Research Proposal Submitted to the National Science Foundation

Proposed Proposed Proposed
Amount: Effective Date: Duration:
$ 60,132 (Direct Cost) June 1, 1974 24 Months

88,394 (Including
Indirect Cost)

Title: Carbon-13 Nuclear Magnetic Resonance of Steroids

Principal Investigator: Submitting Institution:

Carl Djerassi Stanford University
Professor of Chemis Department of Chemistry

Stanford, California 94305

Make grant to Stanford University

 

 

 

Endorsements:
Principal Department Institutional
Investigator Vice-Chairman Admin. Official
Name arl pierase! D. A. Skoog
Signature LL a
Title Professor of Chem. Vice-Chairman

 

Telephone 415-321-2300 X2783 415-321-2300 x2502

Date Dec. 17, 1973 Dec. 17, 1973
ABSTRACT

Carbon~13 nuclear magnetic resonance (CMR) spectra show a marked
sensitivity to such important features of chemical structure as carbon
hybridization, electronegativity of heteroatoms, branching and steric
crowding. Potentially, CMR is an extremely rich source of structural
data in organic chemistry, capable of rivalling or even surpassing
proton magnetic resonance. In the research proposed here, we intend to
develop this potential in the field of steroid chemistry.

The factors which determine the CMR spectra of steroids are only
modestly well understood. We have begun, and propose here to continue,
a systematic study of families of closely-related steroids (keto- and
hydroxy-androstanes and cholestanes) with the conviction that only
through such a systematic study can the basic factors governing the CMR
spectra of steroids be brought to light. We intend to quantify those
factors as predictive rules which relate spectra to structures, and to
develop computerized methods for using those rules to extract structural
information from the CMR spectra of unknown steroids. We also propose
to develop several chemical methods (derivatization procedures) for

augmenting the information-content of such spectra.
I. BACKGROUND

Within the last twenty years, the phenomenon of nuclear magnetic

1
resonance ’

2 (NMR) has evolved from little more than a laboratory
curiosity to one of the most powerful analytical tools in chemistry.
The experiment itself consists of observing, in an applied magnetic
field, the resonance frequencies (in the radio-frequency range) of

Magnetic nuclei in a liquid chemical sample. The analysis of NMR

spectra yields chemical shifts and coupling constants which reflect,

 

respectively, the chemical environments of and the bonding or spatial
relationships between atoms whose nuclei are magnetic.

Because protons are magnetic, interacting particularly strongly
with electromagnetic fields, and because they are present in virtually
all organic compounds, proton NMR (PMR) has found broad usefulness in
organic chemistry. The literature on PMR spectroscopy is huge, and
frequently it is found that PMR spectra yield chemical information which
would be difficult, if not impossible, to obtain by any other method.
The determination of structure and conformation, °?4 the analysis of

29 the study of rate processes” and the elucidation of

mixtures,
reaction mechanisms’ have all been aided substantially by PMR
techniques.

Other nuclei frequently observed via NMR are F-19, P-31 and C-13.
The first two are not common in organic compounds and are thus used for
more specialized studies. Carbon, by definition, occurs in all organic
molecules, but only about 1% of all carbon nuclei are the magnetic

isotope C-13. This, together with the fact that C-13 nuclei are almost

two orders of magnitude less sensitive than protons to the NMR
~4-
experiment, has hampered the widespread use of C-13 NMR (CMR) as an
analytical tool for organic chemists. However, recent instrumental
advances such as pulsed Fourier-transform techniques® and
noise-modulated proton decoupling” |! have made it possible to obtain
natural~abundance CMR spectra of even large molecules (e.g., steroids)
or low-concentration (ca. 0.05 M) samples within a reasonably short
time (0.5 - 10 hr.).

