Predicting the diastereoselectivity of Rh-mediated intramolecular C-H insertion

Article abstract of DOI:10.1021/ja9515213

Rhodium-mediated cyclization of the α-diazo ester 1 proceeds with high diastereoselectivity, to give the trisubstituted cyclopentane 5. A computational model (ZINDO and Molecular Mechanics) based on our current mechanistic understanding of the reaction is presented. This model correctly predicts the dominant diastereomer from the cyclization of 1 and the eight (Table 2) other α-diazo esters studied thus far.

Full text of DOI:10.1021/ja9515213

J. Am. Chem. Soc. 1996, 118, 547-556
547
Predicting the Diastereoselectivity of Rh-Mediated
Intramolecular C-H Insertion
Douglass F. Taber,* Kamfia K. You, and Arnold L. Rheingold
Contribution from the Department of Chemistry and Biochemistry, UniVersity of Delaware,
Newark, Delaware 19716
ReceiVed May 10, 1995X
Abstract: Rhodium-mediated cyclization of the R-diazo ester 1 proceeds with high diastereoselectivity, to give the
trisubstituted cyclopentane 5. A computational model (ZINDO and Molecular Mechanics) based on our current
mechanistic understanding of the reaction is presented. This model correctly predicts the dominant diastereomer
from the cyclization of 1 and the eight (Table 2) other R-diazo esters studied thus far.
Introduction
the construction of highly-alkylated cyclopentanes with control
of both relative and absolute configuration. As enantiomerically
pure acyclic fragments of high enantiomeric purity are readily
available, one way to fill this gap would be to develop methods
for cyclization that proceed with high diastereoselectivity relative
to existing stereogenic centers that are then included in the ring.
We now report that the Rh-mediated cyclizations2-5 of substi-
tuted R-diazo esters 1, 2, 3, and 4 do indeed proceed with the
desired high diastereoselectivity. We also present a computa-
tional model,5-7 based on the cyclization of the R-diazo ester
1, that accurately predicted the dominant diastereomer from the
cyclization of the R-diazo esters 2, 3, 4, and 42.
The development of new methods for the stereocontrolled
construction of carbocycles is fundamental to the development
of target-directed organic synthesis. While many approaches
for the preparation of enantiomerically-pure cyclopentanes have
been put forward,1 there is still a need for general strategies for
X Abstract published in AdVance ACS Abstracts, January 1, 1996.
(1) For leading references to alternative methods for the enantioselective
construction of highly substituted cyclopentanes, see: (a) Allan, R. D.;
Johnston, G. A. R.; Twitchin, B. Aust. J. Chem. 1979, 32, 2517. (b)
Takahashi, T.; Naito, Y.; Tsuji, J. J. Am. Chem. Soc. 1981, 103, 5261. (c)
Colombo, L.; Gennari, C.; Resnati, G.; Scolastico, C. Synthesis, 1981, 74.
(d) Arita, M.; Adachi, K.; Ito, Y.; Sawai, H.; Ohno, M. J. Am. Chem. Soc.
1983, 105, 4048. (e) Ziegler, F. E.; Mencel, J. J.; Tetrahedron Lett. 1983,
1859. (f) Ritterskamp, P.; Demuth, M.; Schaffner, K. J. Org. Chem. 1984,
49, 1155. (g) Marino, J. P.; Fernandez de la Pradilla, R.; Laborde, E. J.
Org. Chem. 1984, 5280. (h) Block, E.; Wall, A.; Zubieta, J. J. Am. Chem.
Soc. 1985, 107, 1783. (i) Binns, M. R.; Goodridge, R. J.; Haynes, R. K.;
Ridley, D. D. Tetrahedron Lett. 1985, 6381. (j) Shirai, R.; Tanaka, M.;
Koga, K. J. Am. Chem. Soc. 1986, 108, 543. (k) Posner, G. H.; Switzer, C.
J. Am. Chem. Soc. 1986, 108, 1239. (l) Johnson, C. R.; Penning, T. D. J.
Am. Chem. Soc. 1986, 108, 5655. (m) Stork, G.; Sher, P. M.; Chen, H. L.
J. Am. Chem. Soc. 1986, 108, 6384. (n) Corey, E. J.; Naef, R.; Hannon, F.
J. J. Am. Chem. Soc. 1986, 108, 7116. (o) Meyers, A. I.; Lefker, B. A. J.
Org. Chem. 1986, 51, 1541. (p) Hua, D. H.; Venkataraman, S.; Coulter,
M. J.; Sinai-Zingde, G. J. Org. Chem. 1987, 52, 719. (q) Burgess, K. J.
Org. Chem. 1987, 52, 2046. (r) Klunder, A. J. H.; Huizinga, W. B.; Sessnik,
P. J. M.; Zwanenburg, B. Tetrahedron Lett. 1987, 28, 357. (s) Smith, A.
B., III; Dunlap, N. K.; Sulikowski, G. A. Tetrahedron Lett. 1988, 439. (t)
Trigalo, F.; Buisson, D.; Azerad, R. Tetrahedron Lett. 1988, 29, 6109. (u)
Llera, J. M.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 5544. (v) Snider, B.
B.; Ke, Y. Tetrahedron Lett. 1989, 30, 2465. (w) Burkholder, T. P.; Fuchs,
P. L. J. Am. Chem. Soc. 1990, 112, 9601. (x) Stafford, J. A.; Heathcock, C.
H. J. Org. Chem. 1990, 55, 5433. (y) Brown, R. T.; Ford, M. J. Tetrahedron
Lett. 1990, 2029. (z) Asaoka, M.; Hayashibe, S.; Sonoda, S.; Takei, H.
Tetrahedron Lett. 1990, 31, 4761. (aa) King, S. B.; Ganem, B. J. Am. Chem.
Soc. 1991, 113, 5089. (bb) Brown, M. J.; Harrison, T.; Overman, L. E. J.
Am. Chem. Soc. 1991, 113, 5378. (cc) Taber, D. F.; Silverberg, L. J.;
Robinson, E. D. J. Am. Chem. Soc. 1991, 113, 6639. (dd) Chadha, N. K.;
Batcho, A. D.; Tang, P. C.; Courtney, L. F.; Cook, C. M.; Wovkulich, P.
M.; Uskokovic, M. R. J. Org. Chem. 1991, 56, 4714. (ee) Fang, C. L.;
Suemune, H.; Sakai, K. J. Org. Chem. 1992, 57, 4300. (ff) Quinkert, G.;
Muller, T.; Koniger, A.; Schultheis, O.; Sickenberger, B.; Durner, G.
Tetrahedron Lett. 1992, 33, 3469. (gg) Kigoshi, H.; Imamura, Y.; Mizuta,
K.; Niwa, H.; Yamada, K. J. Am. Chem. Soc. 1993, 115, 3056. (hh)
Hanessian, S.; Gomtsyan, A.; Payne, A.; Herve, Y.; Beaudoin, S. J.
Org.Chem. 1993, 58, 5032. (ii) Henly, R.; Elie, C. J. J.; Buser, H. P.; Ramos,
G.; Moser, H. E. Tetrahedron Lett. 1993, 34, 2923. (jj) Doyle, M. P.;
Dyatkin, A. B.; Roos, G. H. P.; Canas, F.; Pierson, D. A.; van Basten, A.
J. Am. Chem. Soc. 1994, 116, 4507. (kk) Sasai, H.; Arai, T.; Shibasaki, M.
J. Am. Chem. Soc. 1994, 116, 1571. (ll) Koch, A.; Reymond, J. L.; Lerner,
R. A. J. Am. Chem. Soc. 1994, 116, 803. (mm) Trost, B. M.; Bunt, R. C.
J. Am. Chem. Soc. 1994, 116, 4089. (nn) Mashima, K.; Kusano, K.; Sato,
N.; Matsumura, Y.; Nozaki, K.; Kumobayashi, H.; Sayo, N.; Hori, Y.;
Ishizaki, T.; Akutagawa, S.; Takaya, H. J. Org. Chem. 1994, 59, 3064.
(oo) Berl, V.; Helmchen, G.; Preston, S. Tetrahedron Lett. 1994, 35, 233.
(pp) Zhu, J.; Klunder, A. J. H.; Zwanenburg, B. Tetrahedron Lett. 1994,
35, 2787.
Not all Rh-mediated intramolecular C-H insertion reactions
will proceed to give a single dominant diastereomer. Our
(2) For a detailed account of regioselectivity and diastereoselectivity in
the Rh-mediated cyclization of R-diazo â-keto esters, see: Taber, D. F.;
Ruckle, R. E., Jr. J. Am. Chem. Soc. 1986, 108, 7686.
0002-7863/96/1518-0547$12.00/0 © 1996 American Chemical Society

548 J. Am. Chem. Soc., Vol. 118, No. 3, 1996
Taber et al.
Scheme 1
Scheme 2
With 11 in hand, we needed to effect R-diazo transfer.9
Formylation of 11 followed by diazo transfer was not successful.
However, we found that diazo transfer could be accomplished
by first benzoylating10 the ester enolate, then cleaving the
benzoyl group with DBU11 and 4-nitrobenzenesulfonylazide12
to afford 1.
Cyclization of 1 proceeded smoothly to give 5 as a single
1
diastereomer (>95% pure by 13C NMR). As the H NMR of
interest in this initial investigation has been to develop a model
for the transition state that will allow us to discern those
cyclizations that will proceed with high diastereoselectivity.
5 was ambiguous, the relative configuration of 5 was established
by X-ray analysis of the derived 4-bromobenzenesulfonate 12.
Preparation and Cyclization of r-Diazo Ester 2. To
prepare 2, we started with the bromo ester 13 (Scheme 2).
Condensation of the derived phosphorane with propiophenone
followed by hydrogenation gave ester 14. Benzoylation by the
procedure described above gave a mixture of methyl and ethyl
esters, which was then fully exchanged to the methyl ester before
diazo transfer. Cyclization of 2 proceeded to give 6 as the
dominant diastereomer observed (>95% pure by 13C NMR).
