Double diastereoselective intramolecular cyclopropanation to P-chiral [3.1.0]-bicyclic phosphonates

Article abstract of DOI:10.1021/ol026080o

(Matrix Presented) A double diastereotopic differentiation strategy on a phosphonoacetate template is described. The approach utilizes Rh₂(OAc)₄-catalyzed intramolecular cyclopropanation (ICP) employing the (R)-pantolactone auxiliary in the ester functionality of the phosphonoacetate. The olefinic diastereofacial selectivity is governed by inherent electronic and steric interactions in the reacting carbene intermediate, while the group selectivity is dictated by the chiral auxiliary. This approach is being developed as an effective method to access bicyclic P-chiral phosphonates.

Full text of DOI:10.1021/ol026080o

ORGANIC
LETTERS
2
002
Vol. 4, No. 14
357-2360
Double Diastereoselective Intramolecular
Cyclopropanation to P-Chiral
2
[3.1.0]-Bicyclic Phosphonates
Joel D. Moore, Kevin T. Sprott, Aaron D. Wrobleski, and Paul R. Hanson*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045-7582
phanson@ku.edu
Received April 26, 2002
ABSTRACT
2 4
A double diastereotopic differentiation strategy on a phosphonoacetate template is described. The approach utilizes Rh (OAc) -catalyzed
intramolecular cyclopropanation (ICP) employing the (R)-pantolactone auxiliary in the ester functionality of the phosphonoacetate. The olefinic
diastereofacial selectivity is governed by inherent electronic and steric interactions in the reacting carbene intermediate, while the group
selectivity is dictated by the chiral auxiliary. This approach is being developed as an effective method to access bicyclic P-chiral phosphonates.
The synthesis of new phosphorus-containing compounds has
continued to gain interest due to their impressive chemical
and biological profiles. In particular, the utility of a number
report a double diastereotopic differentiation/intramolecular
cyclopropanation (ICP) on a diazophosphonoacetate template.
This strategy utilizes the (R)-pantolactone ester auxiliary to
derive nonracemic, P-chiral [3.1.0]-bicyclic phosphonates.
Intramolecular cyclopropanation (ICP) mediated by
Rh (OAc) continues to provide a powerful tool for the
1
of P-chiral compounds has prompted new methods for their
2
synthesis. Our interest in the utilization of molecular
3
symmetry en route to P-chiral compounds now leads us to
2
4
construction of constrained systems from their diazo precur-
sors, with high levels of diastereoselectivity and enantio-
selectivity having been achieved in numerous instances.4
Although R-diazophosphonoacetates have been heavily uti-
(
1) (a) Quin, L. D. A Guide to Organophosphorus Chemistry; Wiley-
Interscience: New York, 2000. (b) Mader, M. M.; Bartlett, P. A. Chem.
ReV. 1997, 97, 1281-1301. (c) Franz, J. E.; Mao, M. K.; Sikorski, J. A.
Glyphosate: A Unique Global Herbicide; American Chemical Society:
Washington, DC, 1997. (d) Engel, R. Handbook of Organo-phosphorus
Chemistry; Marcel Dekker: New York, 1992. (e) Kafarski, P.; Lejczak, B.
Phosphorus, Sulfur, Silicon 1991, 63, 193-215.
4
c,5
lized in organic synthesis, relatively few examples exist
6
for the ICP of R-diazophosphonoacetates. Our interest in
(2) For reviews on the asymmetric synthesis of phosphorus compounds,
including P-chiral phosphorus compounds, see: (a) Kolodiazhnyi, O. I.
Tetrahedron: Asymmetry 1998, 9, 1279-1332. (b) Pietrusiewicz, K. M.;
Zablocka, M. Chem. ReV. 1994, 94, 1375-1411. For recent examples of
the synthesis and use of P-chiral compounds, see: (c) Han, L.-B.; Zhao,
C.-Q.; Onozawa, S.-y.; Goto, M.; Tanaka, M. J. Am. Chem. Soc. 2002,
(4) (a) Doyle, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Ruppar, D. A. J.