The research to date!” indicates that C-13 chemical shifts (which
constitute the primary data usually collected in the CMR experiment)
cover a broad range (ca. 200 p.p.m.) relative to H-1 shifts (ca. 10
p-p.m.), and are highly sensitive to hybridization, electronegativity of
substituents, branching and steric crowding. Thus CMR spectroscopy is
‘potentially a rich and highly useful source of structural data. As
further advances in instrumental design take place, CMR spectroscopy
will become an increasingly available and infcrmative tool in organic

chemistry.
II. OBJECTIVES AND SIGNIFICANCE

The research proposed herein is directed toward understanding the
factors which determine C-13 chemical shifts in steroids and toward
developing computer~based methods whereby a chemist can obtain
structural information from spectra of unknown steroids. This class of
compounds was chosen for two reasons. First, the steroid skeleton is
more or less rigid, providing a relatively controlled framework within
which to study the effects of steric hindrance and other geometrical
factors upon C-13 shifts. Second, a great fraction of steroid and
natural products chemistry involves the identification or verification
of steroid structures, and thus we expect our results to be of
significant practical utility.

At the current level of understanding of C-13 chemical shifts, it
is not now possible to predict the CMR spectrum of a given steroid with
much certainty, although by referring to simple model systems, one can
often rationalize the signs and general magnitudes of the spectral
changes which take place when the nature and position of substituents
are altered. It is now a challenging problem simply to assign the
spectrum of a known steroid, that is to identify which observed peaks
belong to which carbons.

The first definitive study of the CMR of steroids was presented
only four years ago by Roberts et al.? In that report, the
assigned spectra of nearly thirty assorted steroids are presented, with
the assignment task accomplished "...using specific single-frequency and
off-resonance proton decoupling, hydroxyl acetylation effects on

chemical shifts, deuteration, and substituent influences in analogous
-6-

W

: 1
compounds.... Since then, several other authors “ have reported

research on the CMR of steroids, but only recently has the systematic:

study!» 16

of families of closely related stercids begun. We have
reported !® the assigned spectra of fourteen keto-substituted
androstanes and cholestanes, where the keto group occupies every
possible position around the skeleton. We are currently collecting data
on a similar series of hydroxy-substituted steroids, and work is also in
progress!’ on the series of steroids containing one endocyclic
double-bond. The initial stage or our proposed research is to complete
the hydroxyl series and to obtain the CMR spectra of several
bifunctional (e.g., dihydroxy and keto-hydroxy) steroids. With such a
collection of systematic data available, we will be able to study the
influence upon C-13 shifts of these three types of functionality, alone
and in combination, which are by far the most common types occurring in
natural steroids. From these data, we expect to be able to extract
rules which will allow the accurate prediction of CMR spectra of
steroias containing these groups. Zurcher '8-20 has derived an
extremely useful set of rules relating skeletal substitutions in
steroids to changes in the PMR shifts of protons in angular methyl
groups. The C-13 rules we seek will relate not only to angular methyl
groups but to all carbons in the skeleton, and will thus provide a great
deal more information than the ZUrcher rules. These CMR rules will
also form the base for our proposed work in the computerized
interpretation of CMR data (vide infra).

As a second portion of our work, we propose a study of reversible

derivatization procedures which will aid in the assignment of the

spectra of known steroids, and in the analysis of the spectra of unknown
-7-

steroids. Roberts and co-workers > have found that acetylation of a
hydroxyl group in a steroid produces characteristic changes, due
primarily to steric effects, in the shifts of carbons close to that
group. They have used this effect in assigning such shifts. We propose
to study the effects of other hydroxyl-group derivatives, specifically,
the 2,4,6-trimethylbenzoate (benzoates themselves, in our hands, have
not shown any advantages over acetates), trifluoroacetate and the
trimethylsilyl ether. These derivatives have different steric and
electronic properties than do acetates, and should thus produce
different patterns of spectral change, providing a convenient means of
augmenting the information—content of ordinary CMR spectra. We also
propose to observe the C-13 shift changes which take place upon cyclic
ketalization of carbonyl groups, and we expect that such changes will be
useful in determining the local environment of keto groups in steroids.