The relative configuration of 6 was assigned on the basis of
1H and 13C chemical shifts. Thus, the phenyl and the methyl
must be trans, as the methyl resonates at δ 0.95. If the methyl
and the phenyl were cis one to another, the methyl group would
be expected to be shifted significantly upfield.13
The relationship between the methyl group and the ester was
also assigned to be trans on the basis of the 13C chemical shift
of the methine carbon bearing the ester. The known3,14 trans
and cis 2-octyl cyclopentanecarboxylates have methine carbons
at δ 50.4 and 46.5, respectively. That the ester-bearing methine
in 6 resonates at δ 51.6 supports the trans assignment.
Results
Preparation and Cyclization of R-Diazo Ester 1. The
requisite ester 11 (Scheme 1) was prepared by alkylation of
ethyl phenylacetate 9 with 1-bromopropane. Coupling of the
tosylate of the derived alcohol 10 with allyl magnesium chloride
proceeded smoothly, to give the alkene. Ozonolysis followed
by oxidation8 then gave 11. We found that this homologation
sequence was more rapid and efficient than alternatives based
on malonate or acetate anion alkylation.
(3) (a) For the first observation of the efficient cyclization of simple
R-diazo esters, see: Taber, D. F.; Hennessy, M. J.; Louey, J. P. J. Org.
Chem. 1992, 57, 436. (b) For the first report of the cyclization of
(enantiomerically pure) 3 to 7, in the context of a total synthesis of the
Dendrobatid alkaloid 251F, see: Taber, D. F.; You, K. K. J. Am. Chem.
Soc. 1995, 117, 5757.
(4) For leading references to other studies of Rh-mediated intramolecular
C-H insertion, see: (a) Doyle, M. P.; Dyatkin, A. B.; Roos, G. H. P.;
Canas, F.; Pierson, D. A.; van Basten, A.; Mu¨ller, P.; Polleux, P. J. Am.
Chem. Soc. 1994, 116, 4507. (b) Wang, P.; Adams, J. J. Am. Chem. Soc.
1994, 116, 3296. (c) Doyle, M. P. In Homogeneous Transition Metal
Catalysts in Organic Synthesis; Moser, W. R., Slocum, D. W., Eds.; ACS
Advanced Chemistry Series 230; American Chemical Society: Washington,
D.C., 1992; Chapter 30. (d) Taber, D. F. ComprehensiVe Organic Synthesis;
Pattenden, G., Ed., Pergamon Press: Oxford, 1991; Vol. 3, p 1045. (e)
Padwa, A.; Austin, D. J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1797.
(5) For related analyses of transition states for Rh carbene insertions,
see: (a) Doyle, M. P.; Westrum, L. J.; Wolthius, W. N. E.; See, M. M.;
Boone, W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc. 1993, 115,
958. (b) Brown, K. C.; Kodadek, T. J. Am. Chem. Soc. 1992, 114, 8336.
(c) Pirrung, M. C.; Morehead, A. T., Jr. J. Am. Chem. Soc. 1994, 116,
8991. (d) Davies, H. M. L.; Huby, N. J. S.; Cantrell, W. R., Jr.; Olive, J.
L. J. Am. Chem. Soc. 1993, 115, 9468.
(6) Both ZINDO and molecular mechanics were used as implemented
on the Tektronix CAChe workstation. For leading references to ZINDO, a
semiempirical program that has been paramatrized for the first two rows
of transition metals, see: (a) Zerner, M. C.; Loew, G. W.; Kirchner, R. F.;
Mueller-Westerhoff, U. T. J. Am. Chem. Soc. 1980, 102, 589. (b) Anderson,
W. P.; Cundari, T. R.; Drago, R. S.; Zerner, M. C. Inorg. Chem. 1990, 29,
1.
Preparation and Cyclization of r-Diazo Ester 3. The
preparation of 3 started with the enantiomerically pure â-hy-
droxy ester 16 (Scheme 3), which we had prepared previously.1cc
Ethylation following the procedure of Frater15 gave the anti ester,
(9) For an overview of diazo transfer chemistry, see: (a) Regitz, M.;
Maas, G. Diazo Compounds: Properties and Synthesis; Academic Press:
Orlando, 1986. (b) Askani, R.; Taber, D. F. ComprehensiVe Organic
Synthesis; E. Winterfeldt, Ed., Pergamon: Oxford, 1991; Vol. 6, p 103.
(10) (a) For benzoylation of a ketone followed by diazo transfer, see:
Metcalf, B. W.; Jund, K.; Burkhart, J. P. Tetrahedron Lett. 1980, 21, 15.
(b) More recently, trifluoroacetylation has been used to activate ketones
for diazo transfer: Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S.
Z. J. Org. Chem. 1990, 55, 1959.
(11) For the use of DBU to promote diazo transfer, see: (a)Baum, J. S.;
Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth. Commun. 1987, 17,
1709. (b) Koteswar Rao, Y.; Nagarajan, M. J. Org. Chem. 1989, 54, 5678.
(12) (a) Evans, seeking azide transfer, reported occasional partial
conversion of an ester enolate to the R-diazo ester: Evans, D. A.; Britton,
T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011. (b)
We have optimized this procedure: Taber, D. F.; You, K.; Song, Y. J.
Org. Chem. 1995, 60, 1093.
(7) For an analogous experimental/computational study of intramolecular
diene cyclozirconation, see: Taber, D. F.; Louey, J. P.; Wang, Y.; Nugent,
W. A.; Dixon, D. A.; Harlow, R. L. J. Am. Chem. Soc. 1994, 116, 9457.
(8) Williams, D. R.; Klingler, F. D.; Allen, E. E.; Lichtenthaler, F. W.
Tetrahedron Lett. 1988, 29, 5087.
(13) Taber, D. F.; Meagley, R. P. Tetrahedron Lett. 1994, 35, 7909.
(14) Louey, James P. Ph.D. Dissertation, University of Delaware, 1994.
(15) Frater, G. HelV. Chim. Acta 1979, 62, 2825.

DiastereoselectiVity of Rh-Mediated Cyclization
J. Am. Chem. Soc., Vol. 118, No. 3, 1996 549
which on reduction and protection gave the acetonide 17.
Oxidative cleavage, as above, followed by diazo transfer then
gave 3.
Scheme 3
Cyclization of 3 proceeded cleanly, to give 7 as the only
diastereomer observed (>95% pure by 13C NMR before
chromatographic separation). The relative configuration of 7
was assigned by a combination of COSY and NOE techniques.
The most significant observations were a 4.1% NOE between
the methyl group and the equatorial H at C-7 and a 5.7% NOE
between the methyl group and the H at C-2. The lack of an
NOE between the ring fusion H’s confirmed the trans ring
fusion. Given the rigid nature of the chair conformation of the
six-membered ring, these observations then secure the relative
configuration of 7. This facile preparation of a polyalkylated
cyclopentane with control of relative and (through the use of
the readily available enantiomerically pure starting material)
absolute configuration underscores the likely utility of this
approach in target-directed synthesis.
Preparation and Cyclization of r-Diazo Ester 4. We
prepared the complementary R-diazo ester 4 (Scheme 4) from
butyraldehyde 19 by aldol condensation followed again by
Frater15 alkylation. It is noteworthy that in this case the
cyclization proceeded to give 8 (>95% pure by 13C NMR),
which is not the most stable diastereomer of the product. That
the single dominant diastereomer from the cyclization was in
fact 8 was confirmed by deprotection with spontaneous lacton-
ization to give 23.
Scheme 4
NOE studies supported our assignment of structure 23 to the
product from deprotection of acetonide 8. The cis nature of
the ring fusion was demonstrated by a 3.8% NOE between the
two ring fusion hydrogens. An NOE of 6.1% between the ring
fusion hydrogen R to the carbonyl and the adjacent methyl group
confirms that the methyl group is exo on the bicyclic system.
The diastereotopic protons of the single methylene could be
distinguished. One showed a 9.7% NOE to the methyl group,
and the other showed a 4.5% NOE to the proton a to the
hydroxyl group. Finally, that same proton R to the hydroxyl
group did not show an NOE with the ring fusion methine.
with concomitant loss of N2 would then give the intermediate
Rh carbene complex 27.
The mechanism by which this intermediate Rh carbene
complex 27 reacts can be more easily understood if it is written
as the inverted ylide 28. This species would clearly be
electrophilic at carbon. The initial complex of the electron-
deficient carbon with the electron density in the target C-H
could be depicted (29) as a three-center, two-electron bond.5a
We hypothesized that this complexation would be rapid and
reversible,16 and that for bond formation to proceed, a somewhat
different transition state (30), in which the C-Rh bond is
aligned with the target C-H bond, would be required. As the
C-H insertion reaction proceeded, the electron pair in the C-H
bond would drop down to form the new C-C bond, and at the
same time the electron pair in the C-Rh bond would slide over
Discussion
Mechanism of the Cyclization. An understanding of the
mechanism4,5 for Rh-mediated intramolecular C-H insertion
begins with the recognition that these R-diazo carbonyl deriva-
tives can also be seen as the stabilized ylides, such as 24
(Scheme 5). The catalytic Rh(II) carboxylate 25 is Lewis acidic,
with vacant coordination sites at the apical positions. Com-
plexation of the electron density at the diazo carbon with an
open Rh coordination site would give 26. Back donation of
electron density from the proximal Rh to the carbene carbon5c
(16) For reversible Rh complexation with a C-H bond, see: (a) Weiller,
B. H.; Wasserman, E. P.; Bergman, R. G.; Moore, C. B.; Pimentel, G. C.
J. Am. Chem. Soc. 1989, 111, 8288. (b) Wasserman, E. P.; Moore, C. B.;
Bergman, R. G. Science 1992, 255, 315.

550 J. Am. Chem. Soc., Vol. 118, No. 3, 1996
Taber et al.
Scheme 5
the six-membered ring), whereas in 34 the Rh carbene is pointed
toward the flip of the incipient cyclopentane ring (a “boat-like”
transition state). As 1 (Scheme 1) cyclizes to 5, in which the
methyl and the phenyl are on the same face of the cyclopentane,
we concluded that at the point of commitment to product
formation, the transition state leading to cyclization is chair-
like (33, Chart 1) rather than boat-like (34).
