload-
dition with vinyl ethers in the presence of MAD or MAPh
as the Lewis acids. The stereochemical course of the
intramolecular [3 + 2] reaction is determined by (1) the
configuration of the anomeric center, (2) the length of the
tether, and (3) the geometry of the dipolarophile. E-
Dipolarophiles react more selectively than the Z-isomers
and particularly when tethered to the nitronate by three
methylene groups. The tandem sequence can be carried
out with high enantioselectivity with chiral vinyl ether
(-)-29. The origin of selectivity is the high diastereo-
facial bias for [4 + 2] cycloaddition with MAPh as the
Lewis acid. This process allows simple access to aza-
propellanes with high selectivity.
Improvements in the overall process will require newer
methods for the synthesis of 2-nitroalkenes and the
employment of chiral auxiliaries of greater facial bias.10d
In addition, applications to the synthesis of spirocyclic
alkaloids are planned.
to either the distal or the proximal face of the nitronate
ring in 30 relative to the auxiliary. A distal orientation
places the dipolarophile tether on the opposite face of the
nitronate ring relative to the auxiliary x, ultimately
leading to the major R-hydroxy lactam. Folding of the
dipolarophile tether to the proximal face of the nitronate
ring relative to the auxiliary, ix, invokes an unfavorable
steric interaction between the enoate and the auxiliary.
The [3 + 2] cycloaddition via this latter pathway would
lead to the minor R-hydroxy lactam enantiomer, Scheme
26.
On the basis of the product distribution alone, it is not
possible to identify the origin of the erosion of diastereo-
selectivity in the tandem cycloaddition; imperfect asym-
metric induction in the initial [4 + 2] cycloaddition and/
or imperfect proximal/distal nitronate face selectivity in
the [3 + 2] cycloaddition. Both are possible contributors
and could be distinguished if the diastereomeric ratio of
30 were known.
Exp er im en ta l Section
Gen er a l Meth od s. See the Supporting Information.
Meth yl (E)-7-Nitr o-2,7-octa d ien oa te ((E)-1). To a stirred
solution of sodium nitrite (1.29 g, 18.70 mmol) in distilled
water (6 mL) at rt was added, dropwise, a solution of mercuric
perchlorate trihydrate (4.25 g, 9.35 mmol) in water (6 mL).
After 10 min, this clear yellow solution was added dropwise
to a foil-covered flask containing a heterogeneous mixture of
methyl (E)-2,7-octadienoate ((E)-5) (1.44 g, 9.35 mmol) and
water (6 mL). The mixture was then mechanically stirred.
After 24 h, CH2Cl2 (50 mL) was added and the organic layer
washed with water (20 mL). The combined aqueous layers
were then re-extracted with CH2Cl2 (2 × 20 mL), and the
combined organic phase was dried (MgSO4). Removal of the
solvent in vacuo afforded a viscous yellow oil (3.46 g) that was
used immediately.
To a solution of this nitromercurial in CH2Cl2 (25 mL) in a
foil-covered flask at rt was added, dropwise, triethylamine (957
µL, 6.92 mmol). After 20 min, the crude reaction mixture was
filtered through a short pad of silica (40 mm × 60 mm), eluting
with CH2Cl2 (100 mL) to remove precipitated mercury. Re-
moval of the solvent by rotary evaporation and silica gel
column chromatography (5%, 10%, 15% EtOAc/pentane) gave
162 mg (11%) of recovered methyl (E)-2,7-octadienoate (E)-5
followed by the nitroalkene (E)-1 675 mg (36%), as a pale
The observation that asymmetric tandem cycloaddition
using MAD as the Lewis acid produces R-hydroxy lactam
23 in racemic form (Schemes 14 and 15) can be under-
stood on the basis of the poor diastereofacial bias found

1614 J . Org. Chem., Vol. 63, No. 5, 1998
Denmark and Middleton
yellow oil: 1H NMR (300 MHz) δ 6.84 (m, 1 H,), 6.35 (s, 1 H),
5.75 (d, J ) 15.5, 1 H), 5.50 (s, 1 H), 3.61 (s, 3 H), 2.53 (t, J )
7.7, 2 H), 2.19 (m, 2 H), 1.63 (m, 2 H); 13C NMR (75.5 MHz) δ
166.44, 157.10, 147.44, 121.56, 117.38, 51.13, 30.88, 29.19,
25.22; IR (CCl4) 1729 (s), 1661 (w), 1534 (s) cm-1; MS (70 eV)
m/z 168 (35), 91 (100); TLC Rf 0.28 (hexane/EtOAc, 4/1). Anal.
Calcd for C9H13NO4 (199.21): C, 54.26; H, 6.58; N, 7.03.
Found: C, 54.17; H, 6.59; N, 7.13.
Meth yl (Z)-7-Nitr o-2,7-octa d ien oa te ((Z)-1). To a stirred
solution of sodium nitrite (1.49 g, 21.58 mmol) in distilled
water (6 mL) at rt was added, dropwise, a solution of mercuric
perchlorate trihydrate (4.90 g, 10.79 mmol) in distilled water
(6 mL). After 15 min, this clear yellow solution was added
dropwise to a foil-covered flask containing a heterogeneous
mixture of methyl (Z)-2,7-octadienoate ((E)-5) (1.51 g, 9.81
mmol) and water (6 mL). The mixture was then mechanically
stirred. After 39 h, CH2Cl2 (80 mL) was added and the organic
layer washed with water (60 mL). The combined aqueous
layers were then back-extracted with CH2Cl2 (2 × 40 mL), and
the combined organic phase was dried (MgSO4). Removal of
the solvent in vacuo afforded a viscous yellow oil that was used
immediately.
vacuo afforded a viscous yellow oil (1.64 g) that was used
immediately. To a solution of this nitromercurial in CH2Cl2
(12 mL) in a foil-covered flask at rt was added, dropwise,
triethylamine (441 µL, 3.19 mmol). After 15 min, the crude
reaction mixture was filtered through a short pad of silica (30
mm × 30 mm), eluting with CH2Cl2 (100 mL) to remove
precipitated mercury. Removal of the solvent by rotary
evaporation and silica gel column chromatography (5%, 10%
EtOAc/hexane) afforded 437 mg (52%) of nitroolefin (Z)-2 as a
pale yellow oil: 1H NMR (300 MHz) δ 6.33 (d, J ) 1.5, 1 H),
6.14 (dt, J ) 7.5, 1 H), 5.71 (dd, J ) 11.5, 1.3, 1 H), 5.50 (s, 1
H), 3.61 (s, 3 H), 2.65-2.52 (m, 4 H), 1.54-1.42 (m, 4 H); 13C
NMR δ (75.5 MHz) 166.44, 157.70, 149.55, 119.55, 116.98,
50.77, 29.56, 28.07, 27.84, 26.45; IR (CCl4) 1724 (s), 1701 (m),
1646 (s), 1530 (s) cm-1; MS (70 eV) m/z 182 (26); TLC Rf 0.50
(hexane/EtOAc, 4/1). Anal. Calcd for C10H15NO4 (213.23): C,
56.33; H, 7.09; N, 6.57. Found: C, 56.33; H, 7.08; N, 6.56.