It has been found? |>24

that the presence of a paramagnetic complexing
agent (e.g., a "lanthanide shift" reagent) causes large changes in C-13
chemical shifts of alcohols and ketones. These changes can be related
to the geometry of the complex, which reflects the geometry of the
Alcohol or ketone itself. We intend to explore the use of such
shift-reagents in assisting the interpretation of steroidal CMR spectra.
Of particular interest will be the difference between %~ and p-hydroxy
steroids: It is expected that the grossly different steric environments
of axial vs. equatorial hydroxyl groups will have a pronounced effect
upon the geometry of the complex, and thus, very different
lanthanide-shift patterns should result. If so, the effect should

provide a convenient means for distinguishing the stereochemistry of

sterols.
-8-

A third facet of the proposed research involves the development of
computerized techniques for automatically extracting structural
information from CMR spectra. This represents a logical growth of our
Heuristic DENDRAL project,-> 8 an eight-year joint effort between our
laboratories and the Departments of Genetics and Computer Science. The
purpose of the project is to develop applications of heuristic programming
(“artificial intelligence") to problems in chemical inference, with the
bulk of the effort directed toward the computerized interpretation of
mass-spectroscopic (MS) data. In the early DENDRAL research, 7"?7>
only saturated, acyclic, monofunctional compounds were treated, but we
have recently reported the successful identification of the structures
ef estrogenic steroids° (and mixtures thereof”’) via the
computerized interpretation of MS data. As the complexity of compound
classes has increased, we have felt a growing need for sources of
structural data other than MS. CMR data show a sensitivity to
stereochemistry and substituent placement which complements, rather than
duplicates, MS-derived information, and thus CMR is the ideal candidate.

We have demonstrated~® the feasibility of using CMR data in
automated structure analysis. Using a detailed and accurate set of
predictive rules”? for saturated, acyclic amines, we have constructed
a computer program which can "reason out" the structure of such an
amine, starting from its empirical formula and CMR spectrum. A similar
effort is proposed for the steroids (at least, those containing
endocyclic double bonds, carbonyl groups and hydroxyl substituents) in
which structural information would be inferred from CMR data using

accurate predictive rules. This information could then be integrated

with the results obtained from derivatization or special CMR techniques,
-9-

and (if necessary) from MS analysis to yield possible structures. Not
only would such a system have substantial utility, but it would
represent an important advance in the "state of the art" in both CMR

spectroscopy and chemical information-processing.
-10—

III. PLAN OF RESEARCH
A. CMR Spectra of Steroids.

We plan to complete the series of sterols by synthesizing 1f-, 2«-,
46-, 7x-, 9X-, 1-, 14«K-, 16%- and 174-androstanols or cholestanols,
whose CMR spectra (pulsed Fourier-transform spectra, obtained at 25 Mhz.
using noise~modulated proton decoupling) will be recorded and assigned.
We have worked out likely synthetic pathways for the preparaticn of
these using commonly accepted procedures and starting from compounds
available in our laboratories. In order to test the extent of
additivity relationships and of various interactions of substituents, we
shall similarly synthesize and record the spectra of two or three dozen
dihydroxy and keto-hydroxy androstanes and cholestanes. The candidates
chosen will depend upon the results of the analysis of the
monofunctional steroids.

Using statistical procedures similar to those of Dalling and
Grant, °° and of Lindeman and Adams, >! we shall attempt to correlate
structural variables with chemical shifts, the goal being the derivation
of an accurate set of substituent parameters for steroids. In assessing
the effects of steric crowding and skeletal distortion, we plan to
utilize a computerized, classical-mechanical model of molecular
structure, such as the Westheimer-type models recently reviewed by

Schleyer.>"

B. Derivatization
~11-

We propose to analyze the changes in C-13 shifts which take place
when the hydroxyl group in several of the above androstanols and
cholestanols is derivatized to the 2,4,6-trimethylbenzoate,
trifluoroacetate and trimethylsilyl ether. We propose similarly to
investigate the effects of ketalizing (with ethylene glycol) several
androstanones and cholestanones.

We propose to analyze the effects of lanthanide shift reagents (in
varying concentrations) upon the CMR spectra of several of the hydroxy-
and keto-steroids, with particular emphasis upon pairs of sterols which
differ only in the orientation of the hydroxyl group.

These investigations will be directed toward the development of a
repertoire of non-destructive, chemical methods for increasing the

‘information available frem CMR spectra.
C. Computerized Interpretation of CMR Data.