Application of the Computational Model
Cyclization of r-Diazo Esters. There are four chair-like
diastereomeric transition states for the cyclization of 1, 35, 36,
38, and 40 (Table 1), each leading to one of the four possible
diastereomeric products. With the Rh catalyst locked and the
angles and bonds as stated, we minimized each of the four
transition states with molecular mechanics.6 Transition state
35 was found to be the lowest in energy, by 5.3 kcal/mol
compared to the next most stable. This contrasts with the
relative stability of the four diastereomeric products, 5, 37, 39,
and 41 (Table 1), which are quite comparable one to another.
For each of the other R-diazo esters (Table 2), this compu-
tational approach reliably predicted the dominant diastereomer
from the cyclization. It is noteworthy that in the case of 4, the
computational method predicted that 8, not the most stable
diastereomer of the product, should be the one produced. This
was, in fact, observed (Scheme 4).
Cyclization of r-Diazo â-Keto Esters. We had previously
reported2 diastereoselectivity in the cyclization of R-diazo â-keto
esters. These results are summarized in Table 2, Entries 5-8.
We have found that the computational approach outlined above
can be extended to these systems also. Entries 6-8 delineate
the lower limit of this computational approach: when the two
most favorable diastereomeric transition states are found to differ
by less than 2.0 kcal/mol, the cyclization may not proceed with
high diastereoselectivity.
Again, for this computational approach to be at all meaning-
ful, it is requisite that the four diastereomeric transition states
(30, Scheme 5) be fully equilibrating, that is, that the complex-
ation of the Rh carbene with the target C-H must be rapidly
reversible.16 The correlation between the computational and
experimental results presented here does not conclusively
demonstrate such equilibration. It remains to be seen as we
extend this approach to other substituted R-diazo esters whether
the correlation is maintained.
Electron-Withdrawing Effects of Remote Substituents.
The observance of alkene 15 from the cyclization of 2 underlines
a key consideration that governs the use of Rh-mediated
intramolecular C-H insertion in target-directed synthesis. We2
and others4,19 have observed that a proximal electron-withdraw-
ing group will attenuate the reactivity of a target C-H bond.
In 1, the electron-withdrawing phenyl group inhibits â-hydride
elimination, and the cyclization proceeds efficiently. In 2, the
electron-withdrawing phenyl group inhibits intramolecular C-H
insertion, and the (no longer inhibited) â-hydride elimination
proceeds at a competitive rate.
to form the new C-H bond. This would give the product (31)
and release the initial Rh species 25, completing the catalytic
cycle. We have used this hypothetical transition state (30) to
predict the stereochemical course of the intramolecular Rh-
mediated C-H insertion reaction and have found it to be
effectively predictive.
The actual product from a cyclization will be determined as
the intermediate carbene commits to a particular diastereomeric
transition state. If these diastereomeric transition states are
indeed in full thermal equilibrium, then computational modeling
of the diastereomeric transition states (30) could allow us to
predict which would be favored, and thus which diastereomeric
product would be formed.
Development of the Computational Model. To construct
17
the transition state 30,6,7 we minimized Rh2(OAc)4 with
ZINDO and locked the resultant bond lengths and bond angles.
To maintain the expected carbene geometry, we locked the Rh-
Rh-C bond angle at 180°. To secure overlap between the
C-Rh bond and the target C-H bond, we established weak
bonds (meaningful in molecular mechanics) between the two
incipiently bonding carbons and between the target H and the
proximal Rh. As Mechanics tends to rehybridize weakly bonded
carbons, we also found it necessary to lock the H-C-C-C
dihedral angle of the target C-H at 60° (or, in the inverted
transition state, -60°), to maintain sp3 geometry.
The cyclization of 4 is the first example of Rh-mediated
intramolecular C-H insertion of an R-diazo ester having a
â-ternary center. The methine C-H of the ternary center is
much more electron rich, and so much more susceptible to
elimination,3 than the C-H of a methylene. In the case of 4,
there are, by design, two electron-withdrawing ether oxygens
γ to the carbonyl and thus â to the C-H, making it less electron
rich and thus less likely to eliminate.20
There are still two possibilities for the transition state,
illustrated (Chart 1) for the rhodium carbene derived from the
R-diazo ester 1. In transition state 33, the Rh carbene is pointed
away from the flip of the incipient cyclopentane ring (a “chair-
like” transition state, counting the five carbons and the Rh in
(17) We used Rh(II)2(acetate)4 in the model, and Rh(II)2(octanoate)4 in
the cyclizations. While the computational predictions are consistent with
the experimental obervations (Tables 1 and 2), we2 and others18 have shown
that ligand substitution can affect the diastereoselectivity of Rh-mediated
intramolecular C-H insertion.
(19) Stork, G.; Nakatani, K. Tetrahedron Lett. 1988, 29, 2283.
(20) Note that while an H â to an ether is deactivated for Rh-mediated
insertion, the R-H of an ether is activated.4b
(18) Hashimoto, S.-i.; Watanabe, N.; Ikegami, S. Tetrahedron Lett. 1992,
33, 2709.

DiastereoselectiVity of Rh-Mediated Cyclization
J. Am. Chem. Soc., Vol. 118, No. 3, 1996 551
Chart 1
Table 1. Calculated Relative Energies of Transition States and
Products
guided by the combined computational and experimental
approach outlined here, should become a useful tool in the
armamentarium of the organic synthesis chemist. Nevertheless,
the work outlined here is only a bare beginning. While it
appears to be possible, with this approach, to pick out those
R-diazo esters that will cyclize with high diastereoselectivity,
the method put forward is not sufficient to distinguish small
differences in energy between closely competing transition
states. We eagerly await the more precise computational
methods that might effectively address these small differences.
∆
∆
Experimental Section22
Calculations. Structure minimization was carried out using mo-
lecular mechanics and ZINDO programs provided in the Tektronics
CAChe System, Version 2.8. CAChe uses an augmented version of
Allinger’s MM2 force field.
2-Phenylpentan-1-ol (10). n-Butyllithium (26.6 mL, 63.3 mmol,
2.38 M in hexane) was added to a stirring solution of diisopropylamine
(9.5 mL, 68.21 mmol) in THF (120 mL) at -78 °C. After 10 min,
ethyl phenylacetate (9); (8.0 g, 48.7 mmol) and 1-bromopropane (7.19
g, 58.5 mmol) were added sequentially to the reaction mixture. The
mixture was stirred with warming to room temperature over 12 h. The
reaction mixture was quenched with saturated aqueous NH4Cl (100
mL) and diluted with ethyl ether (70 mL). The organic layer was
separated and the aqueous layer was extracted with 1:3 ethyl acetate/
petroleum ether (3 × 60 mL). The combined organic extract was dried
(Na2SO4), concentrated, and chromatographed to yield the alkylated
ester (7.08 g) as a pale yellow oil, TLC Rf ) 0.71 (10% ethyl acetate/
petroleum ether). 1H NMR (δ): 7.43-7.20 (m, 5 H), 4.18-3.99 (m,
2 H), 3.56 (t, J ) 7.3 Hz, 1 H), 2.01 (m, 1 H), 1.77 (m, 1 H), 1.31 (m,
2 H), 1.27 (t, J ) 7.1 Hz, 3 H), 0.93 (t, J ) 7.2 Hz, 3 H). 13C NMR
(δ): d: 13.79, 14.11, 51.53, 127.0, 127.9, 128.5; u 20.72, 35.69, 60.57,
139.4, 174.1. IR (cm-1): 3027, 2930, 2872, 1738, 1603, 1494, 1453,
1164. MS (m/z, %): 206 (M+, 15), 164 (100), 133 (79), 104 (43).
HRMS calcd for C13H18O2 206.1307, found 206.1266.
Lithium aluminum hydride (2.22 g, 58.5 mmol) was added to a
solution of the alkylated ethyl ester (6.50 g, 31.5 mmol) in THF (100
mL). The reaction mixture was heated to reflux for 10 h, then cooled
to 0 °C. H2O (3 mL), aqueous 10% NaOH (3 mL), and H2O (9 mL)
were added sequentially to the grayish reaction mixture over a period
of 2 h. Substantial gas and heat evolution were observed, and the
reaction mixture turned into a white suspension. This suspension was
filtered and the residue was rinsed with three portions of ethyl acetate
(90 mL). The combined filtrate was concentrated and chromatographed
to give the alcohol 10 (4.50 g, 63% yield from 9) as a colorless oil,
TLC Rf ) 0.51 (20% ethyl acetate/petroleum ether). 1H NMR (δ):
Conclusion
The creation of new methods for the enantioselective
construction of carbocycles is fundamental to the development
of target-directed organic synthesis. The computational ap-
proach outlined here should allow the design of other R-diazo
esters that will also cyclize with high diastereoselectivity. This
approach will be complementary to the elegant enantioselective
C-H insertions developed by Doyle3a and Ikegami,21 allowing
the direct construction of more highly-substituted cyclopentanes
with control of relative and absolute configuration. Diastereo-
selective Rh-mediated cyclization of a substituted R-diazo ester,
(21) (a) Hashimoto, S.-i.; Watanabe, N.; Sato, T.; Shiro, M.; Ikegami,
S. Tetrahedron Lett. 1993, 33, 5109. (b) Hashimoto, S.-i.; Watanabe, N.;
Kawano, K.; Ikegami, S. Synth. Commun. 1994,24, 3277.
(22) For a general experimental procedure, see: Taber, D. F.; Houze, J.
B. J. Org. Chem. 1994, 59, 4004.

552 J. Am. Chem. Soc., Vol. 118, No. 3, 1996
Taber et al.
Table 2. Calculated T.S. Energy Differences and Diastereomeric Ratios
∆
∆
a Cyclization was carried out using rhodium octanoate. b Cyclization was carried out using rhodium acetate.
7.38-7.20 (m, 5 H), 3.75 (m, 2 H), 2.77 (m, 1 H), 1.61 (m, 2 H), 1.36
(s br, 1 H), 1.23 (m, 2 H), 0.88 (t, J ) 7.2 Hz, 3 H). 13C NMR (δ):
d 14.2, 48.5, 126.7, 128.1, 128.7; u 20.5, 34.3, 67.7, 142.6. IR (cm-1):
3346, 2930, 2871, 1602, 1493, 1453, 1379. MS (m/z, %): 164 (M+,
26), 147 (36), 133 (100), 115 (21), 103 (67). HRMS calcd for C11H16O
164.1202, found 164.1210.