Meth yl (2R*,2a R*,5a R*)-8-Bu toxyocta h yd r o-1,9-d ioxa -
9a -a za cyclop en t[c]in d en e-2-ca r boxyla te (16). To a solu-
tion of BHT (5.28 g, 24.0 mmol) in toluene (18 mL) at rt was
slowly added Me3Al (6.00 mL, 12 mmol, 2 M solution in
toluene). The solution was then stirred at rt for 60 min.
To a solution of this nitromercurial in CH2Cl2 (30 mL) in a
foil-covered flask at rt was added, dropwise, triethylamine
(1.09 mL, 7.90 mmol). After 30 min, the crude reaction
mixture was filtered through a short pad of Florisil (50 mm ×
60 mm), eluting with CH2Cl2 (300 mL) to remove precipitated
mercury. Removal of the solvent by rotary evaporation and
silica gel column chromatography (5%, 10%, 15% EtOAc/
pentane) gave 74 mg (4%) of nitroolefin (Z)-1 as an impure
yellow oil: 1H NMR (200 MHz) δ 6.43 (d, J ) 1.6, 1 H), 6.24-
6.14 (m, 1 H), 5.83 (br d, J ) 11.9, 1 H), 5.58 (br s, 1 H), 3.70
(s, 3 H), 2.77-2.59 (m, 4 H), 1.77-1.66 (m, 2 H).
Meth yl (E)-8-Nitr o-2,8-n on adien oate ((E)-2). To a stirred
solution of sodium nitrite (1.20 g, 17.38 mmol) in distilled
water (8 mL) at rt was added, dropwise, a solution of mercuric
perchlorate trihydrate (3.94 g, 8.69 mmol) in water (8 mL).
After 10 min, this clear yellow solution was added dropwise
to a foil-covered flask containing a heterogeneous mixture of
methyl (E)-2,8-nonadienoate ((E)-9) (1.46 g, 8.69 mmol) and
water (8 mL). The mixture was then mechanically stirred.
After 22 h, CH2Cl2 (100 mL) was added and the organic layer
washed with water (100 mL). The combined aqueous layers
were then re-extracted with CH2Cl2 (2 × 50 mL), and the
combined organic phase was dried (MgSO4). Removal of the
solvent in vacuo afforded a viscous yellow oil (3.92 g) that was
used immediately.
To a solution of this nitromercurial in CH2Cl2 (45 mL) in a
foil-covered flask at rt was added, dropwise, triethylamine
(1.05 mL, 7.62 mmol). After 25 min, the crude reaction
mixture was filtered through a short pad of silica (40 mm ×
50 mm), eluting with CH2Cl2 (200 mL) to remove precipitated
mercury. Removal of the solvent by rotary evaporation and
silica gel column chromatography (5%, 10%, 15% EtOAc/
hexane) yielded 1.04 g (56%) of nitroolefin (E)-2 as a pale
yellow oil: 1H NMR (300 MHz) δ 6.93 (dt, J ) 7.0, 1 H), 6.42
(d, J ) 1.5, 1 H), 5.82 (dt, J ) 15.6, 1.1, 1 H), 5.54 (s, 1 H),
3.71 (s, 3 H), 2.60 (t, J ) 6.3, 2 H), 2.23 (m, 2 H), 1.56 (m, 4
H); 13C NMR (75.5 MHz) δ 166.64, 157.54, 148.35, 121.12,
117.03, 51.13, 31.13, 29.60, 27.02, 26.40; IR (CCl4) 1728 (s),
1659 (s), 1532 (s) cm-1; MS (70 eV) m/z 182 (37), 79 (100); TLC
Rf 0.29 (hexane/EtOAc, 4/1). Anal. Calcd for C10H15NO4
(213.23): C, 56.33; H, 7.09; N, 6.57. Found: C, 56.30; H, 7.09;
N, 6.60.
Meth yl (Z)-8-Nitr o-2,8-n on adien oate ((Z)-2). To a stirred
solution of sodium nitrite (541 mg, 7.83 mmol) in distilled
water (3 mL) at rt was added, dropwise, a solution of mercuric
perchlorate trihydrate (1.78 g, 3.92 mmol) in water (3 mL).
After 10 min, this clear yellow solution was added dropwise
to a foil-covered flask containing a heterogeneous mixture of
methyl (Z)-2,8-nonadienoate ((Z)-9) (658 mg, 3.92 mmol) and
water (3 mL). The mixture was then mechanically stirred.
After 24 h, CH2Cl2 (40 mL) was added and the aqueous layer
extracted with CH2Cl2 (2 × 15 mL). The combined organic
layers were then dried (MgSO4). Removal of the solvent in
To a solution of methyl (E)-7-nitro-2,7-octadienoate ((E)-1)
(597 mg, 3.0 mmol) and butyl vinyl ether (2.43 mL, 18.0 mmol,
6.0 equiv) in CH2Cl2 (5 mL) at -78 °C was added slowly,
dropwise, freshly prepared MAD solution (18 mL, 9.0 mmol,
3.0 equiv). After 40 min, H2O (20 mL) was added at -78 °C,
the cooling bath removed, and the mixture allowed to stir for
3 min. CH2Cl2 (80 mL) was added and the organic phase
washed with H2O (2 × 60 mL). The combined aqueous phase
was re-extracted with CH2Cl2 (50 mL), and the combined
organic phase was washed with aqueous sodium potassium
tartrate solution (100 mL) and dried (MgSO4). The CH2Cl2
was removed in vacuo and the remaining toluene solution
heated to 75 °C for 85 min. The mixture was cooled, the
toluene removed in vacuo, and the residue purified by silica
gel column chromatography (5%, 10%, 15% TBME/pentane)
to furnish 677 mg (76%) of nitroso acetal 16 as a colorless
viscous oil: 1H NMR (300 MHz) δ 4.75 (br t, J ) 2.5, 1 H),
4.31 (d, J ) 3.1, 1 H), 3.87 (ddd, J ) 10.0, 6.8, 4.9, 1 H), 3.74
(s, 3 H), 3.39 (ddd, J ) 10.0, 6.8, 4.9, 1 H), 3.28 (m, 1 H), 2.15
(m, 1 H), 1.96-1.46 (m, 11 H), 1.35 (m, 2 H), 0.87 (t, J ) 7.3,
3 H); 13C NMR (75.5 MHz) δ 171.90, 99.68, 87.94, 84.07, 67.33,
52.26, 47.65, 38.71, 31.90, 31.41, 27.59, 25.41, 23.47, 19.15,
13.84; IR (CCl4) 1738 (s), 1455 (m) cm-1; MS (70 eV) m/z 226
(11); TLC Rf 0.41 (hexane/EtOAc, 4/1). Anal. Calcd for C15H25
-
NO5 (299.37): C, 60.18; H, 8.42; N, 4.68; Found: C, 60.06; H,
8.37; N, 4.72.
Meth yl (2R*,2aS*S,5aS*)-8-Bu toxyoctah ydr o-1,9-dioxa-
9a -a za cyclop en t[c]in d en e-2-ca r boxyla te (18). To a solu-
tion of BHT (354 mg, 1.61 mmol) in toluene (1.6 mL) at rt was
slowly added Me3Al (402 µL, 0.80 mmol, 2 M solution in
toluene). The solution was then stirred at rt for 20 min.