There are three phases to our proposed research in this area, all
of which will make use of the heuristic programming techniques developed
in our DENDRAL project.

First, we intend to develop a program to assist in the assignment
of spectra obtained in parts A and B, using currently available
techniques (i.e., using rules for acyclic systems together with
analogies from appropriate model systems). The purpose here is twofold:
On one hand, such a program will hasten a time-consuming procedure (in
our work, the assignment of spectra requires about as much time as the
preparation of samples and the recording of spectra, combined), while on

the other hand, it will provide a context within which to develop
~12-

techniques applicable to the more difficult problem of structure
identification. Specifically, we will need methods for expressing CMR
rules as efficient computer code, and for deciding whether a good,
unambiguous fit occurs between predicted and observed data.

Secondly, we intend to utilize the rules derived in part A,
together with derivatization information from B, to write what is called
a "planning" program in the DENDRAL terminology. Such a program is
designed to examine the spectrum of an unknown and, referring to a set
of heuristics, to attempt to verify the presence or absence specific
structural features in the unknown. Whereas the predictive rules allow
one te predict a spectrum from a given structure, the heuristics
represent transformations of the rules which allow one to infer
structural information from a given spectrum. The primary challenge in
constructing the planning program will be the design of heuristics which
are as informative as possible, yet which run efficiently. This program
will be a useful analytic tool in itself, and will be used in the third
phase of our proposed research.

This third phase will involve merging the planning program with the
existing DENDRAL system, which analyzes MS data for steroids.
Modifications will be made to the structure~generation program, which
can construct all possible sets of acyclic substituents from a given set
of atoms and attach those substituents in all possible ways to a given
cyclic skeleton. The structure generator now makes use of MS-planner
information, constructing only those steroids which are consistent with
it. We shall modify the algorithm to make use of the output from both
the MS and the CMR planners, and shall extend the algorithm to consider

questions of stereochemistry, which are currently ignored. We believe
~13-

that the augmented DENDRAL system will have the capacity to identify,
unambiguously, the structures of a wide variety of steroids using
information from just these two spectroscopic sources.

The programs will be written in the LISP language, and will thus be
compatible with the rest of the DENDRAL system. Computer time on the
PDP-10 will be provided through the NIH-funded SUMEX facility at
Stanford, and we request no support in this proposal for computer
facilities. Programs developed in our proposed research will be

available to the scientific community over the ARPA computer network,
IV.

10.

11.

12.

13.

14.

15.

~14-
REFERENCES

J. W. Emsley, J. Feeney and L. H. Sutcliffe, High Resolution
Nuclear Magnetic Resonance Spectroscopy, Pergamon Press, New
York, 1965.

L. M. Jackman and S. Sternhell, Applications of Nuclear Magnetic
Resonance Spectroscopy to Organic Chemistry, 2nd. Eda., Pergamon
Press, New York, 1969,

 

See, e.g., J. B. Lambert, Accounts Chem. Res., 4, 87(1971).

See, e.p., F. A. Anet and R. Anet in Determination of Organic
Structures by Physical Methods, F. C. Nachod and J. J.
Zuckerman, eds., V. 4, Academic Press, New York, 1971, pp 344-420,

 

See, e.g., J. P. Heeshan in The Characterization of Chemical
Purity. Organic Compounds, L. A. K. Stavely, ed., Butterworths,
London, 1971, pp 137- 147.

 

See, e.g., C. H. Baumford and C. F. H. Tipper, Comprehensive
Chemical Kinetics, V. 1, Elsevier Publ. Co., New York, 1969,
pp 142-149,

See, e.g., H. R. Ward, Accounts Chem. Res., 5, 18(1972).

T. C. Farar and E. D. Becker, Pulse and Fourier-Transform NMR,
Academic Press, New York, 1971.

 

F. J. Weigert, M. Jautelat and J. D. Roberts, Proc. Nat. Acad,
Sci. U. S., 6G, 1152(1968).

L. F. Johnson and M. E. Tate, Can. J. Chem., 47, 63(1969).
R. R. Ernst, J. Chem. Phys., 45, 3845(1966).

G. C. Levy and G. L. Nelson, Carbon-13 Nuclear Magnetic Resonance
for Organic Chemists, Wiley—Interscience, New York, 1972.