Methyl 3-Phenylheptanoate (11). p-Toluenesulfonyl chloride (4.88
g, 25.6 mmol) was added to a mixture of alcohol 10 (3.50 g, 21.3 mmol)
in pyridine (10 mL) and CH2Cl2 (30 mL) at room temperature. The
reaction mixture was stirred at room temperature for 12 h, then
partitioned between CH2Cl2 and 10% aqueous HCl. The combined
organic extract was dried (Na2SO4), concentrated, and chromatographed
to give the tosylate (6.04 g) as a white powder, TLC Rf ) 0.58 (20%
ethyl acetate/petroleum ether). 1H NMR (δ): 7.63 (d, J ) 8.4 Hz, 2
H), 7.21 (m, 5 H), 7.11 (m, 2 H), 4.18 (m, 2 H), 2.89 (m, 1 H), 2.41
(s, 3 H), 1.73 (m, 1 H), 1.57 (m, 1 H), 1.18 (m, 2 H), 0.82 (t, J ) 7.1
Hz, 3 H); 13C NMR (δ): d: 13.87, 21.59, 44.82, 126.9, 127.8, 128.5,
129.7; u 20.09, 33.87, 73.97, 132.5, 140.5, 144.5.
13 h, saturated aqueous NH4Cl (20 mL) was added. The organic layer
was separated and the aqueous layer was extracted with 1:4 ethyl
acetate/petroleum ether (3 × 40 mL). The combined organic extract
was dried (Na2SO4), concentrated, and chromatographed to give the
coupled product (4.74 g) as a colorless oil, TLC Rf ) 0.76 (10% ethyl
acetate/petroleum ether). 1H NMR (δ): 7.22 (m, 5 H), 5.72 (m, 1 H),
4.91 (m, 2 H), 2.53 (m, 1 H), 1.88 (q, J ) 7.2, 1 H), 1.60 (m, 4 H),
1.15 (m, 2 H), 0.86 (t, J ) 7.2 Hz, 3 H). 13C NMR (δ): d 14.12,
45.13, 125.8, 127.7, 128.2, 138.9; u 20.67, 31.75, 36.03, 39.16, 114.3,
145.8. MS (m/z, %): 188 (M+, 21), 146 (89), 133 (67), 118 (100).
HRMS calcd for C14H20 188.1566, found 188.1571.
A stream of ozone was passed through a solution of the above alkene
(2.47 g, 13.1 mmol) in CH2Cl2 (130 mL) at -70 °C until the red
indicator (Sudan Red) was decolorized (11 min). The ozone was turned
off and the reaction mixture was flushed with N2. Triphenylphosphine
(4.1 g, 15.8 mmol) was added, and the reaction mixture was allowed
to warm to room temperature over 13 h. The reaction mixture was
concentrated and the residue was diluted with 9:1 CH3OH/H2O (33
mL). NaHCO3 (11.0 g, 0.13 mol) and a solution of bromine (30 mL,
1.95 M in 9:1 CH3OH/H2O) were added sequentially to the reaction
mixture. The mixture turned bright orange, with gas evolution. After
Allylmagnesium chloride (35 mL, 69.1 mmol, 2.0 M in THF) was
added to an ice-cold solution of the tosylate (11.0 g, 34.57 mmol) in
THF (115 mL). After stirring with warming to room temperature for

DiastereoselectiVity of Rh-Mediated Cyclization
J. Am. Chem. Soc., Vol. 118, No. 3, 1996 553
10 min of stirring, Na2S2O3‚5H2O (25.0 g, 0.10 mol) was added to the
reaction mixture. The mixture was instantly decolorized, with additional
gas evolution. The mixture was diluted with H2O (20 mL) and ether
(20 mL). The organic phase was separated, and the aqueous phase
was extracted with ether (3 × 40 mL). The combined organic extract
was dried (Na2SO4), concentrated, and chromatographed to give the
desired ester 11 (1.98 g, 45% yield from 10) as a pale yellow oil, TLC
Rf ) 0.56 (10% ethyl acetate/petroleum ether). 1NMR (δ): 7.41-7.0
(m, 5 H), 3.61 (s, 3 H), 2.48 (m, 1 H), 2.18-1.80 (m, 4 H), 1.58 (m,
2 H), 1.17 (m, 2 H), 0.86 (t, J ) 7.2 Hz, 3 H). 13C NMR (δ): d 14.0,
45.2, 51.3, 126.1, 127.6, 128.3; u 20.6, 31.7, 32.2, 40.0, 144.6, 174.1.
IR (cm-1): 3027, 2931, 2872, 1738, 1603, 1494, 1453, 1377, 1202;
MS (m/z, %): 220 (M+, 28), 188 (44), 146 (42), 133 (31), 117 (100).
HRMS calcd for C14H20O2 220.1464, found 220.1469.
Methyl 2-Diazo-4-phenylheptanoate (1). Sodium hydride (0.8 g,
27.0 mmol, 80% in mineral oil), methyl benzoate (2.2 mL, 18.0 mmol),
and 2 drops of CH3OH were added sequentially to an ice-cold solution
of ester 11 (1.98 g, 9.0 mmol) in DME (40 mL). The reaction mixture
was heated to reflux for 13 h, then was chilled to room temperature.
Aqueous acetate buffer (10 mL, 0.25 M, pH ) 5) was added to the
reaction mixture, followed by ether (10 mL). The resultant mixture
was extracted with 30% ethyl acetate/petroleum ether (3 × 30 mL).
The combined organic extract was dried (Na2SO4), concentrated, and
chromatographed to give the diastereomeric benzoyl esters (2.77 g) as
a pale yellow oil, TLC Rf ) 0.41 (10% ethyl acetate/petroleum ether).
1H NMR (δ): 7.79-7.0 (m, 10 H), 4.16 (m, 1 H), 3.78, 3.83 (2s, total
3 H), 2.48 (m, 2 H), 2.11 (m, 2 H), 1.61 (m, 2 H), 1.18 (m, 2 H), 0.82
(m, 3 H). 13C NMR (δ): d 14.0, 43.4, 44.0, 51.2, 52.1, 52.4, 52.5,
126.1, 126.4, 127.7, 127.9, 128.5, 128.6, 128.7, 133.4; u 20.5, 20.6,
35.8, 36.2, 39.1, 39.4, 135.3, 136.6, 143.9, 144.0, 170.3, 170.5, 195.5,
195.6.
rinsed with three portions of ethyl acetate (3 × 20 mL). The combined
organic fitrate was concentrated to give the crude alcohol (0.3 g, 1.60
mmol) as a yellow oil. 1H NMR (δ): 7.34-7.07 (m, 5 H), 3.68 (s, 3
H), 3.26 (m, 1 H), 2.60-2.03 (m, 4 H), 1.97 (m, 1 H), 1.36 (q, J )
11.3 Hz, 1 H), 1.13 (d, J ) 6.3 Hz, 3 H). 13C NMR (δ): d 19.7, 37.6,
44.1, 48.9, 125.8, 126.9, 128.2; u 37.2, 44.4, 66.3, 145.8.
p-Bromobenzenesulfonyl chloride (0.25 g, 1.0 mmol) was added to
a mixture of the crude alcohol (0.3 g, 1.6 mmol) in CH2Cl2 (2 mL)
and pyridine (2 mL). After stirring for 10 h, the reaction mixture was
partitioned between CH2Cl2 and, sequentially, 10% aqueous HCl and
brine. The combined CH2Cl2 extract was dried (Na2SO2), concentrated,
and chromatographed to give the desired product 8 (0.60 g) as a white
solid, TLC Rf ) 0.54 (10% ethyl acetate/petroleum ether). This white
solid was recrystallized from heptane/ether (9:1) to give colorless
crystals (0.56 g, 87% yield from 2), mp ) 125 °C. The relative
configurations were established by X-ray crystallography. 1H NMR
(δ): 7.80-7.17 (m, 9 H), 4.05 (m, 2 H), 3.02 (m,1 H), 2.20 (m, 1 H),
2.0-1.71 (m, 4 H), 1.34 (q, J ) 11.7 Hz, 1 H), 1.05 (d, J ) 6.5 Hz,
3 H). 13C NMR (δ): d 19.2, 37.8, 34.8, 45.7, 126.0, 126.8, 128.3,
129.3, 132.6; u 36.9, 44.1, 73.7, 128.9, 135.2, 145.0; IR (cm-1): 3026,
2951, 1573, 1471, 1364, 1187, 1089; MS (m/z, %): 408 (M+, 5), 238
(10), 172 (100), 157 (88), 143 (87), 129 (41), 117 (25), 104 (73). HRMS
calcd for C19H21O3SBr 408.0395, found 408.0395.
Ethyl 5-Phenylheptanoate (14). Triphenylphosphine (19.0 g, 71.8
mmol) and ethyl 4-bromobutyrate 13 (10.0 g, 51.3 mmol) were mixed
and heated to 120 °C. After 15 min, the white solid mixture melted
into a clear yellow glass. After being cooled to room temperature, the
solid was dissolved with CH2Cl2 (6 mL) and the resultant mixture was
rinsed with ether (3 × 50 mL) and dried (P2O5) to give the crude
phosphonium salt (22.5 g, 49.2 mmol) as a white powder, mp ) 143
°C. 1H NMR (δ): 8.0-7.61 (m, 15 H), 4.09 (m, 2 H), 3.95 (m, 2 H),
2.94 (t, J ) 6.5 Hz, 2 H), 2.01 (m, 2 H), 1.21 (q, J ) 7.4 Hz, 3 H).
Sodium bistrimethylsilyamide (12.8 mL, 12.8 mmol, 1.0 M in THF)
was added to a stirring solution of the above phosphonium salt (5.3 g,
11.6 mmol) in THF (35 mL) at -5 °C. After stirring for 10 min, the
orange ylide was chilled to -75 °C and propiophenone (1.7 mL, 12.8
mmol) was added. The reaction mixture was allowed to warm to room
temperature over 6 h, then was quenched with saturated aqueous NH4-
Cl (20 mL). The organic phase was separated and the aqueous phase
was extracted with 40% ethyl acetate/petroleum ether (3 × 30 mL).