To a solution of methyl (Z)-7-nitro-2,7-octadienoate ((Z)-1)
(40 mg, 0.2 mmol) and butyl vinyl ether (163 mL, 1.21 mmol,
6.0 equiv) in CH2Cl2 (1 mL) at -78 °C was added slowly,
dropwise, freshly prepared MAD solution (1.5 mL, 0.6 mmol,
3.0 equiv). After 30 min, H2O (2 mL) was added at -78 °C,
the cooling bath removed, and the mixture allowed to stir for
5 min. CH2Cl2 (10 mL) was added and the organic phase
washed with H2O (2 × 5 mL). The combined aqueous phase
was re-extracted with CH2Cl2 (5 mL), and the combined
organic phase was washed with aqueous sodium potassium
tartrate solution (100 mL) and dried (MgSO4). The CH2Cl2
was removed in vacuo, and the remaining toluene solution was
heated to 70 °C for 55 min. The mixture was cooled, the
toluene removed in vacuo, and the residue purified by silica
gel column chromatography (5%, 10% TBME/pentane) to
furnish 37.4 mg (62%) of nitroso acetal 18 as a colorless viscous
oil (isolated as an inseparable ca. 10/1 mixture of diastereo-
mers): 1H NMR (200 MHz) δ 5.30 (d, J ) 7.6, 1 H), 4.88 (m,
1 H), 3.91-3.83 (m, 1 H), 3.77 (s, 3 H), 3.50-3.41 (m, 1 H),
2.86-2.72 (m, 1 H), 1.98-1.20 (m, 16 H), 0.90 (t, J ) 7.3, 3
H); TLC Rf 0.61 (hexane/EtOAc, 4/1).

Tandem Inter [4 + 2]/Intra [3 + 2] Cycloadditions
J . Org. Chem., Vol. 63, No. 5, 1998 1615
Meth yl (2R*,2aR*,6aR*)-9-Bu toxyoctah ydr o-1,10-dioxa-
10a -a za cycloh ex[c]in d en e-2-ca r boxyla te (20). To a solu-
tion of BHT (2.32 g, 10.56 mmol) in toluene (5 mL) at rt was
slowly added Me3Al (2.64 mL, 5.28 mmol, 2 M solution in
toluene). The solution was then stirred at rt for 45 min.
To a solution of methyl (E)-8-nitro-2,8-nonadienoate ((E)-2)
(281 mg, 1.32 mmol) and butyl vinyl ether (1.07 mL, 7.92
mmol, 6.0 equiv) in CH2Cl2 (3 mL) at -78 °C was added slowly,
dropwise, the freshly prepared MAD solution (5.6 mL, 3.9
mmol, 2.9 equiv). After 55 min, H2O (20 mL) was added at
-78 °C, the cooling bath removed, and the mixture allowed to
stir for 2 min. CH2Cl2 (10 mL) was added and the organic
phase washed with H2O (2 × 10 mL). The combined aqueous
phase was re-extracted with CH2Cl2 (10 mL) and the combined
organic phase dried (MgSO4). The CH2Cl2 was removed in
vacuo, and the remaining toluene solution was heated to 70
°C for 240 min. The mixture was cooled, the toluene removed
in vacuo, and the residue purified by silica gel column
chromatography (10%, 15%, 20% EtOAc/pentane) to give
nitroso acetal 20 347 mg (84%) as a colorless viscous oil: 1H
NMR (300 MHz) δ 4.83 (t, J ) 4.6, 1 H), 4.56 (d, J ) 9.7, 1 H),
3.92 (ddd, J ) 11.7, 6.9, 4.9, 1 H), 3.76 (s, 3 H), 3.43 (ddd, J )
11.7, 6.9, 4.9, 1 H), 2.92 (m, 1 H), 2.04-1.44 (m, 10 H), 1.41-
1.19 (m, 6 H), 0.88 (t, J ) 7.3, 3H); 13C NMR (75.5 MHz) δ
171.60, 100.64, 82.61, 71.90, 67.49, 52.35, 43.44, 31.44, 30.67,
26.12, 24.19, 22.12, 21.03, 20.28, 19.15, 13.86; IR (CCl4) 1736
(s), 1455 (s) cm-1; MS (70 eV) m/z 240 (34), 121 (100); TLC Rf
0.26 (hexane/EtOAc, 4/1). Anal. Calcd for C16H27NO5
(313.40): C, 61.32; H, 8.68; N, 4.47. Found: C, 61.22; H, 8.68;
N, 4.47.
Meth yl (2R*,2a S*,6a S*)-9-Bu toxyocta h yd r o-1,10-d ioxa -
10a -a za cycloh ex[c]in d en e-2-ca r boxyla te (22). To a solu-
tion of BHT (1.88 g, 8.56 mmol) in toluene (6 mL) at rt was
slowly added Me3Al (2.14 mL, 4.28 mmol, 2 M solution in
toluene). The solution was then stirred at rt for 30 min.
To a solution of methyl (Z)-8-nitro-2,8-nonadienoate ((E)-2)
(227 mg, 1.07 mmol) and butyl vinyl ether (860 mL, 6.39 mmol,
6.0 equiv) in CH2Cl2 (4 mL) at -78 °C was added slowly,
dropwise, the freshly prepared MAD solution (6 mL, 3.2 mmol,
3.0 equiv). After 40 min, H2O (10 mL) was added at -78 °C,
the cooling bath removed, and the mixture allowed to stir for
3 min. CH2Cl2 (10 mL) was then added, the aqueous phase
was extracted with CH2Cl2 (2 × 15 mL), and the combined
organic phase was dried (MgSO4). The CH2Cl2 was removed
in vacuo, and the remaining toluene solution was heated to
100 °C for 230 min. The mixture was cooled, the toluene
removed in vacuo, and the residue purified by silica gel column
chromatography (5%, 10% TBME/pentane) to afford 215 mg
(64%) of nitroso acetal 22 as a colorless viscous oil (isolated
as an inseparable ca.. 3.5:1 mixture of diastereomers): 1H
NMR (300 MHz) δ 4.98 (d, J ) 11.4, 1 H), 4.84 (t, J ) 5.2, 1
H), 4.69 (dd, J ) 9.5, 1.9, 0.3 H), 3.94-3.85 (m, 1.3 H), 3.78 (s,
1.05 H), 3.77 (s, 3 H), 3.54 (m, 0.3 H), 3.43 (m, 1 H), 3.16 (m,
0.3 H), 2.31-1.18 (m, 20.2 H), 0.97-0.83 (m, 4 H); 13C NMR
(75.5 MHz) δ (major diastereomer) 170.92, 100.30, 81.67, 71.64,
67.44, 52.20, 42.65, 31.50, 30.34, 26.68, 24.30, 21.10, 20.85,
20.62, 19.27, 13.90. (minor diastereomer) 100.54, 81.30, 70.54,
69.50, 38.85, 33.10, 31.63, 27.06, 26.14, 21.15, 21.05, 19.08,
13.84, three carbons missing ((C(1′′)), (C(2′′)) and one CH2));
IR (CCl4) 1761 (s), 1736 (s) cm-1; MS (70 eV) m/z 240 (35), 121
(100); TLC Rf 0.45 (EtOAc/hexane, 7/3). Anal. Calcd for
(d, J ) 5.2, 1 H), 4.41 (dd, J ) 9.7, 5.2, 1 H), 3.57-3.47 (m, 1
H), 3.08-2.99 (m, 1 H), 2.55 (dt, J ) 9.3, 2.7, 1 H), 2.20-2.15
(m, 1 H), 2.07-1.98 (m, 2 H), 1.81-1.63 (m, 2 H), 1.61-1.43
(m, 4 H), 1.36-1.26 (m, 1 H); 13C NMR (75.5 MHz, CDCl3) δ
176.55, 77.43, 72.64, 43.73, 40.46, 37.56, 35.61, 25.53, 25.30,
24.85; IR (KBr) 3287 (br), 1680 (s) cm-1; MS (70 eV) m/z 182
(M+ + 1, 12), 181 (M+, 90), 152 (100); TLC Rf 0.18 (EtOAc).