Am. Chem. Soc. 1995, 117, 11021. (b) Davies, H. M. L.; Bruzinski, P. R.;
Lake, D. H.; Kong, N.; Fall, M. J. J. Am. Chem. Soc. 1996, 118, 6897. (c)
Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds; John Wiley & Sons: New York,
1998. (d) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911-936. (e)
Doyle, M. P. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
Wiley: New York, 2000; pp 191-228. (f) Kirkland, T. A.; Colucci, J.;
Geraci, L. S.; Marx, M. A.; Schneider, M.; Kaelin, D. E., Jr.; Martin, S. F.
J. Am. Chem. Soc. 2001, 123, 12432-12433. (g) Barris, M.; Perez-Prieto,
J.; Stiriba, S.-E.; Lahuerta, P. Org. Lett. 2001, 3, 3317-3319.
1
24, 3842-3843. (d) Al-Masum, M.; Kumaraswamy, G.; Livinghouse, T.
J. Org. Chem. 2000, 65, 4776-4778. (e) Denmark, S. E.; Stavenger, R.
A.; Wong, K.-T.; Su, X. J. Am. Chem. Soc. 1999, 121, 4982-4991. (f)
Gilbertson, S. R.; Genov, D. G.; Rheingold, A. L. Org. Lett. 2000, 2, 2885-
2
888. (g) Buono, G.; Chiodi, O.; Wills, M. Synlett 1999, 377-388. (h)
Denmark, S. E.; Chen, C.-T. J. Am. Chem. Soc. 1995, 117, 11879-11897.
(3) Stoianova, D. S.; Hanson, P. R. Org. Lett. 2000, 2, 1769-1772.
1
0.1021/ol026080o CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/11/2002

Scheme 1a
a
Reagents and conditions: (a) Rh
dr ) 5.5:1; (b) formic acid, neat; (c) (COCl)
°C to rt; (d) NaN , CH CN, H O; (e) toluene, reflux; (f) t-BuOH,
reflux, 50% (five steps).
2
(OAc)
4
, CH
2
Cl
2
, reflux, 91%;
2
, CH
2
Cl
2
, DMF (cat.)
0
3
3
2
the development of new strategies to P-chiral compounds
led us to explore a double diastereotopic differentiation
strategy on the unique R-diazodiallylphosphonoacetate sys-
tem (Scheme 1). This system contains a prochiral phosphorus
atom bearing two enantiotopic olefins, with each olefin
possessing two diastereotopic faces, and thus is an ideal
substrate for the study we now report.
We previously reported that the ICP of R-diazodiallyl-
phosphonoacetate 1a proceeds to produce a pair of racemic
diastereomers (2a-cis-P
R
/2a-cis-P
S R
and 2a-trans-P /2a-trans-
6b
P
S
). In this previous study, the level of diastereofacial
Figure 1. Conformations of reacting carbene.
selectivity was found to be dependent on the size of the ester
2
group R (Figure 1). We recently applied a Curtius rear-
rangement sequence (Scheme 1) that has allowed us to
transform the major-bicyclophosphonoacetate 2a into the
crystalline carbamate 3. X-ray crystallographic analysis of
this carbamate unequivocally confirmed the cis-relationship
between the phosphonyl oxygen and the N-Boc group shown
in (()-3-cis (Scheme 1).
The diastereoselectivity can be rationalized by analyzing
the plausible conformations shown in Figure 1 (for simplicity,
we depict only those conformations involving interaction of
7
the re-face of the rhodium carbene). These conformations
employ the widely accepted Doyle/Davies model4 which
invokes carbene transfer occurring on a rhodium template
in a nonsynchronous manner. A number of steric and
electronic factors may be operative in governing the dia-
stereofacial selectivity obtained from these four conforma-
tions. These include (i) the facial orientation between the
,8
(5) (a) Moody, C. J.; Miller, D. J. Tetrahedron 1998, 54, 2257-2268
and references therein. For the use of R-diazophosphonates as reagents in
organic synthesis. see: (b) Gilbert, J. C.; Weerasooriya, U.; Giamalva, D.