The combined organic extract was dried (Na2SO4), concentrated, and
chromatographed to give the coupled alkene ester (1.81 g) as a colorless
oil, TLC Rf ) 0.70 (10% ethyl acetate/petroleum ether). 1H NMR
(δ): 7.28-7.0 (m, 5 H), 5.41 (m, 1 H), 4.11 (q, J ) 7.1 Hz, 2 H),
2.38-2.20 (m, 6 H), 1.23 (t, J ) 7.1 Hz, 3 H), 0.97 (t, J ) 6.5 Hz, 3
H); 13C NMR (δ): d 12.9, 14.2, 123.5, 126.5, 128.1, 128.2; u 24.4,
32.1, 34.7, 60.2, 141.0, 144.2, 173.5. MS (m/z, %): 232 (M+, 35),
187 (10), 157 (14), 145 (48), 129 (100), 115 (29). HRMS: calcd for
C15H20O2, 232.1464, found 232.1473.
The above alkene ester (1.07 g, 4.6 mmol) was added to a solution
of palladium on carbon (0.2 g, 10%) in ethanol (10 mL). The reaction
mixture was stirred under an atmosphere of H2. After the uptake of
H2 had ceased (9 h), the reaction mixture was filtered with Celite and
the filtrate was concentrated in vacuo. The trace of unhydrogenated
alkene was removed by ozonolysis. Thus, the concentrated residue
was diluted with 2:1 CH2Cl2/ethanol (40 mL). A stream of ozone was
passed through the reaction mixture at -75 °C until the solution turned
pale blue. The ozone was turned off and the reaction mixture was
flushed with N2. NaBH4 (0.1 g, 2.63 mmol) was added to the reaction
mixture which was then warmed to room temperature. After 2 h, the
reaction mixture was quenched with 10% aqueous HCl (10 mL) and
diluted with CH2Cl2 (20 mL). The organic extract was separated and
the aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The
combined organic phase was dried (Na2SO4), concentrated, and
chromatographed to give the ethyl ester 14 (0.89 g, 53% yield from
13) as a colorless oil, TLC Rf ) 0.70 (10% ethyl acetate/petroleum
ether). 1H NMR (δ): 7.30-7.11 (m, 5 H), 4.09 (q, J ) 7.1 Hz, 2 H),
2.40 (m, 1 H), 2.22 (t, J ) 7.5 Hz, 2 H), 1.80-1.41 (m, 6 H), 1.21 (t,
J ) 7.1 Hz, 3 H), 0.76 (t, J )7.4 Hz, 3 H). 13C NMR (δ): d 12.1,
14.2, 47.6, 125.9, 127.7, 128.2; u 23.1, 29.6, 34.4, 35.8, 60.1, 145.3,
173.6. IR (cm-1): 2931, 1733, 1692, 1452, 1373, 1155, 1036, 757.
MS (m/z, %): 234 (M+, 10), 206 (63), 188 (30), 156 (26), 131 (21),
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.6 mL, 10.5 mmol) and 4-ni-
trobenzenesulfonyl azide (2.4 g, 10.5 mmol in 5 mL CH2Cl2) were
added to an ice-cold solution of the benzoyl ester (1.86 g, 5.2 mmol)
in CH2Cl2 (20 mL). After warming to room temperature (1 h), aqueous
phosphate buffer (8 mL, 0.5 M, pH ) 7) was added to the reaction
mixture. After stirring for an additional 30 min, the reaction mixture
was partitioned between CH2Cl2 and brine. The combined organic
extract was dried (Na2SO4), concentrated, and chromatographed to give
1 (1.20 g, 81% yield from 11) as a bright yellow oil, TLC Rf ) 0.55
(10% ethyl acetate/petroleum ether). 1H NMR (δ): 7.35-7.09 (m, 5
H), 3.67 (s, 3 H), 2.80 (m, 1 H), 2.62 (dd, J ) 5.8, 14.7 Hz, 1 H), 2.48
(dd, J ) 9.2, 14.7 Hz, 1 H), 1.65 (m, 2 H), 1.24 (m, 2 H), 0.86 (t, J )
7.2 Hz, 3 H). 13 C NMR (δ): d 14.0, 44.7, 51.8, 126.6, 127.6, 128.5;
u 20.5, 30.9, 37.7, 143.7, 168.0; IR (cm-1): 2931, 2083, 1692, 1603,
1441, 1335, 1128, 701. MS (m/z, %): 187 (11), 171 (5), 157 (3), 131
(3), 128 (8), 120 (23), 119 (100), 116 (12), 104 (3), 100(45); HRMS
calcd for C14H18O2N2 246.1369 (218.1307 loss of N2), found 218.1311.
Methyl (1R*,2R*,4S*)-2-Methyl-4-phenylcyclopanecarboxylate
(5). CH2Cl2 (25 mL) was passed through a pad of K2CO3 into the
diazo compound 1 (1.2 g, 4.9 mmol). A catalytic amount of rhodium
octanoate (2 mg, 0.0026 mmol) was added to the reaction mixture.
The bright yellow reaction mixture was instantly decolorized with the
evolution of gas. After the gas evolution had ceased (10 min), the
reaction mixture was concentrated in vacuo. The dark green residue
was chromatographed, eluting with 2% ethyl acetate/petroleum ether,
to give a single diastereomer 5 (0.97 g, 91% yield) as a colorless oil,
TLC Rf ) 0.58 (5% ethyl acetate/petroleum ether). 1H NMR (δ):
7.35-7.09 (m, 5 H), 3.61 (s, 3 H), 3.19 (m, 1 H), 2.35-2.20 (m, 4 H),
1.98 (m, 1 H), 1.31 (q, J ) 11.1 Hz, 1 H), 1.10 (d, J ) 6.3 Hz, 3 H).
13
C NMR (δ): d 19.6, 39.8, 44.6, 51.0, 51.6, 126.0, 126.9, 128.3; u
37.6, 44.0, 145.0, 146.7. IR (cm-1): 2954, 1732, 1603, 1495, 1436,
1370. MS (m/z, %): 218 (M+, 33), 186 (34), 158 (94), 143 (31), 118
(56), 115 (21), 101 (100). HRMS calcd for C14H18O2 218.1307, found
218:1301.
(1R*,2R*,4S*)-2-Methyl-4-phenylcyclopentylmethyl 4-Bromoben-
zenesulfonate (12). Lithium aluminum hydride (0.14 g, 3.6 mmol)
was added to an ice-cold solution of the cyclopentane 5 (0.39 g, 1.8
mmol) in THF (8 mL). After stirring at room temperature for 2 h,
H2O (1.5 mL), aqueous 10% NaOH (1.5 mL), and H2O (5 mL) were
added sequentially at 0 °C. The reaction mixture turned into a white
suspension. This white suspension was filtered and the residue was

554 J. Am. Chem. Soc., Vol. 118, No. 3, 1996
Taber et al.
117 (100). HRMS calcd for C15H22O2 234.1620, found 234.1617. Anal.
Calcd for C15H22O2: C, 76.88; H, 9.46. Found C, 76.77; H, 9.71.
Methyl 2-Diazo-5-phenylheptanoate (2). Sodium hydride (0.37
g, 9.36 mmol, 60% in mineral oil), methyl benzoate (0.80 mL, 6.24
mmol), and 2 drops of CH3OH were added sequentially to an ice-cold
solution of ester 14 (0.73 g, 3.12 mmol) in DME (15 mL). The reaction
mixture was heated to reflux for 12 h, then was cooled to room
temperature. The reaction mixture was quenched with a solution of
acetate buffer (8 mL, 0.25 M, pH ) 5), then was diluted with ethyl
ether (10 mL). The organic phase was separated and the aqueous phase
was extracted with 30% ethyl acetate/petroleum ether (3 × 30 mL).
The combined organic extract was dried (Na2SO4) and concentrated in
vacuo. The oily residue was dissolved in CH3OH (15 mL). K2CO3
(0.90 g, 6.52 mmol) was added to the reaction mixture, and the mixture
was heated to reflux for 8 h, then was cooled to room temperature.
The reaction mixture was filtered and the filtrate was concentrated and
chromatographed to give the diastereomeric methyl benzoyl esters (0.86
g, 85% yield) as pale yellow oil, TLC Rf ) 0.48 (10% ethyl acetate/
petroleum ether). 1H NMR (δ): 7.94-7.0 (m, 10 H), 4.21 (m, 1 H),
3.63 (2s, total 3 H), 2.41 (m, 1 H), 2.02-1.42 (m, 6 H), 0.72 (m, 3 H).
13C NMR (δ): d 12.0, 47.5, 47.8, 52.4, 53.9, 56.2, 126.1, 127.7, 128.3,
128.5, 128.7; u 27.1, 27.2, 29.6, 29.8, 33.8, 34.1, 136.1, 144.7, 144.9,
170.3, 170.4, 194.9, 195.2.
34.0, 143.5, 176.6. IR (cm-1): 2954, 2871, 1733, 1435, 1161. MS
(m/z, %): 218 (M+, 89), 187 (26), 158 (63), 132 (33), 117 (100), 104
(73). HRMS calcd for C14H18O2 218.1307, found 218.1311.
Methyl (2S,3S)-2-Ethyl-3-hydroxy-7-methyl-6-octenoate. n-Bu-
tyllithium (74 mL, 0.17 mol, 2.31 M in hexane) was added to a stirring
solution of diisopropylamine (19.0 g, 0.18 mol) in THF (150 mL) at
-75 °C. After warming up to -50 °C, â-hydroxy ester 16 (14.4 g,
77.4 mmol) was added neat and the temperature was raised to -30
°C. Iodoethane (8.7 mL, 0.1 mol) in HMPA (60 mL) was added, and
the reaction mixture was stirred with warming to room temperature
over 4 h. Saturated aqueous NH4Cl (60 mL) was added to quench the
reaction mixture. The organic layer was separated and the aqueous
layer was extracted with 30% ethyl acetate/petroleum ether. The
combined extracts were dried (Na2SO4) and concentrated. The residue
was chromatographed with 8% ethyl acetate/petroleum ether to give
the desired alkylated product (10.8 g, 70% yield) as a pale yellow oil,
TLC Rf ) 0.51 (20% ethyl acetate/petroleum ether). 1H NMR (δ):
5.10 (m, 1 H), 3.71 (s, 3 H), 3.69 (m, 1 H), 2.53 (d, J ) 8.0 Hz, 1 H),
2.20 (m, 3 H), 1.76 (m, 2 H), 1.71 (s, 3 H), 1.63 (s, 3 H), 1.48 (m, 2
H), 0.92 (t, J ) 7.4 Hz, 3 H). 13C NMR (δ)SPCLN d 11.8, 17.6, 25.7,
51.5, 52.6, 71.6, 123.7; u 22.7, 24.3, 35.5, 132.3, 176.0. IR (cm-1):
3465, 1736, 1670, 1437, 1376, 1171. MS (m/z, %): 214 (M+, 1), 196
(52), 137 (24), 136 (93), 131 (22), 125 (20), 121 (39), 113 (43), 107
(46), 102 (100). HRMS calcd for C12H22O3 214.1569, found 214.1573.