Anal. Calcd for C10H15NO2 (181.24): C, 66.27; H, 8.34; N, 7.73.
Found: C, 66.26; H, 8.38; N, 7.74.
(1R*,6a R*,10a R*)-Octa h yd r o-1-h yd r oxy-2H-cycloh exa -
[h ]p yr r olizin -2-on e (24). A hetereogeneous mixture of ni-
troso acetal 20 (593 mg, 1.89 mmol) and methanol-washed
Raney nickel (spatula tip) in methanol (20 mL) was stirred at
rt under an atmosphere of hydrogen at 160 psi for 21 h. The
reaction mixture was filtered through a short pad of silica (30
mm × 15 mm), eluting with CH2Cl2 (150 mL) to remove the
catalyst. The filtrate was concentrated under reduced pres-
sure and the residue was purified by silica gel column
chromatography (EtOAc) and recrystallization (EtOAc/hexane)
to give 227 mg (75%) of hydroxy lactam 24 as a white
crystalline solid: mp 180.5-182 °C; 1H NMR (300 MHz) δ 5.77
(d, J ) 4.9, 1 H), 4.13 (dd, J ) 5.0, 6.1, 1 H), 3.46 (m, 1 H),
3.14 (m, 1 H), 2.52-1.41 (m, 11 H), 1.39-1.27 (m, 1 H), 1.20-
1.03 (m, 1 H); 13C NMR (75.5 MHz) δ 174.51, 79.12, 69.82,
45.67, 39.87, 35.03, 34.69, 25.70, 23.17, 23.07, 22.13; IR (KBr)
3250 (br), 1671 (s) cm-1; MS (70 eV) m/z 195 (M+, 76), 152
(100); TLC Rf 0.22 (EtOAc). Anal. Calcd for C11H17NO2
(195.26): C, 67.66; H, 8.78; N, 7.17. Found: C, 67.73; H, 8.72;
N, 7.20.
(1R*,6a S*,10a S*)-Octa h yd r o-1-h yd r oxy-2H-cycloh exa -
[h ]p yr r olizin -2-on e (25). A hetereogeneous mixture of ni-
troso acetal 22 (141 mg, 0.45 mmol) and methanol-washed
Raney nickel (spatula tip) in methanol (10 mL) was stirred at
rt under an atmosphere of hydrogen at 160 psi for 36 h. The
reaction mixture was filtered through a short pad of silica (10
mm × 10 mm), eluting with CH2Cl2 (400 mL) to remove the
catalyst. The filtrate was concentrated under reduced pres-
sure, and the residue was purified by silica gel column
chromatography (EtOAc) and recrystallization (EtOAc/hexane)
to furnish 59 mg (76%) of hydroxy lactam 25 as a white
crystalline solid: mp 106-108 °C; 1H NMR (300 MHz) δ 4.52
(dd, J ) 3.1, 11.2, 1 H), 3.93 (d, J ) 3.5, 1 H), 3.57 (m, 1 H),
3.13 (m, 1 H), 2.19-1.12 (m, 13 H); 13C NMR (125.8 MHz) δ
174.13, 73.65, 65.27, 51.97, 41.03, 35.43, 34.98, 25.03, 23.61,
22.79, 20.85; IR (CDCl3) 1684 (s) cm-1; MS (70 eV) m/z 196
(M+ + 1, 11), 195 (M+, 90), 152 (100); TLC Rf 0.23 (EtOAc).
Anal. Calcd for C11H17NO2 (195.26): C, 67.66; H, 8.78; N, 7.17.
Found: C, 67.76; H, 8.78; N, 7.20.
(1S*,6a R*,10a R*)-Oct a h yd r o-1-O-[im id a zoyl(t h ioca r -
bon yl)]-2H-cycloh exa [h ]p yr r olizin -2-on e (26). A solution
of hydroxy lactam (()-24 (71 mg, 0.36 mmol) and 1,1′-
(thiocarbonyl)diimidazole (97 mg, 0.55 mmol) in CH2Cl2 (4 mL)
was heated under reflux for 44 h. The solution was cooled,
the solvent removed in vacuo, and the residue purified by silica
gel column chromatography (80%, EtOAc/hexane) and recrys-
tallization (EtOAc/hexane) to give 44 mg (78%) of xanthate
ester 26 as a white crystalline solid: mp 148-149 °C; 1H NMR
(300 MHz) δ 8.35 (s, 1 H), 7.64 (s, 1 H), 7.00 (s, 1 H), 6.58 (d,
J ) 11.6, 1 H), 3.64 (ddd, J ) 13.8, 5.0, 4.1, 1 H), 3.16 (m, 1
H), 2.39 (br dd, J ) 11.3, 3.2, 1 H), 2.22-1.38 (m, 11 H), 1.27-
1.18 (m, 1 H); 13C NMR (75.5 MHz) δ 184.03, 166.90, 137.00,
130.79, 118.21, 81.63, 64.87, 50.04, 41.35, 35.39, 35.08, 24.90,
23.54, 22.46, 20.84; IR (CCl4) 1721 (s) cm-1; MS (70 eV) m/z
305 (M+, 4), 194 (100). Anal. Calcd for C15H19N3O5S
(305.39): C, 58.99; H, 6.27; N, 13.76; S, 10.50. Found: C,
58.80; H, 6.33; N, 13.65; S, 10.44.
C
16H27NO5 (313.40): C, 61.32; H, 8.68; N, 4.47. Found: C,
61.21; H, 8.74; N, 4.52.