 

H. J. Reich, M. Jautelat, M. T. Messe, F. J. Weigert and J. D.
Roberts, J. Amer, Chem. Soc., 91, 7445(1969).

K. Tori, H. Ishii, Z. W. Wolkowski, C. Cachaty, M. Sangare, F.
Pirion and G. Lucas, Tetrahedron Lett., 1077(1973) and references
therein.

T. A. Wittstruck and K. I. H. Williams, J. Org. Chem. es 38, 1542
(1973).
16.

17.

18.
19,

20.
21.
22,

23.

24.

25.

26.

27.
28.

29.
30.
31,

32.

-15-

H. Eggert and C. Djerassi, J. Org. Chem., 38, 3788(1973).

Work in progress at the Orsted Institute in Copenhagen, Denmark
by H. Eggert.

R. F. Zurcher, Helv. Chim. Acta, 46, 2054(1963).
R. F. Zurcher, Helv. Chim. Acta, 44, 1380(1961).

N. S. Bhacca and D. H. Williams, Applications of NMR Spectroscopy
in Organic Chemistry, Holden-Day, San Francisco, 1964, pp 13-23.

 

See, e.g., J. Briggs, F. A. Hart, G. P. Moss and E. W. Randall,
Chem. Commun., 1132(1971).

J. D. Roberts, G. E. Hawkes, A. W. Roberts and D. W. Roberts,
J. Amer. Chem. Soc., submitted for publication.

B. G. Buchanan, A. M. Duffield and A. V. Robertson in
Mass Spectrometry, Techniques and Applications, G. W. A.
Milne, ed., John Wiley & Sons, Inc., 1971, pp 121-177.

 

A. Buchs, A. B. Delfino, C. Djerassi, A. M. Duffield, B. G.
Buchanan, E. A. Feigenbaum, J. Lederberg, G. Schroll and G.
Sutherland, Advances in Mass Spectroscopy, D, 314(1971).

 

A. Buchs, A, B. Delfino, A. M. Duffield, C. Djerassi, B. G.
Buchanan, E. A. Feigenbaum and J. Lederberg, Helv. Chim. Acta,
53, 1394(1970) and previous papers in the series.

D. H. Smith, B. G. Buchanan, R. S. Engelmore, A. M. Duffield, A.
Yeo, E. A. Feigenbaum, J. Lederberg and C. Djerassi, J. Amer.

Chem. Soc., 94, 5962(1972).

D. H. Smith, B. G. Buchanan, R. S. Engelmore, H. Aldercreutz and
C. Djerassi, J. Amer. Chem. Soc., 95, 6078(1973).

R. E. Carhart and C. Djerassi, J. Chem. Soc. (Perkin JT),
1753(1973).

H. Eggert and C. Djerassi, J. Amer. Chem. Soc., 95, 3710(1973).

D. K. Balling and D. M. Grant, J. Amer. Chem. Soc., 89, 6612(1967).

en re rs SEN HE NEN

L. P. Lindeman and J. Q. Adams, Analyt. Chem., 43, 1245(1971).

J. E. Williams, P. J. Stang and P. V. R. Schleyer, Ann. Rev. Phys.
Chem., 19, 531(1968).
-16-

V. FACILITIES AVAILABLE

1.

Instrumentation.

(a) Varian XL-100 NMR spectrometer. Departmental instrument,

 

equipped for Fourler-transform CMR spectroscopy with or
without proton decoupling (single-frequency or noise-
modulated). This is among the most sensitive CMR instruments
currently available.

(b) Computer Facilities. Installation of a PDP-10 computer, funded

by the National Institutes of Health as part of the SUMEX
resource at Stanford (a national resource devoted to the
application of artificial intelligence in medicine and related
fields), is scheduled for March, 1974. Computer facilittes
will be available to us for the computer-related aspects of the
project proposed here (primarily, part III, section C).

2, Personnel associated with the project.

(a) Principal Investigator.

Carl Djerassi, born 1923; Kenyon College, A.B. (summa cum
laude), 1942; University of Wisconsin, Ph.D., 1945.