(4S,5R)-2,2-Dimethyl-5-ethyl-4-(4-methyl-3-pentenyl)-1,3-diox-
ane (17). Lithium aluminum hydride (2.3 g, 61.0 mmol) was added
to a solution of the above alkylated â-hydroxy ester (6.1 g, 30.5 mmol)
in THF (75 mL). The reaction mixture was heated to reflux for 10 h,
then was cooled to 0 °C. H2O (3 mL), 10% aqueous NaOH (3 mL),
and H2O (9 mL) were added sequentially to the grayish reaction mixture
over a period of 1 h. Substantial gas and heat evolution were observed,
and the reaction mixture turned into a white paste. The reaction mixture
was filtered with ethyl acetate and the filtrate was concentrated to give
the desired crude diol (5.6 g). 1H NMR (δ)SPCLN 5.17 (m, 1 Η),
3.91 (m, 1 Η), 3.69 (m, 2 H), 3.03 (br s, 1 H), 2.82 (br s, 1 H), 2.11
(m, 2 H), 1.73 (s, 3 H), 1.65 (s, 3 H), 1.60 (m, 2 H), 1.41 (m, 3 H),
0.96 (t, J ) 7.4 Hz, 3 H). 13C NMR (δ)SPCLN d 11.6, 17.6, 25.0,
46.0, 75.5, 123.9; u 21.4, 24.4, 35.5, 63.6, 132.3.
p-Toluenesulfonic acid monohydrate (1.2 g, 6.1 mmol) was added
to a stirring solution of the crude diol (5.6 g) in dimethoxypropane (70
mL). After 0.5 h, NaHCO3 (1.3 g, 15.3 mmol) was added to neutralize
the reaction mixture. The reaction mixture was filtered and the filtrate
was concentrated and chromatographed directly to give 17 (5.8 g, 53%
yield from 16) as a pale yellow oil, TLC Rf ) 0.89 (10% ethyl acetate/
petroleum ether). 1H NMR (δ): 5.09 (m, 1 H), 3.86 (dd, J ) 5.0,
11.6 Hz, 1 H), 3.51 (m, 2 H), 2.18 (m, 2 H), 1.68 (s, 3 H), 1.61 (s, 3
H), 1.39 (s, 3 H), 1.38 (s, 3 H), 1.38 (m, 2 H), 1.07 (m, 2 H), 0.86 (t,
J ) 7.3 Hz, 3 H). 13C NMR (δ): d 10.9, 17.8, 19.3, 25.7, 29.5, 40.4,
72.5, 124.3; u 21.0, 23.4, 33.1, 64.0, 97.9, 131.5. IR: (cm-1): 2926,
2859, 1457, 1379, 1264, 1199. MS (m/z, %): 226 (M+, 3), 211 (M+-
CH3, 20), 168 (55), 150 (50), 135 (48), 121 (88), 111 (100), 109 (52),
107 (29). HRMS calcd for C14H26O2: 226.1934 (211.1699 loss of CH3),
found 211.1695.
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.2 mL, 1.3 mmol) and 4-ni-
trobenzenesulfonyl azide (0.3 g, 1.3 mmol) were added to an ice-cold
solution of the methyl benzoyl ester (0.22 g, 0.68 mmol) in CH2Cl2 (4
mL). After stirring for 1 h with warming to room temperature, aqueous
phosphate buffer (3 mL, 0.5 M, pH ) 7) was added and stirring was
continued for an additional 30 min. The reaction mixture was
partitioned between CH2Cl2 and brine. The combined organic extract
was dried (Na2SO4), concentrated, and chromatographed to give the
desired diazo compound 2 (0.17 g, 83% yield from 14) as a bright
yellow oil, TLC Rf ) 0.53 (10% ethyl acetate/petroleum ether). 1H
NMR (δ): 7.38-7.09 (m, 5 H), 3.73 (s, 3 H), 2.45 (m, 1 H), 2.16 (m,
2 H), 2.0-1.60 (m, 4 H), 0.77 (t, J ) 7.4 Hz, 3 H). 13C NMR (δ): d
12.1, 47.1, 51.8, 126.2, 127.6, 128.4; u 21.4, 29.8, 34.1, 144.4, 167.7.
IR (cm-1): 2928, 2080, 1695, 1494, 1437, 1354, 1190, 1129, 701. MS
(m/z, %): 218 (M+ - N2, 3), 187 (4), 157 (9), 129 (12), 128 (13), 120
(10), 119 (100), 117 (8), 115 (12), 103 (7), 100 (38). HRMS calcd for
C14H18O2N2 246.1369 (218.1307 loss of N2), found 218.1311.
Methyl (1R*,2R*,3S*)-2-Methy-3-phenylcyclopentanecarboxylate
(6). A solution of dry CH2Cl2 (7 mL) was passed through a pad of
K2CO3 into the bright yellow diazo compound 2 (110.9 mg, 0.45 mmol).
A catalytic amount of rhodium octanoate (1 mg, 1.31 µmol) was added
to this bright yellow reaction mixture. The mixture was instantly
decolorized with the evolution of gas. After the gas evolution had
ceased (5 min), the reaction mixture was concentrated and chromato-
graphed to yield a mixture (80.15 mg, 87%) of cyclized and eliminated
1
esters (2.6:1 by H NMR integration).
This mixture was then diluted with 2:1 CH2Cl2/CH3OH (8 mL). A
stream of ozone was passed through the reaction mixture at -75 °C
until the solution turned pale blue. The reaction mixture was flushed
with N2, then sodium borohydride (0.1 g, 2.6 mmol) was added and
the cooling bath was removed. After 2 h, 10% aqueous HCl was added
to quench the reaction. The resultant mixture was partitioned between
CH2Cl2 and saturated aqueous NH4Cl. The combined organic extract
was dried (Na2SO4) and concentrated in vacuo. The pale brown oily
residue was chromatographed, eluting with 3% ethyl acetate/petroleum
ether, to give the cyclized product 6 (60.44 mg, 62% yield from 2) as
a clear pink oil, TLC Rf ) 0.48 (10% ethyl acetate/petroleum ether)
followed by the alcohol (16.86 mg, 23% yield from the ozonized
byproduct alkene 15).
Methyl (4S,5R)-2,2-Dimethyl-5-ethyl-1,3-dioxane-4-propionate
(18). A stream of ozone was passed through a solution of 17 (5.4 g,
24.1 mmol) in CH2Cl2 (250 mL) at -75 °C. After 20 min, the red
indicator (Sudan Red) was decolorized, and the ozone was turned off.
The reaction mixture was flushed with N2, and triphenylphosphine (7.6
g, 28.9 mmol) was added. The mixture was allowed to warm to room
temperature over 10 h. The reaction mixture was then concentrated
and the residue was dissolved in 1:9 H2O/CH3OH (60 mL). NaHCO3
(40 g, 0.48 mol) and Br2 (5 mL, 96.3 mmol, 1.95 M in 1:9 H2O/CH3-
OH) were added sequentially to the reaction mixture, turning the mixture
bright orange. After stirring for 10 min, Na2S2O3‚5H2O (36.0 g, 0.14
mol) was added. The orange reaction mixture decolorized instantly
with evolution of gas. The reaction mixture was partitioned between
ether and brine. The combined ethereal extract was dried (Na2SO4),
concentrated, and chromatographed to give the ester 18 (4.3 g, 78%
yield from 17) as colorless oil, TLC Rf ) 0.68 (20% ethyl acetate/
petroleum ether). 1H NMR (δ): 3.88 (dd, J ) 4.4, 11.6 Hz, 1 H),
3.68 (s, 3 H), 3.52 (m, 2 H), 2.43 (m, 2 H), 2.07 (m, 1 H), 1.68 (m, 1
H), 1.49 (m, 2 H), 1.39 (s, 3 H), 1.35 (s, 3 H), 1.09 (m, 1 H), 0.87 (t,
Alcohol. TLC Rf ) 0.31 (10% ethyl acetate/petroleum ether). 1H
NMR (δ): 7.36-7.04 (m, 5 H), 3.71 (t, J ) 6.8 Hz, 2 H), 2.83 (m, 1
H), 1.67 (m, 2 H), 1.43 (s br, 1 H), 1.26 (m, 2 H), 0.88 (t, J ) 7.3 Hz,
3 H); 13C NMR (δ): d 128.5, 127.9, 126.7, 47.3, 14.1; u 143.0, 67.6,
35.2, 20.2; IR (cm-1): 3348 (br), 2871, 1607, 1490, 1455. MS (m/z,
%): 165 (M+ - H+, 2), 164 (10), 147 (14), 134 (25), 133 (39), 105
(13). HRMS calcd for C11H16O 164.1202, found 164.1211.