(1R*,6a R*,9a R*)-Octa h yd r o-1-h yd r oxy-2H-cyclop en ta -
[h ]p yr r olizin -2-on e (23). A heterogeneous mixture of nitroso
acetal 16 (251 mg, 0.84 mmol) and methanol-washed Raney
nickel (spatula tip) in methanol (15 mL) was stirred at rt under
1 atm of hydrogen for 37.5 h. The reaction mixture was
filtered through a short pad of silica (30 mm × 40 mm), eluting
with CH2Cl2 (150 mL) to remove the catalyst. The filtrate was
concentrated under reduced pressure, and the residue was
purified by silica gel column chromatography (40%, 60%, 80%,
100% EtOAc/pentane) and recrystallization (EtOAc/pentane)
to yield 116 mg (76%) of hydroxy lactam 23 as a white
crystalline solid: mp 139-140 °C; 1H NMR (300 MHz) δ 5.55
(6a R*,10a R*)-Octa h yd r o-2H-cycloh exa [h ]p yr r olizin -2-
on e (28). To a refluxing solution of xanthate ester 26 (89 mg,
0.29 mmol) in benzene (12.5 mL) was added a solution of Bu3-
SnH (102 µL, 0.35 mmol, 1.2 equiv) and AIBN (10 mg, 0.06
mmol, 5 mol %) in benzene (2.5 mL) over 4 h via syringe pump.
The reaction was then heated under reflux for a further 13.5
h and cooled and the solvent removed in vacuo. The residue
was then purified by silica gel column chromatography (40%,
60%, 80%, 100% EtOAc/hexane) to give 38 mg (73%) of tricyclic

1616 J . Org. Chem., Vol. 63, No. 5, 1998
Denmark and Middleton
lactam 28 as a colorless oil: 1H NMR (300 MHz) δ 3.54-3.47
(m, 1 H), 3.08 (m, 1 H), 2.75 (m, 1 H), 2.29-2.04 (m, 4 H),
1.90-1.83 (m, 1 H), 1.74-1.33 (m, 8 H), 1.19-1.10 (m, 1 H);
13C NMR (125.8 MHz) δ 173.45, 68.95, 43.09, 40.53, 39.17,
35.11, 33.33, 26.30, 25.56, 22.32, 20.53; MS (70 eV) m/z 179
(19), 137 (10), 136 (100), 95 (11), 67 (8), 42 (14).
mL, 5.56 mmol, 2M solution in toluene). The solution was then
stirred at rt for 25 min.
To a solution of methyl (E)-8-nitro-2,8-nonadienoate (E)-2
(296 mg, 1.39 mmol) and (1R,2S)-[(2-phenylcyclohexyl)oxy]-
ethene (-)-29 (842 mg, 4.17 mmol, 3.0 equiv) in CH2Cl2 (5 mL)
at -78 °C was added slowly, dropwise, the freshly prepared
MAPh solution (14 mL, 3.9 mmol, 2.8 equiv). After 40 min,
H2O (20 mL) was added at -78 °C, the cooling bath removed,
and the mixture allowed to stir for 2 min. Water (30 mL) was
then added, the aqueous phase extracted with CH2Cl2 (2 × 60
mL), and the combined organic phase dried (MgSO4). The CH2-
Cl2 was removed in vacuo, and the remaining toluene solution
was heated to 75 °C for 240 min. The mixture was cooled,
the toluene removed in vacuo, and the residue purified by silica
gel column chromatography (10%, 15%, 20%, TBME/pentane)
to afford 545 mg (95%) of nitroso acetal 33 as a colorless,
viscous oil: 1H NMR (300 MHz) δ 7.38-7.13 (m, 5 H), 4.52 (d,
J ) 9.8, 1 H), 4.09 (t, J ) 5.2, 1 H), 3.77 (s, 3 H), 3.71-3.63
(m, 2 H), 2.77 (br dd, J ) 9.6, 3.7, 1 H), 2.57-2.40 (m, 2 H),
1.97-1.17 (m, 18 H); 13C NMR (75.5 MHz) δ 171.29, 144.23,
127.69, 127.59, 125.71, 101.35, 82.28, 81.20, 71.62, 52.02,
51.09, 43.57, 34.07, 32.50, 30.19, 25.99, 25.65, 24.98, 23.65,
21.77, 20.80, 20.03; IR (CCl4) 1734 (s), 1451 (s) cm-1; MS (70
eV) m/z 209 (11), 91 (100); TLC Rf 0.43 (hexane/EtOAc, 7/3).
Anal. Calcd for C24H33NO5 (415.53): C, 69.37; H, 8.01; N, 3.37.
Found: C, 69.52; H, 8.23; N, 3.25.
(-)-(1S,6a S,9a S)-Octa h yd r o-1-h yd r oxy-2H-cyclop en ta -
[h ]p yr r olizin -2-on e ((-)-23). A heterogeneous mixture of
nitroso acetal 31 (161 mg, 0.40 mmol) and methanol-washed
Raney nickel (spatula tip) in methanol (15 mL) was stirred at
room under an atmosphere of hydrogen (160 psi) for 14.5 h.
The reaction mixture was filtered through a short pad of silica
(20 mm × 10 mm, eluting with CH2Cl2 (200 mL)) to remove
the catalyst. The filtrate was concentrated under reduced
pressure, and the residue was purified by silica gel column
chromatography (80%, 100% EtOAc/pentane) to give 70 mg
(98%) of recovered (-)-2-phenylcyclohexanol and 57 mg (78%)
of hydroxy lactam (-)-23 as a white crystalline solid. The
chromatographic and spectroscopic data for hydroxy lactam
(-)-23 were consistent with those for (()-23 isolated from the
reaction of (()-16 and it also displayed [R]D -90.65° (1.0,
CHCl3).
(1R*,6a R*,10a R*)-Oct a h yd r o-1-O-[im id a zoyl(t h ioca r -
bon yl)]-2H-cycloh exa [h ]p yr r olizin -2-on e (27). A solution
of hydroxy lactam (()-25 (40 mg, 0.21 mmol) and 1,1′-
(thiocarbonyl)diimdazole (77 mg, 0.43 mmol, 2.1 equiv) in CH2-
Cl2 (5 mL) was heated under reflux for 16 h. The solution
was cooled, the solvent removed in vacuo, and the residue
purified by silica gel column chromatography (50%, 70%, 80%,
100% EtOAc/hexane) and recrystallization (EtOAc/hexane) to
give 44 mg (78%) of xanthate ester 27 as a white crystalline
solid: mp 141-143 °C; 1H NMR (300 MHz) δ 8.35 (s, 1 H),
7.64 (m, 1 H), 7.06 (m, 1 H), 6.36 (d, J ) 6.7, 1 H), 3.65 (ddd,
J ) 12.3, 8.0, 6.1, 1 H), 3.26 (m, 1 H), 2.46-2.41 (m, 1 H),
2.31-2.17 (m, 2 H), 2.15-1.88 (m, 3 H), 1.79-1.42 (m, 5 H),
1.37-1.11 (m, 2 H); 13C NMR (75.5 MHz) δ 183.36, 167.45,
137.05, 131.08, 118.25, 86.67, 69.03, 44.65, 40.91, 35.06, 34.77,
25.82, 23.13, 22.65, 21.71; IR (KBr) 1694 (s) cm-1; MS (10 eV)
m/z 305 (M+, 7), 194 (100); TLC Rf 0.24 (hexane/EtOAc, 4/1).
Anal. Calcd for C15H19N3O2S (305.39): C, 58.99; H, 6.27; N,
13.76; S, 10.50. Found: C, 58.88; H, 6.29; N, 13.68; S, 10.47.