Honots: Hon. D.Sc., Nat'l. Univ. of Mexico (1953), Kenyon
College (1958), Fed. Univ. Rio de Janeiro (1969), Worchester
Polytechnic Inst. (1972). Member, U.S. National Academy of
Sciences, American Academy of Arts and Sciences, German Academy
of Natural Scientists (Leopoldina), Royal Swedish Academy of
Sciences, Brazilian Academy of Sciences, Mexican Academy for
Scientific Investigation, Phi Beta Kappa. Hon. Fellow, Britich
Chemical Society, Phi Lambda Upsilon, American Academy of
Pharmaceutical Sciences, Mexican Chemical Society. Numerous
hon. lectureships including 1964 Centenary Lecturer (British
Chemical Society), 1969 Annual Chemistry Lecturer (Swedish
Academy of Engineering), 1972 Scheele Lecturer (Swedish
Pharmaceutical Society). Recipient of American Chemical
Society Award in Pure Chemistry (1958), Baekeland Medal (1959),
Fritzsche Award (1960), Award for Creative Invention (1963),
Intra-Science Foundation Award (1969), Freedman Patent Award
of the American Institute of Chemists (1971), National Medal
of Science (1973).

Academic Experience: Professor of Chemistry, Stanford
University, 1959-present; Associate Professor (1952-1954) and
Professor (1954-1959), Wayne State University.

Industrial Research Experience: Ciba Pharmaceutical Co.,
Summit, N.J.: 1942-1943 and 1945-1949. Syntex Corporation:
Associate Director of Chemical Research (Mexico City) 1949-
1952, Research Vice President (Mexico City) 1957-1960; (Palo
Alto, California) 1960-1968, President, Syntex Research 1968-
1972, President, Zoecon Corporation (Palo Alto) 1968-present.
Editorial Boards: (Current) Journal of the Americal Chemical
Society, Steroids, Tetrahedron, Organic Mass Spectrometry.
(b)

-~17-

Publications: Author or co-author of six books and
approximately 800 publications dealing with natural products
(notably steroids, terpenoids, alkaloids and antibiotics),
medicinal chemistry (primarily antihistamines, oral
contraceptives and anti-inflammatory agents) and applications
of physical methods (mass spectrometry, optical rotatory
dispersion, magnetic circular dichroism) to organic and
biochemical problems.

Postdoctoral Research Associate.

Raymond Edgar Carhart, born 1946; Northwestern University, A.B.
(with honors), 1968; California Institute of Technology, Ph.D.
(Chem.), 1972.

Honors: Member of Phi Beta Kappa, Sigma Xi, Phi Lambda
Upsilon; NIH postdoctoral Fellow, 1972-present; NSF predoctoral
Fellow, 1968-1972,

Experience: Dr. Carhart has a background in Physical Organic
Chemistry, with particular emphasis upon computer applications.
As an undergraduate and graduate student, he has had direct
research experience in organic synthesis, X-ray crystallography,
quantum chemistry and PMR and CMR spectroscopy. As an NIH
Fellow in our Computer Science Department, he has worked for
the past year developing applications of artificial
intelligence in CMR spectroscopy. He is currently analyzing
the CMR data from the series of keto-substituted androstanes
and cholestanes, and is also involved in some aspects of the
DENDRAL program for the generation of cyclic chemical
structures.

 

Publications:

R. E. Carhart and C. Djerassi, "Applications of Artificial
Intelligence for Chemical Inference. Part XI. Analysis of
Carbon-13 Nuclear Magnetic Resonance Data for Structure
Eludication of Acyclic Amines," J. Chem. Soc. (Perkin II),
1753(1973).

R. E. Carhart and J. D. Roberts, "Nuclear Magnetic Resonance

Spectroscopy. Analysis of the My and 136 Spectra of

Br ‘°c, '*cu,Br," rg. Mag. Res., 3, 139(1971).

J. B. Lambert, R. E. Carhart and P. W. R. Corfield, "The Shape
of Chair Six-Membered Rings. 4,4~Diphenylcyclohexanone," J.
Amer, Chem, Soc., 91, 3567(1969).