6. 1H NMR (δ): 7.41-7.10 (m, 5 H), 3.71 (s, 3 H), 2.53 (m, 2 H),
2.26-1.89 (m, 4 H), 2.0-1.83 (m, 1 H), 0.95 (d, J ) 6.4 Hz, 3 H). 13
C
NMR (δ): d 17.2, 46.8, 51.6, 51.6, 54.5, 126.3, 127.5, 128.4; u 28.2,

DiastereoselectiVity of Rh-Mediated Cyclization
J. Am. Chem. Soc., Vol. 118, No. 3, 1996 555
J ) 7.3 Hz, 3 H). 13C NMR (δ): d 10.9, 19.3, 29.4, 40.4, 51.4, 72.4;
u 20.9, 28.3, 29.7, 63.9, 98.0, 174.3. IR (cm-1): 2965, 1740, 1438,
1380, 1201, 1165, 1124, 868. MS (m/s, %): 215 (M+ - CH3, 45),
172 (10), 156 (7), 155 (71), 141 (52), 140 (21), 123 (100), 117 (92),
113 (29), 111 (60), 110 (25), 101(7). HRMS calcd for C12H22O4
230.1518 (215.1284 loss of CH3), found 215.1279. Anal. Calcd for
C12H22O4: C, 62.58; H 9.63. Found C, 62.89; H 9.76.
Methyl (4S,5R)-r-Diazo-2,2-dimethyl-5-ethyl-1,3-dioxanepropi-
onate (3). Sodium hydride (0.6 g, 15 mmol, 60% in mineral oil),
methyl benzoate (1.36 g, 10.0 mmol), and 2 drops of CH3OH were
added sequentially to an ice-cold solution of ester 18 (1.15 g, 5.0 mmol)
in DME (25 mL). The grayish mixture was heated to reflux for 13 h,
during which time it turned dark brown. Aqueous acetate buffer (7
mL, 0.25 M, pH ) 5) was added to the reaction mixture, followed by
ether (15 mL). The organic layer was separated and the aqueous layer
was extracted with 30% ethyl acetate/petroleum ether (3 × 20 mL).
The combined organic extract was dried (NaSO4), concentrated, and
chromatographed to give the diastereomeric benzoyl esters (1.5 g, 93%
yield) as a yellow oil, TLC Rf ) 0.42 (20% ethyl acetate/petroleum
ether). 1H NMR (δ): 8.14-7.23 (m, 5 H), 3.86 (m, 1 H), 3.36, 3.73
(2s, total 3 H), 3.70-3.37 (m, 2 H), 2.70-2.41 (m, 1 H), 2.07-1.78
(m, 1 H), 1.48 (m, 2 H), 1.34-1.23 (4s, total 6 H), 1.09 (m, 2 H), 0.91
(t, J) 7.4 Hz, 3 H).
DBU (1.3 mL, 8.6 mmol) and 4-nitrobenzenesulfonyl azide (2.0 g,
8.6 mmol) were added sequentially to a solution of the benzoyl ester
(1.4 g, 4.4 mmol) in CH2Cl2 (20 mL) at 0 °C. After warming to room
temperature (0.5 h), the reaction mixture was quenched with aqueous
phosphate buffer (13 mL, 0.5 M, pH ) 7). The CH2Cl2 layer was
separated and the aqueous layer was extracted with CH2Cl2 (3 × 20
mL). The combined organic extract was dried (Na2SO4), concentrated,
and chromatographed to give 3 (1.4 g, 78% from 18) as a bright yellow
oil, TLC Rf ) 0.43 (10% ethyl acetate/petroleum ether). 1H NMR
(δ): 3.89 (dd, J ) 5.8, 11.6 Hz, 1 H), 3.76 (s, 3H), 3.74 (m, 1 H), 3.56
(t, J ) 11.6 Hz, 1 H), 2.68 (dd, J ) 2.9, 15.2 Hz, 1 H), 2.41 (dd, J )
7.0, 15.2 Hz, 1 H), 1.56 (m, 4 H), 1.59 (s, 3 H), 1.55 (s, 3 H), 0.89 (t,
J ) 7.4 Hz, 3 H). 13C NMR (δ): d 27.6, 36.1, 46.1, 56.0, 58.6, 90.1;
u 33.8, 37.7, 43.6, 80.5, 114.9, 167.9. IR (cm-1): 2960, 2078, 1699,
1437, 1221. MS (m/s, %): 228 (M+ - N2, 3), 213 (19), 198 (74), 197
(24), 183 (6), 140 (13), 117 (100). HRMS calcd for C12H20O4N2
256.1424 (228.1362 loss of N2), found 228.1366.
to a stirring solution of diisopropylamine (7.6 mL, 55.0 mmol) in THF
(25 mL) at -75 °C. After the reaction mixture was warmed to -50
°C, â-hydroxy ester (4.0 g, 25.0 mmol) was added. At -20 °C, allyl
bromide (2.4 mL, 27.4 mmol) in 6 mL of HMPA was added to the
reaction mixture. After stirring in room temperature for 4 h, the reaction
mixture was partitioned between 40% ethyl acetate/petroleum ether and
saturated aqueous NH4Cl. The combined organic phase was dried
(MgSO4), concentrated, and chromatographed to afford 20 (3.35 g, 41%
yield from 19) as a colorless oil, TLC Rf ) 0.41 (20% ethyl acetate/
petroleum ether). 1H NMR (δ): 5.78 (m, 1 H), 5.06 (m, 2 H), 4.18 (q,
J ) 7.2 Hz, 2 H), 3.71 (m, 1 H), 2.62 (d, J ) 8.0 Hz, 1 H), 2.46 (m,
3 H), 1.63-1.42 (m, 4 H), 1.30 (t, J ) 7.2 Hz, 3 H), 0.93 (t, J ) 6.9
Hz, 3 H). 13C NMR (δ): d 13.9, 14.2, 50.4, 71.5, 134.9; u 18.9, 33.8,
37.7, 60.5, 117.1, 174.9. IR (cm-1): 3464 (br), 2959, 2874, 1733,
1642, 1470, 1377, 1180. MS (m/z, %): 200 (M+, 16), 182 (21), 157
(72), 129 (34), 128 (60), 111 (37), 109 (37), 100 (100). HRMS calcd
for C10H18O3 200.1413, found 200.1422.
(4S*,5R*)-2,2-Dimethyl-5-(2-propenyl)-4-propyl-1,3-dioxane (21).
Lithium aluminum hydride (1.71 g, 45.0 mmol) was added to an ice-
cold solution of 20 (3.0 g, 15.0 mmol) in THF (75 mL). The grayish
reaction mixture was heated to reflux for 13 h, then was cooled to 0
°C. H2O (2 mL), 10% aqueous NaOH (2 mL), and H2O (6 mL) were
added sequentially to the grayish mixture, turning it into a white
suspension. This white suspension was filtered and the residue was
rinsed with ethyl acetate. The combined filtrate was concentrated to
give the crude diol (2.25 g). 1H NMR (δ): 5.81 (m, 1 H), 5.16 (m, 2
H), 3.93 (m, 1 H), 3.76 (m, 2 H), 2.80-2.37 (m, 2 H), 2.29-2.07 (m,
2 H), 1.83-1.03 (m, 5 H), 0.95 (t, J ) 6.9 Hz, 3 H).
p-TsOH‚H2O (0.57 g, 3.0 mmol) was added to a stirring solution of
the above crude diol (2.25 g) in dimethyoxypropane (30 mL). After
10 min, NaHCO3 (1.26 g, 15.0 mmol) was added, and stirring was
continued for an additional hour. The reaction mixture was filtered,
and the filtrate was concentrated and chromatographed to give 21 (2.64
g, 89%) as a colorless oil, TLC Rf ) 0.87 (10% ethyl acetate/petroleum
ether). 1H NMR (δ): 5.71 (m, 1 H), 5.06 (m, 2 H), 3.74 (dd, J ) 5.2
Hz, 11.6 Hz, 1 H), 3.54 (t, J ) 11.6 Hz, 2 H), 2.17 (m, 1 H), 1.62-
1.41 (m, 3 H), 1.41-1.23 (m, 3 H), 1.41 (s, 3 H), 1.38 (s, 3 H), 0.90
(t, J ) 6.8 Hz, 3 H). 13C NMR (δ): d 14.0, 19.5, 29.3, 38.6, 72.8,
135.3; u 18.2, 33.0, 35.2, 64.0, 98.1, 116.7. IR (cm-1): 2926, 2871,
1458, 1379, 1198, 1171, 995. MS (m/z, %): 184 (13), 183 (M+
-
CH3, 100), 155 (11), 131 (14), 123 (36), 110 (7), 99 (8), 97 (17), 95
(19). HRMS calcd for C12H22O2 198.1620, found 198.1633.
Methyl (1S,2S,3aS,7aR)-1,5,5-Timethyl-4,6-dioxa-(2,3,3a,4,5,6,7,7a)-
octahydroindene-2-carboxylate (7). CH2Cl2 (40 mL) was passed
through a pad of K2CO3 into the bright yellow diazo ester 3 (2.1 g, 8.2
mmol). A catalytic amount of Rh2Oct4 (0.9 mg, 1.16 µmol) was added
to the reaction mixture. The mixture was decolorized instantly with
evolution of gas. After the gas evolution had ceased (5 min), the
mixture was concentrated and chromatographed directly to give a single
diastereomer 7 (1.8 g, 89% yield from 3) as a pale yellow oil, TLC Rf
) 0.38 (10% ethyl acetate/petroleum ether). The relative configuration
was established by NOE experiments. 1H NMR (δ): 3.89 (dd, J )
5.8, 11.6 Hz, 1 H), 3.80 (m, 2 H), 3.61 (s, 3 H), 2.44 (m, 1H), 2.26 (m,
1 H), 1.81 (m, 2 H), 1.42 (s, 3 H), 1.39 (s, 3 H), 1.31 (m, 1 H), 1.16
(d, J ) 7.6 Hz, 3 H). 13C NMR (δ): d 18.3, 19.7, 29.7, 36.9, 47.0,
49.1, 51.9, 73.8; u 32.7, 65.5, 99.5, 176.6. IR (cm-1): 2954, 1735,
1459, 1381, 1264, 1178, 1113. MS (m/z, %): 213 (M+ - CH3, 42),
153 (11), 139 (33), 127 (30), 121 (21), 111(49), 93 (100). HRMS
calcd for C12H20O4 228.1362 (213.1127 loss of CH3), found 213.1132.
Ethyl (2S*,3S*)-2-(1-Hydroxybutyl)-4-pentenoate (20). n-Butyl-
lithium (76 mL, 0.17 mol, 2.18 M in hexane) was added to a solution
of diisopropylamine (25.3 mL, 0.18 mol) in THF (200 mL) at -75 °C.