(6a R*,10a R*)-Octa h yd r o-2H-cycloh exa [h ]p yr r olizin -2-
on e (28). To a refluxing solution of xanthate ester 27 (90 mg,
0.29 mmol) in benzene (12.5 mL) was added a solution of Bu3-
SnH (112 µL, 0.38 mmol) and AIBN (9.8 mg, 0.06 mmol, 5 mol
%) in benzene (2.5 mL) over 4 h by syringe pump. The reaction
was then heated under reflux for a further 14 h and cooled
and the solvent removed in vacuo. The residue was then
purified by silica gel column chromatography (EtOAc) to give
44 mg (85%) of tricyclic lactam 28 as a colorless oil. The
chromatographic and spectroscopic data for 28 were consistent
with those for 28 isolated from the reaction of xanthate 26.
Meth yl (2S,2a S,5a S,8S)-8-[[(1R,2S)-2-P h en ylcycloh ex-
yl]oxy]-1,9-d ioxa -9a -a za cyclop en t [c]in d en e-2-ca r b oxy-
la te (31). To a solution of 2,6-diphenylphenol (2.85 g, 11.60
mmol) in toluene (17.1 mL) at rt was slowly added Me3Al (2.90
mL, 5.80 mmol, 2 M solution in toluene). The solution was
then stirred at rt for 25 min.
(-)-(1S,6a S,9a S)-Octa h yd r o-1-h yd r oxy-2H-cycloh exa -
[h ]p yr r olizin -2-on e ((-)-24). A heterogeneous mixture of
nitroso acetal 33 (247 mg, 0.60 mmol) and methanol-washed
Raney nickel (spatula tip) in methanol (15 mL) was stirred at
room under an atmosphere of hydrogen (160 psi) for 17 h. The
reaction mixture was filtered through a short pad of silica (20
mm × 10 mm, eluting with CH2Cl2 (150 mL)) to remove the
catalyst. The filtrate was concentrated under reduced pres-
sure, and the residue was purified by silica gel column
chromatography (EtOAc) to give 99 mg (94%) of recovered (-)-
2-phenylcyclohexanol and 87 mg (75%) of hydroxy lactam (-)-
24 as a white crystalline solid. The chromatographic and
spectroscopic data for hydroxy lactam (-)-24 were consistent
with those for (()-24 isolated from the reaction of (()-20, and
it also displayed [R]D -83.27° (1.0, CHCl3).
To a solution of methyl (E)-7-nitro-2,7-octadienoate ((E)-1)
(289 mg, 1.45 mmol) and (1R,2S)-[(2-phenylcyclohexyl)oxy]-
ethene (-)-29 (880 mg, 4.36 mmol, 3.0 equiv) in CH2Cl2 (5 mL)
at -78 °C was added slowly, dropwise, the freshly prepared
MAPh solution (15 mL, 4.35 mmol, 3.0 equiv). After 55 min,
H2O (20 mL) was added at -78 °C, the cooling bath removed,
and the mixture allowed to stir for 3 min. CH2Cl2 (30 mL)
and water (50 mL) were then added, the aqueous phase
extracted with CH2Cl2 (2 × 50 mL), and the combined organic
phase dried (MgSO4). The CH2Cl2 was removed in vacuo, and
the remaining toluene solution was heated to 80 °C for 135
min. The mixture was cooled, the toluene removed in vacuo,
and the residue purified by silica gel column chromatography
(10%, 20%, 30% EtOAc/hexane) to give 569 mg (98%) of nitroso
acetal 31 as a white solid as a mixture of diastereomers: mp
111-122 °C. A portion (58 mg) of this material was recrystal-
lized (EtOAc/hexane) to give 47 mg of a highly crystalline white
solid: mp 135-137 °C; 1H NMR (300 MHz) δ 7.27-7.14 (m, 5
H), 4.27 (d, J ) 3.0, 1 H), 3.98 (t, J ) 3.9, 1 H), 3.72 (s, 3 H),
3.69-3.60 (m, 1 H), 3.16-3.13 (m, 1 H), 2.56-2.47 (1 H, m),
2.42-2.38 (1 H, m), 2.03-1.18 (17 H, m); 13C NMR (75.5 MHz)
δ 171.96, 144.58, 127.94, 127.88, 126.08, 100.47, 87.93, 84.08,
81.00, 52.26, 51.42, 47.98, 38.75, 34.08, 32.93, 32.07, 27.70,
(1R*,6a R*,9a R*)-3,5-Din it r o-N-[(oct a h yd r o-2-oxo-2H -
cyclop en ta [h ]p yr r olizin -1-yl)oxy]ben za m id e (32). A so-
lution 3,5-dinitrobenzoyl azide (170 mg, 0.716 mmol) in toluene
(6 mL) was heated under reflux for 10 min. To this was added
a solution of hydroxy lactam (()-23 (108 mg, 0.60 mmol) in
toluene (2 mL) and the mixture refluxed for 75 min during
which time a pale yellow precipitate formed. The solution was
cooled, the solvent removed in vacuo, and the residue was
purified by silica gel column chromatography (50%, 100%,
EtOAc/hexane) and recrystallization (EtOAc/hexane) to give
171 mg (73%) of carbamate (()-32 as a pale yellow crystalline
25.91, 25.25, 25.03, 23.62; IR (KBr) 1728 (s), 1447 (s) cm-1
;
MS (70 eV) m/z 195 (13), 91 (100); TLC Rf 0.49 (major
diastereomer), 0.45 (minor diastereomer) (EtOAc/hexane, 7/3).
Anal. Calcd for C23H31NO5 (401.50): C, 68.80; H, 7.78; N, 3.49.
Found: C, 68.74; H, 7.80; N, 3.52.
Meth yl (2S,2a S,6a S,9S)-9-[(1R,2S)-2-P h en ylcycloh exy-
oxy]-1,10-d ioxa -10a -a za cycloh e x[c]in d e n e -2-ca r b oxy-
la te (33). To a solution of 2,6-diphenylphenol (2.74 g, 11.12
mmol) in toluene (17.2 mL) at rt was slowly added Me3Al (2.78
1
solid: mp 241-243 °C; H NMR (300 MHz) δ 10.14 (br, 1 H),
8.66 (s, 2 H), 8.64 (s, 1 H), 5.55 (d, J ) 10, 1 H), 3.75 (m, 1 H),
3.17 (m, 1 H), 2.87 (m, 1 H), 2.72 (m, 1 H), 2.18 (m, 1 H), 1.95
(m, 1 H), 1.83-1.43 (m, 6 H); 13C NMR (125.8 MHz) δ 171.68,
152.56, 148.71, 141.27, 117.97, 112.48, 78.12, 74.95, 42.37,
41.12, 37.66, 35.63, 26.47, 25.51, 25.11; IR (KBr) 3196 (m),
1740 (s), 1680 (s) cm-1; MS (70 eV) m/z 209 (100); TLC Rf 0.27

Tandem Inter [4 + 2]/Intra [3 + 2] Cycloadditions
J . Org. Chem., Vol. 63, No. 5, 1998 1617
(hexane/EtOAc, 2/1); HPLC tR (()-32 6.93 and 15.28 min
(column B, hexane/EtOAc, 65/35, 1.5 mL/min). Anal. Calcd
for C17H18N4O7 (390.35): C, 52.31; H, 4.65; N, 14.35. Found:
C, 52.29; H, 4.62%, N, 14.33.