Tetrahedron Lett. 1979, 4619-4622. For the use of R-diazophosphonates
in ylide rearrangements, see: (b) Gulea, M.; Marchand, P.; Masson, S.;
Saquet, M.; Collignon, N. Synthesis 1998, 1635-1639. (d) Moore, J. D.;
Sprott, K. T.; Hanson, P. R. Synlett 2001, 605-608.
8
reacting olefin and rhodium carbene (A-type or B-type), in
which a B-type orientation is favored for electronic stabiliza-
tion reasons, (ii) the orientation of the RhdC and PdO
π-systems (s-trans or s-cis), in which “opposing” dipole
interactions between the PdO and the Rh-carbene moieties
would favor the s-trans orientation, (iii) a possible anomeric
effect in the proposed s-cis conformations whereby there is
(
6) For the use of R-diazophosphonates in ICP reactions, see: (a) Callant,
P.; D’Haenens, L.; Vandewalle, M. Synth. Commun. 1984, 14, 155-161.
b) Hanson, P. R.; Sprott, K. T.; Wrobleski, A. D. Tetrahedron Lett. 1999,
(
4
0, 1455-1458. (c) For a review containing examples of intermolecular
cyclopropanation reactions of R-diazophosphonates, see: (d) Regitz, M.
Angew. Chem. 1975, 87, 259-268.
(7) Note: the corresponding four enantiomeric conformations resulting
from si-face attack of the rhodium carbene are not shown. The re-face of
the carbene is defined as follows:
9
an axial preference for the P-OR group, and (iv) a possible
eclipsing interaction between the olefin terminus and the ester
group thereby favoring the “B-Type” transition states. In this
complex analysis, undoubtedly a combination of effects is
at play.
In considering an additional group selective transforma-
tion10 layered into this analysis, control of the reacting face
of the carbene (re vs si) ultimately determines enantio-
selectivity (P-chirality) within a diastereomeric pair. We
considered two possible modes of governing a group
selective transformation: (i) auxiliary-based substrate control
(
(
8) Davies, H. M. L.; Doan, B. D. J. Org. Chem. 1999, 64, 8501-8508.
9) Chang, J.-W. A.; Gorenstein, D. G. Tetrahedron 1987, 43, 5187-
5
196.
(10) For reviews of both diastereotopic and enantiotopic differentiation,
see: (a) Magnuson, S. R. Tetrahedron 1995, 51, 2167-2213. (b) Schreiber,
S. L.; Poss, C. S. Acc. Chem. Res. 1994, 27, 9-17. See also: (c) Hoye, T.
R.; Peck, D. R.; Trumper, P. K. J. Am. Chem. Soc. 1981, 103, 5618. (d)
Hoye, T. R.; Peck, D. R.; Swanson, T. A. J. Am. Chem. Soc. 1984, 106,
738. (e) Schreiber, S. L.; Wang, Z. J. Am. Chem. Soc. 1985, 107, 5303.
f) Ward, D. Chem. Soc. ReV. 1990, 19, 1-19.
2
(
2358
Org. Lett., Vol. 4, No. 14, 2002

1
1
resulting in double diastereotopic differentiation and (ii)
12
asymmetric reagent control, which we are currently inves-
tigating.
In our substrate-controlled approach, the auxiliary is
incorporated into the ester functionality of 1a. Our initial
efforts focused on the use of the menthol- and 8-phenyl-
menthol-based auxiliaries due to previous successes by Rein
and co-workers in the desymmetrization of meso-dialdehydes
1
3
using chiral phosphonates containing menthol auxiliaries.