After warming up to -60 °C, ethyl acetate (13.5 mL, 0.14 mol)
followed by n-butyraldehyde (19, 12.5 mL, 0.14 mol) were added. After
the mixture was stirred for 2 h with warming to room temperature,
saturated aqueous NH4Cl (80 mL) was added. The organic layer was
separated and the aqueous layer was extracted with 40% ethyl acetate/
petroleum ether (3 × 80 mL). The combined organic extract was dried
(MgSO4), concentrated, and chromatographed to give the desired
â-hydroxy ester (13.54 g, 61% yield) as a colorless oil, TLC Rf ) 0.37
(20% ethyl acetate/petroleum ether). 1H NMR (δ): 4.18 (q, J ) 7.2
Hz, 2 H), 4.02 (m, 1 H), 3.06 (br s, 1 H), 2.55-2.28 (m, 2 H), 1.62-
1.28 (m, 4 H), 1.29 (t, J ) 7.2 Hz, 3 H), 0.94 (t, J ) 6.9 Hz, 3 H).
n-Butyllithium (24 mL, 32.4 mmol, 2.18 M in hexane) was added
Methyl (4S*,5R*)-2,2-dimethyl-4-propyl-1,3-dioxane-5-acetate
(22). A stream of ozone was passed through a solution of 21 (2.1 g,
10.6 mmol) in CH2Cl2 (100 mL) at -76 °C. After 11 min, the solution
turned pale blue and the ozone was turned off. The reaction mixture
was flushed with N2, and triphenylphosphine (2.80 g, 10.6 mmol) was
added. The reaction mixture was warmed to room temperature for 5
h. It was then concentrated, and the residue was diluted with 9:1 CH3-
OH/H2O (45 mL). NaHCO3 (3.56 g, 42.4 mmol) was added followed
by a stock solution of bromine (22 mL, 1.95M in 9:1 CH3OH/H2O).
After 10 min, Na2S2O3‚5H2O (15.8 g, 63.6 mmol) was added and the
bright orange reaction mixture was decolorized with evolution of gas.
H2O (15 mL) and ethyl ether (40 mL) were added to the reaction
mixture. The organic layer was separated and the aqueous layer was
extracted with Et2O (3x 40 mL). The combined organic extract was
dried (Na2SO4), concentrated, and chromatographed to give the desired
ester 22 (2.02 g, 83% yield from 21) as a colorless oil, TLC Rf ) 0.61
(20% ethyl acetate/petroleum ether). 1H NMR (δ): 3.78 (dd, J ) 5.3,
11.5 Hz, 1 H), 3.66 (s, 3 H), 3.54 (m, 2 H), 2.31 (m, 1 H), 2.06 (m, 2
H), 1.52-1.24 (m, 4 H), 1.42 (s, 3 H), 1.38 (s, 3 H), 0.89 (t, J ) 7.1
Hz, 3 H). 13C NMR (δ): d 13.9, 19.5, 29.1, 36.3, 51.7, 72.0; u 18.0,
33.3, 35.1, 63.7, 98.3, 172.2. IR (cm-1): 2958, 2872, 1741, 1438,
1380, 1264, 1198, 1171; MS (m/z, %): 215 (M+ - CH3, 31), 172 (5),
155 (67), 141 (44), 140 (15), 129 (65), 123 (100), 113 (31), 112 (16),
110 (17), 101 (49). HRMS calcd for C12H22O4 230.1518 (215.1284
loss of CH3), found 215.1290.
Methyl (4S*,5R*)-r-Diazo-2,2-dimethyl-4-propyl-1,3-dioxane-5-
acetate (4). Methyl benzoate (0.57 mL, 4.61 mmol), NaH (0.3 g, 7.50
mmol), and 2 drops of CH3OH were added sequentially to a ice-cold
solution of ester 22 (0.53 g, 2.30 mmol) in DME (12 mL). The grayish
reaction mixture was warmed to reflux for 13 h. Aqueous acetate buffer

556 J. Am. Chem. Soc., Vol. 118, No. 3, 1996
Taber et al.
(10 mL, 0.25 M, pH ) 5) and Et2O (20 mL) were added to the reaction
mixture. The organic layer was separated and the aqueous layer was
extracted with Et2O (3 × 20 mL). The combined ethereal extract was
dried (K2CO3), concentrated, and chromatographed to give the diastereo-
meric benzoyl esters (0.68 g, 89% yield) as a pale yellow oil, TLC Rf
) 0.53 (20% ethyl acetate/petroleum ether). 1H NMR (δ): 8.15-7.40
(m, 5 H), 4.49 (dd, J ) 4.6 Hz, 5.9 Hz, 1 H), 4.09-3.74 (m, 3 H),
3.60, 3.65 (2s, total 3 H), 2.40 (m, 1 H), 1.58-1.20 (m, 10 H), 0.87
(m, 3 H).
DBU (0.32 mL, 2.14 mmol) and 4-nitrobenzenesulfonyl azide (0.26
g, 2.14 mmol) were added sequentially to a ice-cold solution of the
above benzoyl ester (0.42 g, 1.26 mmol) in CH2Cl2 (6 mL). After the
reaction mixture was warmed to room temperature (0.5 h), the reaction
mixture was quenched with aqueous phosphate buffer (4 mL, 0.5 M,
pH ) 7). The CH2Cl2 layer was separated and the aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The combined extract was dried
(K2CO3), concentrated, and chromatographed to give the desired diazo
product 4 (0.27 g, 74% yield from 22) as a bright yellow oil, TLC Rf
) 0.69 (20% ethyl acetate/petroleum ether. 1H NMR (δ): 3.89 (d, J
) 7.6 Hz, 1 H), 3.82 (m, 2 H), 3.77 (s, 3 H), 2.47 (q, J ) 7.6 Hz, 1
H), 1.63-1.26 (m, 4 H), 1.46 (s, 3 H), 1.40 (s, 3 H), 0.90 (t, J ) 7.1
Hz, 3 H). 13C NMR (δ): d 13.9, 19.4, 29.1, 35.2, 52.0, 69.8; u 18.1,
29.7, 36.0, 61.8, 98.6, 166.9. IR (cm-1): 2958, 2873, 2087, 1701,
1437, 1338, 1199, 1134. MS (m/z, %): 213 (M+ - CH3 - N2, 8),
185 (11), 170 (14), 153 (26), 139 (24), 138 (30), 127 (100), 121 (15),
111 (33), 110 (17). HRMS calcd for C12H20O4N2 256.1424 (228.1362
loss of N2), found 228.1377.
1 H), 1.95 (m, 1 H), 1.46 (s, 3 H), 1.42 (s, 3 H), 1.91 (m, 1 H), 1.15
(d, J ) 7.9 Hz, 3 H). 13C NMR (δ): d 19.7, 22.0, 29.6, 32.6, 43.5,
48.6, 51.5, 72.5; u 38.8, 63.6, 99.2, 174.8. IR (cm-1): 2956, 2872,
1732, 1459, 1380, 1265, 1167. MS (m/z, %): 213 (M+ - CH3, 18),
153 (9), 139 (39), 127 (11), 121 (13), 111 (39), 110 (54), 100 (100).
HRMS calcd for C12H20O4 228.1362 (213.1127 loss of CH3), found
213.1119.
Lactone 23. p-TsOH‚H2O (80.1 mg, 0.43 mmol) was added to a
stirring solution of 8 (89.2 mg, 0.39 mmol) in THF (3 mL). After 0.5
h, the reaction mixture was partitioned between ether and saturated
aqueous NaHCO3. The combined organic phase was dried (Na2SO4),
concentrated, and chromatographed to give lactone 23 (54.3 mg, 99%
yield from 8) as a pale yellow oil, TLC Rf ) 0.47 (10% ethyl acetate/
petroleum ether). The relative configurations was established by NOE
experiments. 1H NMR (δ): 4.43 (dd, J ) 7.4, 9.7 Hz, 1 H), 4.23 (dd,
J ) 2.8 Hz, 9.7 Hz, 1 H), 4.11 (q, J ) 7.7 Hz, 1 H), 2.87 (m, 1 H),
2.69 (dd, J ) 5.1, 9.9 Hz, 1 H), 2.35 (m, 1 H), 2.17 (m, 2 H), 1.46 (m,
1 H), 1.27 (d, J ) 6.8 Hz, 3 H). 13C NMR (δ): d 21.7, 36.2, 48.4,
49.7, 78.7; u 44.0, 70.8, 180.0. IR (cm-1): 3422 (br), 2960, 2872,
1765, 1458, 1378, 1181, 1088, 1050. MS (m/z, %): 157 (M++ H+,
2), 113 (3), 112 (4), 110 (3), 97 (10), 95 (2), 85 (15), 84 (100). HRMS
calcd for C8H12O3 156.0786, found 156.0809.
Acknowledgment. We thank M. P. Doyle and M. C. Pirrung
for helpful discussions and Zeneca Pharmaceuticals for financial
support.
Methyl (1S*,2R*,3aS*,7aR*)-2,5,5-Timethyl-4,6-dioxa-(2,3,3a,4,-
5,6,7,7a)-octahydroindene-1-carboxylate (8). CH2Cl2 (5 mL) was
passed through a pad of K2CO3 into the bright yellow diazo ester 4
(110.0 mg, 0.43 mmol). A catalytic amount of Rh2Oct4 (0.9 mg, 1.16
µmol) was added to the reaction mixture. The mixture was instantly
decolorized with evolution of gas. After the gas evolution had ceased
(6 min), the mixture was concentrated and chromatographed directly
to give a single diastereomer 8 (89.2 mg, 91% yield from 4) as a pale
yellow oil, TLC Rf ) 0.41 (10% ethyl acetate/petroleum ether). 1H
NMR (δ): 4.02-3.80 (m, 3 H), 3.67 (s, 3 H), 2.47 (m, 2H), 2.26 (m,
Supporting Information Available: 1H and 13C NMR
spectra for all new compounds (40 pages). This material is
contained in many libraries on microfiche, immediately follows
this article in the microfilm version of the journal, can be ordered
from the ACS, and can be downloaded from the Internet; see
any current masthead page for ordering information and Internet
access instructions.
JA9515213