δ 7.51-7.47 (m, 2 H), 7.40-7.32 (m, 3 H), 5.38 (d, J ) 9.8, 1
H), 4.90 (s, 1 H), 3.63 (m, 1 H), 3.48 (s, 3 H), 3.11 (m, 1 H),
2.74 (m, 1 H), 2.15-2.03 (m, 2 H), 1.86-1.77 (m, 2 H), 1.63-
1.33 (m, 6 H); 13C NMR (125.8 MHz) δ 170.74, 170.22, 135.72,
128.70, 128.51, 126.87, 82.64, 77.33, 74.84, 57.61, 42.75, 41.02,
37.58, 35.88, 26.11, 25.41, 25.39; IR (KBr) 3457 (m), 1715 (s),
1455 (s) cm-1; MS (70 eV) 121 (100); TLC Rf 0.36 (hexane/
EtOAc, 7/3); HPLC tR 9.28 min (column A, EtOAc/hexane, 1/1,
1.5 mL/min). Anal. Calcd for C19H23NO4 (329.40): C, 69.28;
H, 7.04; N, 4.25. Found: C, 69.25; H, 7.09; N, 4.21.
(1R*,6a R*,10a R*)-3,5-Din itr o-N-[(octa h yd r o-2-oxo-2H-
cycloh exa [h ]p yr r olizin -1-yl)oxy]ben za m id e (34). A solu-
tion 3,5-dinitrobenzoyl azide (158 mg, 0.67 mmol) in toluene
(7 mL) was heated under reflux for 10 min. To this was added
a solution of hydroxy lactam (()-24 (118 mg, 0.61 mmol) in
toluene (2 mL) and the mixture refluxed for 75 min, during
which time a pale yellow precipitate formed. The solution was
cooled, the solvent removed in vacuo, and the residue purified
by silica gel column chromatography (50%, 100% EtOAc/
hexane) and recrystallization (EtOAc/hexane) to yield 223 mg
(91%) of carbamate (()-34 as a pale yellow crystalline solid:
mp 262-265 °C; 1H NMR (300 MHz) δ 10.11 (br s, 1 H), 8.70-
8.63 (m, 3H), 5.62 (d, J ) 6.9, 1 H), 3.64 (ddd, J ) 12.2, 8.0,
6.2, 1 H), 3.17 (m, 1 H), 2.31-2.26 (m, 2 H), 2.10-2.02 (m, 1
H), 1.94-1.20 (m, 10 H); 13C NMR (125.8 MHz) δ 169.47, 152
37, 148.76, 141.24, 117.84, 112.60, 80.31, 70.06, 44.23, 40.50,
35.15, 34.69, 26.03, 22.78, 22.68, 22.26; IR (KBr) 3193 (m),
1738 (s), 1676 (s) cm-1; MS (70 eV) m/z 209 (100); TLC Rf 0.26
(hexane/EtOAc, 2/1); HPLC tR (()-34 9.06 and 17.35 min
(column B, hexane/EtOAc, 7/3, 1.5 mL/min). Anal. Calcd for
1
Data for more polar diastereomer 35b: mp 98-99 °C; H
NMR (300 MHz) δ 7.49-7.45 (m, 2 H), 7.39-7.33 (m, 3 H),
5.40 (d, J ) 9.7, 1 H), 4.93 (s, 1 H), 3.63 (m, 1 H), 3.44 (s, 3 H),
3.13 (m, 1 H), 2.65 (m, 1 H), 2.13-1.98 (m, 2 H), 1.82-1.76
(m, 1 H), 1.66-1.48 (m, 2 H), 1.28-1.06 (m, 4 H), 0.72-0.66
(m, 1 H); 13C NMR (125.8 MHz) δ 170.83, 169.79, 136.10,
128.81, 128.56, 127.41, 81.81, 77.37, 74.96, 57.40, 42.91, 40.98,
37.44, 35.90, 25.58, 25.41, 25 17; MS (70 eV) m/z 121 (100);
TLC Rf 0.26 (hexane/EtOAc, 7/3); HPLC tR 24.30 min (column
A, EtOAc/hexane, 1/1, 1.5 mL/min). Anal. Calcd for C19H23
-
NO4 (329.40): C, 69.28; H, 7.04; N, 4.25. Found: C, 69.14; H,
6.99; N, 4.21.
(1S,6aS,10S)-r-Meth oxyoctah ydr o-2-oxo-2H-cycloh exa-
[h ]p yr r olizin -1-ylben zen ea cetic Acid Ester (36a ) a n d
(1R,6a R,10R)-r-Meth oxyocta h yd r o-2-oxo-2H-cycloh exa -
[h ]p yr r olizin -1-ylben zen ea cetic Acid Ester (36b). To a
solution of DMF (77 µL, 0.93 mmol) in acetonitrile (2 mL) at
0 °C was added oxalyl chloride (63 µL, 0.73 mmol) dropwise.
After 2 min, a solution of (S)-(+)-R-methoxyphenylacetic acid
(110 mg, 0.66 mmol) in acetonitrile (1 mL) was added and the
mixture allowed to stir at 0 °C for 15 min. To this was then
added a solution of hydroxy lactam (()-24 (145 mg, 0.66 mmol)
and pyridine (107 µL, 1.32 mmol, 2 equiv) in acetonitrile (1
mL). After 70 min, CH2Cl2 (20 mL) was added and the organic
layer washed with aqueous saturated CuSO4 solution (2 × 20
mL) and dried (MgSO4). The solvent was removed under
reduced pressure, and the residue was purified by silica gel
column chromatography (40%, 50%, 60%, 70% EtOAc/pentane)
to give 63 mg (28%) of 36a and 89 mg (39%) of 36b as a
separable mixture of diastereomers.
C
18H20N4O7 (404.38): C, 53.46; H, 4.99; N, 13.86. Found: C,
53.35; H, 4.94; N, 13.83.
(-)-(1S,6a S,9a S)-3,5-Din itr o-[(octa h yd r o-2-oxo-2H-cy-
clop en t a [h ]p yr r olizin -1-yl)oxy]ben za m id e ((-)-32).
A
solution 3,5-dinitrobenzoyl azide (25 mg, 0.11 mmol) in toluene
(2 mL) was heated under reflux for 10 min. To this was added
a solution of hydroxy lactam (-)-23 (16 mg, 0.09 mmol) in
toluene (1 mL) and the mixture refluxed for 110 min during
which time a solid precipitated. The solution was cooled, the
solvent removed in vacuo, and the residue purified by silica
gel column chromatography (50%, 70%, 100% EtOAc/hexane)
to give benzamide 32 24 mg (71%) as a white solid. The
chromatographic and spectroscopic data for benzamide (-)-
32 were consistent with those for (()-32 isolated from the
reaction of (()-23: TLC Rf 0.30 (hexane/EtOAc, 1/1); HPLC
tR (1R)-32, 7.08 min (8.2%); tR (1S)-32, 15.20 min (91.8%)
(column B, hexane/EtOAc, 65/35, 1.5 mL/min).