We investigated the Rh (OAc) -catalyzed ICP of both 1b
2
4
and 1c using various solvents (Table 1). Although modest
Table 1. Selectivities of Menthol-Based Cyclopropanations
Figure 2. Steric interactions with rhodium wall.
5
, utilization of the (R)-pantolactone auxiliary effectively
blocks the si-face of the carbenoid carbon of 5, thus allowing
preferential access to the re-face from one of the four
conformations depicted in Figure 1. However, the “A-type”
transition states have little contribution toward the final
products due to their dependence of a positive charge build-
entry
substrate
conditions
selectivity
1
2
3
4
5
1b
1c
1c
1c
1c
CH2Cl2, reflux
CH2Cl2, rt
Et2O, reflux
CH2Cl2, reflux
PhH, reflux
3.2:3.2:1.5:1.0
4.1:3.3:2.5:3.0
1.5:1.3:1.1:1.0
4.9:4.1:1.1:1.0
2.2:2.0:1.2:1.0
up on a primary carbon. Therefore, we believe the trans-P
and cis-P diastereomers would arise from stereochemical
R
S
a
All selectivities were found using H-decoupled 31P spectroscopy. b The
1
leakage via si-face attack of the carbenoid carbon and the
reactions proceeding through analogous “B-type” transition
states.
unambiguous assignment of each diastereomer was not made.
Synthesis of 4 began with commercially available tert-
butylchloroacetate (7) (Scheme 2). Conversion to the iodide
levels of diastereoselectivity were seen, these auxiliaries
proved to be ineffective in differentiating the two faces of
the rhodium carbene.14 It is worth noting that temperature
had a substantial effect on the diastereoselectivity (Table 1,
entries 2 and 4).
Scheme 2a
We next explored the (R)-pantolactone auxiliary, which
Davies and co-workers had previously demonstrated to be
an effective auxiliary in carbenoid-mediated cyclopropan-
1
5
ations. The carbonyl moiety in this auxiliary is thought to
chelate to the metallo-carbenoid center effectively “locking”
the molecule in a rigid conformation and therefore blocking
access to one face of the carbene. Davies has shown that an
unfavorable steric interaction between the gem-dimethyl
moiety and the rhodium wall in the (R)-pantolactone auxiliary
ultimately favors si-face coordination and therefore re-face
attack (Figure 2). When applied to the rhodium carbenoid
a
Reagents and conditions: (a) KI, CH
, neat, 88%; (c) HCO H, neat, >99%; (d) HBTU, TEA, (R)-
pantolactone, CH CN, 83%; (e) NaH, TsN , THF, 90%.
3
CN, >99%; (b) P(O-
allyl)
3
2
3
3
3
under Finkelstein conditions (NaI, CH CN) followed by
16
Arbuzov reaction with triallyl phosphite yielded diallyl tert-
butylphosphonoacetate 8 in 88% over two steps. Subsequent
deprotection with formic acid, esterification with (R)-
pantolactone utilizing HBTU coupling protocol, and final
diazo transfer with NaH and TsN generated the desired
3
cyclopropanation precursor 4 in high yield.
(
11) (a) Kurth, M. J.; Brown, E. G. J. Am. Chem. Soc. 1987, 109, 6844-
6
1
845. (b) McKew, J. C.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem.
994, 59, 3389. (c) See ref 10.
(12) (a) Martin, S. F.; Spaller, M. R.; Liras, S.; Hartmann, B. J. Am.
Chem. Soc. 1994, 116, 4493-4494. (b) Trost, B. M.; Van Vranken, D. L.;
Bingel, C. J. Am. Chem. Soc. 1992, 114, 9327-9343.
(
13) (a) Norrby, P.-O.; Brandt, P.; Rein, T. J. Org. Chem. 1999, 64,
5
845-5852. (b)Vares, L.; Rein, T. Org. Lett. 2000, 2, 2611-2614. (c) Tullis,
J. S.; Vares, L.; Kann, N.; Norrby, P.-O.; Rein, T. J. Org. Chem. 1998, 63,
Intramolecular cyclopropanation of 4 employing the (R)-
pantolactone ester auxiliary produced the major diastereomer
8
284-8294.