J. B, Lambert, R. E. Carhart, P. W. R. Corfield and J. H.
Enemark, "A Comparison of Solid- and Liquid-Phase Conformations;
4,4-Diphenylcyclohexanone, a Flattened Chair," Chem. Commun.,
999(1968).

J. B. Lambert, R. G. Keske, R. E. Carhart and A. P. Jovanovich,
"The Conformational Rivalry between the Non-bonding Electron

Pair and the Proton on Nitrogen," J. Amer, Chem. Soc., 89,
3761(1967).
~18-
VI. CURRENT SUPPORT AND PENDING APPLICATIONS

Principal Investigator:

 

Field of Research Source of Support Annual Amount Termination Date
Current:

Organic Mass NIH Grant No. 5 RO1 $52,306 9/30/75
Spectrometry AM 04257-13

Marine Natural NIH Grant No. 2 RO1 75,650 12/31/77
Products GM AM 06840-15

Pending:

Magnetic Circular NSF Appl. # P3P3689 27,640
Dichroism in
Organic Molecules

Postdoctoral Research Associate:

 

Current:
Dr. Carhart now holds an NIH postdoctoral Fellowship (# 1 FO2

GM54009-01 BPS) in the amount of $7500 per year, to terminate
on 9/17/74.

This Application is not being submitted to any other Agency.
-19~

VII. RESEARCH GRANT PROPOSAL BUDGET

A.

First year beginning 6/1/74
Second year beginning 6/1/75
First
ear
SALARIES AND WAGES:
1, Principal Investigator;
Carl Djerassi -
2. Postdoctoral Research Associate,
Computer Science Department;
Raymond E. Carhart (12 calendar man-months) $ 14,000
3. Graduate Student,

Chemistry Department;

Craig van Antwerp ( 6 calendar man-months) 3,180
TOTAL SALARTES AND WAGES: 17,180
STAFF BENEFITS: 17% of sal. & wages 6/1/74-8/31/74

18% of sal. & wages 9/1/74~5/31/75
calculated at 17.75% 3,049
18% of sal. & wages 6/1/75-8/31/75

19% of sal. & wages 9/1/75-5/31/76
calculated at 18.75%

TOTAL SALARIES, WAGES AND STAFF BENEFITS (A + B): 20,229
PERMANENT EQUIPMENT:

None 0
EXPENDABLE SUPPLIES AND EQUIPMENT:

Chemical supplies and equipment 2,000
TRAVEL:

Domestic, for attendance at scientific meetings 800
PUBLICATION COSTS: 1,500

COMPUTER COSTS:

(Provided through the SUMEX facility at Stanford.

No support is requested here) 0
OTHER COSTS:

Hourly rental of departmental CMR instrument

(Varian XL-100) 400 hr. @ $12.50/hr. (sufficient

for approximately 100 CMR spectra each year) 5,000
TOTAL DIRECT COSTS: 29,529
INDIRECT COSTS:

On Campus 47% of total direct costs 13,879
TOTAL COSTS (J + K): 43,408
TOTAL CONTRIBUTIONS FROM OTHER SOURCES: 0
TOTAL ESTIMATED PROJECT COST: 43,408

TOTAL COSTS FOR TWO YEARS: $ 88,394

Second
ear

$ 14,700

3,239
17,939

3,364
21,303

2,000

800
1,500

5,000
30,603

14,383
44,986

44,986
-20-

VIII. COGNIZANT PERSONNEL

Principal Investigator (For Technical and Scientific Matters):

 

Carl Djerassi

Professor of Chemistry >
Department of Chemistry
Stanford University
Stanford, California 94305

Telephone: (415) 321-2300, Extension 2783

For Administrative Matters (Budgets, Property, etc.):

P. M. West, Administrative Officer
Department of Chemistry

Stanford University

Stanford California 94305

Telephone: (415) 321-2300, Extension 2513

For Contractual Matters (Including Overhead and Patent Questions):

Sponsored Projects Office
Old Pavilion

Stanford University
Stanford, California 94305

Telephone: (415) 321-2300, Extension 2883