Data for less polar diastereomer 36a (contaminated with
an inseparable, unidentified, impurity): 1H NMR (300 MHz)
δ 7.46-7.31 (m, 5 H), 5.40 (d, J ) 6.6, 1 H), 4.86 (s, 1 H), 3.60-
3.51 (m, 1 H), 3.46 (s, 3 H), 3.18 (m, 1 H), 2.23-1.07 (m, 13
H); 13C NMR (100 MHz) δ 170.08, 160.06, 135.64, 128.71,
128.58, 126.90, 82.81, 80.17, 69.01, 57.11, 44.56, 40.58, 35.10,
34.50, 25.85, 22.85, 22.30, 1.97; IR (CCl4) 1736 (s), 1709 (s)
cm-1; MS (70 eV) m/z 122 (15), 121 (100); TLC Rf 0.28 (hexane/
EtOAc, 3/2). Data for more polar diastereomer 36b: mp
120.5-121 °C; 1H NMR (300 MHz) δ 7.47-7.28 (m, 5 H), 5.53
(d, J ) 6.7, 1 H), 4.84 (s, 1 H), 3.61-3.45 (m, 1 H), 3.43 (s, 3
H), 3.21-3.12 (m, 1 H), 2.20-2.04 (m, 3 H), 1.89-1.82 (m, 1
H), 1.50-1.18 (m, 6 H), 1.03-0.85 (m, 2 H), 0.25-0.16 (m, 1
H); 13C NMR (125 MHz) δ 169.64, 168.91, 135.83, 128.86,
128.61, 127.62, 82.23, 79.96, 69.00, 57.63, 44.66, 40.55, 34.97,
33.62, 25.77, 22.23, 21.52, 20.96; MS (70 eV) m/z 299 (4), 121
(100); TLC Rf 0.19 (hexane/EtOAc, 3/2). Anal. Calcd for
(-)-(1S,6a S,10a S)-3,5-Din itr o-N-[(octa h yd r o-2-oxo-2H-
cycloh exa [h ]p yr r olizin e-1-yl)oxy]ben za m id e ((-)-34). A
solution of 3,5-dinitrobenzoyl azide (15 mg, 0.06 mmol) in
toluene (1 mL) was heated under reflux for 10 min. To this
was added a solution of hydroxy lactam (-)-24 (10 mg, 0.05
mmol) in toluene (1 mL), and the mixture was heated to reflux
for 65 min. The solution was cooled, the solvent removed in
vacuo, and the residue purified by silica gel column chroma-
tography (50%, 70%, 100% EtOAc/hexane) to give carbamate
(-)-34 (19 mg, 91%) as an off-white solid. The chromato-
graphic and spectroscopic data for carbamate (-)-34 were
consistent with those for (()-34 isolated from the reaction of
(()-34: TLC Rf 0.22 (hexane/EtOAc, 1/1); HPLC tR (1R)-34,
9.3 min (5.6%); tR (1S)-34, 17.2 min (94.4%) (column B, 30%
hexane/EtOAc, 7/3, 1.8 mL/min).
(1S,6a S,9a S)-r-Meth oxyocta h yd r o-2-oxo-2H-cyclop en -
ta [h ]p yr r olizin -1-ylben zen ea cetic Acid Ester (35a ) a n d
(1R,6a R,9a R)-r-Meth oxyocta h yd r o-2-oxo-2H-cyclop en ta -
[h ]p yr r olizin -1-ylben zen ea cetic Acid Ester (35b). To a
solution of DMF (93 µL, 1.20 mmol) in acetonitrile (3 mL) at
0 °C was added oxalyl chloride (77 µL, 0.88 mmol) dropwise.
After 2 min, a solution of (S)-(+)-R-methoxyphenylacetic acid
(133 mg, 0.80 mmol, 1 equiv) in acetonitrile (1 mL) was added
and the mixture allowed to stir at 0 °C for 15 min. To this
was then added a solution of hydroxy lactam (()-23 (145 mg,
0.80 mmol) and pyridine (129 µL, 1.60 mmol, 2 equiv) in
acetonitrile (1 mL). After 55 min, CH2Cl2 (30 mL) was added
and the organic layer washed with aqueous saturated CuSO4
solution (2 × 30 mL) and dried (MgSO4). The solvent was
removed under reduced pressure, and the residue was purified
by silica gel column chromatography (40%, 50%, 605, 70%
EtOAc/pentane) to give 105 mg (40%) of 35a and 118 mg (45%)
of 35b as a separable mixture of diastereomers. Data for less
polar diastereomer 35a : mp 101-102 °C; 1H NMR (300 MHz)
C
20H25NO4 (343.42): C, 69.95; H, 7.34; N, 4.08. Found: C,
69.80; H, 7.33; N, 3.99.
(1S,6a S,9a S)-r-Meth oxyocta h yd r o-2-oxo-2H-cyclop en -
ta [h ]p yr r olizin -1-ylben zen ea cetic Acid Ester (35a ). To
a solution of (S)-(+)-R-methoxyphenylacetyl chloride (13 mg,
0.07 mmol) in CH2Cl2 (2 mL) at 0 °C was added a solution of
hydroxy lactam (-)-51 (11 mg, 0.06 mmol) and pyridine (10
µL, 0.12 mmol, 2 equiv) in CH2Cl2 (0.2 mL). After 65 min,
CH2Cl2 (5 mL) was added and the organic phase washed with
aqueous copper sulfate solution (2 × 5 mL). The aqueous
phase was reextracted with CH2Cl2 (5 mL) and dried and the
solvent removed under reduced pressure. The residue was
purified by silica gel column chromatography (40%, 50%, 60%
EtOAc/hexane) to give 14 mg (70%) of mandelate ester 35a .
The chromatographic and spectroscopic data for mandelate
35a were consistent with those for the less polar diastereomer
35a derived from the reaction of (()-23.

1618 J . Org. Chem., Vol. 63, No. 5, 1998
Denmark and Middleton
(1S,6aS,10S)-r-Meth oxyoctah ydr o-2-oxo-2H-cycloh exa-
[h ]p yr r olizin -1-ylben zen ea cetic Acid Ester (36a ). To a
solution of (S)-(+)-R-methoxyphenylacetyl chloride (12.5 mg,
0.07 mmol) in CH2Cl2 (0.7 mL) at 0 °C was added a solution
of hydroxy lactam (-)-24 (12 mg, 0.06 mmol) and pyridine (10
µL, 0.12 mmol) in CH2Cl2 (0.5 mL). After 70 min, CH2Cl2 (5
mL) was added and the organic phase washed with aqueous
copper sulfate solution (2 × 5 mL). The aqueous phase was
reextracted with CH2Cl2 (5 mL) and dried and the solvent
removed under reduced pressure. The residue was purified
by silica gel column chromatography (40%, 50%, 60% EtOAc/
hexane) to give 11 mg (52%) of mandelate ester 36a . The
chromatographic and spectroscopic data for mandelate 36a
were consistent with those for the less polar diastereomer 36a
derived from the reaction of (()-24.
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (GM-30938) for generous financial
support. We also thank Alexander R. Hurd for a critical
reading of the manuscript.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal details, complete 1H and 13C NMR assignments, and IR
and MS data for all characterized compounds (9 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O9719057