(
(
14) Supporting material: 31P analysis of the menthol-based systems.
15) (a) Davies, H. M. L.; Huby, N. J. S.; Cantrell, W. R., Jr.; Olive, J.
L. J. Am. Chem. Soc. 1993, 115, 9468-9479. (b) Davies, H. M. L.; Cantrell,
W. R. Tetrahedron Lett. 1991, 32, 6509-6512.
(16) Triallyl phosphite was prepared from the reaction of PCl3 and allyl
alcohol in the presence of Et3N and distilled under vacuum.
Org. Lett., Vol. 4, No. 14, 2002
2359

6
-cis-P
R
with good levels of olefin (10.4:1) and diastereo-
17
facial selectivity (6.9:1) (Table 2). The diastereomeric ratios
were conveniently determined using H-decoupled P NMR
analysis.
1
31
Table 2. Selectivities of Pantolactone System
Figure 3. X-ray of major and minor cis-diastereomers.
stereomer is consistent with an s-trans orientation of the
RhdC and PdO π-systems (opposing-dipole) incor-
porating a B-type orientation of the reacting olefin and
occurring from the re-face of the rhodium carbenoid (Figure
1
). Although the s-cis conformations demonstrate the pos-
selectivitya
sibility of a favorable anomeric effect, it appears that the
opposing dipole effect, inherent to the s-trans conformations,
is more dominant.
In conclusion, we have demonstrated an effective double
diastereotopic differentiation strategy on a phosphonoacetate
conditions
6-cis-PR
6-trans-PR
6-cis-PS
6-trans-PS
CH2Cl2, rt
29.1
14.5
12.0
7.4
1.0
1.0
1.0
1.0
2.8
2.2
1.8
1.4
3.6
2.5
2.6
3.0
Et2O, reflux
CH2Cl2, reflux
PhH, reflux
2 4
template utilizing Rh (OAc) -catalyzed ICP employing the
a
1
All selectivities were determined using H-decoupled 31P spectroscopy.
(R)-pantolactone auxiliary. This study represents part of our
continuing program aimed at the synthesis of diverse
P-heterocycles. Additional efforts probing olefinic substituent
effects and utilization of chiral catalysts are underway and
will be reported in due course.
To associate each signal in the H-decoupled 31P NMR
1
spectra to its corresponding diastereomer and to verify the
group and facial selectivity, a correlation experiment was
initially undertaken. Formic acid-mediated hydrolysis of the
racemic mix of cyclopropanated diastereomers 2a (∼6:1, cis:
trans) followed by DCC coupling with the (R)-pantolactone
moiety produced the diastereomers 6, preserving the 6:1 cis:
trans ratio. Subsequent H-decoupled P NMR analysis of
this racemic sample allowed for the assignments of each
diastereomeric pair shown in Table 2.18 Furthermore, both
Acknowledgment. This investigation was supported by
funds provided by the National Institutes of Health (National
Institute of General Medical Sciences, RO1-GM58103) and
the Herman Frasch Foundation (442-HF97, administered by
the American Chemical Society). The authors thank Huw
M. L. Davies for many thoughtful discussions, Dr. David
Vander Velde for assistance with NMR measurements, Dr.
Todd Williams for HRMS analysis, and Dr. Douglas R.
Powell for X-ray analysis.
1
31
of the cis-diastereomers were separated using silica gel
chromatography and X-ray crystallographic analysis of each,
6
-cis-P
R
and 6-cis-P
S
, provided full unambiguous assignment
as the major dia-
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
Figure 3). The production of 6-cis-P
R
(
17) Although good selectivity toward the cis-PR diastereomer is
demonstrated, coelution with the trans diastereomers during flash chroma-
tography hinders facile purification (see Supporting Information).
(18) See Supporting Information.
OL026080O
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Org. Lett., Vol. 4, No. 14, 2002